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Classes

Azole Antifungals

Administration

Grapefruit juice consumption should be avoided.
Hazardous Drugs Classification
NIOSH 2016 List: Group 3
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
INJECTABLES: Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
ORAL TABLETS/CAPSULES/ORAL LIQUID: Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Eye/face and respiratory protection may be needed during preparation and administration.

Oral Administration

Administer oral formulations at least 1 hour before or after meals.

Oral Liquid Formulations

Shake well before each use.
Administer using only the manufacturer supplied oral dispenser.[28158]

Reconstitution method for oral suspension
Review the manufacturer reconstitution instructions for the particular product and package size.
Prior to reconstitution, tap the bottle several times to loosen the powder. Add water and shake vigorously to thoroughly mix.
Do not mix with any other medication or additional flavoring agent or further dilute with water or other liquids.
Storage: Store reconstituted suspension at room temperature for up to 14 days.[28158]

Injectable Administration

For slow intravenous infusion after reconstitution and dilution only. Do not administer voriconazole as an IV bolus injection.
Intravenous therapy should be reserved for those who cannot take voriconazole orally.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

Intravenous Administration

Reconstitution and Dilution
Dilute the 200 mg vial of lyophilized voriconazole with 19 mL of Water for Injection to yield a total of 20 mL with a concentration of 10 mg/mL. Discard the vial if a vacuum does not pull the diluent into the vial. Vigorously shake the vial to dissolve the powder.
Calculate the required volume of 10 mg/mL concentrate based on the patient's weight and dose.
Withdraw a volume of diluent from the IV bottle or bag equivalent to the volume of voriconazole concentrate to be added to the IV bag or bottle. The volume of diluent remaining in the bag or bottle should yield a concentration between 0.5 to 5 mg/mL when the voriconazole concentrate is added.
Withdraw the required volume of voriconazole concentrate from the appropriate number of vials and add to the infusion bag or bottle containing an appropriate diluent, such as 0.9% Sodium Chloride Injection or 5% Dextrose Injection. Discard partially used vials.[28158]

Intermittent IV Infusion
Administer as a slow IV infusion, at a maximum rate of 3 mg/kg/hour over 1 to 3 hours only and at a maximum concentration of 5 mg/mL.
Do not infuse voriconazole concomitantly with blood products or short-term infusions of concentrated electrolytes, even if the 2 infusions are running through separate lines. Voriconazole may be infused at the same time as non-concentrated electrolytes and parenteral nutrition but must be run through a separate line.
IV infusions have been associated with infusion-related events resembling anaphylactoid reactions (faintness, sweating, flushing, tachycardia, chest tightness, rash, and dyspnea) typically occurring within seconds to minutes of the start of the infusion. Discontinue the infusion if these symptoms appear and treat appropriately. It is not known if slowing the rate of the infusion will lessen these reactions.[28158]

Ophthalmic Administration Extemporaneous Compounding-Ophthalmic

Prepare a 1% voriconazole topical ophthalmic solution by adding 19 mL of 0.9% Sodium Chloride Injection to the 200 mg vial of lyophilized powder for parenteral administration.

Adverse Reactions

Severe

visual impairment / Early / 18.7-18.7
optic neuritis / Delayed / 0-2.0
ocular hemorrhage / Delayed / 0-2.0
corneal opacification / Delayed / 0-2.0
keratoconjunctivitis / Early / 0-2.0
papilledema / Delayed / 0-2.0
keratitis / Delayed / 0-2.0
uveitis / Delayed / 0-2.0
night blindness / Delayed / 0-2.0
retinal hemorrhage / Delayed / 0-2.0
optic atrophy / Delayed / 0-2.0
osteonecrosis / Delayed / 0-2.0
toxic epidermal necrolysis / Delayed / 0-2.0
lupus-like symptoms / Delayed / 0-2.0
erythema multiforme / Delayed / 0-2.0
pseudoporphyria / Delayed / 0-2.0
Stevens-Johnson syndrome / Delayed / 0-2.0
exfoliative dermatitis / Delayed / 0-2.0
angioedema / Rapid / 0-2.0
eczema vaccinatum / Delayed / 0-2.0
melanoma / Delayed / 0-2.0
anaphylactoid reactions / Rapid / 0-2.0
hepatic failure / Delayed / 0-2.0
coma / Early / 0-2.0
renal tubular necrosis / Delayed / 0-2.0
hemorrhagic cystitis / Delayed / 0-2.0
oliguria / Early / 0-2.0
epididymitis / Delayed / 0-2.0
anuria / Delayed / 0-2.0
azotemia / Delayed / 0-2.0
suicidal ideation / Delayed / 0-2.0
seizures / Delayed / 0-2.0
Guillain-Barre syndrome / Delayed / 0-2.0
cerebral edema / Early / 0-2.0
hyperkalemia / Delayed / 0-2.0
hemolytic anemia / Delayed / 0-2.0
agranulocytosis / Delayed / 0-2.0
megaloblastic anemia / Delayed / 0-2.0
thrombotic thrombocytopenic purpura (TTP) / Delayed / 0-2.0
disseminated intravascular coagulation (DIC) / Delayed / 0-2.0
aplastic anemia / Delayed / 0-2.0
cyanosis / Early / 0-2.0
pancytopenia / Delayed / 0-2.0
torsade de pointes / Rapid / 0-2.0
heart failure / Delayed / 0-2.0
AV block / Early / 0-2.0
ventricular fibrillation / Early / 0-2.0
stroke / Early / 0-2.0
arrhythmia exacerbation / Early / 0-2.0
pulmonary embolism / Delayed / 0-2.0
atrial fibrillation / Early / 0-2.0
bradycardia / Rapid / 0-2.0
myocardial infarction / Delayed / 0-2.0
ventricular tachycardia / Early / 0-2.0
cardiomyopathy / Delayed / 0-2.0
cardiac arrest / Early / 0-2.0
hematemesis / Delayed / 0-2.0
cholecystitis / Delayed / 0-2.0
esophageal ulceration / Delayed / 0-2.0
peptic ulcer / Delayed / 0-2.0
GI perforation / Delayed / 0-2.0
GI bleeding / Delayed / 0-2.0
pancreatitis / Delayed / 0-2.0
pleural effusion / Delayed / 0-2.0
pulmonary edema / Early / 0-2.0
diabetes insipidus / Delayed / 0-2.0
hearing loss / Delayed / 0-2.0
renal failure (unspecified) / Delayed / 0.4-0.4
fluorosis / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known

Moderate

elevated hepatic enzymes / Delayed / 8.4-23.0
hyperbilirubinemia / Delayed / 4.3-19.4
hypokalemia / Delayed / 16.6-16.7
hallucinations / Early / 2.4-2.4
sinus tachycardia / Rapid / 2.4-2.4
photophobia / Early / 2.2-2.2
nystagmus / Delayed / 0-2.0
conjunctivitis / Delayed / 0-2.0
blepharitis / Early / 0-2.0
bone pain / Delayed / 0-2.0
myopathy / Delayed / 0-2.0
myasthenia / Delayed / 0-2.0
osteoporosis / Delayed / 0-2.0
osteomalacia / Delayed / 0-2.0
ascites / Delayed / 0-2.0
edema / Delayed / 0-2.0
peripheral edema / Delayed / 0-2.0
chest pain (unspecified) / Early / 0-2.0
flank pain / Delayed / 0-2.0
contact dermatitis / Delayed / 0-2.0
furunculosis / Delayed / 0-2.0
psoriasis / Delayed / 0-2.0
hepatitis / Delayed / 0-2.0
cholestasis / Delayed / 0-2.0
hepatomegaly / Delayed / 0-2.0
dysuria / Early / 0-2.0
urinary incontinence / Early / 0-2.0
vaginal bleeding / Delayed / 0-2.0
impotence (erectile dysfunction) / Delayed / 0-2.0
urinary retention / Early / 0-2.0
glycosuria / Early / 0-2.0
hematuria / Delayed / 0-2.0
testicular swelling / Early / 0-2.0
amnesia / Delayed / 0-2.0
euphoria / Early / 0-2.0
peripheral neuropathy / Delayed / 0-2.0
confusion / Early / 0-2.0
ataxia / Delayed / 0-2.0
depression / Delayed / 0-2.0
hypertonia / Delayed / 0-2.0
encephalopathy / Delayed / 0-2.0
delirium / Early / 0-2.0
psychosis / Early / 0-2.0
akathisia / Delayed / 0-2.0
hypercholesterolemia / Delayed / 0-2.0
hypomagnesemia / Delayed / 0-2.0
hyperuricemia / Delayed / 0-2.0
hypernatremia / Delayed / 0-2.0
hypocalcemia / Delayed / 0-2.0
hypophosphatemia / Delayed / 0-2.0
hyponatremia / Delayed / 0-2.0
hypermagnesemia / Delayed / 0-2.0
hyperglycemia / Delayed / 0-2.0
hypercalcemia / Delayed / 0-2.0
hypoglycemia / Early / 0-2.0
thrombocytopenia / Delayed / 0-2.0
leukopenia / Delayed / 0-2.0
lymphadenopathy / Delayed / 0-2.0
anemia / Delayed / 0-2.0
eosinophilia / Delayed / 0-2.0
hypervolemia / Delayed / 0-2.0
splenomegaly / Delayed / 0-2.0
supraventricular tachycardia (SVT) / Early / 0-2.0
hypotension / Rapid / 0-2.0
phlebitis / Rapid / 0-2.0
QT prolongation / Rapid / 0-2.0
hypertension / Early / 0-2.0
peripheral vasodilation / Rapid / 0-2.0
palpitations / Early / 0-2.0
bundle-branch block / Early / 0-2.0
orthostatic hypotension / Delayed / 0-2.0
stomatitis / Delayed / 0-2.0
esophagitis / Delayed / 0-2.0
proctitis / Delayed / 0-2.0
melena / Delayed / 0-2.0
constipation / Delayed / 0-2.0
glossitis / Early / 0-2.0
gingival hyperplasia / Delayed / 0-2.0
oral ulceration / Delayed / 0-2.0
pseudomembranous colitis / Delayed / 0-2.0
dysphagia / Delayed / 0-2.0
cholelithiasis / Delayed / 0-2.0
hypoxia / Early / 0-2.0
hemoptysis / Delayed / 0-2.0
dyspnea / Early / 0-2.0
hyperthyroidism / Delayed / 0-2.0
adrenocortical insufficiency / Delayed / 0-2.0
hypothyroidism / Delayed / 0-2.0
jaundice / Delayed / 1.0-1.0
clastogenesis / Delayed / Incidence not known
Cushing's syndrome / Delayed / Incidence not known

Mild

fever / Early / 5.7-5.7
nausea / Early / 5.4-5.4
rash / Early / 5.3-5.3
vomiting / Early / 4.4-4.4
chills / Rapid / 3.7-3.7
headache / Early / 3.0-3.0
diplopia / Early / 0-2.0
ocular pain / Early / 0-2.0
mydriasis / Early / 0-2.0
xerophthalmia / Early / 0-2.0
myalgia / Early / 0-2.0
arthralgia / Delayed / 0-2.0
muscle cramps / Delayed / 0-2.0
back pain / Delayed / 0-2.0
pelvic pain / Delayed / 0-2.0
asthenia / Delayed / 0-2.0
alopecia / Delayed / 0-2.0
maculopapular rash / Early / 0-2.0
skin discoloration / Delayed / 0-2.0
xerosis / Delayed / 0-2.0
pruritus / Rapid / 0-2.0
cheilitis / Delayed / 0-2.0
photosensitivity / Delayed / 0-2.0
urticaria / Rapid / 0-2.0
injection site reaction / Rapid / 0-2.0
flushing / Rapid / 0-2.0
dysmenorrhea / Delayed / 0-2.0
nightmares / Early / 0-2.0
insomnia / Early / 0-2.0
paresthesias / Delayed / 0-2.0
vertigo / Early / 0-2.0
libido decrease / Delayed / 0-2.0
drowsiness / Early / 0-2.0
dizziness / Early / 0-2.0
tremor / Early / 0-2.0
agitation / Early / 0-2.0
anxiety / Delayed / 0-2.0
purpura / Delayed / 0-2.0
ecchymosis / Delayed / 0-2.0
petechiae / Delayed / 0-2.0
syncope / Early / 0-2.0
abdominal pain / Early / 0-2.0
dyspepsia / Early / 0-2.0
anorexia / Delayed / 0-2.0
xerostomia / Early / 0-2.0
flatulence / Early / 0-2.0
gingivitis / Delayed / 0-2.0
diarrhea / Early / 0-2.0
sinusitis / Delayed / 0-2.0
infection / Delayed / 0-2.0
rhinitis / Early / 0-2.0
cough / Delayed / 0-2.0
pharyngitis / Delayed / 0-2.0
influenza / Delayed / 0-2.0
epistaxis / Delayed / 0-2.0
dysgeusia / Early / 0-2.0
tinnitus / Delayed / 0-2.0
otalgia / Early / 0-2.0

Common Brand Names

VFEND

Dea Class

Description

IV and oral azole antifungal drug
Indicated for aspergillosis, candidiasis, candidemia, and as salvage therapy for Scedosporium and Fusarium sp. infections
Associated with visual disturbances, QT prolongation, and phototoxicity

Dosage And Indications

For the treatment of candidemia and other serious invasive candidiasis infections.
NOTE: Voriconazole is FDA-approved for candidemia in nonneutropenic patients only.
Intravenous dosage Adults

6 mg/kg/dose IV every 12 hours on day 1, followed by 3 to 4 mg/kg/dose IV every 12 hours. In clinical trials, patients with candidemia received 3 mg/kg/dose IV every 12 hours, and patients with other deep tissue Candida infections received 4 mg/kg/dose IV every 12 hours. Selection of the appropriate dose should be based on the nature and severity of the infection. If patient is unable to tolerate 4 mg/kg/dose IV, reduce dose to 3 mg/kg/dose IV every 12 hours. Treat for 2 weeks after documented clearance from the bloodstream and resolution of signs and symptoms for invasive candidiasis without metastatic complications. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158] Guidelines recommend as alternative therapy for nonneutropenic patients with C. krusei or C. glabrata infections and additional mold coverage for neutropenic patients if desired.[60487]

Adolescents 15 to 17 years

Children and Adolescents 12 to 14 years weighing 50 kg or more

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours. May increase the dose by 1 mg/kg increments for inadequate response; if not tolerated, reduce dose by 1 mg/kg increments. Treat for 2 weeks after documented clearance from the bloodstream and resolution of signs and symptoms for invasive candidiasis without metastatic complications. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158] Higher doses, such as those recommended in children 2 to 11 years, are recommended in this population, as some pharmacokinetic data have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses.[54736] [54776] Guidelines recommend as alternative therapy for nonneutropenic patients with C. krusei or C. glabrata infections and additional mold coverage for neutropenic patients if desired.[60487]

Children 2 to 11 years

Infants† and Children younger than 2 years†

Optimal dosing is not well established. 9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours is recommended. This dose has been shown to provide comparable exposure in children 2 to 11 years to adults receiving 6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours.[54736] [54737] [60487] A maintenance dose of 4 mg/kg/dose every 12 hours in children provided comparable exposure to that seen in adults receiving 3 mg/kg/dose every 12 hours.[32393] [54736] However, it is unknown if this dosing strategy will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years.[54753] Treat for 2 weeks after documented clearance from the bloodstream and resolution of signs and symptoms for invasive candidiasis without metastatic complications. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. [60487] Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations.[54742] [54743] [54744] [54745] [54747] [54755] Guidelines recommend voriconazole as alternative therapy for nonneutropenic patients with C. krusei or C. glabrata infections and additional mold coverage for neutropenic patients if desired.[60487]

Neonates†

Safe and effective use has not been established; very limited data are available. Case reports describe the use of IV voriconazole doses ranging from 2 mg/kg/dose every 12 hours to 6 mg/kg/dose every 8 hours for the treatment of fungal infections in neonates (primarily premature neonates).[33867] [33868] [33869] [54740] A case series in 6 premature neonates younger than 32 weeks gestational age (postnatal age 7 to 50 days) used IV voriconazole doses of 6 mg/kg/dose IV every 8 hours for persistent candidemia. The dose was increased to 7 mg/kg/dose IV every 8 hours in 1 patient due to concurrent use of the CYP2C19 inducer, phenytoin. After voriconazole initiation, Candida eradication occurred within 3 to 7 days; the duration of voriconazole treatment was 18 to 24 days. Voriconazole serum concentrations were not measured in this study. No significant adverse events were reported, and no retinopathy was observed.[54740] Another report describes the use of 6 mg/kg/dose IV every 8 hours for the treatment of disseminated Candida albicans infection in a 14-day old neonate (27 weeks gestation at birth) who was also receiving the CYP2C19 inducer phenobarbital.[33867] Two other reports describe the successful use of lower doses, 2 to 4 mg/kg/dose IV every 12 hours, in 3 premature neonates for the treatment of cutaneous Aspergillus infections.[33868] [33869] Treat for 2 weeks after documented clearance from the bloodstream and resolution of signs and symptoms for invasive candidiasis without metastatic complications.[33870] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Because of reports of adverse visual effects in adults and children, some experts express concern over unknown effects on the developing retina of neonates.[33870]

Oral dosage Adults weighing 40 kg or more

200 mg PO every 12 hours after IV loading dose. Increase the dose to 300 mg PO every 12 hours for inadequate response; if not tolerated, reduce dose by 50 mg increments to minimum 200 mg PO every 12 hours.[28158] Alternatively, 400 mg PO every 12 hours for 2 doses, followed by 200 mg PO every 12 hours.[60487] Treat for 2 weeks after documented clearance from the bloodstream and resolution of signs and symptoms for invasive candidiasis without metastatic complications. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158] Guidelines recommend as alternative therapy for nonneutropenic patients with C. krusei or C. glabrata infections and additional mold coverage for neutropenic patients if desired.[60487]

Adults weighing less than 40 kg

100 mg PO every 12 hours after IV loading dose. Increase the dose to 150 mg PO every 12 hours for inadequate response; if not tolerated, reduce dose to minimum 100 mg PO every 12 hours.[28158] Alternatively, 400 mg PO every 12 hours for 2 doses, followed by 200 mg PO every 12 hours.[60487] Treat for 2 weeks after documented clearance from the bloodstream and resolution of signs and symptoms for invasive candidiasis without metastatic complications. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158] Guidelines recommend as alternative therapy for nonneutropenic patients with C. krusei or C. glabrata infections and additional mold coverage for neutropenic patients if desired.[60487]

Adolescents 15 to 17 years weighing 40 kg or more

Adolescents 15 to 17 years weighing less than 40 kg

Children and Adolescents 12 to 14 years weighing 50 kg or more

200 mg PO every 12 hours after IV loading dose. Increase the dose to 300 mg PO every 12 hours for inadequate response; if not tolerated, reduce dose by 50 mg increments to minimum 200 mg PO every 12 hours. Alternatively, 400 mg PO every 12 hours for 2 doses, followed by 200 mg PO every 12 hours. Treat for 2 weeks after documented clearance from the bloodstream and resolution of signs and symptoms for invasive candidiasis without metastatic complications. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Guidelines recommend as alternative therapy for nonneutropenic patients with C. krusei or C. glabrata infections and additional mold coverage for neutropenic patients if desired.

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose (Max: 350 mg/dose) PO every 12 hours after IV loading dose. May increase the dose by 1 mg/kg or 50 mg increments up to the maximum dose for inadequate response; if not tolerated, reduce dose by 1 mg/kg or 50 mg increments. Treat for 2 weeks after documented clearance from the bloodstream and resolution of signs and symptoms for invasive candidiasis without metastatic complications. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158] Higher doses, such as those recommended in children 2 to 11 years, are recommended in this population, as some pharmacokinetic data have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses.[54736] [54776] Guidelines recommend as alternative therapy for nonneutropenic patients with C. krusei or C. glabrata infections and additional mold coverage for neutropenic patients if desired.[60487]

Children 2 to 11 years

9 mg/kg/dose (Max: 350 mg/dose) PO every 12 hours after IV loading dose. May increase the dose by 1 mg/kg or 50 mg increments up to the maximum dose for inadequate response; if not tolerated, reduce dose by 1 mg/kg or 50 mg increments. Treat for 2 weeks after documented clearance from the bloodstream and resolution of signs and symptoms for invasive candidiasis without metastatic complications. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158] Guidelines recommend as alternative therapy for nonneutropenic patients with C. krusei or C. glabrata infections and additional mold coverage for neutropenic patients if desired.[60487]

Infants† and Children younger than 2 years†

Optimal dosing is not well established. 9 mg/kg/dose PO every 12 hours is recommended and this dose has been shown to provide comparable exposure in children 2 to 11 years as adults receiving 200 mg PO every 12 hours. However, it is unknown if this dose will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years. Treat for 2 weeks after documented clearance from the bloodstream and resolution of signs and symptoms for invasive candidiasis without metastatic complications. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years and with oral administration, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations. Guidelines recommend as alternative therapy for nonneutropenic patients with C. krusei or C. glabrata infections and additional mold coverage for neutropenic patients if desired.

Neonates†

Safe and effective use has not been established; very limited data are available. One report describes 2 term neonates who received oral doses of 4 mg/kg/dose every 12 hours after IV treatment with amphotericin B for Candida infections. Voriconazole was administered for 2 to 3 weeks without any significant toxicity or drug interactions. Another case report describes 2 neonates, 23 and 24 weeks gestation at birth, who received initial oral doses of 2 mg/kg/dose every 12 hours after IV therapy for cutaneous Aspergillus infections. In the first case, peak and trough concentrations on day 12 of oral therapy were 0.5 mcg/mL and less than 0.2 mcg/mL. The dosage was increased to 3.5 mg/kg/dose PO every 12 hours, and repeat peak and trough concentrations were 1.4 and 0.7 mcg/mL 20 days after the dosage increase. Because the patient was clinically improving, no further dosage increases were made. In the second case, the patient continued 2 mg/kg/dose PO every 12 hours for 10 days after IV therapy, at which time antifungal therapy was discontinued. The peak concentration measured 2 hours after previous dose on the last day of therapy was reported as 0.4 mcg/mL. The authors of this report suggest that voriconazole plasma concentrations be used primarily to avoid toxicity and that dosage titrations should be based on clinical response. Treat for 2 weeks after documented clearance from the bloodstream and resolution of signs and symptoms for invasive candidiasis without metastatic complications. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Because of reports of adverse visual effects in adults and children, some experts express concern over unknown effects on the developing retina of neonates.

For the primary treatment of invasive aspergillosis. Intravenous dosage Adults

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. If patient is unable to tolerate maintenance therapy, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement.[28158] Higher dosages have been used in some case reports.[26836] [26837] Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.[61353]

Adolescents 15 to 17 years

Children and Adolescents 12 to 14 years weighing 50 kg or more

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours. May increase dose in 1 mg/kg increments for inadequate response if initial dose is tolerated; if initial dose is not tolerated, reduce dose by 1 mg/kg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement.[28158] Higher doses, such as those recommended in children 2 to 11 years, are recommended in this population, as some pharmacokinetic data have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses.[54736] [54776] Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.[61353]

Children 2 to 11 years

Infants† and Children younger than 2 years†

Optimal dosing in infants and children younger than 2 years not well established. 9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours is recommended by guidelines. This dose has been shown to provide comparable exposure in children 2 to 11 years to adults receiving 6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours.[54736] [54737] [61353] A maintenance dose of 4 mg/kg/dose every 12 hours in children provided comparable exposure to that seen in adults receiving 3 mg/kg/dose every 12 hours.[32393] [54736] However, it is unknown if this dosing strategy will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years.[54753] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations.[54742] [54743] [54744] [54745] [54747] [54755] Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.[61353]

Oral dosage Adults weighing 40 kg or more

200 mg PO every 12 hours beginning after at least 7 days of IV voriconazole therapy. Increase to 300 mg PO every 12 hours for inadequate response; if not tolerated, taper by 50 mg increments to minimum 200 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158] Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.[61353]

Adults weighing less than 40 kg

100 mg PO every 12 hours beginning after at least 7 days of IV voriconazole therapy. Increase to 150 mg PO every 12 hours for inadequate response; if not tolerated, reduce dose to minimum 100 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158] Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.[61353]

Adolescents 15 to 17 years weighing 40 kg or more

Adolescents 15 to 17 years weighing less than 40 kg

Children and Adolescents 12 to 14 years weighing 50 kg or more

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose PO every 12 hours (Max: 350 mg/dose) beginning after at least 7 days of IV voriconazole therapy. May increase dose in 1 mg/kg or 50 mg increments up to the maximum dose for inadequate response if initial dose is tolerated; if initial dose is not tolerated, reduce dose by 1 mg/kg or 50 mg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158] Higher doses, such as those recommended in children 2 to 11 years, are recommended in this population, as some pharmacokinetic data have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses.[54736] [54776] Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.[61353]

Children 2 to 11 years

Infants† and Children younger than 2 years†

Optimal dosing in infants and children younger than 2 years is not well established. 9 mg/kg/dose PO every 12 hours is recommended by guidelines. This dose has been shown to provide comparable exposure in children 2 to 11 years as adults receiving 200 mg PO every 12 hours.[54736] [61353] However, it is unknown if this dose will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years.[54753] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years and with oral administration, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations.[54742] [54743] [54744] [54745] [54747] [54755] Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.[61353]

For the treatment of CNS infections, including meningitis. For step-down therapy of CNS infections due to Blastomyces dermatitidis† after initial treatment with amphotericin B . Oral dosage Adults

200 to 400 mg PO twice daily for at least 12 months and until resolution of CSF abnormalities. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[34215]

Adolescents 15 to 17 years

200 mg PO twice daily for at least 12 months and until resolution of CSF abnormalities. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Children and Adolescents 12 to 14 years weighing 50 kg or more

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg PO twice daily for at least 12 months and until resolution of CSF abnormalities. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Children 2 to 11 years

For the treatment of CNS infections due to Aspergillus sp.. Intravenous dosage Adults

6 mg/kg/dose IV every 12 hours on day 1, then 4 mg/kg/dose IV every 12 hours. If patient is unable to tolerate maintenance therapy, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement.[28158] Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks, with duration dependent on level of immunosuppression, extent of disease, and disease improvement.[61353] Longer treatment is often necessary. In a retrospective study of patients with CNS aspergillosis, the median duration of voriconazole treatment was 51 days (range, 1 to 1,128 days).[61956]

Adolescents 15 to 17 years

6 mg/kg/dose IV every 12 hours on day 1, then 4 mg/kg/dose IV every 12 hours. If patient is unable to tolerate maintenance therapy, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement.[28158] Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.[61353] Longer treatment is often necessary. In a retrospective study of patients with CNS aspergillosis, the median duration of voriconazole treatment was 51 days (range, 1 to 1,128 days).[61956]

Children and Adolescents 12 to 14 years weighing 50 kg or more

6 mg/kg/dose IV every 12 hours on day 1, then 4 mg/kg/dose IV every 12 hours. If patient is unable to tolerate maintenance therapy, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement.[28158] Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.[61353] Longer treatment is often necessary. In a retrospective study of patients with CNS aspergillosis, the median duration of voriconazole treatment was 51 days (range, 1 to 1,128 days).[61956]

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose IV every 12 hours on day 1, then 8 mg/kg/dose IV every 12 hours. May increase dose in 1 mg/kg increments for inadequate response if initial dose is tolerated; if initial dose is not tolerated, reduce dose by 1 mg/kg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement.[28158] Higher doses, such as those recommended in children 2 to 11 years, are recommended in this population, as some pharmacokinetic data have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses.[54736] [54776] Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.[61353] Longer treatment is often necessary. In a retrospective study of patients with CNS aspergillosis, the median duration of voriconazole treatment was 51 days (range, 1 to 1,128 days).[61956]

Children 2 to 11 years

9 mg/kg/dose IV every 12 hours on day 1, then 8 mg/kg/dose IV every 12 hours. May increase dose in 1 mg/kg increments for inadequate response if initial dose is tolerated; if initial dose is not tolerated, reduce dose by 1 mg/kg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement.[28158] Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.[61353] Longer treatment is often necessary. In a retrospective study of patients with CNS aspergillosis, the median duration of voriconazole treatment was 51 days (range, 1 to 1,128 days).[61956]

Infants and Children younger than 2 years†

Optimal dosing in infants and children younger than 2 years not well established. 9 mg/kg/dose IV every 12 hours on day 1, then 8 mg/kg/dose IV every 12 hours is recommended by guidelines. This dose has been shown to provide comparable exposure in children 2 to 11 years to adults receiving 6 mg/kg/dose IV every 12 hours on day 1, then 4 mg/kg/dose IV every 12 hours.[54736] [54737] [61353] A maintenance dose of 4 mg/kg/dose every 12 hours in children provided comparable exposure to that seen in adults receiving 3 mg/kg/dose every 12 hours.[32393] [54736] However, it is unknown if this dosing strategy will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years.[54753] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations.[54742] [54743] [54744] [54745] [54747] [54755] Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.[61353] Longer treatment is often necessary. In a retrospective study of patients with CNS aspergillosis, the median duration of voriconazole treatment was 51 days (range, 1 to 1,128 days).[61956]

Oral dosage Adults weighing 40 kg or more

Adults weighing less than 40 kg

Adolescents 15 to 17 years weighing 40 kg or more

Adolescents 15 to 17 years weighing less than 40 kg

Children and Adolescents 12 to 14 years weighing 50 kg or more

Children and Adolescents 12 to 14 years weighing less than 50 kg

Children 2 to 11 years

9 mg/kg/dose PO every 12 hours (Max: 350 mg/dose) beginning after at least 7 days of IV voriconazole therapy. May increase dose in 1 mg/kg or 50 mg increments up to the maximum dose for inadequate response if initial dose is tolerated; if initial dose is not tolerated, reduce dose by 1 mg/kg or 50 mg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158] Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.[61353] Longer treatment is often necessary. In a retrospective study of patients with CNS aspergillosis, the median duration of voriconazole treatment was 51 days (range, 1 to 1,128 days).[61956]

Infants† and Children younger than 2 years†

For the treatment of CNS infections due to Coccidioides sp.†. Oral dosage Adults

200 to 400 mg PO every 12 hours as an alternative to fluconazole. Continue suppressive therapy for lifelong. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Adolescents

For the treatment of meningitis due to Histoplasma capsulatum† in persons living with HIV. Oral dosage Adults

400 mg PO every 12 hours for 1 day, then 200 mg PO every 12 hours for at least 12 months and until resolution of abnormal CSF findings in patients who are intolerant to itraconazole after induction therapy with liposomal amphotericin B. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[34362]

Adolescents

For the treatment of esophageal candidiasis, including fluconazole-refractory disease. Oral dosage Adults weighing 40 kg or more

200 mg PO every 12 hours for 14 to 21 days as an alternative.[34362] [60487] The FDA-approved dosage is 200 mg PO every 12 hours for at least 14 days and for at least 7 days after symptom resolution. Increase the dose to 300 mg PO every 12 hours for inadequate response; if not tolerated, reduce dose by 50 mg increments to minimum 200 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158]

Adults weighing less than 40 kg

100 mg PO every 12 hours for 14 to 21 days as an alternative.[34362] [60487] The FDA-approved dosage is 100 mg PO every 12 hours for at least 14 days and for at least 7 days after symptom resolution. Increase the dose to 150 mg PO every 12 hours for inadequate response; if not tolerated, reduce dose to minimum 100 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158]

Adolescents 15 to 17 years weighing 40 kg or more

Adolescents 15 to 17 years weighing less than 40 kg

Children and Adolescents 12 to 14 years weighing 50 kg or more

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose (Max: 350 mg/dose) PO every 12 hours for 14 to 21 days as an alternative. [60487] The FDA-approved dosage is 9 mg/kg/dose (Max: 350 mg/dose) PO every 12 hours for at least 14 days and for at least 7 days after symptom resolution. May increase the dose by 1 mg/kg or 50 mg increments up to the maximum dose for inadequate response; if not tolerated, reduce dose by 1 mg/kg or 50 mg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158] Higher doses, such as those recommended in children 2 to 11 years, are recommended in this population, as some pharmacokinetic data have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses.[54736] [54776]

Children 2 to 11 years

Infants† and Children younger than 2 years†

Optimal dosing is not well established. 9 mg/kg/dose PO every 12 hours for 14 to 21 days is recommended and this dose has been shown to provide comparable exposure in children 2 to 11 years as adults receiving 200 mg PO every 12 hours. However, it is unknown if this dose will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years and with oral administration, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations.

Intravenous dosage Adults†

200 mg IV every 12 hours for 14 to 21 days as an alternative.[34362] [60487] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Adolescents 15 to 17 years†

200 mg IV every 12 hours for 14 to 21 as an alternative.[34362] [60487] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Children and Adolescents 12 to 14 years weighing 50 kg or more†

200 mg IV every 12 hours for 14 to 21 days as an alternative.[34361] [34362] [60487] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Children and Adolescents 12 to 14 years weighing less than 50 kg

4 mg/kg/dose IV every 12 hours for 14 to 21 days as an alternative. [60487] The FDA-approved dosage is 4 mg/kg/dose IV every 12 hours for at least 14 days and for at least 7 days after symptom resolution. May increase the dose in 1 mg/kg increments for inadequate response; if initial dose is not tolerated, reduce dose by 1 mg/kg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158]

Children 2 to 11 years

4 mg/kg/dose IV every 12 hours for 14 to 21 days as an alternative. [60487] The FDA-approved dosage is 4 mg/kg/dose IV every 12 hours for at least 14 days and for at least 7 days after symptom resolution. May increase the dose in 1 mg/kg increments for inadequate response; if not tolerated, reduce dose by 1 mg/kg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158]

Infants† and Children younger than 2 years†

Optimal dosing is not well established. 9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours for 14 to 21 days is recommended. This dose has been shown to provide comparable exposure in children 2 to 11 years to adults receiving 6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours.[34361] [54736] [60487] A maintenance dose of 4 mg/kg/dose every 12 hours in children provided comparable exposure to that seen in adults receiving 3 mg/kg/dose every 12 hours.[32393] [54736] However, it is unknown if this dosing strategy will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years.[54753] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations.[54742] [54743] [54744] [54745] [54747] [54755]

For the treatment of cardiovascular system infections, including endocarditis, myocarditis, pericarditis, and infected pacemaker, implantable cardiac defibrillator (ICD), or ventricular assist devices (VAD). For the treatment of Candida cardiovascular system infections†. Oral dosage Adults

200 to 300 mg PO every 12 hours as alternative step-down therapy to fluconazole for susceptible isolates. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. For endocarditis, treat for at least 6 weeks after valve replacement. For infected cardiac hardware, treat for at least 4

to 6 weeks after hardware removal.

Adolescents 15 to 17 years

Children and Adolescents 12 to 14 years weighing 50 kg or more

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose PO every 12 hours (Max: 350 mg/dose) as alternative step-down therapy to fluconazole for susceptible isolates. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. For endocarditis, treat for at least 6 weeks after valve replacement. For infected cardiac hardware, treat for at least 4 to 6 weeks after hardware removal. Higher doses, such as those recommended in children 2 to 11 years, are recommended in this population, as some pharmacokinetic data have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses.

Children 2 to 11 years

Infants and Children younger than 2 years

Optimal dosing in infants and children younger than 2 years not well established. 9 mg/kg/dose PO every 12 hours is recommended by guidelines and this dose has been shown to provide comparable exposure in children 2 to 11 years as adults receiving 200 mg PO every 12 hours.[54736] [60487] However, it is unknown if this dose will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years.[54753] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. For endocarditis, treat for at least 6 weeks after valve replacement. For infected cardiac hardware, treat for at least 4 to 6 weeks after hardware removal.[60487] Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years and with oral administration, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations.[54742] [54743] [54744] [54745] [54747] [54755] Guidelines recommend voriconazole as an alternative step-down therapy to fluconazole for susceptible isolates.[60487]

For the treatment of Aspergillus cardiovascular system infections. Intravenous dosage Adults

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. If patient is unable to tolerate maintenance therapy, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement.[28158] Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement; longer treatment duration is often necessary. After surgical replacement of an infected valve, consider lifelong antifungal therapy.[61353]

Adolescents 15 to 17 years

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. If patient is unable to tolerate maintenance therapy, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement.[28158] Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement; longer treatment duration is often necessary. After surgical replacement of an infected valve, consider lifelong antifungal therapy.[61353]

Children and Adolescents 12 to 14 years weighing 50 kg or more

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. If patient is unable to tolerate maintenance therapy, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement.[28158] Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement; longer treatment duration is often necessary. After surgical replacement of an infected valve, consider lifelong antifungal therapy.[61353]

Children and Adolescents 12 to 14 years weighing less than 50 kg

Children 2 to 11 years

9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours. May increase dose in 1 mg/kg increments for inadequate response if initial dose is tolerated; if initial dose is not tolerated, reduce dose by 1 mg/kg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement.[28158] Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement; longer treatment duration is often necessary. After surgical replacement of an infected valve, consider lifelong antifungal therapy.[61353]

Infants† and Children younger than 2 years†

Oral dosage Adults weighing 40 kg or more

Adults weighing less than 40 kg

Adolescents 15 to 17 years weighing 40 kg or more

Adolescents 15 to 17 years weighing less than 40 kg

Children and Adolescents 12 to 14 years weighing 50 kg or more

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose PO every 12 hours (Max: 350 mg/dose) beginning after at least 7 days of IV voriconazole therapy. May increase dose in 1 mg/kg or 50 mg increments up to the maximum dose for inadequate response if initial dose is tolerated; if initial dose is not tolerated, reduce dose by 1 mg/kg or 50 mg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Higher doses, such as those recommended in children 2 to 11 years, are recommended in this population, as some pharmacokinetic data have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses. Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement; longer treatment duration is often necessary. After surgical replacement of an infected valve, consider lifelong antifungal therapy.

Children 2 to 11 years

Infants† and Children younger than 2 years†

Optimal dosing in infants and children younger than 2 years is not well established. 9 mg/kg/dose PO every 12 hours is recommended by guidelines. This dose has been shown to provide comparable exposure in children 2 to 11 years as adults receiving 200 mg PO every 12 hours. However, it is unknown if this dose will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years and with oral administration, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations. Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement; longer treatment duration is often necessary. After surgical replacement of an infected valve, consider lifelong antifungal therapy.

For the treatment of invasive pulmonary aspergillosis and other Aspergillus respiratory infections (i.e., pneumonia, tracheobronchitis, sinusitis, aspergilloma). Intravenous dosage Adults

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. If patient is unable to tolerate maintenance therapy, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement. Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.

Adolescents 15 to 17 years

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. If patient is unable to tolerate maintenance therapy, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement. Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.

Children and Adolescents 12 to 14 years weighing 50 kg or more

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. If patient is unable to tolerate maintenance therapy, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement. Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours. May increase dose in 1 mg/kg increments for inadequate response if initial dose is tolerated; if initial dose is not tolerated, reduce dose by 1 mg/kg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement. Higher doses, such as those recommended in children 2 to 11 years, are recommended in this population, as some pharmacokinetic data have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses. Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.

Children 2 to 11 years

Infants† and Children younger than 2 years†

Optimal dosing in infants and children younger than 2 years not well established. 9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours is recommended by guidelines. This dose has been shown to provide comparable exposure in children 2 to 11 years to adults receiving 6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. A maintenance dose of 4 mg/kg/dose every 12 hours in children provided comparable exposure to that seen in adults receiving 3 mg/kg/dose every 12 hours. However, it is unknown if this dosing strategy will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations. Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.

Oral dosage Adults weighing 40 kg or more

200 mg PO every 12 hours beginning after at least 7 days of IV voriconazole therapy. Increase to 300 mg PO every 12 hours for inadequate response; if not tolerated, taper by 50 mg increments to minimum 200 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.

Adults weighing less than 40 kg

100 mg PO every 12 hours beginning after at least 7 days of IV voriconazole therapy. Increase to 150 mg PO every 12 hours for inadequate response; if not tolerated, reduce dose to minimum 100 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.

Adolescents 15 to 17 years weighing 40 kg or more

200 mg PO every 12 hours beginning after at least 7 days of IV voriconazole therapy. Increase to 300 mg PO every 12 hours for inadequate response; if not tolerated, taper by 50 mg increments to minimum 200 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.

Adolescents 15 to 17 years weighing less than 40 kg

100 mg PO every 12 hours beginning after at least 7 days of IV voriconazole therapy. Increase to 150 mg PO every 12 hours for inadequate response; if not tolerated, reduce dose to minimum 100 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.

Children and Adolescents 12 to 14 years weighing 50 kg or more

200 mg PO every 12 hours beginning after at least 7 days of IV voriconazole therapy. Increase to 300 mg PO every 12 hours for inadequate response; if not tolerated, taper by 50 mg increments to minimum 200 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose PO every 12 hours (Max: 350 mg/dose) after at least 7 days of IV voriconazole therapy. May increase dose in 1 mg/kg or 50 mg increments up to the maximum dose for inadequate response if initial dose is tolerated; if initial dose is not tolerated, reduce dose by 1 mg/kg or 50 mg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Higher doses, such as those recommended in children 2 to 11 years, are recommended in this population, as some pharmacokinetic data have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses. Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.

Children 2 to 11 years

Infants† and Children younger than 2 years†

Optimal dosing in infants and children younger than 2 years is not well established. 9 mg/kg/dose PO every 12 hours is recommended by guidelines. This dose has been shown to provide comparable exposure in children 2 to 11 years as adults receiving 200 mg PO every 12 hours. However, it is unknown if this dose will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years and with oral administration, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations. Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.

For the treatment of intraabdominal infections, including intraabdominal candidiasis and peritoneal dialysis-related peritonitis. For the treatment of intraabdominal candidiasis.
NOTE: The manufacturer recommends use in nonneutropenic patients only.
Intravenous dosage Adults

6 mg/kg/dose IV every 12 hours on day 1, followed by 3 to 4 mg/kg/dose IV every 12 hours. Treat for at least 14 days after symptom resolution or after last positive culture, whichever is longer. If patient is unable to tolerate 4 mg/kg/dose IV, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Adolescents 15 to 17 years

Children and Adolescents 12 to 14 years weighing 50 kg or more

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours. May increase dose in 1 mg/kg increments for inadequate response if initial dose is tolerated; if initial dose is not tolerated, reduce dose by 1 mg/kg increments. Treat for at least 14 days after symptom resolution or after last positive culture, whichever is longer. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Higher doses, such as those recommended in children 2 to 11 years, are recommended in this population, as some pharmacokinetic data have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses.

Children 2 to 11 years

9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours. May increase dose in 1 mg/kg increments for inadequate response if initial dose is tolerated; if initial dose is not tolerated, reduce dose by 1 mg/kg increments. Treat for at least 14 days after symptom resolution or after last positive culture, whichever is longer. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Infants† and Children younger than 2 years†

Optimal dosing in infants and children younger than 2 years not well established. 9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours is recommended by guidelines. This dose has been shown to provide comparable exposure in children 2 to 11 years to adults receiving 6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. Treat for at least 14 days after symptom resolution or after last positive culture, whichever is longer. A maintenance dose of 4 mg/kg/dose every 12 hours in children provided comparable exposure to that seen in adults receiving 3 mg/kg/dose every 12 hours. However, it is unknown if this dosing strategy will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations.

Neonates†

Safe and effective use has not been established; very limited data are available. Case reports describe the use of IV voriconazole doses ranging from 2 mg/kg/dose every 12 hours to 6 mg/kg/dose every 8 hours for the treatment of fungal infections in neonates (primarily premature neonates). One case series in 6 premature neonates younger than 32 weeks gestational age (postnatal age 7 to 50 days) used IV voriconazole doses of 6 mg/kg/dose IV every 8 hours for persistent candidemia. The dose was increased to 7 mg/kg/dose IV every 8 hours in 1 patient due to concurrent use of the CYP2C19 inducer, phenytoin. After voriconazole initiation, Candida eradication occurred within 3 to 7 days; the duration of voriconazole treatment was 18 to 24 days. Voriconazole serum concentrations were not measured in this study. No significant adverse events were reported and no retinopathy was observed. Another report describes the use of 6 mg/kg/dose IV every 8 hours for the treatment of disseminated Candida albicans infection in a 14-day-old neonate (27 weeks' gestation at birth) who was also receiving the CYP2C19 inducer phenobarbital. The authors of this report recommend that a dosing interval of every 8 hours be considered when voriconazole is coadministered with extensive CYP2C19 inducers. Two other reports describe the successful use of lower doses, 2 to 4 mg/kg/dose IV every 12 hours, in 3 premature neonates for the treatment of cutaneous aspergillosis. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Because of reports of adverse visual effects in adults and children, some experts express concern over unknown effects on the developing retina of neonates.

Oral dosage Adults weighing 40 kg or more

200 mg PO every 12 hours after IV loading dose. Increase to 300 mg PO every 12 hours for inadequate response; if not tolerated, taper by 50 mg increments to minimum 200 mg PO every 12 hours. Alternatively, guidelines suggest 400 mg PO every 12 hours for 2 doses, followed by maintenance dosage. Treat for at least 14 days after symptom resolution or after last positive culture, whichever is longer. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Adults weighing less than 40 kg

100 mg PO every 12 hours after IV loading dose. Increase to 150 mg PO every 12 hours for inadequate response; if not tolerated, reduce dose to minimum 100 mg PO every 12 hours. Alternatively, guidelines suggest 400 mg PO every 12 hours for 2 doses, followed by maintenance dosage. Treat for at least 14 days after symptom resolution or after last positive culture, whichever is longer. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Adolescents 15 to 17 years weighing 40 kg or more

Adolescents 15 to 17 years weighing less than 40 kg

Children and Adolescents 12 to 14 years weighing 50 kg or more

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose PO every 12 hours (Max: 350 mg/dose) after IV loading dose. May increase dose in 1 mg/kg or 50 mg increments up to the maximum dose for inadequate response if initial dose is tolerated; if initial dose is not tolerated, reduce dose by 1 mg/kg or 50 mg increments. Treat for at least 14 days after symptom resolution or after last positive culture, whichever is longer. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Higher doses, such as those recommended in children 2 to 11 years, are recommended in this population, as some pharmacokinetic data have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses.

Children 2 to 11 years

Infants† and Children younger than 2 years†

Optimal dosing in infants and children younger than 2 years not well established. 9 mg/kg/dose PO every 12 hours is recommended by guidelines and this dose has been shown to provide comparable exposure in children 2 to 11 years as adults receiving 200 mg PO every 12 hours. However, it is unknown if this dose will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years. Treat for at least 14 days after symptom resolution or after last positive culture, whichever is longer. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years and with oral administration, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations.

For the treatment of peritoneal dialysis-related peritonitis due to filamentous fungi such as Aspergillus. Intermittent Intraperitoneal dosage† Adults

2.5 mg/kg/dose intraperitoneally every 24 to 48 hours.

Intravenous dosage Adults

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours for 6 to 8 weeks and for at least 14 days after catheter removal. If patient is unable to tolerate maintenance therapy, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158] [61353]

Adolescents 15 to 17 years

Children and Adolescents 12 to 14 years weighing 50 kg or more

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours for 6 to 8 weeks and for at least 14 days after catheter removal. May increase dose in 1 mg/kg increments for inadequate response if initial dose is tolerated; if initial dose is not tolerated, reduce dose by 1 mg/kg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158] Higher doses, such as those recommended in children 2 to 11 years, are recommended in this population, as some pharmacokinetic data have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses.[54736] [54776]

Children 2 to 11 years

Infants† and Children younger than 2 years†

Optimal dosing in infants and children younger than 2 years not well established. 9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours for 6 to 8 weeks and for at least 14 days after catheter removal. This dose has been shown to provide comparable exposure in children 2 to 11 years to adults receiving 6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. A maintenance dose of 4 mg/kg/dose every 12 hours in children provided comparable exposure to that seen in adults receiving 3 mg/kg/dose every 12 hours. However, it is unknown if this dosing strategy will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations.

Oral dosage Adults weighing 40 kg or more

200 mg PO every 12 hours for 6 to 8 weeks and for at least 14 days after catheter removal. Increase to 300 mg PO every 12 hours for inadequate response; if not tolerated, taper by 50 mg increments to minimum 200 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Adults weighing less than 40 kg

100 mg PO every 12 hours for 6 to 8 weeks and for at least 14 days after catheter removal. Increase to 150 mg PO every 12 hours for inadequate response; if not tolerated, reduce dose to minimum 100 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Adolescents 15 to 17 years weighing 40 kg or more

Adolescents 15 to 17 years weighing less than 40 kg

Children and Adolescents 12 to 14 years weighing 50 kg or more

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose PO every 12 hours (Max: 350 mg/dose) for 6 to 8 weeks and for at least 14 days after catheter removal. May increase dose in 1 mg/kg or 50 mg increments up to the maximum dose for inadequate response if initial dose is tolerated; if initial dose is not tolerated, reduce dose by 1 mg/kg or 50 mg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Higher doses, such as those recommended in children 2 to 11 years, are recommended in this population, as some pharmacokinetic data have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses.

Children 2 to 11 years

Infants† and Children younger than 2 years†

Optimal dosing in infants and children younger than 2 years is not well established. 9 mg/kg/dose PO every 12 hours for 6 to 8 weeks and for at least 14 days after catheter removal. This dose has been shown to provide comparable exposure in children 2 to 11 years as adults receiving 200 mg PO every 12 hours. However, it is unknown if this dose will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years and with oral administration, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations.

For the treatment of bone and joint infections (i.e., osteomyelitis and infectious arthritis) caused by Aspergillus sp.. Intravenous dosage Adults

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. If patient is unable to tolerate maintenance therapy, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement.[28158] Guidelines suggest voriconazole as primary therapy. Treat for at least 8 weeks; prolonged antifungal therapy (more than 6 months) is frequently necessary. In addition, surgical debridement where feasible is recommended as an adjunct to systemic antifungal therapy.[61353]

Adolescents 15 to 17 years

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. If patient is unable to tolerate maintenance therapy, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement.[28158] Guidelines suggest voriconazole as primary therapy. Treat for at least 8 weeks; prolonged antifungal therapy (more than 6 months) is frequently necessary. In addition, surgical debridement where feasible is recommended as an adjunct to systemic antifungal therapy.[61353]

Children and Adolescents 12 to 14 years weighing 50 kg or more

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. If patient is unable to tolerate maintenance therapy, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement. Guidelines suggest voriconazole as primary therapy. Treat for at least 8 weeks; prolonged antifungal therapy (more than 6 months) is frequently necessary. In addition, surgical debridement where feasible is recommended as an adjunct to systemic antifungal therapy.

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours. May increase dose in 1 mg/kg increments for inadequate response if initial dose is tolerated; if initial dose is not tolerated, reduce dose by 1 mg/kg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement. Higher doses, such as those recommended in children 2 to 11 years, are recommended in this population, as some pharmacokinetic data have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses. Guidelines suggest voriconazole as primary therapy. Treat for at least 8 weeks; prolonged antifungal therapy (more than 6 months) is frequently necessary. In addition, surgical debridement where feasible is recommended as an adjunct to systemic antifungal therapy.

Children 2 to 11 years

Infants† and Children younger than 2 years†

Optimal dosing in infants and children younger than 2 years not well established. 9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours is recommended by guidelines. This dose has been shown to provide comparable exposure in children 2 to 11 years to adults receiving 6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. A maintenance dose of 4 mg/kg/dose every 12 hours in children provided comparable exposure to that seen in adults receiving 3 mg/kg/dose every 12 hours. However, it is unknown if this dosing strategy will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations. Guidelines suggest voriconazole as primary therapy. Treat for at least 8 weeks; prolonged antifungal therapy (more than 6 months) is frequently necessary. In addition, surgical debridement where feasible is recommended as an adjunct to systemic antifungal therapy.

Oral dosage Adults weighing 40 kg or more

200 mg PO every 12 hours beginning after at least 7 days of IV voriconazole therapy. Increase to 300 mg PO every 12 hours for inadequate response; if not tolerated, taper by 50 mg increments to minimum 200 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Guidelines suggest voriconazole as primary therapy. Treat for at least 8 weeks; prolonged antifungal therapy (more than 6 months) is frequently necessary. In addition, surgical debridement where feasible is recommended as an adjunct to systemic antifungal therapy.

Adults weighing less than 40 kg

100 mg PO every 12 hours beginning after at least 7 days of IV voriconazole therapy. Increase to 150 mg PO every 12 hours for inadequate response; if not tolerated, reduce dose to minimum 100 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Guidelines suggest voriconazole as primary therapy. Treat for at least 8 weeks; prolonged antifungal therapy (more than 6 months) is frequently necessary. In addition, surgical debridement where feasible is recommended as an adjunct to systemic antifungal therapy.

Adolescents 15 to 17 years weighing 40 kg or more

200 mg PO every 12 hours beginning after at least 7 days of IV voriconazole therapy. Increase to 300 mg PO every 12 hours for inadequate response; if not tolerated, taper by 50 mg increments to minimum 200 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Guidelines suggest voriconazole as primary therapy. Treat for at least 8 weeks; prolonged antifungal therapy (more than 6 months) is frequently necessary. In addition, surgical debridement where feasible is recommended as an adjunct to systemic antifungal therapy.

Adolescents 15 to 17 years weighing less than 40 kg v>

100 mg PO every 12 hours beginning after at least 7 days of IV voriconazole therapy. Increase to 150 mg PO every 12 hours for inadequate response; if not tolerated, reduce dose to minimum 100 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Guidelines suggest voriconazole as primary therapy. Treat for at least 8 weeks; prolonged antifungal therapy (more than 6 months) is frequently necessary. In addition, surgical debridement where feasible is recommended as an adjunct to systemic antifungal therapy.

Children and Adolescents 12 to 14 years weighing 50 kg or more

200 mg PO every 12 hours beginning after at least 7 days of IV voriconazole therapy. Increase to 300 mg PO every 12 hours for inadequate response; if not tolerated, taper by 50 mg increments to minimum 200 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Guidelines suggest voriconazole as primary therapy. Treat for at least 8 weeks; prolonged antifungal therapy (more than 6 months) is frequently necessary. In addition, surgical debridement where feasible is recommended as an adjunct to systemic antifungal therapy.

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose PO every 12 hours (Max: 350 mg/dose) beginning after at least 7 days of IV voriconazole therapy. May increase dose in 1 mg/kg or 50 mg increments up to the maximum dose for inadequate response if initial dose is tolerated; if initial dose is not tolerated, reduce dose by 1 mg/kg or 50 mg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Higher doses, such as those recommended in children 2 to 11 years, are recommended in this population, as some pharmacokinetic data have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses. Guidelines suggest voriconazole as primary therapy. Treat for at least 8 weeks; prolonged antifungal therapy (more than 6 months) is frequently necessary. In addition, surgical debridement where feasible is recommended as an adjunct to systemic antifungal therapy.

Children 2 to 11 years

Infants† and Children younger than 2 years†

Optimal dosing in infants and children younger than 2 years is not well established. 9 mg/kg/dose PO every 12 hours is recommended by guidelines. This dose has been shown to provide comparable exposure in children 2 to 11 years as adults receiving 200 mg PO every 12 hours. However, it is unknown if this dose will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years and with oral administration, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations. Guidelines suggest voriconazole as primary therapy. Treat for at least 8 weeks; prolonged antifungal therapy (more than 6 months) is frequently necessary. In addition, surgical debridement where feasible is recommended as an adjunct to systemic antifungal therapy.

For the treatment of fungal skin and skin structure infections. For the treatment of disseminated cutaneous candidiasis.
NOTE: The manufacturer recommends use in nonneutropenic patients only.
Intravenous dosage Adults

6 mg/kg/dose IV every 12 hours on day 1, followed by 3 to 4 mg/kg/dose IV every 12 hours. In clinical trials, patients with candidemia received 3 mg/kg/dose IV every 12 hours, and patients with other deep tissue Candida infections received 4 mg/kg/dose IV every 12 hours. Selection of the appropriate dose should be based on the nature and severity of the infection. If patient is unable to tolerate 4 mg/kg/dose IV, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158] Guidelines recommend voriconazole as alternative therapy for nonneutropenic patients with C. krusei or C. glabrata infections and additional mold coverage for neutropenic patients if desired.[60487]

Adolescents 15 to 17 years

6 mg/kg/dose IV every 12 hours on day 1, followed by 3 to 4 mg/kg/dose IV every 12 hours. In clinical trials, patients with candidemia received 3 mg/kg/dose IV every 12 hours, and patients with other deep tissue Candida infections received 4 mg/kg/dose IV every 12 hours. Selection of the appropriate dose should be based on the nature and severity of the infection. If patient is unable to tolerate 4 mg/kg/dose IV, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158] [54757] Guidelines recommend voriconazole as alternative therapy for nonneutropenic patients with C. krusei or C. glabrata infections and additional mold coverage for neutropenic patients if desired.[60487]

Children and Adolescents 12 to 14 years weighing 50 kg or more

6 mg/kg/dose IV every 12 hours on day 1, followed by 3 to 4 mg/kg/dose IV every 12 hours. In clinical trials, patients with candidemia received 3 mg/kg/dose IV every 12 hours, and patients with other deep tissue Candida infections received 4 mg/kg/dose IV every 12 hours. Selection of the appropriate dose should be based on the nature and severity of the infection. If patient is unable to tolerate 4 mg/kg/dose IV, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158] [54757] Guidelines recommend voriconazole as alternative therapy for nonneutropenic patients with C. krusei or C. glabrata infections and additional mold coverage for neutropenic patients if desired.[60487]

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours. May increase dose in 1 mg/kg increments for inadequate response if initial dose is tolerated; if initial dose is not tolerated, reduce dose by 1 mg/kg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158] Higher doses, such as those recommended in children 2 to 11 years, are recommended in this population, as some pharmacokinetic data have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses.[54736] [54776] Guidelines recommend voriconazole as alternative therapy for nonneutropenic patients with C. krusei or C. glabrata infections and additional mold coverage for neutropenic patients if desired.[60487]

Children 2 to 11 years

Infants† and Children younger than 2 years†

Optimal dosing in infants and children younger than 2 years not well established. 9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours is recommended by guidelines. This dose has been shown to provide comparable exposure in children 2 to 11 years to adults receiving 6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours.[54736] [54737] [60487] A maintenance dose of 4 mg/kg/dose every 12 hours in children provided comparable exposure to that seen in adults receiving 3 mg/kg/dose every 12 hours.[32393] [54736] However, it is unknown if this dosing strategy will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years.[54753] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations.[54742] [54743] [54744] [54745] [54747] [54755] Guidelines recommend voriconazole as alternative therapy for nonneutropenic patients with C. krusei or C. glabrata infections and additional mold coverage for neutropenic patients if desired.[60487]

Oral dosage Adults weighing 40 kg or more

200 mg PO every 12 hours after IV loading dose. Increase to 300 mg PO every 12 hours for inadequate response; if not tolerated, taper by 50 mg increments to minimum 200 mg PO every 12 hours.[28158] Alternatively, guidelines suggest 400 mg PO every 12 hours for 2 doses, followed by maintenance dosage.[60487] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Guidelines recommend voriconazole as alternative therapy for nonneutropenic patients with C. krusei or C. glabrata infections and additional mold coverage for neutropenic patients if desired.[60487]

Adults weighing less than 40 kg

100 mg PO every 12 hours after IV loading dose. Increase to 150 mg PO every 12 hours for inadequate response; if not tolerated, reduce dose to minimum 100 mg PO every 12 hours.[28158] Alternatively, guidelines suggest 400 mg PO every 12 hours for 2 doses, followed by maintenance dosage.[60487] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Guidelines recommend voriconazole as alternative therapy for nonneutropenic patients with C. krusei or C. glabrata infections and additional mold coverage for neutropenic patients if desired.[60487]

Adolescents 15 to 17 years weighing 40 kg or more

200 mg PO every 12 hours after IV loading dose. Increase to 300 mg PO every 12 hours for inadequate response; if not tolerated, taper by 50 mg increments to minimum 200 mg PO every 12 hours.[28158] Alternatively, guidelines suggest 400 mg PO every 12 hours for 2 doses, followed by maintenance dosage.[60487] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158] Guidelines recommend voriconazole as alternative therapy for nonneutropenic patients with C. krusei or C. glabrata infections and additional mold coverage for neutropenic patients if desired.[60487]

Adolescents 15 to 17 years weighing less than 40 kg

100 mg PO every 12 hours after IV loading dose. Increase to 150 mg PO every 12 hours for inadequate response; if not tolerated, reduce dose to minimum 100 mg PO every 12 hours.[28158] Alternatively, guidelines suggest 400 mg PO every 12 hours for 2 doses, followed by maintenance dosage.[60487] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158] Guidelines recommend voriconazole as alternative therapy for nonneutropenic patients with C. krusei or C. glabrata infections and additional mold coverage for neutropenic patients if desired.[60487]

Children and Adolescents 12 to 14 years weighing 50 kg or more

200 mg PO every 12 hours after IV loading dose. Increase to 300 mg PO every 12 hours for inadequate response; if not tolerated, taper by 50 mg increments to minimum 200 mg PO every 12 hours.[28158] Alternatively, guidelines suggest 400 mg PO every 12 hours for 2 doses, followed by maintenance dosage.[60487] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158] Guidelines recommend voriconazole as alternative therapy for nonneutropenic patients with C. krusei or C. glabrata infections and additional mold coverage for neutropenic patients if desired.[60487]

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose PO every 12 hours (Max: 350 mg/dose) after IV loading dose. May increase dose in 1 mg/kg or 50 mg increments up to the maximum dose for inadequate response if initial dose is tolerated; if initial dose is not tolerated, reduce dose by 1 mg/kg or 50 mg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[28158] Higher doses, such as those recommended in children 2 to 11 years, are recommended in this population, as some pharmacokinetic data have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses.[54736] [54776] Guidelines recommend voriconazole as alternative therapy for nonneutropenic patients with C. krusei or C. glabrata infections and additional mold coverage for neutropenic patients if desired.[60487]

Children 2 to 11 years

Infants† and Children younger than 2 years†

Optimal dosing in infants and children younger than 2 years not well established. 9 mg/kg/dose PO every 12 hours is recommended by guidelines and this dose has been shown to provide comparable exposure in children 2 to 11 years as adults receiving 200 mg PO every 12 hours.[54736] [60487] However, it is unknown if this dose will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years.[54753] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years and with oral administration, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations.[54742] [54743] [54744] [54745] [54747] [54755] Guidelines recommend voriconazole as alternative therapy for nonneutropenic patients with C. krusei or C. glabrata infections and additional mold coverage for neutropenic patients if desired.[60487]

For the treatment of cutaneous aspergillosis. Intravenous dosage Adults

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. If patient is unable to tolerate maintenance therapy, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement.[28158] Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.[61353]

Adolescents 15 to 17 years

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. If patient is unable to tolerate maintenance therapy, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement. Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.

Children and Adolescents 12 to 14 years weighing 50 kg or more

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. If patient is unable to tolerate maintenance therapy, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement.[28158] Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.[61353]

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours. May increase dose in 1 mg/kg increments for inadequate response if initial dose is tolerated; if initial dose is not tolerated, reduce dose by 1 mg/kg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement. Higher doses, such as those recommended in children 2 to 11 years, are recommended in this population, as some pharmacokinetic data have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses. Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.

Children 2 to 11 years

Infants† and Children younger than 2 years†

Oral dosage Adults weighing 40 kg or more

Adults weighing less than 40 kg

Adolescents 15 to 17 years weighing 40 kg or more

Adolescents 15 to 17 years weighing less than 40 kg

Children and Adolescents 12 to 14 years weighing 50 kg or more

Children and Adolescents 12 to 14 years weighing less than 50 kg

Children 2 to 11 years

Infants† and Children younger than 2 years†

For the treatment of serious fungal infections caused by Scedosporium apiospermum (scedosporiosis) in patients intolerant of, or refractory to, other therapy. Intravenous dosage Adults

6 mg/kg/dose IV every 12 hours on day 1, then 4 mg/kg/dose IV every 12 hours. If patient is unable to tolerate maintenance therapy, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement. Duration of treatment is based on the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response. Higher dosages have been used in some case reports. Good activity has been shown against the Scedosporium species.

Adolescents 15 to 17 years

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. If patient is unable to tolerate maintenance therapy, reduce dose to 3 mg/kg/dose IV every 12 hours.[28158] Higher dosages have been used in some case reports. Good activity has been shown against the Scedosporium species.[26836] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement. Duration of treatment is based on the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response.[28158]

Children and Adolescents 12 to 14 years weighing 50 kg or more

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. If patient is unable to tolerate maintenance therapy, reduce dose to 3 mg/kg/dose IV every 12 hours.[28158] Higher dosages have been used in some case reports. Good activity has been shown against the Scedosporium species.[26836] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement. Duration of treatment is based on the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response.[28158]

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours. May increase dose in 1 mg/kg increments for inadequate response if initial dose is tolerated; if initial dose is not tolerated, reduce dose by 1 mg/kg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement. Duration of treatment is based on the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response.[28158] Higher doses, such as those recommended in children 2 to 11 years, are recommended in this population, as some pharmacokinetic data have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses.[54736] [54776]

Children 2 to 11 years

Infants† and Children younger than 2 years†

Oral dosage Adults weighing 40 kg or more

200 mg PO every 12 hours beginning after at least 7 days of intravenous voriconazole therapy. Increase to 300 mg PO every 12 hours for inadequate response; if not tolerated, taper by 50 mg increments to minimum 200 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Duration of treatment is based on the severity of the patients' underlying disease, recovery from immunosuppression, and clinical response.

Adults weighing less than 40 kg

100 mg PO every 12 hours beginning after at least 7 days of intravenous voriconazole therapy. Increase to 150 mg PO every 12 hours for inadequate response; if not tolerated, reduce dose to minimum 100 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Duration of treatment is based on the severity of the patients' underlying disease, recovery from immunosuppression, and clinical response.

Adolescents 15 to 17 years weighing 40 kg or more

Adolescents 15 to 17 years weighing less than 40 kg

Children and Adolescents 12 to 14 years weighing 50 kg or more

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose PO every 12 hours (Max: 350 mg/dose) beginning after at least 7 days of intravenous voriconazole therapy. May increase dose in 1 mg/kg or 50 mg increments up to the maximum dose for inadequate response if initial dose is tolerated; if initial dose is not tolerated, reduce dose by 1 mg/kg or 50 mg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Duration of treatment is based on the severity of the patients' underlying disease, recovery from immunosuppression, and clinical response.[28158] Higher doses, such as those recommended in children 2 to 11 years, are recommended in this population, as some pharmacokinetic data have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses.[54736] [54776]

Children 2 to 11 years

Infants† and Children younger than 2 years†

For the treatment of serious fungal infections caused by Fusarium sp. (fusariosis) in patients intolerant of, or refractory to, other therapy. Intravenous dosage Adults

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. If patient is unable to tolerate maintenance therapy, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement. Duration of treatment is based on the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response.[28158]

Adolescents 15 to 17 years

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. If patient is unable to tolerate maintenance therapy, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement. Duration of treatment is based on the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response.[28158]

Children and Adolescents 12 to 14 years weighing 50 kg or more

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. If patient is unable to tolerate maintenance therapy, reduce dose to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement. Duration of treatment is based on the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response.[28158]

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours. May increase dose in 1 mg/kg increments for inadequate response if initial dose is tolerated; if initial dose is not tolerated, reduce dose by 1 mg/kg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy can be considered after 7 days if there is clinical improvement. Duration of treatment is based on the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response.[28158] Higher doses, such as those recommended in children 2 to 11 years, are recommended in this population, as some pharmacokinetic data have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses.[54736] [54776]

Children 2 to 11 years

Infants† and Children younger than 2 years†

Optimal dosing in infants and children younger than 2 years not well established. 9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours is recommended by guidelines. This dose has been shown to provide comparable exposure in children 2 to 11 years to adults receiving 6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. A maintenance dose of 4 mg/kg/dose every 12 hours in children provided comparable exposure to that seen in adults receiving 3 mg/kg/dose every 12 hours. However, it is unknown if this dosing strategy will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations.

Oral dosage Adults weighing 40 kg or more

Adults weighing less than 40 kg

Adolescents 15 to 17 years weighing 40 kg or more

Adolescents 15 to 17 years weighing less than 40 kg

100 mg PO every 12 hours beginning after at least 7 days of intravenous voriconazole therapy. Increase to 150 mg PO every 12 hours for inadequate response; if not tolerated, reduce dose to minimum 100 mg PO every 12 hour. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Duration of treatment is based on the severity of the patients' underlying disease, recovery from immunosuppression, and clinical response.

Children and Adolescents 12 to 14 years weighing 50 kg or more

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose PO every 12 hours (Max: 350 mg/dose) beginning after at least 7 days of intravenous voriconazole therapy. May increase dose in 1 mg/kg or 50 mg increments up to the maximum dose for inadequate response if initial dose is tolerated; if initial dose is not tolerated, reduce dose by 1 mg/kg or 50 mg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Duration of treatment is based on the severity of the patients' underlying disease, recovery from immunosuppression, and clinical response. Higher doses, such as those recommended in children 2 to 11 years, are recommended in this population, as some pharmacokinetic data have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses.

Children 2 to 11 years

Infants† and Children younger than 2 years†

For the treatment of fungal ophthalmic infection†, including endophthalmitis† and chorioretinitis†. For the treatment of Candida endophthalmitis and chorioretinitis. Intravenous dosage Adults

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Clinical practice guidelines suggest voriconazole as primary therapy for Candida endophthalmitis. Intravitreal voriconazole or amphotericin B should also be given for Candida endophthalmitis with macular involvement. Treat for at least 4 to 6 weeks with final duration depending on stabilization or resolution of lesions.

Adolescents 15 to 17 years

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Clinical practice guidelines suggest voriconazole as primary therapy for Candida endophthalmitis. Intravitreal voriconazole or amphotericin B should also be given for Candida endophthalmitis with macular involvement. Treat for at least 4 to 6 weeks with final duration depending on stabilization or resolution of lesions.

Children and Adolescents 12 to 14 years weighing 50 kg or more

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Clinical practice guidelines suggest voriconazole as primary therapy for Candida endophthalmitis. Intravitreal voriconazole or amphotericin B should also be given for Candida endophthalmitis with macular involvement. Treat for at least 4 to 6 weeks with final duration depending on stabilization or resolution of lesions.

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours is recommended by clinical practice guidelines. This dose has been shown to provide comparable exposure to adults receiving 6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Some pharmacokinetic data in adolescents have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses, suggesting that higher doses, such as those recommended in children 2 to 11 years, may be needed in this population. In addition, significant interpatient pharmacokinetic variability exists in children, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Clinical practice guidelines suggest voriconazole as primary therapy for Candida endophthalmitis. Intravitreal voriconazole or amphotericin B should also be given for Candida endophthalmitis with macular involvement. Treat for at least 4 to 6 weeks with final duration depending on stabilization or resolution of lesions.

Children 2 to 11 years

9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours is recommended by clinical practice guidelines. This dose has been shown to provide comparable exposure to adults receiving 6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours and is also recommended in the European prescribing information for voriconazole. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. A maintenance dose of 4 mg/kg/dose every 12 hours in children provided comparable exposure to that seen in adults receiving 3 mg/kg/dose every 12 hours. Pharmacokinetic data have shown that children require higher doses than adults to achieve equivalent exposure because children have a higher capacity for voriconazole elimination due to linear kinetics at doses of 3 to 4 mg/kg/dose every 12 hours. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations. Clinical practice guidelines suggest voriconazole as primary therapy for Candida endophthalmitis. Intravitreal voriconazole or amphotericin B should also be given for Candida endophthalmitis with macular involvement. Treat for at least 4 to 6 weeks with final duration depending on stabilization or resolution of lesions.

Infants and Children younger than 2 years

Optimal dosing in infants and children younger than 2 years is not well established. 9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours is recommended by clinical practice guidelines. This dose has been shown to provide comparable exposure in children 2 to 11 years to adults receiving 6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. A maintenance dose of 4 mg/kg/dose every 12 hours in children provided comparable exposure to that seen in adults receiving 3 mg/kg/dose every 12 hours. However, it is unknown if this dosing strategy will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations. Clinical practice guidelines suggest voriconazole as primary therapy for Candida endophthalmitis. Intravitreal voriconazole or amphotericin B should also be given for Candida endophthalmitis with macular involvement. Treat for at least 4 to 6 weeks with final duration depending on stabilization or resolution of lesions.

Neonates

old neonate (24 weeks gestational age at birth) with cutaneous aspergillosis. A case series in 6 premature neonates less than 32 weeks gestational age (postnatal age 7 to 50 days) used IV voriconazole doses of 6 mg/kg/dose IV every 8 hours for persistent Candida bloodstream infections. The dose was increased to 7 mg/kg/dose IV every 8 hours in 1 patient due to concurrent use of the CYP2C19 inducer, phenytoin. After voriconazole initiation, Candida eradication occurred within 3 to 7 days; the duration of voriconazole treatment was 18 to 24 days. Voriconazole serum concentrations were not measured in this study. No significant adverse events were reported and no retinopathy was observed. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Because of reports of adverse visual effects in adults and children, some experts express concern over unknown effects on the developing retina of neonates. Although neonatal specific recommendations are not available, clinical practice guidelines suggest voriconazole as primary therapy for Candida endophthalmitis. Intravitreal voriconazole or amphotericin B should also be given for Candida endophthalmitis with macular involvement. Treat for at least 4 to 6 weeks with final duration depending on stabilization or resolution of lesions.

Oral dosage Adults

300 mg PO every 12 hours after IV loading dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Clinical practice guidelines suggest voriconazole as primary therapy for Candida endophthalmitis. Intravitreal voriconazole or amphotericin B should also be given for Candida endophthalmitis with macular involvement. Treat for at least 4 to 6 weeks with final duration depending on stabilization or resolution of lesions.

Adolescents 15 to 17 years

Children and Adolescents 12 to 14 years weighing 50 kg or more

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose (Max: 350 mg/dose) PO every 12 hours is recommended by clinical practice guidelines. This dose has been shown to provide comparable exposure to adults receiving 200 mg PO every 12 hours and is also recommended in the European prescribing information for voriconazole. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Some pharmacokinetic data in adolescents have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses, suggesting that higher doses, such as those recommended in children 2 to 11 years, may be needed in this population. In addition, significant interpatient pharmacokinetic variability exists in children, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Clinical practice guidelines suggest voriconazole as primary therapy for Candida endophthalmitis. Intravitreal voriconazole or amphotericin B should also be given for Candida endophthalmitis with macular involvement. Treat for at least 4 to 6 weeks with final duration depending on stabilization or resolution of lesions.

Children 2 to 11 years

9 mg/kg/dose (Max: 350 mg/dose) PO every 12 hours is recommended by clinical practice guidelines. This dose has been shown to provide comparable exposure to adults receiving 200 mg PO every 12 hours and is also recommended in the European prescribing information for voriconazole. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years and with oral administration, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations. Clinical practice guidelines suggest voriconazole as primary therapy for Candida endophthalmitis. Intravitreal voriconazole or amphotericin B should also be given for Candida endophthalmitis with macular involvement. Treat for at least 4 to 6 weeks with final duration depending on stabilization or resolution of lesions.

Infants and Children younger than 2 years

Optimal dosing in infants and children younger than 2 years not well established. 9 mg/kg/dose PO every 12 hours is recommended by clinical practice guidelines and this dose has been shown to provide comparable exposure in children 2 to 11 years as adults receiving 200 mg PO every 12 hours. However, it is unknown if this dose will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years and with oral administration, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations. Clinical practice guidelines suggest voriconazole as primary therapy for Candida endophthalmitis. Intravitreal voriconazole or amphotericin B should also be given for Candida endophthalmitis with macular involvement. Treat for at least 4 to 6 weeks with final duration depending on stabilization or resolution of lesions.

Neonates

Safe and effective use has not been established; very limited data are available. Clinical practice guidelines recommend conventional amphotericin B or fluconazole for neonatal candidiasis. One report describes 2 term neonates who received oral doses of 4 mg/kg/dose every 12 hours following IV treatment with amphotericin B for Candida infections. Voriconazole was administered for 2 to 3 weeks without any significant toxicity or drug interactions. Another case report describes 2 neonates, 23 and 24 weeks gestation at birth, who received initial oral doses of 2 mg/kg/dose every 12 hours after IV therapy for cutaneous aspergillosis. In the first case, peak and trough concentrations on day 12 of oral therapy were 0.5 mcg/mL and less than 0.2 mcg/mL. The dosage was increased to 3.5 mg/kg/dose PO every 12 hours, and repeat peak and trough concentrations were 1.4 and 0.7 mcg/mL 20 days after the dosage increase. Because the patient was clinically improving, no further dosage increases were made. In the second case, the patient continued 2 mg/kg/dose PO every 12 hours for 10 days after IV therapy, at which time antifungal therapy was discontinued. The peak concentration measured 2 hours after previous dose on the last day of therapy was reported as 0.4 mcg/mL. The authors of this report suggest that voriconazole plasma concentrations be used primarily to avoid toxicity and that dosage titrations should be based on clinical response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Because of reports of adverse visual effects in adults and children, some experts express concern over unknown effects on the developing retina of neonates. Although neonatal specific recommendations are not available, clinical practice guidelines suggest voriconazole as primary therapy for Candida endophthalmitis. Intravitreal voriconazole or amphotericin B should also be given for Candida endophthalmitis with macular involvement. Treat for at least 4 to 6 weeks with final duration depending on stabilization or resolution of lesions.

Intravitreal dosage Adults

100 mcg by intravitreal injection in combination with systemic voriconazole for Candida endophthalmitis with macular involvement.

Infants, Children, and Adolescents

Data are very limited in pediatric patients. One case report describes the successful use of intravitreal voriconazole 50 mcg/0.1 mL in a 9-year-old with fungal endophthalmitis. Two further injections of 200 mcg/0.1 mL were necessary. Clinical practice guidelines recommend intravitreal voriconazole 100 mcg in combination with systemic voriconazole for Candida endophthalmitis with macular involvement.

Neonates

Data are very limited in neonates. One case report describes the use of 2 doses of intravitreal voriconazole 2.5 mcg/0.05 mL, given 1 week apart, in a 15-day-old term neonate with Candida endophthalmitis. Intravitreal voriconazole was given in combination with intravitreal antibiotics (vancomycin and ceftazidime) and topical voriconazole, moxifloxacin, tobramycin, and homatropine. Endophthalmitis resolved 40 days after the first injection of voriconazole. Although neonatal specific recommendations are not available, clinical practice guidelines recommend intravitreal voriconazole in combination with systemic antifungal for Candida endophthalmitis with macular involvement.

For the treatment of Aspergillus endophthalmitis. Intravenous dosage Adults

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Clinical practice guidelines suggest systemic voriconazole in combination with intravitreal voriconazole or amphotericin B as primary therapy for Aspergillus endophthalmitis.

Adolescents 15 to 17 years

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Clinical practice guidelines suggest systemic voriconazole in combination with intravitreal voriconazole or amphotericin B as primary therapy for Aspergillus endophthalmitis.

Children and Adolescents 12 to 14 years weighing 50 kg or more

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Clinical practice guidelines suggest systemic voriconazole in combination with intravitreal voriconazole or amphotericin B as primary therapy for Aspergillus endophthalmitis.

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours is recommended by clinical practice guidelines and this dose has been shown to provide comparable exposure as adults receiving 6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. Some pharmacokinetic data in adolescents have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses, suggesting that higher doses, such as those recommended in children 2 to 11 years, may be needed in this population. In addition, significant interpatient pharmacokinetic variability exists in children, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Clinical practice guidelines suggest systemic voriconazole in combination with intravitreal voriconazole or amphotericin B as primary therapy for Aspergillus endophthalmitis.

Children 2 to 11 years

Infants and Children younger than 2 years

Optimal dosing in infants and children younger than 2 years not well established. 9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours is recommended by clinical practice guidelines. This dose has been shown to provide comparable exposure in children 2 to 11 years to adults receiving 6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. A maintenance dose of 4 mg/kg/dose every 12 hours in children provided comparable exposure to that seen in adults receiving 3 mg/kg/dose every 12 hours. However, it is unknown if this dosing strategy will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations. Clinical practice guidelines suggest systemic voriconazole in combination with intravitreal voriconazole or amphotericin B as primary therapy for Aspergillus endophthalmitis.

Neonates

Safe and effective use has not been established; very limited data are available. Case reports describe the use of IV voriconazole doses ranging from 2 mg/kg/dose every 12 hours to 6 mg/kg/dose every 8 hours for the treatment of fungal infections in neonates (primarily premature neonates). One case report describes 2 premature neonates who received voriconazole 2 mg/kg/dose IV every 12 hours after failing liposomal amphotericin B therapy for cutaneous aspergillosis. A trough concentration of 0.4 mcg/mL was measured while one neonate was receiving 1.7 mg/kg/dose every 12 hours. Because the patient was clinically improving, the dosage was not increased. Both neonates clinically improved within 2 weeks, and IV therapy was converted to oral voriconazole after 15 and 18 days. No adverse effects were noted. A dose of 4 mg/kg/dose IV every 12 hours in combination with liposomal amphotericin B (5 mg/kg/dose IV every 24 hours) and micafungin (8 mg/kg/dose IV every 24 hours) was also successfully used in a 13-day old neonate (24 weeks gestational age at birth) with cutaneous aspergillosis. A case series in 6 premature neonates less than 32 weeks gestational age (postnatal age 7 to 50 days) used IV voriconazole doses of 6 mg/kg/dose IV every 8 hours for persistent Candida bloodstream infections. The dose was increased to 7 mg/kg/dose IV every 8 hours in 1 patient due to concurrent use of the CYP2C19 inducer, phenytoin. After voriconazole initiation, Candida eradication occurred within 3 to 7 days; the duration of voriconazole treatment was 18 to 24 days. Voriconazole serum concentrations were not measured in this study. No significant adverse events were reported and no retinopathy was observed. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Because of reports of adverse visual effects in adults and children, some experts express concern over unknown effects on the developing retina of neonates. Although specific neonatal recommendations are not available, clinical practice guidelines suggest systemic voriconazole in combination with intravitreal voriconazole or amphotericin B as primary therapy for Aspergillus endophthalmitis.

Oral dosage Adults

200 to 300 mg PO every 12 hours after IV loading dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Clinical practice guidelines suggest systemic voriconazole in combination with intravitreal voriconazole or amphotericin B as primary therapy for Aspergillus endophthalmitis.

Adolescents 15 to 17 years

Children and Adolescents 12 to 14 years weighing 50 kg or more

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose (Max: 350 mg/dose) PO every 12 hours is recommended by clinical practice guidelines. This dose has been shown to provide comparable exposure to adults receiving 200 mg PO every 12 hours is also recommended in the European prescribing information for voriconazole. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Some pharmacokinetic data in adolescents have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses, suggesting that higher doses, such as those recommended in children 2 to 11 years, may be needed in this population. In addition, significant interpatient pharmacokinetic variability exists in children, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Clinical practice guidelines suggest systemic voriconazole in combination with intravitreal voriconazole or amphotericin B as primary therapy for Aspergillus endophthalmitis.

Children 2 to 11 years

9 mg/kg/dose (Max: 350 mg/dose) PO every 12 hours is recommended by clinical practice guidelines. This dose has been shown to provide comparable exposure to adults receiving 200 mg PO every 12 hours and is also recommended in the European prescribing information for voriconazole. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years and with oral administration, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations. Clinical practice guidelines suggest systemic voriconazole in combination with intravitreal voriconazole or amphotericin B as primary therapy for Aspergillus endophthalmitis.

Infants and Children younger than 2 years

Optimal dosing in infants and children younger than 2 years is not well established. 9 mg/kg/dose PO every 12 hours is recommended by clinical practice guidelines. This dose has been shown to provide comparable exposure in children 2 to 11 years as adults receiving 200 mg PO every 12 hours. However, it is unknown if this dose will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years and with oral administration, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations. Clinical practice guidelines suggest systemic voriconazole in combination with intravitreal voriconazole or amphotericin B as primary therapy for Aspergillus endophthalmitis.

Neonates

Safety and efficacy have not been established; very limited data are available. One report describes 2 neonates, 23 and 24 weeks gestation at birth, who received initial oral doses of 2 mg/kg/dose every 12 hours after IV therapy for cutaneous aspergillosis. In the first case, peak and trough concentrations on day 12 of oral therapy were 0.5 mcg/mL and less than 0.2 mcg/mL. The dosage was increased to 3.5 mg/kg/dose PO every 12 hours, and repeat peak and trough concentrations were 1.4 and 0.7 mcg/mL 20 days after the dosage increase. Because the patient was clinically improving, no further dosage increases were made. In the second case, the patient continued 2 mg/kg/dose PO every 12 hours for 10 days after IV therapy, at which time antifungal therapy was discontinued. The peak concentration measured 2 hours after previous dose on the last day of therapy was reported as 0.4 mcg/mL. The authors of this report suggest that voriconazole plasma concentrations be used primarily to avoid toxicity and that dosage titrations should be based on clinical response. Another case report describes 2 term neonates who received oral doses of 4 mg/kg/dose every 12 hours following IV treatment with amphotericin B for Candida infections. Voriconazole was administered for 2 to 3 weeks without any significant toxicity or drug interactions. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Because of reports of adverse visual effects in adults and children, some experts express concern over unknown effects on the developing retina of neonates. Although specific neonatal recommendations are not available, clinical practice guidelines suggest systemic voriconazole in combination with intravitreal voriconazole or amphotericin B as primary therapy for Aspergillus endophthalmitis.

Intravitreal dosage Adults

100 mcg by intravitreal injection in combination with systemic voriconazole.

Infants, Children, and Adolescents

Neonates

For the treatment of fungal keratitis†. Ophthalmic dosage Adults

1 drop (1% solution) to the affected eye(s) every 30 minutes while awake for the first month then every 1 to 2 hours for a minimum of 8 weeks in combination with oral voriconazole therapy. In severe cases, voriconazole 10 mcg/0.1 mL by intracameral injection was also used. Voriconazole has been reported to successfully treat fungal keratitis due to such species as Alternaria sp., Fusarium solani, and Scedosporium apiospermum. Clinical practice guidelines recommend voriconazole as an alternative to natamycin for the treatment of Aspergillus keratitis.

Oral dosage Adults

200 to 400 mg PO twice daily for a minimum of 8 weeks in combination with ophthalmic voriconazole. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. If oral voriconazole therapy is not tolerated, intravenous therapy may be used. Voriconazole has been reported to successfully treat fungal keratitis due to such species as Alternaria sp., Fusarium solani, and Scedosporium apiospermum.

For the treatment of fluconazole-refractory oropharyngeal candidiasis (thrush)†. Oral dosage Adults

200 mg PO twice daily for up to 28 days as an alternative. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Adolescents 15 to 17 years

200 mg PO twice daily for up to 28 days as an alternative. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Children and Adolescents 12 to 14 years weighing 50 kg or more

200 mg PO twice daily for up to 28 days as an alternative. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose (Max: 350 mg/dose) PO every 12 hours for up to 28 days as an alternative. This dose has been shown to provide comparable exposure to adults receiving 200 mg PO every 12 hours and is also recommended in the European prescribing information for voriconazole. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Some pharmacokinetic data in adolescents have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses, suggesting that higher doses, such as those recommended in children 2 to 11 years, may be needed in this population. Significant interpatient pharmacokinetic variability exists in children, particularly with oral administration, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Some children and adolescents will require higher doses to achieve therapeutic concentrations.

Children 2 to 11 years

9 mg/kg/dose (Max: 350 mg/dose) PO every 12 hours for up to 28 days as an alternative. This dose has been shown to provide comparable exposure to adults receiving 200 mg PO every 12 hours and is also recommended in the European prescribing information for voriconazole. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years and with oral administration, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations.

Infants and Children younger than 2 years

Optimal dosing is not well established. 9 mg/kg/dose PO every 12 hours for up to 28 days as an alternative. This dose has been shown to provide comparable exposure in children 2 to 11 years as adults receiving 200 mg PO every 12 hours. However, it is unknown if this dose will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years and with oral administration, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations.

For the treatment of allergic bronchopulmonary aspergillosis†. Oral dosage Adults

200 mg PO every 12 hours as an alternative to itraconazole in patients with asthma or cystic fibrosis. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Adolescents 15 to 17 years

Children and Adolescents 12 to 14 years weighing 50 kg or more

Children and Adolescents 12 to 14 years weighing less than 50 kg

9 mg/kg/dose (Max: 350 mg/dose) PO every 12 hours is recommended by guidelines. This dose has been shown to provide comparable exposure to adults receiving 200 mg PO every 12 hours and is also recommended in the European prescribing information for voriconazole. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Some pharmacokinetic data in adolescents have shown a lower exposure in younger adolescents (12 to 14 years) with low body weight (less than 50 kg) when given the recommended adult doses, suggesting that higher doses, such as those recommended in children 2 to 11 years, may be needed in this population. In addition, significant interpatient pharmacokinetic variability exists in children, particularly with oral administration, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Voriconazole is recommended as an alternative to itraconazole in patients with asthma or cystic fibrosis.

Children 2 to 11 years

9 mg/kg/dose (Max: 350 mg/dose) PO every 12 hours is recommended by guidelines. This dose has been shown to provide comparable exposure to adults receiving 200 mg PO every 12 hours and is also recommended in the European prescribing information for voriconazole. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years and with oral administration, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations. Voriconazole is recommended as an alternative to itraconazole in patients with asthma or cystic fibrosis.

Infants and Children 1 year

Optimal dosing in infants and children younger than 2 years is not well established. 9 mg/kg/dose PO every 12 hours is recommended by guidelines. This dose has been shown to provide comparable exposure in children 2 to 11 years as adults receiving 200 mg PO every 12 hours. However, it is unknown if this dose will be adequate in younger children as pharmacokinetic data are limited. In a study of 30 children (1 month and older) receiving IV or oral voriconazole, the median dose necessary to achieve therapeutic concentrations was 38 mg/kg/day in children younger than 5 years. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Significant interpatient pharmacokinetic variability exists in children, particularly in children younger than 3 years and with oral administration, and measuring voriconazole serum concentrations is essential to aid in dosage adjustments. Many children require much higher doses to achieve therapeutic concentrations. Voriconazole is recommended as an alternative to itraconazole in patients with asthma or cystic fibrosis.

For empiric treatment for presumed fungal infection in patients with febrile neutropenia†. Intravenous and Oral dosage Adults, Adolescents, and Children 12 years and older

In a large trial, 6 mg/kg IV every 12 hours as a loading dose on day 1, then 3 mg/kg IV every 12 hours. Patients can be switched to 200 mg PO every 12 hours after at least 3 days of IV therapy. If response is inadequate, increase IV maintenance dose to 4 mg/kg IV or 300 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In clinical trials, patients continued therapy for up to 3 days after neutrophil recovery or up to 12 weeks with documented invasive fungal infection. Statistically, voriconazole did not meet the composite objective of a comparison study with amphotericin B lipid formulation for use in empiric therapy of febrile neutropenia. The FDA advisory committee unanimously recommended against this indication given the present data. However, guidelines suggest voriconazole as an empiric therapy option for patients at high risk for invasive mold infections. Smaller trials have used similar dosing.

For fungal prophylaxis† (e.g., candidiasis prophylaxis†, aspergillosis prophylaxis†) in high-risk patients. Intravenous dosage Children and Adolescents

6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. For hematopoietic stem cell transplant (HSCT) recipients, prophylaxis is started on the day of transplantation and usually continued from 30 to 180 days posttransplantation depending on protocol, duration of immunosuppression, and risk factors. For patients receiving intensive chemotherapy, antifungal prophylaxis is usually continued until recovery of absolute neutrophil count (ANC) more than 1,000 cells/mm3 for 3 consecutive days. In a prospective study of 127 high-risk patients with neutropenia after HSCT or intensive chemotherapy, the success rate with voriconazole was 72.9%. In another study in only HSCT recipients, the success rate with voriconazole was 48.7%, which was significantly better than the success rate with itraconazole (33.2%; p less than 0.01). Change to oral therapy as soon as feasible.

Oral dosage Adults

200 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Aspergillosis clinical practice guidelines suggest voriconazole prophylaxis as an alternative to posaconazole for high-risk patients, including allogeneic hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) and neutropenic patients with acute myelogenous leukemia or myelodysplastic disease. In neutropenic patients with cancer, candidiasis prophylaxis is recommended in patients with substantial risk, such as allogeneic hematopoietic stem cell transplant (HSCT) recipients or those undergoing intensive remission-induction or salvage-induction chemotherapy for acute leukemia.

Children and Adolescents

4 mg/kg/dose (Max: 200 mg/dose) PO every 12 hours. Some studies have used a loading dose of 6 mg/kg/dose PO every 12 hours on day 1. Doses of 100 mg PO every 12 hours for children weighing less than 40 kg and 50 mg PO every 12 hours for children weighing less than 20 kg have also been used; however, these doses may be inadequate for children at the upper end of the weight ranges. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. For hematopoietic stem cell transplant (HSCT) recipients, prophylaxis is started on the day of transplantation and usually continued from 30 to 180 days posttransplantation depending on protocol, duration of immunosuppression, and risk factors. For patients receiving intensive chemotherapy, antifungal prophylaxis is usually continued until recovery of absolute neutrophil count (ANC) more than 1,000 cells/mm3 for 3 consecutive days. In a prospective study of 127 high-risk patients with neutropenia after HSCT or intensive chemotherapy, the success rate with voriconazole was 72.9%. In another study in only HSCT recipients, the success rate with voriconazole was 48.7%, which was significantly better than the success rate with itraconazole (33.2%; p less than 0.01).

For the treatment of cryptococcosis†. Oral dosage Adults

200 mg PO twice daily for 6 to 12 months as an alternative for mild-to-moderate pulmonary disease or 200 to 400 mg PO twice daily for 10 to 12 weeks as an alternative for salvage consolidation therapy for relapsed disease. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For the treatment of mild to moderate pulmonary coccidioidomycosis† in persons living with HIV.
NOTE: For CNS infections, see meningitis indication.
NOTE: Mild to moderate infections may include patients with focal pneumonia or positive serology but with mild or without illness.[34362] Oral dosage Adults

400 mg PO twice daily for 1 day, then 200 mg PO twice daily as an alternative therapy in patients who failed to respond to itraconazole or fluconazole. May discontinue therapy in patients who have clinically responded to 3 months or more of antifungal therapy and who have a CD4 count of 250 cells/mm3 or more, virological suppression on antiretrovirals, and continued monitoring for recurrence can be performed using serial chest radiograph and coccidioidal serology. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Adolescents

For the treatment of less severe disseminated histoplasmosis† in HIV-infected patients. Oral dosage Adults

400 mg PO twice daily for 1 day, then 200 mg PO twice daily for at least 12 months as an alternative in patients who are only moderately ill and intolerant to itraconazole.[34362]

Adolescents

400 mg PO twice daily for 1 day, then 200 mg PO twice daily for at least 12 months as an alternative in patients who are only moderately ill and intolerant to itraconazole.[34362]

For the treatment of talaromycosis† in HIV-infected patients. For induction therapy of talaromycosis in HIV-infected patients†. Intravenous dosage Adults

6 mg/kg IV every 12 hours on day 1, followed by 4 mg/kg IV every 12 hours for 2 weeks as alternative therapy then oral voriconazole or itraconazole for consolidation therapy and itraconazole for chronic suppressive therapy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Adolescents

Oral dosage Adults

600 mg PO every 12 hours on day 1, followed by 400 mg PO every 12 hours for 2 weeks as alternative therapy then oral voriconazole or itraconazole for consolidation therapy and itraconazole for chronic suppressive therapy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Adolescents

For consolidation therapy of talaromycosis in HIV-infected patients†. Oral dosage Adults

200 mg PO twice daily for 10 weeks after induction therapy as alternative therapy then itraconazole for chronic suppressive therapy.

Adolescents

200 mg PO twice daily for 10 weeks after induction therapy as alternative therapy then itraconazole for chronic suppressive therapy.

For secondary histoplasmosis prophylaxis† (i.e., long term suppressive therapy) in HIV-infected patients. Oral dosage Adults

200 mg PO twice daily as an alternative to itraconazole. Consider discontinuation if patients have received treatment for at least 1 year, have negative blood cultures, have a serum or urine Histoplasma antigen below the level of quantification, have an undetectable viral load, and have a CD4 count of more than 150 cells/mm3 on antiretroviral therapy for at least 6 months. Resume secondary prophylaxis if the CD4 count decreases below 150 cells/mm3. Guidelines recommend secondary prophylaxis for patients with severe disseminated or CNS infection after completing at least 12 months of therapy and relapse despite appropriate initial therapy.[34362]

Adolescents

For the treatment of blastomycosis†.
NOTE: For CNS infections, see meningitis.
For the treatment of mild to moderate pulmonary or disseminated extrapulmonary blastomycosis†. Oral dosage Adults

400 mg PO twice daily for 1 day followed by 200 mg PO twice daily for 6 to 12 months in patients unable to take itraconazole. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For step-down therapy of moderately severe or severe pulmonary or disseminated extrapulmonary blastomycosis† after initial treatment with amphotericin B. Oral dosage Adults

400 mg PO twice daily for 1 day followed by 200 mg PO twice daily to complete a total of at least 12 months of therapy in patients unable to take itraconazole. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[64722]

†Indicates off-label use

Dosing Considerations

Hepatic Impairment

Adults
When initiating therapy, patients with baseline LFTs (AST, ALT) up to 5 times the upper limit of normal do not require dosage adjustments. Patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) should receive the standard loading dose, then receive 50% of the normal maintenance dosage. Voriconazole use should be avoided in severe hepatic cirrhosis (Child-Pugh Class C) unless the benefit clearly outweighs the risk.[28158]

Pediatric patients
Dosage adjustments for pediatric patients with hepatic impairment have not been established.[28158]

Renal Impairment

Adults
No dosage adjustment is required for any degree of renal impairment when using oral voriconazole.[28158]
CrCl 50 mL/minute or more: No dosage adjustment needed for IV voriconazole.
CrCl less than 50 mL/minute: Only administer oral voriconazole to these patients; avoid IV voriconazole (due to potential for accumulation of the IV vehicle sulfobutyl ether betacyclodextrin sodium) unless the benefit of IV therapy clearly outweighs the risk. If increases in serum creatinine occur in patients receiving IV voriconazole with CrCl less than 50 mL/minute, consider switching to oral voriconazole.[28158]

Pediatrics patients
Dosage adjustments for pediatric patients with renal impairment have not been established.[28158]

Intermittent hemodialysis
Voriconazole is dialyzed with a clearance of 121 mL/minute in a 4 hour dialysis session; however, supplemental dosing is not required following hemodialysis. The IV vehicle, sulfobutyl ether betacyclodextrin sodium is dialyzed with a clearance of 55 mL/minute.[28158]

Continuous hemodialysis (CAVHD, CVVHD)
Voriconazole is dialyzed with a clearance of 121 mL/minute in a 4 hour dialysis session; however, supplemental dosing is not required following hemodialysis. The IV vehicle, sulfobutyl ether betacyclodextrin sodium is dialyzed with a clearance of 55 mL/minute.[28158]

Drug Interactions

Abacavir; Dolutegravir; Lamivudine: (Moderate) Use caution if coadministration of voriconazole with dolutegravir is necessary, as the systemic exposure of dolutegravir may be increased resulting in an increase in treatment-related adverse reactions. Voriconazole is a strong CYP3A4 inhibitor. Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A.
Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Concomitant administration of voriconazole and zidovudine may result in a reduction in the clearance of zidovudine.
Abemaciclib: (Major) If coadministration with voriconazole is necessary, reduce the dose of abemaciclib to 100 mg PO twice daily in patients on either of the recommended starting doses of either 200 mg or 150 mg twice daily. In patients who have had already had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the dose of abemaciclib to 50 mg PO twice daily. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. If voriconazole is discontinued, increase the dose of abemaciclib to the original dose after 3 to 5 half-lives of voriconazole. Abemaciclib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 2.5-fold in cancer patients.
Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and voriconazole; significantly increased acalabrutinib exposure may occur. If short-term voriconazole use is unavoidable, interrupt acalabrutinib therapy. Wait at least 24 hours after voriconazole is discontinued before resuming acalabrutinib at the previous dosage. Acalabrutinib is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with voriconazole may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of voriconazole could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If voriconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Voriconazole is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with voriconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of voriconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If voriconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Voriconazole is a strong inhibitor of CYP3A4.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of voriconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like voriconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If voriconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Ibuprofen: (Moderate) Voriconazole is a substrate and inhibitor of cytochrome P450 isoenzyme 2C9, which is the isoenzyme responsible for the metabolism of ibuprofen. Thus, increased plasma concentrations of ibuprofen is possible. The clinical significance of this potential interaction is unknown. If voriconazole is administered concurrently with ibuprofen, monitor for NSAID-related side-effects, such as fluid retention or GI irritation, and adjust the dose of the NSAID, if needed.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of voriconazole is necessary. If voriconazole is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like voriconazole can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If voriconazole is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Adagrasib: (Contraindicated) Avoid concomitant use of adagrasib and voriconazole. Concomitant use may increase concentrations of both medications and result in additive risk for QT/QTc prolongation and torsade de pointes (TdP). The use of voriconazole with a CYP3A substrate that causes QT prolongation, such as adagrasib, is contraindicated per the manufacturer of voriconazole. If use is necessary, wait for adagrasib levels to reach steady state (approximately 8 days after initiation), monitor for voriconazole -related adverse effects, and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Concomitant use before adagrasib steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib is a CYP3A substrate and strong CYP3A inhibitor, voriconazole is a CYP3A substrate and strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Ado-Trastuzumab emtansine: (Major) Avoid coadministration of voriconazole with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until voriconazole has cleared from the circulation (approximately 3 half-lives of voriconazole) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; voriconazole is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
Albuterol; Budesonide: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and budesonide. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Concomitant oral administration of another strong CYP3A4 inhibitor increased oral budesonide systemic exposure by 8-fold. Voriconazole is a strong CYP3A4 inhibitor, and budesonide is a CYP3A4 substrate.
Alfentanil: (Moderate) Alfentanil is metabolized by the cytochrome P450 3A4 isoenzyme. Agents that inhibit CYP3A4 activity, such as voriconazole, may decrease systemic clearance of alfentanil leading to increased or prolonged effects.
Alfuzosin: (Contraindicated) Alfuzosin is contraindicated for use with voriconazole due to the potential for serious/life-threatening reactions, including hypotension and QT prolongation. Coadministration is expected to reduce the metabolism and increase systemic exposure to alfuzosin. Alfuzosin is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; voriconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes. Coadministration of another strong CYP3A4 inhibitor increased the alfuzosin AUC by 2.5-fold to 3.2-fold.
Almotriptan: (Moderate) The maximum recommended starting dose of almotriptan is 6.25 mg if coadministration with voriconazole is necessary; do not exceed 12.5 mg within a 24-hour period. Concomitant use of almotriptan and voriconazole should be avoided in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased almotriptan exposure by approximately 60%.
Alosetron: (Moderate) Concomitant use of alosetron with voriconazole may result in increased serum concentrations of alosetron and increase the risk for adverse reactions. Caution and close monitoring are advised if these drugs are used together. Alosetron is a substrate of hepatic isoenzyme CYP3A4; voriconazole is a strong inhibitor of this enzyme. In a study of healthy female subjects, another strong CYP3A4 inhibitor increased mean alosetron AUC by 29%.
Alprazolam: (Contraindicated) Coadministration of voriconazole and alprazolam is contraindicated due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with voriconazole, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased alprazolam exposure by 2.7- to 3.98-fold.
Amiodarone: (Major) Avoid coadministration of amiodarone and voriconazole due to the potential for increased amiodarone concentrations and additive effects on the QT interval. There have been reports of prolonged QT intervals, with or without torsade de pointes (TdP), during concomitant use of amiodarone and azole antifungals. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Voriconazole has also been associated with QT prolongation and rare cases of TdP, cardiac arrest, and sudden death. In addition, coadministration of voriconazole (a strong CYP3A4 inhibitor) with amiodarone (a CYP3A4 substrate) may result in elevated amiodarone plasma concentrations and could further increase the risk for adverse events, including QT prolongation. Similarly, amiodarone may inhibit the CYP2C9 metabolism of voriconazole, and could theoretically lead to elevated plasma concentrations of voriconazole when coadministered. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Amitriptyline: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering voriconazole with amitriptyline. Voriconazole has been associated with prolongation of the QT interval and rare cases of arrhythmias, including TdP. Tricyclic antidepressants (TCAs), such as amitriptyline, share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, voriconazole inhibits CYP3A4 and amitriptyline is partially metabolized by CYP3A4. Coadministration may result in elevated amitriptyline serum concentrations. Monitor for an increased response to amitriptyline if coadministered with voriconazole.
Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with voriconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Voriconazole is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Amlodipine; Atorvastatin: (Major) Use caution and the lowest atorvastatin dose necessary if coadministration with voriconazole is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Voriconazole inhibits the CYP3A4-mediated metabolism of atorvastatin. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with voriconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Voriconazole is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Amlodipine; Benazepril: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with voriconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Voriconazole is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Amlodipine; Celecoxib: (Major) Isoenzyme CYP2C9 is responsible for the metabolism of many nonsteroidal antiinflammatory drugs. Voriconazole is known to be an inhibitor of CYP2C9 and may lead to increased plasma levels of some NSAIDs, such as celecoxib. The clinican should consider introducing the NSAID at the lowest recommended dose in patients receiving voriconazole. Monitor for NSAID-related side effects, such as GI irritation, fluid retention or increased blood pressure, GI bleeding, or renal dysfunction and adjust the dose of the NSAID if needed. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with voriconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Voriconazole is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Amlodipine; Olmesartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with voriconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Voriconazole is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Amlodipine; Valsartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with voriconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Voriconazole is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with voriconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Voriconazole is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Caution is advised when administering voriconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as clarithromycin. Both drugs have been associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. In addition, both drugs are substrates and inhibitors of CYP3A4. Coadministration may result in increased plasma concentrations of both drugs, thereby further increasing the risk for adverse events. Azithromycin can be considered as an alternative macrolide antimicrobial if appropriate for the clinical circumstance, due to its lack of metabolism via CYP3A4. If these drugs are given together, closely monitor for prolongation of the QT interval and other adverse effects such as drowsiness, fatigue, dry mouth, nausea, or insomnia. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy. (Moderate) Reduce the omeprazole dose by one-half when initiating voriconazole therapy in patients who are currently receiving omeprazole at doses of 40 mg/day or greater. Levels of omeprazole may increase by up to 2-fold due to CYP2C19 and CYP3A4 inhibition by voriconazole.
Amphotericin B lipid complex (ABLC): (Moderate) In vitro and in vivo animal studies of the combination of amphotericin B and imidazoles suggest that imidazole antifungal agents may induce fungal resistance to amphotericin B. Combination therapy should be administered with caution, especially in immunocompromised patients.
Amphotericin B liposomal (LAmB): (Moderate) In vitro and in vivo animal studies of the combination of amphotericin B and imidazoles suggest that imidazole antifungal agents may induce fungal resistance to amphotericin B. Combination therapy should be administered with caution, especially in immunocompromised patients.
Amphotericin B: (Moderate) In vitro and in vivo animal studies of the combination of amphotericin B and imidazoles suggest that imidazole antifungal agents may induce fungal resistance to amphotericin B. Combination therapy should be administered with caution, especially in immunocompromised patients.
Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include voriconazole.
Apalutamide: (Contraindicated) Coadministration of voriconazole with apalutamide is contraindicated due to decreased plasma concentrations of voriconazole; exposure to apalutamide may also increase. Voriconazole is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Voriconazole plasma concentrations may be reduced by roughly 95%; doubling the dose of voriconazole did not restore adequate exposure to voriconazole during concomitant use with another strong CYP3A4 inducer.
Apomorphine: (Moderate) Exercise caution when administering apomorphine concomitantly with voriconazole since concurrent use may increase the risk of QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use of voriconazole with aprepitant, fosaprepitant due to substantially increased exposure of aprepitant; increased voriconazole exposure may also occur. If coadministration cannot be avoided, use caution and monitor for an increase in voriconazole- and aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. Voriconazole is a strong CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased the AUC of aprepitant by approximately 5-fold, and the mean terminal half-life by approximately 3-fold. Voriconazole is also a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor. When administered as a single oral or single intravenous dose, the inhibitory effect of aprepitant on CYP3A4 is weak and did not result in a clinically significant increase in the AUC of a sensitive substrate.
Aripiprazole: (Contraindicated) Avoid concomitant use of aripiprazole and voriconazole due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use also increases aripiprazole exposure and risk for side effects. If concomitant use is necessary, an aripiprazole dosage reduction is required; management recommendations vary by aripiprazole dosage form and CYP2D6 metabolizer status. For aripiprazole oral dosage forms, administer half of the usual dose; administer a quarter of the usual dose to patients known to be poor metabolizers of CYP2D6. For monthly extended-release aripiprazole injections (Abilify Maintena), reduce the dosage from 400 mg to 300 mg/month or from 300 mg to 200 mg/month; administer 200 mg/month to patients known to be poor metabolizers of CYP2D6. For extended-release aripiprazole injections given once every 2 months (Abilify Asimtufii), reduce the dosage from 960 mg to 720 mg; avoid use in patients known to be poor metabolizers of CYP2D6. Further dosage reductions may be required in patients who are also receiving a CYP2D6 inhibitor; see individual product prescribing information for details. Aripiprazole is CYP3A and CYP2D6 substrate, voriconazole is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. (Contraindicated) Avoid concomitant use of aripiprazole and voriconazole due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use also increases aripiprazole exposure and risk for side effects. If concomitant use is necessary, an aripiprazole dosage reduction is required; management recommendations vary by aripiprazole dosage form and CYP2D6 metabolizer status. For extended-release aripiprazole lauroxil injections (Aristada), reduce the dose to the next lowest strength; no dosage adjustment is required for patients tolerating 441 mg. For extended-release aripiprazole lauroxil injections (Aristada) in patients who are known to be poor metabolizers of CYP2D6, reduce the dose to 441 mg; no dosage adjustment is necessary for patients already tolerating 441 mg. For fixed dose extended-release aripiprazole lauroxil injections (Aristada Initio), avoid concomitant use because the dose cannot be modified. Further dosage reductions may be required in patients who are also receiving a CYP2D6 inhibitor; see individual product prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is CYP3A and CYP2D6 substrate, voriconazole is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation.
Armodafinil: (Minor) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as voriconazole are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed.
Arsenic Trioxide: (Major) If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with arsenic trioxide include voriconazole.
Artemether; Lumefantrine: (Major) Avoid coadministration of voriconazole with artemether due to an increased risk for QT prolongation and torsade de pointes (TdP). If coadministration cannot be avoided, consider ECG monitoring. Systemic exposure of artemether may also be increased resulting in an increase in artemether-related adverse reactions. Voriconazole is a strong CYP3A4 inhibitor that has been associated with rare cases of torsade de pointes, cardiac arrest, and sudden death. Artemether is a CYP3A4 substrate that has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased artemether exposure by 2.3-fold. (Major) Avoid coadministration of voriconazole with lumefantrine due to an increased risk for QT prolongation and torsade de pointes (TdP). If coadministration cannot be avoided, consider ECG monitoring. Systemic exposure of lumefantrine may also be increased resulting in an increase in lumefantrine-related adverse reactions. Voriconazole is a strong CYP3A4 inhibitor that has been associated with rare cases of torsade de pointes, cardiac arrest, and sudden death. Lumefantrine is a CYP3A4 substrate that has also been associated with QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased lumefantrine exposure by 1.6-fold. No dosage adjustments are required by the manufacturer, but patients should be monitored for adverse events, including QT prolongation.
Asciminib: (Moderate) Closely monitor for asciminib-related adverse reactions if concurrent use of asciminib 200 mg twice daily with voriconazole is necessary as asciminib exposure may increase. Asciminib is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor.
Asenapine: (Major) Avoid coadministration of asenapine and voriconazole due to the potential for additive effects on the QT interval; increased exposure to asenapine is also possible. Both drugs have been associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. In addition, coadministration of voriconazole (a CYP3A4 inhibitor) with asenapine (a CYP3A4 substrate) may result in elevated asenapine plasma concentrations and could increase the risk for adverse events, including QT prolongation. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Aspirin, ASA; Butalbital; Caffeine: (Contraindicated) Voriconazole is contraindicated for use with long-acting barbiturates, such as butalbital containing products. Barbiturates are CYP3A4 and CYP2C9 inducers and may increase the metabolism and reduce the effective serum concentrations of voriconazole. Barbiturates are also substrates for CYP2C9, and voriconazole may theoretically increase the serum concentrations of the barbiturates.
Aspirin, ASA; Carisoprodol: (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as voriconazole, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with voriconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of voriconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If voriconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Voriconazole is a strong inhibitor of CYP3A4. (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as voriconazole, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
Aspirin, ASA; Omeprazole: (Moderate) Reduce the omeprazole dose by one-half when initiating voriconazole therapy in patients who are currently receiving omeprazole at doses of 40 mg/day or greater. Levels of omeprazole may increase by up to 2-fold due to CYP2C19 and CYP3A4 inhibition by voriconazole.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of voriconazole is necessary. If voriconazole is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like voriconazole can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If voriconazole is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Atazanavir: (Major) Avoid concurrent use of voriconazole and atazanavir boosted with ritonavir, unless the benefits justify the risks. If used together, health care providers are advised to monitor for loss of virologic and fungal efficacy, as well as potential voriconazole-related adverse effects. In one drug-drug interaction study, coadministration resulted in decreased atazanavir pharmacokinetic parameters (AUC, Cmax, Cmin). The pharmacokinetic parameter of voriconazole were also altered; however the effect depended a functional CYP2C19 allele. In this study, the pharmacokinetic parameters of voriconazole were reduced in patients with at least one function CYP2C19 allele, and elevated in patients without a function CYP2C19 allele. No pharmacokinetic data are available for concurrent use of voriconazole and unboosted atazanavir.
Atazanavir; Cobicistat: (Major) Avoid concurrent use of voriconazole and atazanavir boosted with ritonavir, unless the benefits justify the risks. If used together, health care providers are advised to monitor for loss of virologic and fungal efficacy, as well as potential voriconazole-related adverse effects. In one drug-drug interaction study, coadministration resulted in decreased atazanavir pharmacokinetic parameters (AUC, Cmax, Cmin). The pharmacokinetic parameter of voriconazole were also altered; however the effect depended a functional CYP2C19 allele. In this study, the pharmacokinetic parameters of voriconazole were reduced in patients with at least one function CYP2C19 allele, and elevated in patients without a function CYP2C19 allele. No pharmacokinetic data are available for concurrent use of voriconazole and unboosted atazanavir. (Major) Avoid concurrent use of voriconazole with regimens containing cobicistat and atazanavir or darunavir. Use of these drugs together may result in increase plasma concentrations of cobicistat, atazanavir, and darunavir; effects on the voriconazole concentrations has not been determined.
Atogepant: (Major) Avoid use of atogepant and voriconazole when atogepant is used for chronic migraine. Limit the dose of atogepant to 10 mg PO once daily for episodic migraine if coadministered with voriconazole. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of CYP3A and voriconazole is a strong CYP3A inhibitor. Coadministration with a strong CYP3A inhibitor resulted in a 5.5-fold increase in atogepant overall exposure and a 2.15-fold increase in atogepant peak concentration.
Atomoxetine: (Moderate) Concomitant use of atomoxetine and voriconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Atorvastatin: (Major) Use caution and the lowest atorvastatin dose necessary if coadministration with voriconazole is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Voriconazole inhibits the CYP3A4-mediated metabolism of atorvastatin.
Atorvastatin; Ezetimibe: (Major) Use caution and the lowest atorvastatin dose necessary if coadministration with voriconazole is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Voriconazole inhibits the CYP3A4-mediated metabolism of atorvastatin.
Atovaquone; Proguanil: (Minor) Proguanil is metabolized to cycloguanil by CYP2C19. Use caution when combining atovaquone; proguanil with CYP2C19 inhibitors, such as voriconazole.
Avacopan: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of voriconazole is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Avanafil: (Major) Do not use avanafil in patients receiving voriconazole due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the avanafil AUC by 13-fold.
Avapritinib: (Major) Avoid coadministration of avapritinib with voriconazole due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Avatrombopag: (Major) In patients with chronic immune thrombocytopenia (ITP), reduce the starting dose of avatrombopag to 20 mg PO 3 times weekly when used concomitantly with voriconazole. In patients starting voriconazole while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inhibitors such as voriconazole increase avatrombopag exposure, increasing the risk of avatrombopag toxicity.
Axitinib: (Major) Avoid coadministration of axitinib with voriconazole due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after voriconazole is discontinued. Axitinib is a CYP3A4/5 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Azelastine; Fluticasone: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and fluticasone. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Concomitant administration of another strong CYP3A4 inhibitor increased plasma fluticasone propionate exposure resulting in a 45% to 86% decrease in serum cortisol AUC and increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol. Voriconazole is a strong CYP3A4 inhibitor, and fluticasone is a CYP3A4 substrate.
Azithromycin: (Major) Avoid coadministration of azithromycin with voriconazole due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Voriconazole has been associated with prolongation of the QT interval and rare cases of arrhythmias, including TdP.
Beclomethasone: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and beclomethasone. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Voriconazole is a strong CYP3A4 inhibitor, and beclomethasone is a CYP3A4 substrate.
Bedaquiline: (Major) Avoid prolonged (more than 14 consecutive days) concurrent administration of bedaquiline and voriconazole unless the benefits outweigh the risks; increased bedaquiline exposure and additive effects on the QT interval may occur. If concomitant use of these drugs is required, monitor patients for signs and symptoms of bedaquiline-related adverse reactions (e.g., hepatotoxicity) and QT prolongation. Voriconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes. Bedaquiline is a CYP3A substrate that has been reported to prolong the QT interval. Concurrent use of another strong CYP3A4 inhibitor increased bedaquiline exposure by 22%.
Belzutifan: (Moderate) Monitor for anemia and hypoxia if concomitant use of voriconazole with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and voriconazole is a CYP2C19 inhibitor.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with voriconazole may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of voriconazole in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If voriconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Voriconazole is a strong inhibitor of CYP3A4.
Berotralstat: (Moderate) Monitor for increased voriconazole-related adverse effects if coadministered with berotralstat as concurrent use may increase voriconazole exposure. Voriconazole is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased voriconazole exposure by 79%.
Betamethasone: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and betamethasone. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Voriconazole is a strong CYP3A4 inhibitor, and betamethasone is a CYP3A4 substrate.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and voriconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and voriconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Bortezomib: (Moderate) Monitor for signs of bortezomib toxicity and consider a bortezomib dose reduction if coadministration of voriconazole is necessary. Bortezomib exposure may be increased. Bortezomib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased bortezomib exposure by 35%.
Bosentan: (Major) Bosentan is metabolized by CYP2C9 and CYP3A4. Inhibition of these isoenzymes may increase the plasma concentration of bosentan. It is important to review all the medications taken concurrently with bosentan. According to the manufacturer, coadministration of bosentan with a potent CYP2C9 inhibitor plus a CYP3A4 inhibitor is not recommended; large increases in bosentan plasma concentrations are expected with such combinations. Voriconazole potently inhibits CYP2C9 and 3A4 isoenzymes. It is prudent to avoid voriconazole use during bosentan therapy when feasible.
Bosutinib: (Major) Avoid concomitant use of bosutinib and voriconazole; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. The Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
Brentuximab vedotin: (Moderate) Closely monitor for an increase in brentuximab-related adverse reactions, including peripheral neuropathy or gastrointestinal side effects, if coadministration with voriconazole is necessary. Monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased MMAE exposure by approximately 34%.
Brexpiprazole: (Major) Reduce the brexpiprazole dose to half the usual dose if coadministered with voriconazole. Administer one quarter of the usual brexpiprazole dose if the patient is also receiving a strong or moderate CYP2D6 inhibitor or is a known poor metabolizer of CYP2D6. If voriconazole is discontinued, adjust the brexpiprazole dosage to its original level. Brexpiprazole is a CYP3A and CYP2D6 substrate; voriconazole is a strong CYP3A inhibitor. Concomitant use of strong CYP3A inhibitors increased the exposure of brexpiprazole compared to use of brexpiprazole alone.
Brigatinib: (Major) Avoid coadministration of brigatinib with voriconazole if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of voriconazole, resume the brigatinib dose that was tolerated prior to initiation of voriconazole. Brigatinib is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
Bromocriptine: (Major) When bromocriptine is used for diabetes, avoid coadministration with voriconazole ensuring adequate washout before initiating bromocriptine. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may significantly increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; voriconazole is a strong inhibitor of CYP3A4.
Budesonide: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and budesonide. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Concomitant oral administration of another strong CYP3A4 inhibitor increased oral budesonide systemic exposure by 8-fold. Voriconazole is a strong CYP3A4 inhibitor, and budesonide is a CYP3A4 substrate.
Budesonide; Formoterol: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and budesonide. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Concomitant oral administration of another strong CYP3A4 inhibitor increased oral budesonide systemic exposure by 8-fold. Voriconazole is a strong CYP3A4 inhibitor, and budesonide is a CYP3A4 substrate.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and budesonide. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Concomitant oral administration of another strong CYP3A4 inhibitor increased oral budesonide systemic exposure by 8-fold. Voriconazole is a strong CYP3A4 inhibitor, and budesonide is a CYP3A4 substrate.
Bupivacaine Liposomal: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as voriconazole, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
Bupivacaine: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as voriconazole, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
Bupivacaine; Epinephrine: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as voriconazole, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
Bupivacaine; Lidocaine: (Moderate) Monitor for lidocaine-related adverse reactions if coadministration with voriconazole is necessary. Lidocaine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as voriconazole, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
Bupivacaine; Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with voriconazole is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and voriconazole is a moderate CYP2C9 inhibitor. (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as voriconazole, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
Buprenorphine: (Major) Avoid coadministration of voriconazole with buprenorphine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of buprenorphine may also be increased, resulting in increased or prolonged opioid effects, particularly when voriconazole is added after a stable buprenorphine dose is achieved. Buprenorphine is a substrate of CYP3A4 that has been associated with QT prolongation and has a possible risk of TdP. Voriconanzole is a strong CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of TdP, cardiac arrest, and sudden death. If co-administration is necessary, monitor patients for QT prolongation, respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Buprenorphine; Naloxone: (Major) Avoid coadministration of voriconazole with buprenorphine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of buprenorphine may also be increased, resulting in increased or prolonged opioid effects, particularly when voriconazole is added after a stable buprenorphine dose is achieved. Buprenorphine is a substrate of CYP3A4 that has been associated with QT prolongation and has a possible risk of TdP. Voriconanzole is a strong CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of TdP, cardiac arrest, and sudden death. If co-administration is necessary, monitor patients for QT prolongation, respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Buspirone: (Moderate) A low dose of buspirone used cautiously is recommended when coadministered with voriconazole. If a patient has been titrated to a stable dosage of buspirone, a dose adjustment of buspirone may be necessary to avoid adverse events attributable to buspirone. Administering voriconazole with buspirone may increase buspirone concentration and risk for adverse events. Buspirone is a sensitive substrate of CYP3A4. Voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the buspirone AUC by 19-fold with an increased incidence of buspirone-related adverse effects.
Butalbital; Acetaminophen: (Contraindicated) Voriconazole is contraindicated for use with long-acting barbiturates, such as butalbital containing products. Barbiturates are CYP3A4 and CYP2C9 inducers and may increase the metabolism and reduce the effective serum concentrations of voriconazole. Barbiturates are also substrates for CYP2C9, and voriconazole may theoretically increase the serum concentrations of the barbiturates.
Butalbital; Acetaminophen; Caffeine: (Contraindicated) Voriconazole is contraindicated for use with long-acting barbiturates, such as butalbital containing products. Barbiturates are CYP3A4 and CYP2C9 inducers and may increase the metabolism and reduce the effective serum concentrations of voriconazole. Barbiturates are also substrates for CYP2C9, and voriconazole may theoretically increase the serum concentrations of the barbiturates.
Butalbital; Acetaminophen; Caffeine; Codeine: (Contraindicated) Voriconazole is contraindicated for use with long-acting barbiturates, such as butalbital containing products. Barbiturates are CYP3A4 and CYP2C9 inducers and may increase the metabolism and reduce the effective serum concentrations of voriconazole. Barbiturates are also substrates for CYP2C9, and voriconazole may theoretically increase the serum concentrations of the barbiturates. (Moderate) Concomitant use of codeine with voriconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of voriconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If voriconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Voriconazole is a strong inhibitor of CYP3A4.
Butalbital; Aspirin; Caffeine; Codeine: (Contraindicated) Voriconazole is contraindicated for use with long-acting barbiturates, such as butalbital containing products. Barbiturates are CYP3A4 and CYP2C9 inducers and may increase the metabolism and reduce the effective serum concentrations of voriconazole. Barbiturates are also substrates for CYP2C9, and voriconazole may theoretically increase the serum concentrations of the barbiturates. (Moderate) Concomitant use of codeine with voriconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of voriconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If voriconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Voriconazole is a strong inhibitor of CYP3A4.
Cabazitaxel: (Major) Avoid coadministration of cabazitaxel with voriconazole if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and voriconazole is a strong CYP3A4 inhibitor; however, the inhibitory potential is less with voriconazole than with ketoconazole and itraconazole. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Cabotegravir; Rilpivirine: (Moderate) Caution is advised when administering voriconazole with rilpivirine due to the potential for additive effects on the QT interval, increased exposure to rilpivirine, and decreased exposure to voriconazole. Monitor for breakthrough fungal infections in patients receiving rilpivirine with an azole antifungal. Rilpivirine, a CYP3A4 substrate, and voriconazole, a strong CYP3A4 inhibitor, are both associated with QT prolongation; rilpivirine dosage adjustments are not recommended. In addition, concurrent use of rilpivirine decreased exposure to another azole antifungal. A similar interaction may occur with voriconazole.
Cabozantinib: (Major) Avoid concomitant use of cabozantinib and voriconazole due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with voriconazole 2 to 3 days after discontinuation of voriconazole. Cabozantinib is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
Calcifediol: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with voriconazole. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with voriconazole. Voriconazole, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
Cannabidiol: (Moderate) Consider a dose reduction of voriconazole as clinically appropriate, if voriconazole-related adverse reactions occur when administered with cannabidiol. Cannabidiol has the potential to inhibit CYP2C9; voriconazole is a CYP2C9 substrate.
Capmatinib: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with voriconazole is necessary. Capmatinib is a CYP3A substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
Carbamazepine: (Contraindicated) Coadministration of carbamazepine and voriconazole is contraindicated due to the potential for decreased exposure to voriconazole; increased exposure to carbamazepine may also occur. Carbamazepine is an inducer of CYP2C9 and CYP3A4 and both enzymes are responsible for voriconazole metabolism. Significantly reduced plasma levels of voriconazole may occur with carbamazepine use. In addition, carbamazepine is a substrate of CYP3A4, and voriconazole is a strong CYP3A4 inhibitor. Concurrent use may result in elevated carbamazepine serum concentrations.
Cariprazine: (Major) The dose of cariprazine should be reduced in patients also receiving voriconazole. When voriconazole is initiated in a patient who is on a stable dose of cariprazine, reduce the cariprazine dosage by half. For adult patients taking cariprazine 4.5 mg daily, the dosage should be reduced to 1.5 mg or 3 mg daily. For patients taking cariprazine 1.5 mg daily, the dosing frequency should be adjusted to every other day. When initiating cariprazine in a patient who is stable on voriconazole, the patient should be administered 1.5 mg of cariprazine on Day 1 and on Day 3 with no dose administered on Day 2. From Day 4 onward, the dose should be administered at 1.5 mg daily, and then increased to a maximum dose of 3 mg daily. When voriconazole is withdrawn, the cariprazine dosage may need to be increased. Cariprazine is metabolized by CYP3A4 to its major active metabolite. Voriconazole is a strong CYP3A4 inhibitor. Concurrent use with another strong CYP3A4 inhibitor increased the exposure of cariprazine by about 4-fold; increased the AUC of DDCAR metabolite by about 1.5-fold; and decreased DCAR metabolite AUC by about one-third.
Carisoprodol: (Minor) Carisoprodol is extensively metabolized and is a significant substrate of C

YP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as voriconazole, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
Celecoxib: (Major) Isoenzyme CYP2C9 is responsible for the metabolism of many nonsteroidal antiinflammatory drugs. Voriconazole is known to be an inhibitor of CYP2C9 and may lead to increased plasma levels of some NSAIDs, such as celecoxib. The clinican should consider introducing the NSAID at the lowest recommended dose in patients receiving voriconazole. Monitor for NSAID-related side effects, such as GI irritation, fluid retention or increased blood pressure, GI bleeding, or renal dysfunction and adjust the dose of the NSAID if needed.
Celecoxib; Tramadol: (Major) Isoenzyme CYP2C9 is responsible for the metabolism of many nonsteroidal antiinflammatory drugs. Voriconazole is known to be an inhibitor of CYP2C9 and may lead to increased plasma levels of some NSAIDs, such as celecoxib. The clinican should consider introducing the NSAID at the lowest recommended dose in patients receiving voriconazole. Monitor for NSAID-related side effects, such as GI irritation, fluid retention or increased blood pressure, GI bleeding, or renal dysfunction and adjust the dose of the NSAID if needed. (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with voriconazole is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of voriconazole, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Cenobamate: (Moderate) Monitor for reduced efficacy of voriconazole if coadministered with cenobamate as concurrent use may decrease voriconazole exposure. Although specific recommendations are unavailable for use with cenobamate, a dose adjustment may be necessary as a voriconazole dose increase to 400 mg PO twice daily is recommended when administered with another moderate CYP3A4 inducer. Voriconazole is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased voriconazole exposure by 77%.
Ceritinib: (Major) Avoid concomitant use of ceritinib with voriconazole due to increased ceritinib exposure which may increase the incidence and severity of adverse reactions as well as an additive risk of QT prolongation; exposure to voriconazole may also increase. If concomitant use is necessary, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg and monitor for treatment-related adverse reactions. Periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. After voriconazole is discontinued, resume the dose of ceritinib taken prior to initiating voriconazole. Both drugs are CYP3A substrates and strong CYP3A4 inhibitors. Coadministration with a strong CYP3A inhibitor increased ceritinib exposure by 2.9-fold. Ceritinib causes concentration-dependent QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes.
Chlordiazepoxide: (Moderate) Monitor for an increase in chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with voriconazole is necessary; adjust the dose of chlordiazepoxide if necessary. Voriconazole is a strong CYP3A4 inhibitor and chlordiazepoxide is a CYP3A4 substrate.
Chlordiazepoxide; Amitriptyline: (Moderate) Monitor for an increase in chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with voriconazole is necessary; adjust the dose of chlordiazepoxide if necessary. Voriconazole is a strong CYP3A4 inhibitor and chlordiazepoxide is a CYP3A4 substrate. (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering voriconazole with amitriptyline. Voriconazole has been associated with prolongation of the QT interval and rare cases of arrhythmias, including TdP. Tricyclic antidepressants (TCAs), such as amitriptyline, share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, voriconazole inhibits CYP3A4 and amitriptyline is partially metabolized by CYP3A4. Coadministration may result in elevated amitriptyline serum concentrations. Monitor for an increased response to amitriptyline if coadministered with voriconazole.
Chlordiazepoxide; Clidinium: (Moderate) Monitor for an increase in chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with voriconazole is necessary; adjust the dose of chlordiazepoxide if necessary. Voriconazole is a strong CYP3A4 inhibitor and chlordiazepoxide is a CYP3A4 substrate.
Chloroquine: (Major) Avoid coadministration of chloroquine with voriconazole due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Voriconazole has been associated with QT prolongation and rare cases of TdP.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with voriconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of voriconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If voriconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Voriconazole is a strong inhibitor of CYP3A4.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with voriconazole may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of voriconazole could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If voriconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Voriconazole is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of voriconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like voriconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If voriconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Voriconazole is a substrate and inhibitor of cytochrome P450 isoenzyme 2C9, which is the isoenzyme responsible for the metabolism of ibuprofen. Thus, increased plasma concentrations of ibuprofen is possible. The clinical significance of this potential interaction is unknown. If voriconazole is administered concurrently with ibuprofen, monitor for NSAID-related side-effects, such as fluid retention or GI irritation, and adjust the dose of the NSAID, if needed.
Chlorpromazine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering voriconazole with chlorpromazine. Voriconazole has been associated with prolongation of the QT interval and rare cases of arrhythmias, including TdP. Chlorpromazine is also associated with an established risk of QT prolongation and TdP; case reports have included patients receiving therapeutic doses of chlorpromazine.
Chlorpropamide: (Moderate) Voriconazole should be used cautiously with sulfonylureas. The combination of voriconazole and oral antidiabetic agents may result in severe hypoglycemia. Voriconazole may inhibit the metabolism of sulfonylureas. Blood glucose concentrations should be monitored and possible dose adjustments of hypoglycemics may need to be made.
Ciclesonide: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and ciclesonide. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Voriconazole is a strong CYP3A4 inhibitor, and ciclesonide is a CYP3A4 substrate.
Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with voriconazole. Monitor for an increase in cilostazol-related adverse reactions. Voriconazole is a strong CYP3A4 inhibitor and cilostazol is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the cilostazol AUC by 117%.
Cinacalcet: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of voriconazole and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Ciprofloxacin: (Moderate) Concomitant use of ciprofloxacin and voriconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Cisapride: (Contraindicated) Due to the potential for torsade de pointes (TdP), coadministration of cisapride and voriconazole is contraindicated. QT prolongation and ventricular arrhythmias, including TdP and death, have been reported with cisapride. Voriconazole is also associated with prolongation of the QT interval and rare cases of TdP.
Citalopram: (Major) Avoid coadministration of citalopram and voriconazole due to the potential for additive effects on the QT interval; increased exposure to citalopram is also possible. Both drugs have been associated with QT prolongation; voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. If concurrent therapy is considered essential, ECG monitoring is recommended; do not exceed 20 mg per day of citalopram. Voriconazole theoretically might impair the metabolism of citalopram through inhibition of CYP2C19 and CYP3A4. Closely monitor for prolongation of the QT interval and other adverse effects such as drowsiness, fatigue, dry mouth, nausea, or insomnia. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Clarithromycin: (Major) Caution is advised when administering voriconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as clarithromycin. Both drugs have been associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. In addition, both drugs are substrates and inhibitors of CYP3A4. Coadministration may result in increased plasma concentrations of both drugs, thereby further increasing the risk for adverse events. Azithromycin can be considered as an alternative macrolide antimicrobial if appropriate for the clinical circumstance, due to its lack of metabolism via CYP3A4. If these drugs are given together, closely monitor for prolongation of the QT interval and other adverse effects such as drowsiness, fatigue, dry mouth, nausea, or insomnia. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Clindamycin: (Moderate) Monitor for an increase in clindamycin-related adverse reactions with coadministration of voriconazole as concurrent use may increase clindamycin exposure. Clindamycin is a CYP3A4 substrate; voriconazole is a strong inhibitor of CYP3A4.
Clofazimine: (Moderate) Concomitant use of clofazimine and voriconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Clomipramine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering voriconazole with clomipramine. Voriconazole has been associated with prolongation of the QT interval and rare cases of arrhythmias, including TdP. Tricyclic antidepressants (TCAs), such as clomipramine, share pharmacologic properties similar to the Class IA antiarrhythmic agents and may also prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, voriconazole inhibits CYP3A4 and clomipramine is a CYP3A4 substrate. Coadministation may increase the serum concentrations of clomipramine.
Clonazepam: (Moderate) Use voriconazole cautiously and carefully monitor patients receiving concurrent clonazepam due to impaired metabolism of clonazepam leading to exaggerated concentrations and adverse effects, such as CNS and/or respiratory depression. Clonazepam is a CYP3A4 substrate. Voriconazole is a strong CYP3A4 inhibitor.
Clopidogrel: (Moderate) Monitor for reduced clopidogrel efficacy during concomitant use of voriconazole. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19; voriconazole is a weak CYP2C19 inhibitor.
Clorazepate: (Moderate) Use caution if coadministration of voriconazole with clorazepate is necessary, as the systemic exposure of the active metabolite of clorazepate may be increased resulting in an increase in treatment-related adverse reactions; adjust the dose of clorazepate if necessary. Voriconazole is a strong CYP3A4 inhibitor. Clorazepate is a pro-drug converted to N-desmethyldiazepam in the GI tract; N-desmethyldiazepam is metabolized by 2C19 and 3A4.
Clozapine: (Major) Caution is advised when administering voriconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as clozapine. Both drugs have been associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. In addition, coadministration of voriconazole (a CYP3A4 inhibitor) with clozapine (a CYP3A4 substrate) may result in elevated clozapine plasma concentrations and could increase the risk for adverse events, including QT prolongation. Consider reducing the clozapine dose if necessary. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Cobicistat: (Major) Avoid concurrent use of voriconazole with regimens containing cobicistat and atazanavir or darunavir. Use of these drugs together may result in increase plasma concentrations of cobicistat, atazanavir, and darunavir; effects on the voriconazole concentrations has not been determined.
Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with chronic voriconazole therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of voriconazole is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of voriconazole, resume cobimetinib at the previous dose. Use an alternative to voriconazole in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a CYP3A substrate in vitro, and voriconazole is a moderate inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Codeine: (Moderate) Concomitant use of codeine with voriconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of voriconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If voriconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Voriconazole is a strong inhibitor of CYP3A4.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with voriconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of voriconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If voriconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Voriconazole is a strong inhibitor of CYP3A4.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with voriconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of voriconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If voriconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Voriconazole is a strong inhibitor of CYP3A4.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with voriconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of voriconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If voriconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Voriconazole is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of promethazine and voriconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with voriconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of voriconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If voriconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Voriconazole is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of promethazine and voriconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and voriconazole in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Voriconazole can inhibit colchicine's metabolism via CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken a strong CYP3A4 inhibitor like voriconazole in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
Conivaptan: (Contraindicated) Coadministration of conivaptan and voriconazole is contraindicated due to the potential for increased conivaptan exposure. Concomitant use may also increase voriconazole exposure and risk for voriconazole-related adverse effects. Conivaptan is a CYP3A substrate and moderate CYP3A inhibitor; voriconazole is a CYP3A substrate and strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold. Coadministration with another moderate CYP3A inhibitor increased voriconazole exposure by 79%.
Conjugated Estrogens; Medroxyprogesterone: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with voriconazole, a strong CYP3A inhibitor should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via the CYP3A4 in vitro.
Copanlisib: (Major) Avoid the concomitant use of copanlisib and voriconazole if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; voriconazole is a strong CYP3A inhibitor.
Cortisone: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and cortisone. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Voriconazole is a strong CYP3A4 inhibitor, and cortisone is a CYP3A4 substrate.
Crizotinib: (Major) Avoid concomitant use of voriconazole and crizotinib due to increased plasma concentrations of crizotinib, which may increase the incidence and severity of adverse reactions; exposure to voriconazole may also increase. If concomitant use is necessary for adults with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), reduce the dose of crizotinib to 250 mg PO once daily. If concomitant use is necessary for young adult or pediatric patients with anaplastic large cell lymphoma or pediatric patients with IMT, reduce the dose of crizotinib to 250 mg PO twice daily for BSA of 1.7 m2 or more; 200 mg PO twice daily for BSA of 1.17 to 1.69 m2; and 250 mg PO once daily for BSA of 0.81 to 1.16 m2; do not use this combination in patients with a BSA of 0.6 to 0.8 m2. Resume the original crizotinib dose after discontinuation of voriconazole. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Crizotinib is a CYP3A substrate and moderate inhibitor. Voriconazole is a CYP3A substrate and strong CYP3A inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC of single-dose crizotinib by 216%. Concomitant use with another strong CYP3A inhibitor increased the steady-state AUC of crizotinib by 57% compared to crizotinib alone.
Cyclosporine: (Major) The interactions between cyclosporine and systemic azole antifungals, including voriconazole, can be significant. Voriconazole may inhibit the metabolism and lead to increased concentrations of cyclosporine. Plasma cyclosporine concentrations should be monitored closely if voriconazole is added. Reduce cyclosporine doses by one-half when initiating therapy with voriconazole due to voriconazole-induced inhibition of CYP3A4. When voriconazole is discontinued, cyclosporine concentrations should be carefully monitored and the dose increased as needed. In all cases, renal function in these patients should be carefully monitored. Close monitoring of cyclosporine concentrations is required when given in combination with systemic azole antifungals; a 50% reduction in cyclosporine dosage may be required.
Dabrafenib: (Major) The concomitant use of dabrafenib and voriconazole may result in altered levels of either agent. Use of an alternative agent is recommended. If concomitant use of these agents is unavoidable, monitor patients for dabrafenib toxicity (e.g., skin toxicity, ocular toxicity, and cardiotoxicity) and loss of voriconazole efficacy. Dabrafenib is a CYP3A4 substrate, a moderate CYP3A4 inducer, and an inducer of CYP2C isoenzymes via activation of the pregnane X receptor and constitutive androstane receptor nuclear receptors. Voriconazole is a strong CYP3A4 inhibitor and a substrate of CYP3A4, CYP2C9, and CYP2C19.
Daclatasvir: (Moderate) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as voriconazole. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects.
Dapagliflozin; Saxagliptin: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with voriconazole due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively.
Dapsone: (Minor) Voriconazole is known inhibitor of isoenzyme CYP2C9 and theoretically may lead to increased concentrations of drugs that are substrates for this enzyme, including dapsone.
Daridorexant: (Major) Avoid concomitant use of daridorexant and voriconazole. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Darifenacin: (Major) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with voriconazole due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor.
Darunavir: (Major) Coadministration of darunavir and voriconazole is not recommended unless the benefit outweighs the risk. Concurrent administration of darunavir with voriconazole has not been studied; however, there is the potential for a bi-directional inhibition between voriconazole and protease inhibitors. Additionally, administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%. Patients should be monitored for voriconazole toxicity and/or decreased antiretroviral efficacy during coadministration.
Darunavir; Cobicistat: (Major) Avoid concurrent use of voriconazole with regimens containing cobicistat and atazanavir or darunavir. Use of these drugs together may result in increase plasma concentrations of cobicistat, atazanavir, and darunavir; effects on the voriconazole concentrations has not been determined. (Major) Coadministration of darunavir and voriconazole is not recommended unless the benefit outweighs the risk. Concurrent administration of darunavir with voriconazole has not been studied; however, there is the potential for a bi-directional inhibition between voriconazole and protease inhibitors. Additionally, administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%. Patients should be monitored for voriconazole toxicity and/or decreased antiretroviral efficacy during coadministration.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concurrent use of voriconazole with regimens containing cobicistat and atazanavir or darunavir. Use of these drugs together may result in increase plasma concentrations of cobicistat, atazanavir, and darunavir; effects on the voriconazole concentrations has not been determined. (Major) Coadministration of darunavir and voriconazole is not recommended unless the benefit outweighs the risk. Concurrent administration of darunavir with voriconazole has not been studied; however, there is the potential for a bi-directional inhibition between voriconazole and protease inhibitors. Additionally, administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%. Patients should be monitored for voriconazole toxicity and/or decreased antiretroviral efficacy during coadministration.
Dasatinib: (Major) Avoid coadministration of dasatinib and voriconazole due to the potential for increased dasatinib exposure and subsequent toxicity including QT prolongation and torsade de pointes (TdP). An alternative to voriconazole with no or minimal enzyme inhibition potential is recommended if possible. If coadministration cannot be avoided, consider a dasatinib dose reduction to 40 mg PO daily if original dose was 140 mg daily, 20 mg PO daily if original dose was 100 mg daily, or 20 mg PO daily if original dose was 70 mg daily. Stop dasatinib during use of voriconazole in patients receiving dasatinib 60 mg or 40 mg PO daily. If dasatinib is not tolerated after dose reduction, either discontinue voriconazole or stop dasatinib until voriconazole is discontinued. Allow a washout of approximately 1 week after voriconazole is stopped before increasing the dasatinib dose or reinitiating dasatinib. Dasatinib is a CYP3A4 substrate that has the potential to prolong the QT interval; voriconazole is a strong CYP3A4 inhibitor that is associated QT prolongation and rare cases of TdP. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of dasatinib by 4-fold and 5-fold, respectively.
Deflazacort: (Major) Decrease the deflazacort dose to one-third of the recommended dosage with concomitant use of voriconazole and monitor for potential adrenal dysfunction. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Concomitant administration of another strong CYP3A4 inhibitor increased total exposure to 21-desDFZ, the active metabolite of deflazacort, by about 3-fold. Voriconazole is a strong CYP3A4 inhibitor, and deflazacort is a CYP3A4 substrate.
Degarelix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving voriconazole as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes.
Delavirdine: (Moderate) Concurrent administration of delavirdine and voriconazole may theoretically result in increased voriconazole levels. Careful monitoring of therapeutic and adverse effects of voriconazole is recommended when these drugs are given concurrently.
Desflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with voriconazole. Halogenated anesthetics can prolong the QT interval. Voriconazole has been associated with QT prolongation and rare cases of torsades de pointes.
Desipramine: (Minor) Voriconazole is associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, voriconazole inhibits CYP2C19 and CYP3A4. CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs. Desipramine may be affected by this potential interaction, but specific data are lacking. Monitor for an increased response to desipramine if voriconazole is coadministered.
Desogestrel; Ethinyl Estradiol: (Moderate) Voriconazole may increase plasma concentrations of ethinyl estradiol by inhibiting CYP3A4 , resulting in estrogen-related side effects such as nausea and breast tenderness. Ethinyl estradiol, when combined with norethindrone, may also increase the Cmax and AUC of voriconazole.
Deutetrabenazine: (Moderate) Use voriconazole with caution in combination with deutetrabenazine due to additive QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
Dexamethasone: (Moderate) Monitor for steroid-related adverse reactions if coadministration of voriconazole with dexamethasone is necessary, due to increased dexamethasone exposure; Cushing's syndrome and adrenal suppression could potentially occur with long-term use. Consider the use of corticosteroids such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A inhibitors, especially for long-term use. Dexamethasone is primarily metabolized by CYP3A and voriconazole is a strong CYP3A inhibitor. Another strong CYP3A inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
Dexlansoprazole: (Minor) Use caution if coadministration of voriconazole with dexlansoprazole is necessary, as the systemic exposure of dexlansoprazole may be increased resulting in increase in treatment-related adverse reactions. Voriconazole is a strong inhibitor of CYP3A4 and also inhibits CYP2C19. Dexlansoprazole is a substrate of CYP3A and CYP2C19.
Dexmedetomidine: (Moderate) Concomitant use of dexmedetomidine and voriconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Dextromethorphan; Quinidine: (Contraindicated) Quinidine (including dextromethorphan; quinidine) use is contraindicated with voriconazole according to recommendations made by the manufacturer of voriconazole. Voriconazole inhibits the CYP3A4 enzyme that is responsible for quinidine metabolism; elevated and toxic levels of quinidine may occur potentiating the risk for QT prolongation and cardiac arrhythmias (e.g., torsade de pointes).
Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions if coadministration with voriconazole is necessary; decrease the dose of diazepam if necessary. At low concentrations, diazepam is primarily metabolized by CYP2C19; however, CYP3A4 is also involved at higher concentrations. Voriconazole is a strong CYP3A4.
Dichlorphenamide: (Moderate) Use dichlorphenamide and voriconazole together with caution. Dichlorphenamide increases potassium excretion and can cause hypokalemia and should be used cautiously with other drugs that may cause hypokalemia including antifungals. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment. If hypokalemia occurs or persists, consider reducing the dichlorphenamide dose or discontinuing dichlorphenamide therapy.
Diclofenac: (Moderate) Voriconazole is known to be an inhibitor of CYP2C9 and may lead to increased plasma levels of some NSAIDs, including diclofenac. A maximum diclofenac dose of 50 mg twice daily is recommended if voriconazole is administered concurrently with diclofenac. Further, monitor for NSAID-induced toxicity such as GI irritation, GI bleeding, or renal dysfunction.
Diclofenac; Misoprostol: (Moderate) Voriconazole is known to be an inhibitor of CYP2C9 and may lead to increased plasma levels of some NSAIDs, including diclofenac. A maximum diclofenac dose of 50 mg twice daily is recommended if voriconazole is administered concurrently with diclofenac. Further, monitor for NSAID-induced toxicity such as GI irritation, GI bleeding, or renal dysfunction.
Dienogest; Estradiol valerate: (Minor) As voriconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives. (Minor) Estradiol valerate and dienogest are both substrates of CYP3A4. Certain azole antifungals, including fluconazole, itraconazole, ketonconazole, miconazole (systemic formulation only), posaconazole, and voriconazole, are CYP3A4 inhibitors and therefore may inhibit the metabolism of dienogest; estradiol valerate, possibly leading to increased serum concentrations. In a pharmacokinetic study evaluating the effect of ketoconazole on dienogest and estradiol, co-administration with ketoconazole increased the AUC at steady-state for dienogest and estradiol by 2.86 and 1.57-fold, respectively. There was also a 1.94 and 1.65-fold increase of Cmax at steady-state for dienogest and estradiol when co-administered with ketoconazole.
Diltiazem: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with voriconazole is necessary. Concurrent use may result in elevated diltiazem concentrations. Diltiazem is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor.
Diphenhydramine; Ibuprofen: (Moderate) Voriconazole is a substrate and inhibitor of cytochrome P450 isoenzyme 2C9, which is the isoenzyme responsible for the metabolism of ibuprofen. Thus, increased plasma concentrations of ibuprofen is possible. The clinical significance of this potential interaction is unknown. If voriconazole is administered concurrently with ibuprofen, monitor for NSAID-related side-effects, such as fluid retention or GI irritation, and adjust the dose of the NSAID, if needed.
Diphenhydramine; Naproxen: (Moderate) The hepatic isoenzyme CYP2C9 is responsible for the metabolism of many NSAIDs. Voriconazole is known to be an inhibitor of CYP2C9 and may lead to increased plasma levels of some NSAIDs, such as naproxen. The clinical significance of this potential interaction is unknown. Monitor for NSAID-related side-effects, such as fluid retention or GI irritation, and adjust the dose of the NSAID if needed.
Disopyramide: (Major) Caution is advised when administering voriconazole with disopyramide due to the potential for additive effects on the QT interval and increased exposure to disopyramide. Both drugs have been associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. In addition, coadministration of voriconazole (a strong CYP3A4 inhibitor) with disopyramide (a CYP3A4 substrate) may result in elevated disopyramide plasma concentrations and could increase the risk for adverse events, including QT prolongation. Cases of life-threatening interactions have been reported for disopyramide when given with CYP3A4 inhibitors. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Disulfiram: (Moderate) Voriconazole is metabolized by the CYP2C9 isoenzyme, and drugs that are known to be inhibitors of CYP2C9, such as disulfiram, may theoretically lead to elevated plasma levels of voriconazole when coadministered.
Docetaxel: (Major) Avoid coadministration of docetaxel with voriconazole if possible due to increased plasma concentrations of docetaxel. If concomitant use is unavoidable, closely monitor for docetaxel-related adverse reactions and consider a 50% dose reduction of docetaxel. Docetaxel is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased docetaxel exposure by 2.2-fold.
Dofetilide: (Major) Coadministration of dofetilide and voriconazole is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Voriconazole has been associated with QT prolongation and rare cases of TdP.
Dolasetron: (Moderate) Administer dolasetron with caution in combination with voriconazole as concurrent use may increase the risk of QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
Dolutegravir: (Moderate) Use caution if coadministration of voriconazole with dolutegravir is necessary, as the systemic exposure of dolutegravir may be increased resulting in an increase in treatment-related adverse reactions. Voriconazole is a strong CYP3A4 inhibitor. Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A.
Dolutegravir; Lamivudine: (Moderate) Use caution if coadministration of voriconazole with dolutegravir is necessary, as the systemic exposure of dolutegravir may be increased resulting in an increase in treatment-related adverse reactions. Voriconazole is a strong CYP3A4 inhibitor. Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A.
Dolutegravir; Rilpivirine: (Moderate) Caution is advised when administering voriconazole with rilpivirine due to the potential for additive effects on the QT interval, increased exposure to rilpivirine, and decreased exposure to voriconazole. Monitor for breakthrough fungal infections in patients receiving rilpivirine with an azole antifungal. Rilpivirine, a CYP3A4 substrate, and voriconazole, a strong CYP3A4 inhibitor, are both associated with QT prolongation; rilpivirine dosage adjustments are not recommended. In addition, concurrent use of rilpivirine decreased exposure to another azole antifungal. A similar interaction may occur with voriconazole. (Moderate) Use caution if coadministration of voriconazole with dolutegravir is necessary, as the systemic exposure of dolutegravir may be increased resulting in an increase in treatment-related adverse reactions. Voriconazole is a strong CYP3A4 inhibitor. Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A.
Donepezil: (Moderate) Use donepezil with caution in combination with voriconazole as concurrent use may increase the risk of QT prolongation. Clinical monitoring for donepezil-related adverse effects, such as GI or cholinergic effects, is also recommended. The plasma concentrations of donepezil may be elevated when administered concurrently with voriconazole. Voriconazole is a strong inhibitor of CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes. Donepezil is a CYP3A4 substrate; case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Coadministration with another strong CYP3A4 inhibitor increased mean donepezil concentrations by 36%. The clinical significance of this increase is unknown.
Donepezil; Memantine: (Moderate) Use donepezil with caution in combination with voriconazole as concurrent use may increase the risk of QT prolongation. Clinical monitoring for donepezil-related adverse effects, such as GI or cholinergic effects, is also recommended. The plasma concentrations of donepezil may be elevated when administered concurrently with voriconazole. Voriconazole is a strong inhibitor of CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes. Donepezil is a CYP3A4 substrate; case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Coadministration with another strong CYP3A4 inhibitor increased mean donepezil concentrations by 36%. The clinical significance of this increase is unknown.
Doravirine: (Minor) Coadministration of doravirine and voriconazole may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; voriconazole is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Minor) Coadministration of doravirine and voriconazole may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; voriconazole is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Doxazosin: (Moderate) Monitor blood pressure and for signs of hypotension during coadministration. The plasma concentrations of doxazosin may be elevated when administered concurrently with voriconazole. Voriconazole is a strong CYP3A4 inhibitor; doxazosin is a CYP3A4 substrate. Coadministration of doxazosin with a moderate CYP3A4 inhibitor resulted in a 10% increase in mean AUC and an insignificant increase in mean Cmax and mean half-life of doxazosin. Although not studied in combination with doxazosin, strong CYP3A4 inhibitors may have a larger impact on doxazosin concentrations and therefore should be used with caution.
Doxepin: (Major) Voriconazole is associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, voriconazole inhibits CYP2C19, CYP2C9, and CYP3A4. Doxepin is primarily metabolized by CYP2C19 and CYP2D6, and to a lesser extent, by CYP1A2 and CYP2C9. In at least one case, the interaction resulted in an increased incidence of TCA-related side effects, such as dizziness and syncope. In another case, QT-prolongation and torsades de pointes occurred. Doxepin may be affected by this potential interaction, but specific data are lacking. Monitor for an increased response to doxepin if fluconazole, posaconazole, or voriconazole are coadministered.
Doxercalciferol: (Moderate) Cytochrome P450 enzyme inhibitors, such as voriconazole, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy.
Doxorubicin Liposomal: (Major) Avoid coadministration of voriconazole with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Voriconazole is a strong CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of voriconazole with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Voriconazole is a strong CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
Dronabinol: (Moderate) Use caution if coadministration of dronabinol with voriconazole is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate. Voriconazole is a strong CYP3A4 inhibitor and a moderate inhibitor of CYP2C9. Concomitant use may result in elevated plasma concentrations of dronabinol.
Dronedarone: (Contraindicated) Concomitant use of dronedarone and voriconazole is contraindicated. Voriconazole has been associated with prolongation of the QT interval and rare cases of arrhythmias, including TdP. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Droperidol: (Major) Caution is advised when administering voriconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as droperidol. Both drugs have been associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. In addition, coadministration of voriconazole (a CYP3A4 inhibitor) with droperidol (a CYP3A4 substrate) may result in elevated droperidol plasma concentrations and could increase the risk for adverse events, including QT prolongation. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Drospirenone: (Moderate) Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Voriconazole is a strong inhibitor of CYP3A4 and may increase drospirenone concentrations. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly.
Drospirenone; Estetrol: (Moderate) Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Voriconazole is a strong inhibitor of CYP3A4 and may increase drospirenone concentrations. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly.
Drospirenone; Estradiol: (Moderate) Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Voriconazole is a strong inhibitor of CYP3A4 and may increase drospirenone concentrations. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. (Minor) As voriconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Drospirenone; Ethinyl Estradiol: (Moderate) Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Voriconazole is a strong inhibitor of CYP3A4 and may increase drospirenone concentrations. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. (Moderate) Voriconazole may increase plasma concentrations of ethinyl estradiol by inhibiting CYP3A4 , resulting in estrogen-related side effects such as nausea and breast tenderness. Ethinyl estradiol, when combined with norethindrone, may also increase the Cmax and AUC of voriconazole.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Voriconazole is a strong inhibitor of CYP3A4 and may increase drospirenone concentrations. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. (Moderate) Voriconazole may increase plasma concentrations of ethinyl estradiol by inhibiting CYP3A4 , resulting in estrogen-related side effects such as nausea and breast tenderness. Ethinyl estradiol, when combined with norethindrone, may also increase the Cmax and AUC of voriconazole.
Dutasteride: (Moderate) Monitor for dutasteride-related adverse effects (e.g., impotence, decreased libido, breast enlargement) if coadministered with voriconazole. Dutasteride is a CYP3A4 substrate, and voriconazole is a strong CYP3A4 inhibitor. Although the effect of strong CYP3A4 inhibitors on dutasteride has not been defined, dutasteride exposure may increase.
Dutasteride; Tamsulosin: (Major) Concurrent use of tamsulosin and voriconazole is not recommended due to the potential for elevated tamsulosin concentrations. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension, dizziness, and vertigo. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes, and strong inhibitors of CYP3A4 are expected to significantly raise tamsulosin concentrations. Concomitant treatment with another strong CYP3A4 inhibitor increased the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively. (Moderate) Monitor for dutasteride-related adverse effects (e.g., impotence, decreased libido, breast enlargement) if coadministered with voriconazole. Dutasteride is a CYP3A4 substrate, and voriconazole is a strong CYP3A4 inhibitor. Although the effect of strong CYP3A4 inhibitors on dutasteride has not been defined, dutasteride exposure may increase.
Duvelisib: (Major) Reduce duvelisib dose to 15 mg PO twice daily and monitor for increased toxicity when coadministered with voriconazole. Coadministration may increase the exposure of duvelisib. Duvelisib is a CYP3A substrate; voriconazole is a strong CYP3A inhibitor. The increase in exposure to duvelisib is estimated to be approximately 2-fold when used concomitantly with strong CYP3A inhibitors such as voriconazole.
Efavirenz: (Major) Coadministration of standard doses of voriconazole and efavirenz (400 mg PO daily or higher) is contraindicated. If efavirenz and voriconazole must be coadministered, dosage adjustments of both drugs are required. During coadministration, increase the voriconazole maintenance dose to 400 mg PO every 12 hours and decrease the efavirenz dose to 300 mg PO once daily, using the capsule formulation; efavirenz tablets should not be broken. When coadministered, efavirenz (400 mg PO daily) significantly decreased the steady state Cmax and AUC of voriconazole by 61% and 77%, respectively and voriconazole significantly increased the steady state Cmax and AUC of efavirenz by 38% and 44%, respectively. If administered at standard doses, this would pose the risk of voriconazole therapeutic failure and increased efavirenz-related toxicities. In addition, concurrent use may increase the risk for QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. QT prolongation has also been observed during use of efavirenz.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of standard doses of voriconazole and efavirenz (400 mg PO daily or higher) is contraindicated. If efavirenz and voriconazole must be coadministered, dosage adjustments of both drugs are required. During coadministration, increase the voriconazole maintenance dose to 400 mg PO every 12 hours and decrease the efavirenz dose to 300 mg PO once daily, using the capsule formulation; efavirenz tablets should not be broken. When coadministered, efavirenz (400 mg PO daily) significantly decreased the steady state Cmax and AUC of voriconazole by 61% and 77%, respectively and voriconazole significantly increased the steady state Cmax and AUC of efavirenz by 38% and 44%, respectively. If administered at standard doses, this would pose the risk of voriconazole therapeutic failure and increased efavirenz-related toxicities. In addition, concurrent use may increase the risk for QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. QT prolongation has also been observed during use of efavirenz.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of standard doses of voriconazole and efavirenz (400 mg PO daily or higher) is contraindicated. If efavirenz and voriconazole must be coadministered, dosage adjustments of both drugs are required. During coadministration, increase the voriconazole maintenance dose to 400 mg PO every 12 hours and decrease the efaviren z dose to 300 mg PO once daily, using the capsule formulation; efavirenz tablets should not be broken. When coadministered, efavirenz (400 mg PO daily) significantly decreased the steady state Cmax and AUC of voriconazole by 61% and 77%, respectively and voriconazole significantly increased the steady state Cmax and AUC of efavirenz by 38% and 44%, respectively. If administered at standard doses, this would pose the risk of voriconazole therapeutic failure and increased efavirenz-related toxicities. In addition, concurrent use may increase the risk for QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. QT prolongation has also been observed during use of efavirenz.
Elacestrant: (Major) Avoid concomitant use of elacestrant and voriconazole due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased elacestrant overall exposure by 5.3-fold.
Elagolix: (Major) Concomitant use of elagolix 200 mg twice daily and voriconazole for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and voriconazole to 6 months. Monitor for elagolix-related side effects and increased or reduced response to voriconazole. Elagolix is a CYP3A substrate, a weak to moderate CYP3A4 inducer, and a weak CYP2C19 inhibitor; voriconazole is a strong inhibitor of CYP3A, a CYP3A4 substrate, and a CYP2C19 sensitive substrate. Coadministration may increase elagolix plasma concentrations and increase or decrease voriconazole concentrations. In drug interaction studies, coadministration of elagolix with another strong CYP3A inhibitor increased the Cmax and AUC of elagolix by 77% and 120%, respectively.
Elagolix; Estradiol; Norethindrone acetate: (Major) Concomitant use of elagolix 200 mg twice daily and voriconazole for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and voriconazole to 6 months. Monitor for elagolix-related side effects and increased or reduced response to voriconazole. Elagolix is a CYP3A substrate, a weak to moderate CYP3A4 inducer, and a weak CYP2C19 inhibitor; voriconazole is a strong inhibitor of CYP3A, a CYP3A4 substrate, and a CYP2C19 sensitive substrate. Coadministration may increase elagolix plasma concentrations and increase or decrease voriconazole concentrations. In drug interaction studies, coadministration of elagolix with another strong CYP3A inhibitor increased the Cmax and AUC of elagolix by 77% and 120%, respectively. (Moderate) Ethinyl estradiol and norethindrone increases the Cmax and AUC of voriconazole and voriconazole increases the Cmax and AUC of both ethinyl estradiol and norethindrone. (Minor) As voriconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Elbasvir; Grazoprevir: (Moderate) Monitor for an increase in grazoprevir-related adverse reactions if coadministration with voriconazole is necessary. Grazoprevir is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased grazoprevir exposure by 3-fold. (Moderate) Use caution if voriconazole is coadministered with elbasvir, as the systemic exposure of elbasvir may be increased resulting in adverse reactions. Voriconazole is a strong CYP3A4 inhibitor, and elbasvir is a CYP3A4 substrate.
Eletriptan: (Contraindicated) Eletriptan is contraindicated with recent use (i.e., within 72 hours) of voriconazole due to the potential for increased eletriptan exposure. Eletriptan is a sensitive substrate of CYP3A4; voriconazole is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the Cmax and AUC of eletriptan by 3-fold and 6-fold, respectively.
Elexacaftor; tezacaftor; ivacaftor: (Major) If voriconazole and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor to twice a week in the morning, approximately 3 to 4 days apart (i.e., Day 1 and Day 4) when coadministered with voriconazole; omit the evening dose of ivacaftor. Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; voriconazole is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased elexacaftor exposure by 2.8- fold, tezacaftor exposure by 4.5-fold, and ivacaftor exposure by 15.6-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with voriconazole; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); voriconazole is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
Eliglustat: (Major) Avoid coadministration of eliglustat with voriconanzole due to the risk of QT prolongation. Coadministration is contraindicated in intermediate or poor CYP2D6 metabolizers (IMs or PMs), and when concomitantly used with a moderate or strong CYP2D6 inhibitor in all patients. Eliglustat is a CYP3A4 and CYP2D6 substrate that causes PR, QRS, and QT prolongation at elevated plasma concentrations; the risk is highest in CYP2D6 IMs and PMs because a larger portion of the dose is metabolized via CYP3A. Voriconazole is a strong CYP3A4 inhibitor that is also associated with QT prolongation.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concurrent use of voriconazole with regimens containing cobicistat and atazanavir or darunavir. Use of these drugs together may result in increase plasma concentrations of cobicistat, atazanavir, and darunavir; effects on the voriconazole concentrations has not been determined.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concurrent use of voriconazole with regimens containing cobicistat and atazanavir or darunavir. Use of these drugs together may result in increase plasma concentrations of cobicistat, atazanavir, and darunavir; effects on the voriconazole concentrations has not been determined.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Caution is advised when administering voriconazole with rilpivirine due to the potential for additive effects on the QT interval, increased exposure to rilpivirine, and decreased exposure to voriconazole. Monitor for breakthrough fungal infections in patients receiving rilpivirine with an azole antifungal. Rilpivirine, a CYP3A4 substrate, and voriconazole, a strong CYP3A4 inhibitor, are both associated with QT prolongation; rilpivirine dosage adjustments are not recommended. In addition, concurrent use of rilpivirine decreased exposure to another azole antifungal. A similar interaction may occur with voriconazole.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering voriconazole with rilpivirine due to the potential for additive effects on the QT interval, increased exposure to rilpivirine, and decreased exposure to voriconazole. Monitor for breakthrough fungal infections in patients receiving rilpivirine with an azole antifungal. Rilpivirine, a CYP3A4 substrate, and voriconazole, a strong CYP3A4 inhibitor, are both associated with QT prolongation; rilpivirine dosage adjustments are not recommended. In addition, concurrent use of rilpivirine decreased exposure to another azole antifungal. A similar interaction may occur with voriconazole.
Encorafenib: (Contraindicated) Coadministration of voriconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as encorafenib, is contraindicated. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes.
Entrectinib: (Major) Avoid coadministration of entrectinib with voriconazole due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If voriconazole is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of voriconazole. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; voriconazole is a strong CYP3A4 inhibitor that is associated with QT prolongation and rare cases of torsade de pointes (TdP). Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
Enzalutamide: (Contraindicated) Coadministration of voriconazole with enzalutamide is contraindicated due to decreased plasma concentrations of voriconazole. Voriconazole is a CYP2C9, CYP2C19, and CYP3A4 substrate. Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer. Voriconazole plasma concentrations may be reduced by roughly 95%; doubling the dose of voriconazole did not restore adequate exposure to voriconazole during concomitant use with another strong CYP3A4 inducer.
Eplerenone: (Contraindicated) Coadministration of voriconazole and eplerenone is contraindicated. Voriconazole potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
Erdafitinib: (Major) Avoid coadministration of erdafitinib and voriconazole due to the risk of increased plasma concentrations of erdafitinib. If concomitant use is unavoidable, closely monitor for erdafitinib-related adverse reactions and consider dose modifications as clinically appropriate. If voriconazole is discontinued, the dose of erdafitinib may be increased in the absence of drug-related toxicity. Erdafitinib is a substrate of CYP2C9 and CYP3A4. Voriconazole is a moderate CYP2C9 inhibitor and a strong CYP3A4 inhibitor. The mean ratios for the Cmax and AUC of erdafitinib were 105% and 134%, respectively, when coadministered with another strong CYP3A4 inhibitor.
Ergot alkaloids: (Contraindicated) Concurrent administration of voriconazole with ergot alkaloids is contraindicated. Voriconazole may reduce the metabolism of the ergot alkaloids via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergotism (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia, or other serious effects).
Eribulin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering voriconazole with eribulin. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Voriconazole has been associated with prolongation of the QT interval and rare cases of arrhythmias, including TdP. Eribulin has also been associated with QT prolongation.
Erlotinib: (Major) Avoid coadministration of erlotinib with voriconazole if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
Erythromycin: (Major) Caution is advised when administering voriconazole with drugs that are known to prolong that QT interval, such as erythromycin. Both erythromycin and voriconazole are associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Escitalopram: (Moderate) Administer voriconazole with caution in combination with escitalopram due to additive QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Escitalopram has been associated with a risk of QT prolongation and TdP.
Esomeprazole: (Moderate) Monitor for increased drug toxicity as coadministration of esomeprazole and voriconazole may result in increased concentrations of both drugs. Although dose adjustments are not generally needed, patients with Zollinger-Ellison's syndrome who often require higher esomeprazole doses (up to 240mg/day) may require an adjustment in esomeprazole dose. Esomeprazole is metabolized primarily by CYP2C19 and secondarily by CYP3A4 and is also a CYP2C19 inhibitor; voriconazole is a CYP2C19 substrate and inhibitor of CYP2C19 and CYP3A4.
Estazolam: (Moderate) Use caution if coadministration of voriconazole with estazolam is necessary, as the systemic exposure of estazolam may be increased resulting in an increase in treatment-related adverse reactions including sedation and respiratory depression; adjust the dose of estazolam if necessary. Voriconazole is a strong CYP3A4 inhibitor and estazolam is a CYP3A4 substrate.
Estradiol: (Minor) As voriconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Estradiol; Levonorgestrel: (Minor) As voriconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Estradiol; Norethindrone: (Moderate) Ethinyl estradiol and norethindrone increases the Cmax and AUC of voriconazole and voriconazole increases the Cmax and AUC of both ethinyl estradiol and norethindrone. (Minor) As voriconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Estradiol; Norgestimate: (Minor) As voriconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Estradiol; Progesterone: (Moderate) Use caution if coadministration of voriconazole with progesterone is necessary, as the systemic exposure of progesterone may be increased resulting in an increase in treatment-related adverse reactions. Voriconazole is a strong CYP3A4 inhibitor. Progesterone is metabolized primarily by hydroxylation via a CYP3A4. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Minor) As voriconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Eszopiclone: (Major) The total dose of eszopiclone should not exceed 2 mg when administered with voriconazole. Coadministration may increase eszopiclone exposure resulting in increased risk of next-day psychomotor or memory impairment and decreased ability to perform tasks requiring full mental alertness such as driving. CYP3A4 is a primary metabolic pathway for eszopiclone; voriconazole is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased eszopiclone exposure by 2.2-fold.
Ethinyl Estradiol; Norelgestromin: (Moderate) Voriconazole may increase plasma concentrations of ethinyl estradiol by inhibiting CYP3A4 , resulting in estrogen-related side effects such as nausea and breast tenderness. Ethinyl estradiol, when combined with norethindrone, may also increase the Cmax and AUC of voriconazole.
Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Ethinyl estradiol and norethindrone increases the Cmax and AUC of voriconazole and voriconazole increases the Cmax and AUC of both ethinyl estradiol and norethindrone. (Moderate) Voriconazole may increase plasma concentrations of ethinyl estradiol by inhibiting CYP3A4 , resulting in estrogen-related side effects such as nausea and breast tenderness. Ethinyl estradiol, when combined with norethindrone, may also increase the Cmax and AUC of voriconazole.
Ethinyl Estradiol; Norgestrel: (Moderate) Voriconazole may increase plasma concentrations of ethinyl estradiol by inhibiting CYP3A4 , resulting in estrogen-related side effects such as nausea and breast tenderness. Ethinyl estradiol, when combined with norethindrone, may also increase the Cmax and AUC of voriconazole.
Ethosuximide: (Moderate) Monitor for an increase in ethosuximide-related adverse reactions if coadministration with voriconazole is necessary. Ethosuximide is a CYP3A4 substrate with a narrow therapeutic index and voriconazole is a strong CYP3A4 inhibitor.
Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Voriconazole may increase plasma concentrations of ethinyl estradiol by inhibiting CYP3A4 , resulting in estrogen-related side effects such as nausea and breast tenderness. Ethinyl estradiol, when combined with norethindrone, may also increase the Cmax and AUC of voriconazole.
Etonogestrel: (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as voriconazole may increase the serum concentration of etonogestrel.
Etonogestrel; Ethinyl Estradiol: (Moderate) Voriconazole may increase plasma concentrations of ethinyl estradiol by inhibiting CYP3A4 , resulting in estrogen-related side effects such as nausea and breast tenderness. Ethinyl estradiol, when combined with norethindrone, may also increase the Cmax and AUC of voriconazole. (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as voriconazole may increase the serum concentration of etonogestrel.
Etravirine: (Moderate) Monitor for an increase in etravirine-related adverse reactions if concomitant use of voriconazole is necessary. Etravirine is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Concomitant use with voriconazole increased etravirine exposure by 1.4-fold.
Everolimus: (Major) Avoid coadministration of everolimus with voriconazole due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and P-glycoprotein (P-gp) substrate. Voriconazole is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
Ezetimibe; Simvastatin: (Contraindicated) Concurrent use of simvastatin and voriconazole is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if simvastatin is administered concomitantly with potent CYP3A4 inhibitors such as voriconazole. If therapy with voriconazole is unavoidable, simvastatin therapy must be suspended during voriconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
Fedratinib: (Major) Avoid coadministration of fedratinib with voriconazole as concurrent use may increase fedratinib exposure; voriconazole exposure may also increase. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If voriconazole is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Monitor for increased voriconazole adverse effects and adjust the dose as necessary. Fedratinib is a CYP3A4 substrate and moderate CYP3A4 and CYP2C19 inhibitor; voriconazole is a strong CYP3A4 inhibitor and CYP3A4 and CYP2C19 substrate. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
Felbamate: (Minor) Voriconazole is a primary substrate of the CYP2C19 isoenzyme, and also is metabolized to a lesser extent by CYP3A4 and CYP2C9. Theoretically, CYP2C19 inhibitors, such as felbamate, may result in elevated voriconazole serum concentrations when coadministered. Felbamate is known to induce CYP3A4 as well as inhibit CYP2C19, so the net effect of this drug on voriconazole metabolism is not certain.
Felodipine: (Moderate) Concurrent use of felodipine and voriconazole should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased felodipine AUC and half-life by approximately 8-fold and 2-fold, respectively.
Fenofibric Acid: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C19 and CYP2C9 substrates such as voriconazole, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 and CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of voriconazole during coadministration with fenofibric acid.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of voriconazole is necessary. If voriconazole is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like voriconazole can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If voriconazole is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Fesoterodine: (Major) Limit the dose of fesoterodine to 4 mg once daily in adults and pediatric patients weighing more than 35 kg if coadministered with voriconazole. Avoid use of fesoterodine and voriconazole in pediatric patients weighing 25 to 35 kg. Concurrent use may increase fesoterodine exposure. Fesoterodine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor led to approximately a doubling of the overall exposure of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine.
Finasteride; Tadalafil: (Major) Avoid coadministration of voriconazole and tadalafil for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of voriconazole for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the tadalafil AUC after a 20-mg single dose by 312% and Cmax by 22%, relative to the values for tadalafil alone. The same strong inhibitor increased the tadalafil AUC after a 10-mg single dose by 107% and Cmax by 15%, relative to the values for tadalafil alone. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension, syncope, visual changes, and prolonged erection.
Finerenone: (Contraindicated) Concomitant use of finerenone and voriconazole is contraindicated. Concomitant use may increase finerenone exposure and the risk for finerenone-related adverse reactions. Finerenone is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased overall exposure to finerenone by more than 400%.
Fingolimod: (Moderate) Exercise caution when administering fingolimod concomitantly with voriconazole as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes.
Flecainide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering voriconazole with flecainide. Voriconazole has been associated with prolongation of the QT interval and rare cases of arrhythmias, including TdP. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/orTdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval.
Flibanserin: (Contraindicated) The concomitant use of flibanserin and strong CYP3A4 inhibitors, such as voriconazole, is contraindicated. Strong CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a strong CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a strong CYP3A4 inhibitor following flibanserin use, start the strong CYP3A4 inhibitor at least 2 days after the last dose of flibanserin.
Fluconazole: (Contraindicated) Avoid concomitant use of fluconazole and voriconazole due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Monitor for voriconazole-related adverse events, especially, if voriconazole is started within 24 hours after the last dose of fluconazole. Concomitant use increased voriconazole exposure by an average of 79% and may also increase the risk for other voriconazole-related adverse effects; reduced dosing and/or frequency of voriconazole and fluconazole did not eliminate or diminish this effect. Voriconazole is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor.
Fludrocortisone: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and fludrocortisone. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Voriconazole is a strong CYP3A4 inhibitor, and fludrocortisone is a CYP3A4 substrate.
Flunisolide: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and flunisolide. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Voriconazole is a strong CYP3A4 inhibitor, and flunisolide is a CYP3A4 substrate.
Fluocinolone: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and fluocinolone. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Voriconazole is a strong CYP3A4 inhibitor, and fluocinolone is a CYP3A4 substrate.
Fluocinolone; Hydroquinone; Tretinoin: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and fluocinolone. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Voriconazole is a strong CYP3A4 inhibitor, and fluocinolone is a CYP3A4 substrate.
Fluocinonide: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and fluocinonide. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Voriconazole is a strong CYP3A4 inhibitor, and fluocinonide is a CYP3A4 substrate.
Fluoxetine: (Moderate) Concomitant use of fluoxetine and voriconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Fluphenazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering voriconazole with fluphenazine. Voriconazole has been associated with prolongation of the QT interval and rare cases of arrhythmias, including TdP. Fluphenazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
Flurazepam: (Moderate) Monitor for an increase in flurazepam-related adverse reactions, including sedation and respiratory depression, if coadminsitration with voriconazole is necessary; adjust the dose of flurazepam if necessary. Flurazepam is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor.
Flurbiprofen: (Minor) Voriconazole is known to be an inhibitor of CYP2C9 and may lead to increased plasma levels of some NSAIDs, including flurbiprofen. If voriconazole is administered concomitantly with fluribiprofen, monitor for NSAID-induced toxicity, such as GI irritation, GI bleeding or renal dysfunction and adjust the dose of the NSAID if needed.
Fluticasone: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and fluticasone. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Concomitant administration of another strong CYP3A4 inhibitor increased plasma fluticasone propionate exposure resulting in a 45% to 86% decrease in serum cortisol AUC and increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol. Voriconazole is a strong CYP3A4 inhibitor, and fluticasone is a CYP3A4 substrate.
Fluticasone; Salmeterol: (Major) Avoid concomitant use of salmeterol with voriconazole. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose. (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and fluticasone. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Concomitant administration of another strong CYP3A4 inhibitor increased plasma fluticasone propionate exposure resulting in a 45% to 86% decrease in serum cortisol AUC and increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol. Voriconazole is a strong CYP3A4 inhibitor, and fluticasone is a CYP3A4 substrate.
Fluticasone; Umeclidinium; Vilanterol: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and fluticasone. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Concomitant administration of another strong CYP3A4 inhibitor increased plasma fluticasone propionate exposure resulting in a 45% to 86% decrease in serum cortisol AUC and increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol. Voriconazole is a strong CYP3A4 inhibitor, and fluticasone is a CYP3A4 substrate.
Fluticasone; Vilanterol: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and fluticasone. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Concomitant administration of another strong CYP3A4 inhibitor increased plasma fluticasone propionate exposure resulting in a 45% to 86% decrease in serum cortisol AUC and increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol. Voriconazole is a strong CYP3A4 inhibitor, and fluticasone is a CYP3A4 substrate.
Fluvastatin: (Moderate) The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if fluvastatin is administered concomitantly with CYP 3A4 inhibitors including voriconazole.
Fluvoxamine: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), and elevated voriconazole concentrations during concurrent use of fluvoxamine and voriconazole. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, voriconazole is partially metabolized by CYP2C19 and CYP3A4, and fluvoxamine is a potent inhibitor of CYP2C19 and a moderate inhibitor of CYP3A4. Theoretically, drugs that are inhibitors of these enzymes, such as fluvoxamine, may result in decreased clearance and elevated voriconazole serum concentrations when coadministered.
Food: (Major) Advise patients to avoid cannabis use during voriconazole treatment. Concomitant use may alter the exposure of some cannabinoids and increase the risk for adverse reactions. The cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP3A and CYP2C9 substrates and voriconazole is a strong CYP3A and moderate CYP2C9 inhibitor. Concomitant use of a cannabinoid product containing THC and CBD at an approximate 1:1 ratio with another strong CYP3A inhibitor increased THC, 11-OH-THC, and CBD peak exposures by 1.3-, 3-, and 1.9-fold respectively. (Minor) Food may decrease the oral absorption of voriconazole; therefore, oral formulations of voriconazole should be taken 1 hour before or 1 hour after meals.
Formoterol; Mometasone: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and mometasone. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Concomitant administration of another strong CYP3A4 inhibitor increased peak plasma mometasone concentrations to more than 200 pcg/mL (211 to 324 pcg/mL) on day 9 in 4 of 12 subjects. Voriconazole is a strong CYP3A4 inhibitor, and mometasone is a CYP3A4 substrate.
Fosamprenavir: (Moderate) Monitor for increased adverse effects of both drugs if voriconazole is coadministered with fosamprenavir. Concomitant use may increase the exposure of both drugs. Voriconazole is a CYP3A substrate and strong CYP3A inhibitor; fosamprenavir is a CYP3A substrate and moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased voriconazole exposure by 79%.
Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as voriconazole. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Voriconazole has also been associated with QT prolongation and rare cases of TdP. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
Fostamatinib: (Moderate) Monitor for fostamatinib toxicities that may require fostamatinib dose reduction (i.e., elevated hepatic enzymes, neutropenia, high blood pressure, severe diarrhea) if given concurrently with a strong CYP3A4 inhibitor. Concomitant use of fostamatinib with a strong CYP3A4 inhibitor increases exposure to the major active metabolite, R406, which may increase the risk of adverse reactions. R406 is extensively metabolized by CYP3A4; voriconazole is a strong CYP3A4 inhibitor. Coadministration of fostamatinib with another strong CYP3A4 inhibitor increased R406 AUC by 102% and Cmax by 37%.
Fostemsavir: (Moderate) Administer voriconazole with caution in combination with fostemsavir due to additive QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with voriconazole is necessary. Gefitinib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Gemifloxacin: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering voriconazole with gemifloxacin. Voriconazole has been associated with prolongation of the QT interval and rare cases of TdP. Gemifloxacin may also prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Moderate) Use gemtuzumab ozogamicin and voriconazole together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Voriconazole has been associated with QT prolongation and rare cases of TdP.
Gilteritinib: (Major) Consider an alternative to voriconazole during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, frequently monitor for gilteritinib-related adverse effects and cardiac toxicity. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation.
Glasdegib: (Major) Consider an alternative to voriconazole during treatment with glasdegib due to the potential for additive QT prolongation and increased glasdegib exposure. If coadministration cannot be avoided, monitor for increased glasdegib-related adverse events and for increased risk of QT prolongation with more frequent ECG monitoring. Glasdegib is a CYP3A4 substrate that may cause QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Voriconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes. Coadministration of ketoconazole increased the glasdegib AUC by 2.4-fold in a drug interaction study.
Glimepiride: (Moderate) Voriconazole should be used cautiously with sulfonylureas. The combination of voriconazole and oral antidiabetic agents may result in severe hypoglycemia. Voriconazole may inhibit the metabolism of sulfonylureas. Blood glucose concentrations should be monitored and possible dose adjustments of hypoglycemics may need to be made.
Glipizide: (Moderate) Voriconazole should be used cautiously with sulfonylureas. The combination of voriconazole and oral antidiabetic agents may result in severe hypoglycemia. Voriconazole may inhibit the metabolism of sulfonylureas. Blood glucose concentrations should be monitored and possible dose adjustments of hypoglycemics may need to be made.
Glipizide; Metformin: (Moderate) Voriconazole should be used cautiously with sulfonylureas. The combination of voriconazole and oral antidiabetic agents may result in severe hypoglycemia. Voriconazole may inhibit the metabolism of sulfonylureas. Blood glucose concentrations should be monitored and possible dose adjustments of hypoglycemics may need to be made.
Glyburide: (Moderate) Voriconazole should be used cautiously with sulfonylureas. The combination of voriconazole and oral antidiabetic agents may result in severe hypoglycemia. Voriconazole may inhibit the metabolism of sulfonylureas. Blood glucose concentrations should be monitored and possible dose adjustments of hypoglycemics may need to be made.
Glyburide; Metformin: (Moderate) Voriconazole should be used cautiously with sulfonylureas. The combination of voriconazole and oral antidiabetic agents may result in severe hypoglycemia. Voriconazole may inhibit the metabolism of sulfonylureas. Blood glucose concentrations should be monitored and possible dose adjustments of hypoglycemics may need to be made.
Goserelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., goserelin) outweigh the potential risks of QT prolongation in patients receiving voriconazole as concurrent use may increase the risk of QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Androgen deprivation therapy may also prolong the QT/QTc interval.
Granisetron: (Moderate) Administer voriconazole with caution in combination with granisetron due to additive QT prolongation. Granisetron has been associated with QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes.
Grapefruit juice: (Minor) Grapefruit juice may interact with voriconazole, although human data are lacking. In the murine model, grapefruit juice administration lead to increases in voriconazole serum concentrations. The mechanism is most likely inhibition of voriconazole metabolism by CYP3A4. Until further studies are available, it may be prudent to advise patients to avoid consumption of grapefruit juice during voriconazole therapy.
Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of voriconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like voriconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If voriconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Guanfacine: (Major) If coadministration of voriconazole with extended-release (ER) guanfacine is necessary, reduce the guanfacine dosage to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If voriconazole is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Voriconazole may significantly increase guanfacine plasma concentrations.
Halogenated Anesthetics: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with voriconazole. Halogenated anesthetics can prolong the QT interval. Voriconazole has been associated with QT prolongation and rare cases of torsades de pointes.
Haloperidol: (Moderate) Use voriconazole with caution in combination with haloperidol as concurrent use may increase the risk of QT prolongation and haloperidol-related adverse effects. A haloperidol dose reduction may be necessary. Voriconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes. Haloperidol is a CYP3A4 substrate; QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. Mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with CYP3A4 inhibitors.
Histrelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving voriconazole as concurrent use may increase the risk of QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Androgen deprivation therapy may also prolong the QT/QTc interval.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of voriconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like voriconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If voriconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydantoins: (Major) Phenytoin and fosphenytoin clearance can be decreased by drugs that significantly inhibit the cytochrome P450 2C subset of isoenzymes (e.g., CYP2C9 or 2C19), like voriconazole. In a pharmacokinetic study using volunteers, voriconazole increased the mean Cmax and AUC of phenytoin by approximately 70% and 80%, respectively. Frequent monitoring of plasma phenytoin concentrations and observation of the patient for phenytoin toxicity is recommended. In the same study, phenytoin reduced the mean Cmax and AUC of voriconazole by approximately 50% and 70%, respectively. This reduction was due to CYP3A4 or CYP2C9 induction by phenytoin. Recommendations from the manufacturer of voriconazole state that phenytoin or fosphenytoin can be given with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg IV every 12 hours or to 400 mg PO every 12 hours (or 200 mg PO every 12 hours in patients >= 12 years old and weighing < 40 kg). This interaction has not been specifically studied with ethotoin, another hydantoin anticonvulsant.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of voriconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like voriconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If voriconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of voriconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like voriconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If voriconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) Voriconazole is a substrate and inhibitor of cytochrome P450 isoenzyme 2C9, which is the isoenzyme responsible for the metabolism of ibuprofen. Thus, increased plasma concentrations of ibuprofen is possible. The clinical significance of this potential interaction is unknown. If voriconazole is administered concurrently with ibuprofen, monitor for NSAID-related side-effects, such as fluid retention or GI irritation, and adjust the dose of the NSAID, if needed.
Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of voriconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like voriconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If voriconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocortisone: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and hydrocortisone. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Voriconazole is a strong CYP3A4 inhibitor, and hydrocortisone is a CYP3A4 substrate.
Hydroxychloroquine: (Major) Avoid coadministration of voriconazole and hydroxychloroquine due to an increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Hydroxychloroquine prolongs the QT interval. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP).
Hydroxyzine: (Moderate) Concomitant use of hydroxyzine and voriconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Ibrexafungerp: (Major) Decrease the ibrexafungerp dose to 150 mg PO every 12 hours for 1 day if administered concurrently with voriconazole. Coadministration may result in increased ibrexafungerp exposure and toxicity. Ibrexafungerp is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of ibrexafungerp by 5.8-fold and 2.5-fold, respectively.
Ibrutinib: (Major) If ibrutinib is coadministered with voriconazole 200 mg twice daily, reduce the initial ibrutinib dosage to 140 mg/day PO in patients receiving ibrutinib for a B-cell malignancy or 280 mg/day PO in patients aged 12 years and older receiving ibrutinib for chronic graft-versus-host disease (cGVHD). If ibrutinib is coadministered with voriconazole suspension 9 mg/kg (max dose of 350 mg) twice daily, reduce the initial ibrutinib dosage to 160 mg/m2 per day PO in patients aged 1 to 11 years receiving ibrutinib for cGVHD. Resume ibrutinib at the previous dose if voriconazole is discontinued. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with multiple doses of voriconazole increased steady-state ibrutinib exposure by 5.7-fold.
Ibuprofen: (Moderate) Voriconazole is a substrate and inhibitor of cytochrome P450 isoenzyme 2C9, which is the isoenzyme responsible for the metabolism of ibuprofen. Thus, increased plasma concentrations of ibuprofen is possible. The clinical significance of this potential interaction is unknown. If voriconazole is administered concurrently with ibuprofen, monitor for NSAID-related side-effects, such as fluid retention or GI irritation, and adjust the dose of the NSAID, if needed.
Ibuprofen; Famotidine: (Moderate) Voriconazole is a substrate and inhibitor of cytochrome P450 isoenzyme 2C9, which is the isoenzyme responsible for the metabolism of ibuprofen. Thus, increased plasma concentrations of ibuprofen is possible. The clinical significance of this potential interaction is unknown. If voriconazole is administered concurrently with ibuprofen, monitor for NSAID-related side-effects, such as fluid retention or GI irritation, and adjust the dose of the NSAID, if needed.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of voriconazole is necessary. If voriconazole is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like voriconazole can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If voriconazole is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. (Moderate) Voriconazole is a substrate and inhibitor of cytochrome P450 isoenzyme 2C9, which is the isoenzyme responsible for the metabolism of ibuprofen. Thus, increased plasma concentrations of ibuprofen is possible. The clinical significance of this potential interaction is unknown. If voriconazole is administered concurrently with ibuprofen, monitor for NSAID-related side-effects, such as fluid retention or GI irritation, and adjust the dose of the NSAID, if needed.
Ibuprofen; Pseudoephedrine: (Moderate) Voriconazole is a substrate and inhibitor of cytochrome P450 isoenzyme 2C9, which is the isoenzyme responsible for the metabolism of ibuprofen. Thus, increased plasma concentrations of ibuprofen is possible. The clinical significance of this potential interaction is unknown. If voriconazole is administered concurrently with ibuprofen, monitor for NSAID-related side-effects, such as fluid retention or GI irritation, and adjust the dose of the NSAID, if needed.
Ibutilide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering voriconazole with ibutilide. Voriconazole has been associated with prolongation of the QT interval and rare cases of arrhythmias, including TdP. Ibutilide administration can also cause QT prolongation and TdP; proarrhythmic events should be anticipated.
Idelalisib: (Major) Avoid coadministration of idelalisib with voriconazole if possible due to increased exposure of both drugs, potentially resulting in adverse reactions. Voriconazole is a CYP3A4 substrate and strong inhibitor that has been associated with QT prolognation. Idelalisib is also a CYP3A4 substrate and strong inhibitor. Coadministration with another strong CYP3A4 inhibitor increased idelalisib exposure by 1.8-fold.
Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with voriconazole is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Voriconazole is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
Iloperidone: (Major) Avoid concurrent administration of voriconazole and iloperidone. If concurrent use is necessary, the iloperidone dose should be reduced by one-half. Coadministration of voriconazole (a strong CYP3A4 inhibitor) with iloperidone (a CYP3A4 substrate) may result in elevated iloperidone plasma concentrations and may increase the risk for adverse events, including QT prolongation. If voriconazole is subsequently withdrawn, the iloperidone dose should be returned to the previous amount. In addition, both iloperidone and voriconazole are associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Imatinib: (Moderate) Monitor for an increase in imatinib-related adverse reactions if coadministration with voriconazole is necessary. Imatinib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased imatinib exposure by 40%.
Imipramine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering voriconazole with imipramine. Voriconazole has been associated with prolongation of the QT interval and rare cases of arrhythmias, including TdP. Tricyclic antidepressants (TCAs), such as imipramine, share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, voriconazole inhibits CYP3A4 and CYP2C19, and imipramine is a substrate of both CYP3A4 and CYP2C19. Coadministation may increase the serum concentrations of imipramine. Monitor for an increased response to imipramine if coadministered with voriconazole.
Indomethacin: (Minor) Voriconazole is known to be an inhibitor of CYP2C9 and may lead to increased plasma levels of some NSAIDs, such as indomethacin. The clinical significance of this potential interaction is unknown. If voriconazole is used concurrently with indomethacin, monitor for NSAID-related side-effects, such as fluid retention or GI irritation, and adjust the dose of the NSAID if needed.
Infigratinib: (Major) Avoid concomitant use of infigratinib and voriconazole. Coadministration may increase infigratinib exposure, increasing the risk for adverse effects. Infigratinib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC of infigratinib by 622%.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with voriconazole due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an E CG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Voriconazole has been associated with QT prolongation and rare cases of TdP.
Irinotecan Liposomal: (Major) Avoid administration of voriconazole during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Voriconazole is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Irinotecan: (Major) Avoid administration of voriconazole during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Voriconazole is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Isavuconazonium: (Contraindicated) Coadministration of isavuconazonium with voriconazole is contraindicated due to the risk of increased isavuconazole exposure. Isavuconazole is a sensitive substrate of CYP3A4 and voiconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased isavuconazole exposure by 422%. Typically isavuconazonium would not be used in combination with other systemic azole antifungal agents, such as voriconazole, due to similar mechanisms of action and indications for use (duplicate therapies).
Isoflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with voriconazole. Halogenated anesthetics can prolong the QT interval. Voriconazole has been associated with QT prolongation and rare cases of torsades de pointes.
Isoniazid, INH: (Moderate) Voriconazole is a primary substrate of the CYP2C19 isoenzyme. Theoretically, isoniazide, a CYP2C19 inhibitor, may result in elevated voriconazole serum concentrations when coadministered.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Contraindicated) Use of rifampin with voriconazole is contraindicated. Induction of CYP3A4, CYP2C9 and CYP2C19 by rifampin could result in increased voriconazole clearance and impaired antifungal activity. Voriconazole AUC and Cmax may be reduced by roughly 95%. Doubling the dose of voriconazole to 400 mg every 12 hours does not restore adequate exposure to voriconazole during rifampin coadministration. (Moderate) Voriconazole is a primary substrate of the CYP2C19 isoenzyme. Theoretically, isoniazide, a CYP2C19 inhibitor, may result in elevated voriconazole serum concentrations when coadministered.
Isoniazid, INH; Rifampin: (Contraindicated) Use of rifampin with voriconazole is contraindicated. Induction of CYP3A4, CYP2C9 and CYP2C19 by rifampin could result in increased voriconazole clearance and impaired antifungal activity. Voriconazole AUC and Cmax may be reduced by roughly 95%. Doubling the dose of voriconazole to 400 mg every 12 hours does not restore adequate exposure to voriconazole during rifampin coadministration. (Moderate) Voriconazole is a primary substrate of the CYP2C19 isoenzyme. Theoretically, isoniazide, a CYP2C19 inhibitor, may result in elevated voriconazole serum concentrations when coadministered.
Isradipine: (Moderate) Monitor blood pressure and heart rate if coadministration of isradipine with voriconazole is necessary. Concurrent use may result in elevated isradipine concentrations. Isradipine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor.
Istradefylline: (Major) Do not exceed 20 mg once daily of istradefylline if administered with voriconazole as istradefylline exposure and adverse effects may increase. Voriconazole is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Ivabradine: (Contraindicated) Coadministration of voriconazole with ivabradine is contraindicated due to an increase in plasma concentrations of ivabradine, which may exacerbate bradycardia and conduction disturbances. Ivabradine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivabradine exposure by 7.7-fold.
Ivacaftor: (Major) If voriconazole and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with voriconazole due to increased plasma concentrations of ivosidenib and additive QT prolongation and risk of decreased voriconazole exposure and loss of antifungal efficacy. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If voriconazole is discontinued, wait at least 5 half-lives of voriconazole before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Voriconazole is a strong CYP3A4 associated with QT prolongation and rare cases of torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax. Because ivosidenib induces CYP3A4, it is also expected to decrease steady-state exposure to CYP3A4 substrates, such as voriconazole, to a clinically relevant extent.
Ixabepilone: (Major) Avoid concurrent use of ixabepilone and voriconazole due to increased ixabepilone exposure, which may increase the risk of adverse reactions. If concomitant use is unavoidable, reduce the dose of ixabepilone to 20 mg/m2. Ixabepilone is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ixabepilone exposure by 79%.
Ketoprofen: (Minor) Isoenzyme CYP2C9 is responsible for the metabolism of ketoprofen. Voriconazole is known to be an inhibitor of CYP2C9 and may lead to increased plasma levels of ketoprofen. The clinican should consider introducing the NSAID at the lowest recommended dose in patients receiving voriconazole. Monitor for NSAID-related side effects, such as GI irritation, fluid retention or increased blood pressure, GI bleeding, or renal dysfunction and adjust the dose of the NSAID if needed.
Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Concomitant administration of voriconazole and zidovudine may result in a reduction in the clearance of zidovudine.
Lansoprazole: (Moderate) Voriconazole is an inhibitor of the CYP3A and CYP2C19 isozymes and may theoretically reduce the metabolism of substrates of these enzymes, including lansoprazole.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Caution is advised when administering voriconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as clarithromycin. Both drugs have been associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. In addition, both drugs are substrates and inhibitors of CYP3A4. Coadministration may result in increased plasma concentrations of both drugs, thereby further increasing the risk for adverse events. Azithromycin can be considered as an alternative macrolide antimicrobial if appropriate for the clinical circumstance, due to its lack of metabolism via CYP3A4. If these drugs are given together, closely monitor for prolongation of the QT interval and other adverse effects such as drowsiness, fatigue, dry mouth, nausea, or insomnia. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy. (Moderate) Voriconazole is an inhibitor of the CYP3A and CYP2C19 isozymes and may theoretically reduce the metabolism of substrates of these enzymes, including lansoprazole.
Lapatinib: (Major) Avoid coadministration of lapatinib with voriconazole due to increased plasma concentrations of lapatinib; QT prolongation may also occur. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If voriconazole is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have also been reported in postmarketing experience. Voriconazole is a strong CYP3A4 inhibitor that has also been associated with QT prolongation and rare cases of TdP. Concomitant use with another strong CYP3A4 inhibitor increased lapatinib exposure by 3.6-fold and increased the half-life of lapatinib by 1.7-fold.
Larotrectinib: (Major) Avoid coadministration of larotrectinib with voriconazole due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If voriconazole is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of voriconazole. Larotrectinib is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Lefamulin: (Major) Avoid coadministration of lefamulin with voriconazole as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. Lefamulin is a CYP3A4 substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Voriconazole is a strong CYP3A inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes. Coadministration of a strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Lemborexant: (Major) Avoid coadministration of lemborexant and voriconazole as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration of lemborexant with another strong CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
Leniolisib: (Major) Avoid concomitant use of leniolisib and voriconazole due to the risk for increased leniolisib exposure which may increase the risk for adverse effects. Leniolisib is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased leniolisib overall exposure by 2-fold.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with voriconazole due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Voriconazole has also been associated with QT prolongation and rare cases of torsade de pointes.
Lesinurad: (Moderate) Use lesinurad and voriconazole together with caution; voriconazole may increase the systemic exposure of lesinurad. Voriconazole is an inhibitor of CYP2C9 in vitro, and lesinurad is a CYP2C9 substrate.
Lesinurad; Allopurinol: (Moderate) Use lesinurad and voriconazole together with caution; voriconazole may increase the systemic exposure of lesinurad. Voriconazole is an inhibitor of CYP2C9 in vitro, and lesinurad is a CYP2C9 substrate.
Letermovir: (Major) Closely monitor for reduced voriconazole effectiveness and breakthrough fungal infections if coadministration with letermovir is necessary. Coadministration decreased the AUC and Cmax of voriconazole by 44% and 39%, respectively. Voriconazole is a substrate of CYP2C9 and CYP2C19. Letermovir is a CYP2C9 and CYP2C19 inducer.
Leuprolide: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving voriconazole as concurrent use may increase the risk of QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Androgen deprivation therapy may also prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving voriconazole as concurrent use may increase the risk of QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Androgen deprivation therapy may also prolong the QT/QTc interval. (Moderate) Ethinyl estradiol and norethindrone increases the Cmax and AUC of voriconazole and voriconazole increases the Cmax and AUC of both ethinyl estradiol and norethindrone.
Levamlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with voriconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Voriconazole is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Levofloxacin: (Moderate) Concomitant use of levofloxacin and voriconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Levomilnacipran: (Major) Do not exceed a levomilnacipran dose of 80 mg once daily if coadministration with voriconazole is necessary. Levomilnacipran is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased levomilnacipran exposure by about 50%.
Levonorgestrel; Ethinyl Estradiol: (Moderate) Voriconazole may increase plasma concentrations of ethinyl estradiol by inhibiting CYP3A4 , resulting in estrogen-related side effects such as nausea and breast tenderness. Ethinyl estradiol, when combined with norethindrone, may also increase the Cmax and AUC of voriconazole.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Voriconazole may increase plasma concentrations of ethinyl estradiol by inhibiting CYP3A4 , resulting in estrogen-related side effects such as nausea and breast tenderness. Ethinyl estradiol, when combined with norethindrone, may also increase the Cmax and AUC of voriconazole.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) Voriconazole may increase plasma concentrations of ethinyl estradiol by inhibiting CYP3A4 , resulting in estrogen-related side effects such as nausea and breast tenderness. Ethinyl estradiol, when combined with norethindrone, may also increase the Cmax and AUC of voriconazole.
Lidocaine: (Moderate) Monitor for lidocaine-related adverse reactions if coadministration with voriconazole is necessary. Lidocaine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor.
Lidocaine; Epinephrine: (Moderate) Monitor for lidocaine-related adverse reactions if coadministration with voriconazole is necessary. Lidocaine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor.
Lidocaine; Prilocaine: (Moderate) Monitor for lidocaine-related adverse reactions if coadministration with voriconazole is necessary. Lidocaine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor.
Lithium: (Moderate) Concomitant use of lithium and voriconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Lofexidine: (Major) Monitor ECG if lofexidine is coadministered with voriconazole due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP).
Lomitapide: (Contraindicated) Concomitant use of voriconazole and lomitapide is contraindicated. If treatment with voriconazole is unavoidable, lomitapide should be stopped during the course of treatment. Voriconazole is a strong CYP3A4 inhibitor. The exposure to lomitapide was increased 27-fold in the presence of ketoconazole, a strong CYP3A4 inhibitor.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and voriconazole is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate, CYP2C9 substrate, and strong CYP3A4 inhibitor; voriconazole is a CYP3A4 substrate, moderate CYP2C9 inhibitor, and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Loperamide: (Contraindicated) Avoid concomitant use of loperamide and voriconazole due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase loperamide exposure and the risk for other loperamide-related adverse effects; loperamide is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A4 and P-gp inhibitor increased loperamide exposure by 3.8-fold.
Loperamide; Simethicone: (Contraindicated) Avoid concomitant use of loperamide and voriconazole due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase loperamide exposure and the risk for other loperamide-related adverse effects; loperamide is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A4 and P-gp inhibitor increased loperamide exposure by 3.8-fold.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with voriconazole due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. (Major) Coadministration of voriconazole and ritonavir at doses of 400 mg every 12 hours is contraindicated, and coadministration of voriconazole with ritonavir at doses of 100 mg or less should be avoided unless an assessment of the benefit to risk ratio justifies concurrent use. In 1 study, coadministration of ritonavir 400 mg every 12 hours for 9 days resulted in an 82% decrease in voriconazole AUC. Low dose ritonavir (100 mg every 12 hours) decreased voriconazole AUC concentrations by 39%.
Lorlatinib: (Major) Avoid coadministration of lorlatinib with voriconazole due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions; plasma concentrations of voriconazole may also be decreased. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If voriconazole is discontinued, resume the original dose of lorlatinib after 3 half-lives of voriconazole. Lorlatinib is a CYP3A substrate and moderate inducer. Voriconazole is a CYP3A substrate and strong inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
Losartan: (Moderate) Closely monitor blood pressure during coadministration of losartan and voriconazole; adjust the dose of losartan as clinically appropriate. Concomitant use may decrease exposure to the active metabolite of losartan and decrease losartan efficacy. Losartan is a CYP2C9 substrate; voriconazole is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9 inhibitor in two pharmacokinetic studies with healthy volunteers decreased concentrations of the active metabolite of losartan by 30% to 56%.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure during coadministration of losartan and voriconazole; adjust the dose of losartan as clinically appropriate. Concomitant use may decrease exposure to the active metabolite of losartan and decrease losartan efficacy. Losartan is a CYP2C9 substrate; voriconazole is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9 inhibitor in two pharmacokinetic studies with healthy volunteers decreased concentrations of the active metabolite of losartan by 30% to 56%.
Lovastatin: (Contraindicated) Coadministration of lovastatin and voriconazole is contraindicated due to the risk of elevated plasma concentrations of lovastatin leading to myopathy and rhabdomyolysis. Lovastatin is a sensitive CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lovastatin exposure by 11 to 36-fold.
Luliconazole: (Moderate) Theoretically, luliconazole may increase the side effects of voriconazole, which is a CYP2C19 and a CYP3A4 substrate. Monitor patients for adverse effects of voriconazole, such as visual impairment, elevated hepatic enzymes, and QT prolongation. In vitro, therapeutic doses of luliconazole inhibit the activity of CYP2C19 and CYP3A4 and small systemic concentrations may be noted with topical application, particularly when applied to patients with moderate to severe tinea cruris. No in vivo drug interaction trials were conducted prior to the approval of luliconazole.
Lumacaftor; Ivacaftor: (Major) If voriconazole and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of voriconazole; concomitant use is not recommended. Consider alternative antifungals such as fluconazole. If concomitant use of voriconazole is necessary, carefully monitor for antifungal efficacy, and adjust the voriconazole dosage if needed. Lumacaftor; ivacaftor dosage adjustment is not required when voriconazole is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking voriconazole, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking voriconazole. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Voriconazole is a substrate and strong inhibitor (per FDA-approved labeling for lumacaftor; ivacaftor) of CYP3A; it is also a substrate of CYP2C19 and CYP2C9. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor also has the potential to induce CYP2C19 and the combination may induce and inhibit CYP2C9. Lumacaftor's induction of CYP3A may decrease the systemic exposure of voriconazole and decrease its therapeutic efficacy. Although voriconazole is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold.
Lumateperone: (Major) Reduce the dose of lumateperone to 10.5 mg once daily if concomitant use of voriconazole is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor increased lumateperone exposure by approximately 4-fold.
Lurasidone: (Contraindicated) Coadministration of lurasidone with voriconazole is contraindicated due to increased plasma concentrations of lurasidone. Lurasidone is a sensitive CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lurasidone exposure by 9-fold.
Lurbinectedin: (Major) Avoid concomitant use of lurbinectedin and voriconazole due to the risk of increased lurbinectedin exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of lurbinectedin by 50%. Lurbinectedin is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of lurbinectedin by 2.7-fold.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as voriconazole. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes.
Macitentan: (Major) Avoid coadministration of macitentan with voriconazole due to increased plasma concentrations of macitentan. Macitentan is a CYP3A4 substrate and voriconanzole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased macitentan exposure by approximately 2.3-fold.
Mafenide: (Moderate) Voriconazole is metabolized by the CYP2C9 isoenzyme, and drugs that are known to be inhibitors of CYP2C9 may theoretically lead to elevated plasma levels of voriconazole when coadministered. Drugs that are known to be inhibitors of CYP2C9 include sulfonamides.
Maprotiline: (Major) Caution is advised when administering voriconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as maprotiline. Voriconazole has been associated with QT prolongation and rare cases of torsades de pointes (TdP), cardiac arrest, and sudden death. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. In addition, coadministration of voriconazole (a CYP3A4 inhibitor) with maprotiline (a CYP3A4 substrate) may result in elevated maprotiline plasma concentrations and could increase the risk for adverse events, including QT prolongation. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Maraviroc: (Major) Reduce the dose of maraviroc when coadministered with strong CYP3A inhibitors such as voriconazole; coadministration of maraviroc with strong CYP3A inhibitors is contraindicated in patients with CrCL less than 30 mL/min. Adjust the maraviroc dosage as follows when administered with voriconazole (with or without a concomitant CYP3A inducer): adults and children weighing 40 kg or more: 150 mg PO twice daily; children weighing 30 to 39 kg: 100 mg PO twice daily; children weighing 20 to 29 kg: 75 mg PO twice daily (or 80 mg PO twice daily for solution); children weighing 10 to 19 kg: 50 mg PO twice daily; children weighing 2 to 9 kg: use not recommended.
Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with voriconazole due to risk of heart failure due to systolic dysfunction. Concomitant use increases mavacamten exposure. Mavacamten is a CYP2C19 and CYP3A substrate and voriconazole is a weak CYP2C19 inhibitor and strong CYP3A inhibitor. Concomitant use with a strong CYP3A inhibitor is predicted to increase mavacamten overall exposure up to 130%. Concomitant use with another weak CYP2C19 inhibitor in CYP2C19 normal and rapid metabolizers increased overall mavacamten exposure by 48%.
Meclofenamate Sodium: (Moderate) Voriconazole is known to be an inhibitor of CYP2C9 and may lead to increased plasma levels of some NSAIDs, such as meclofenamate. Monitor for NSAID-related side effects, such as GI irritation, fluid retention or increased blood pressure, GI bleeding, or renal dysfunction and adjust the dose of the NSAID if needed.
Medroxyprogesterone: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with voriconazole, a strong CYP3A inhibitor should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via the CYP3A4 in vitro.
Mefenamic Acid: (Moderate) Mefenamic acid is a substrate for CYP450 2C9. Inhibitors of the 2C9 isoenzyme, such as voriconazole, may lead to increased serum concentrations of mefenamic acid. If administered concurrently with mefenamic acid, monitor for NSAID related side effects.
Mefloquine: (Moderate) Caution is advised when administering voriconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as mefloquine. Both drugs have been associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. In addition, coadministration of voriconazole (a strong CYP3A4 inhibitor) with mefloquine (a CYP3A4 substrate) may result in elevated mefloquine plasma concentrations and could increase the risk for adverse events, including QT prolongation. If these drugs are given together, closely monitor for prolongation of the QT interval.
Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with voriconazole is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and voriconazole is a moderate CYP2C9 inhibitor.
Metformin; Repaglinide: (Moderate) A dose reduction of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with voriconazole is necessary. Repaglinide is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased repaglinide exposure by up to 1.5-fold.
Metformin; Rosiglitazone: (Moderate) Because rosiglitazone is metabolized by CYP2C9, exaggerated therapeutic effect or hypoglycemia is possible if rosiglitazone is coadministered with voriconazole.
Metformin; Saxagliptin: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with voriconazole due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively.
Methadone: (Major) Caution is advised when administering voriconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as methadone. If these drugs must be used together, frequent monitoring for adverse events and toxicities related to methadone is recommended; dosage reduction of methadone may be needed. Voriconazole inhibits the primary metabolism of methadone via CYP3A4 inhibition. A clinical study evaluated concurrent use of voriconazole (400 mg PO every 12 hours for 1 day, then 200 mg PO every 12 hours for 4 days) in subjects receiving methadone maintenance dosage (30 to 100 mg PO once daily). Coadministration increased the Cmax and AUC of pharmacologically active R-methadone by 31% and 47%, respectively. In addition, the Cmax and AUC of S-methadone increased by 65% and 103%, respectively. Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation and torsades de pointes, especially at high doses. Voriconazole has been associated with QT prolongation and rare cases of TdP, cardiac arrest, and sudden death. Concurrent use may increase this risk. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Methotrexate: (Moderate) Advise patients to avoid strong, direct sunlight during concomitant methotrexate and voriconazole use due to increased risk of skin toxicity. Methotrexate is associated with ultraviolet (UV) reactivation and voriconazole has been associated with photosensitivity skin reaction.
Methylprednisolone: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and methylprednisolone. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Voriconazole is a strong CYP3A4 inhibitor, and methylprednisolone is a CYP3A4 substrate.
Metronidazole: (Moderate) Concomitant use of metronidazole and voriconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Midazolam: (Moderate) Monitor for an increase in midazolam-related adverse reactions, including sedation and respiratory depression, if coadministration with voriconazole is necessary. Midazolam is a sensitive CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the midazolam AUC by 3.8-fold.
Midostaurin: (Major) Avoid the concomitant use of midostaurin and voriconazole due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions; concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Midostaurin is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Mifepristone: (Major) Avoid coadministration of mifepristone with voriconazole due to the risk of additive QT prolongation; the exposure of both drugs may also be increased. If concomitant use of mifepristone is necessary for the treatment of Cushing's syndrome in a patient already receiving voriconazole, initiate mifepristone at a dose of 300 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with voriconazole is initiated in a patient already receiving mifepristone 300 mg, dosage adjustments are not required. If therapy with voriconazole is initiated in a patient already receiving mifepristone 600 mg, reduce dose of mifepristone to 300 mg and titrate to a maximum of 600 mg if clinically indicated. If therapy with voriconazole is initiated in a patient already receiving 900 mg, reduce dose of mifepristone to 600 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with voriconazole is initiated in a patient already receiving 1,200 mg, reduce the mifepristone dose to 900 mg. Both mifepristone and voriconazole are substrates and strong inhibitors of CYP3A4 that are associated with QT prolongation.
Mirtazapine: (Contraindicated) The concurrent use of voriconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as mirtazapine, is contraindicated. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
Mirvetuximab Soravtansine: (Moderate) Closely monitor for mirvetuximab soravtansine-related adverse reactions if concomitant use of voriconazole is necessary. DM4, the cytotoxic component of mirvetuximab soravtansine, is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Concomitant use may increase unconjugated DM4 exposure.
Mitapivat: (Major) Avoid coadministration of mitapivat with voriconazole due to increased risk of adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors increased mitapivat overall exposure by 3.6 to 4.9-fold.
Mitotane: (Major) Avoid the concomitant use of mitotane with voriconazole. Mitotane is a strong CYP3A4 inducer and voriconazole is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of voriconazole. Coadministration with other strong CYP3A inducers is either contraindicated (i.e., carbamazepine, rifampin, efavirenz, St. John's Wort, long-acting barbiturates) or requires an increased dose of voriconazole (i.e., phenytoin); specific recommendations are not available for use with mitotane or strong CYP3A inducers generally.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and voriconazole. Concomitant use increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may increase mobocertinib exposure and the risk for mobocertinib-related adverse reactions. Mobocertinib is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Use of a strong CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 374% to 419%.
Modafinil: (Minor) Modafinil is significantly metabolized by the CYP3A4 hepatic microsomal enzyme system. Voriconazole is a significant inhibitor of this isoenzyme and may reduce the clearance of modafinil. Headache, nausea and vomiting, nervousness, anxiety, and insomnia may worsen due to increased serum concentrations of modafinil.
Mometasone: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and mometasone. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Concomitant administration of another strong CYP3A4 inhibitor increased peak plasma mometasone concentrations to more than 200 pcg/mL (211 to 324 pcg/mL) on day 9 in 4 of 12 subjects. Voriconazole is a strong CYP3A4 inhibitor, and mometasone is a CYP3A4 substrate.
Moxifloxacin: (Major) Concurrent use of moxifloxacin and voriconazole should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Voriconazole has been associated with prolongation of the QT interval and rare cases of arrhythmias, including TdP. Prolongation of the QT interval has also been reported with administration of moxifloxacin. Post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded.
Nabumetone: (Moderate) Voriconazole is a substrate and inhibitor of cytochrome P450 isoenzyme 2C9, and may lead to increased plasma levels of some NSAIDs, such as nabumetone. The clinical significance of this potential interaction is unknown. If voriconazole is administered concurrently with nabumetone, monitor for NSAID-related side-effects, such as fluid retention or GI irritation, and adjust the dose of the NSAID, if needed.
Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with voriconazole. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor.
Naloxegol: (Contraindicated) Concomitant use of naloxegol with voriconazole is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as voriconazole, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with voriconazole is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
Nanoparticle Albumin-Bound Sirolimus: (Contraindicated) Concomitant use of voriconazole with sirolimus is contraindicated; use may increase sirolimus exposure and risk for adverse effects. Sirolimus is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration has been observed to increase sirolimus peak and overall exposure by 7- and 11-fold, respectively
Naproxen: (Moderate) The hepatic isoenzyme CYP2C9 is responsible for the metabolism of many NSAIDs. Voriconazole is known to be an inhibitor of CYP2C9 and may lead to increased plasma levels of some NSAIDs, such as naproxen. The clinical significance of this potential interaction is unknown. Monitor for NSAID-related side-effects, such as fluid retention or GI irritation, and adjust the dose of the NSAID if needed.
Naproxen; Esomeprazole: (Moderate) Monitor for increased drug toxicity as coadministration of esomeprazole and voriconazole may result in increased concentrations of both drugs. Although dose adjustments are not generally needed, patients with Zollinger-Ellison's syndrome who often require higher esomeprazole doses (up to 240mg/day) may require an adjustment in esomeprazole dose. Esomeprazole is metabolized primarily by CYP2C19 and secondarily by CYP3A4 and is also a CYP2C19 inhibitor; voriconazole is a CYP2C19 substrate and inhibitor of CYP2C19 and CYP3A4. (Moderate) The hepatic isoenzyme CYP2C9 is responsible for the metabolism of many NSAIDs. Voriconazole is known to be an inhibitor of CYP2C9 and may lead to increased plasma levels of some NSAIDs, such as naproxen. The clinical significance of this potential interaction is unknown. Monitor for NSAID-related side-effects, such as fluid retention or GI irritation, and adjust the dose of the NSAID if needed.
Naproxen; Pseudoephedrine: (Moderate) The hepatic isoenzyme CYP2C9 is responsible for the metabolism of many NSAIDs. Voriconazole is known to be an inhibitor of CYP2C9 and may lead to increased plasma levels of some NSAIDs, such as naproxen. The clinical significance of this potential interaction is unknown. Monitor for NSAID-related side-effects, such as fluid retention or GI irritation, and adjust the dose of the NSAID if needed.
Nateglinide: (Moderate) Voriconazole may increase plasma concentrations of nateglinide; if coadministration is necessary, nateglinide dosage adjustment may be required and an increased frequency of glucose monitoring is recommended. Nateglinide is a CYP2C9 substrate and voriconazole is an inhibitor of CYP2C9.
Nefazodone: (Moderate) Voriconazole is metabolized by CYP3A4 and, theoretically, inhibitors of CYP3A4, such as nefazodone, could lead to increased serum levels of voriconazole.
Nelfinavir: (Moderate) Interactions with nelfinavir may occur with voriconazole due to effects of both drugs on the cytochrome P450 3A4 isoenzyme. Until further drug interaction studies are available, administer voriconazole cautiously to patients receiving nelfinavir.
Neomycin; Fluocinolone: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and fluocinolone. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Voriconazole is a strong CYP3A4 inhibitor, and fluocinolone is a CYP3A4 substrate.
Neratinib: (Major) Avoid concomitant use of voriconazole with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
Netupitant, Fosnetupitant; Palonosetron: (Moderate) Monitor for an increase in netupitant-related adverse reactions if coadministration with voriconazole is necessary. Netupitant is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased netupitant exposure by 140%; however, no dosage adjustment is necessary.
Nevirapine: (Moderate) Monitor for an increase in nevirapine-related adverse reactions and breakthrough fungal infections if coadministration of voriconazole and nevirapine is necessary. Nevirapine is a CYP3A substrate and weak CYP3A inducer. Voriconazole is a CYP3A substrate and strong CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor increased nevirapine exposure by 100%; concomitant use with a strong CYP3A4 inhibitor may also increase nevirapine exposure.
Niacin; Simvastatin: (Contraindicated) Concurrent use of simvastatin and voriconazole is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if simvastatin is administered concomitantly with potent CYP3A4 inhibitors such as voriconazole. If therapy with voriconazole is unavoidable, simvastatin therapy must be suspended during voriconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
Nicardipine: (Moderate) Monitor blood pressure and heart rate if coadministration of nicardipine with voriconazole is necessary. Concurrent use may result in elevated nicardipine concentrations. Nicardipine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor.
Nifedipine: (Moderate) Monitor blood pressure and heart rate if coadministration of nifedipine with voriconazole is necessary. Concurrent use may result in elevated nifedipine concentrations. Nifedipine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor.
Nilotinib: (Major) Avoid the concomitant use of nilotinib and voriconazole; significant prolongation of the QT interval may occur. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Voriconazole has been associated with QT interval prolongation as well as rare cases of torsade de pointes. If therapy with voriconazole is necessary, interrupt nilotinib therapy if possible. Monitor closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in adult patients with resistant or intolerant Ph+ CML or to 200 mg once daily in adult patients with newly diagnosed Ph+ CML. If voriconazole is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate of CYP3A4 and voriconazole is a strong inhibitor of CYP3A4.
Nimodipine: (Moderate) Monitor blood pressure and heart rate if coadministration of nimodipine with voriconazole is necessary. Concurrent use may result in elevated nimodipine concentrations. Nimodipine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor.
Nirmatrelvir; Ritonavir: (Major) Coadministration of voriconazole and ritonavir at doses of 400 mg every 12 hours is contraindicated, and coadministration of voriconazole with ritonavir at doses of 100 mg or less should be avoided unless an assessment of the benefit to risk ratio justifies concurrent use. In 1 study, coadministration of ritonavir 400 mg every 12 hours for 9 days resulted in an 82% decrease in voriconazole AUC. Low dose ritonavir (100 mg every 12 hours) decreased voriconazole AUC concentrations by 39%.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with voriconazole due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and voriconazole is a CYP3A4 inhibitor.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Ethinyl estradiol and norethindrone increases the Cmax and AUC of voriconazole and voriconazole increases the Cmax and AUC of both ethinyl estradiol and norethindrone. (Moderate) Voriconazole may increase plasma concentrations of ethinyl estradiol by inhibiting CYP3A4 , resulting in estrogen-related side effects such as nausea and breast tenderness. Ethinyl estradiol, when combined with norethindrone, may also increase the Cmax and AUC of voriconazole.
Norethindrone: (Moderate) Ethinyl estradiol and norethindrone increases the Cmax and AUC of voriconazole and voriconazole increases the Cmax and AUC of both ethinyl estradiol and norethindrone.
Norethindrone; Ethinyl Estradiol: (Moderate) Ethinyl estradiol and norethindrone increases the Cmax and AUC of voriconazole and voriconazole increases the Cmax and AUC of both ethinyl estradiol and norethindrone. (Moderate) Voriconazole may increase plasma concentrations of ethinyl estradiol by inhibiting CYP3A4 , resulting in estrogen-related side effects such as nausea and breast tenderness. Ethinyl estradiol, when combined with norethindrone, may also increase the Cmax and AUC of voriconazole.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Ethinyl estradiol and norethindrone increases the Cmax and AUC of voriconazole and voriconazole increases the Cmax and AUC of both ethinyl estradiol and norethindrone. (Moderate) Voriconazole may increase plasma concentrations of ethinyl estradiol by inhibiting CYP3A4 , resulting in estrogen-related side effects such as nausea and breast tenderness. Ethinyl estradiol, when combined with norethindrone, may also increase the Cmax and AUC of voriconazole.
Norgestimate; Ethinyl Estradiol: (Moderate) Voriconazole may increase plasma concentrations of ethinyl estradiol by inhibiting CYP3A4 , resulting in estrogen-related side effects such as nausea and breast tenderness. Ethinyl estradiol, when combined with norethindrone, may also increase the Cmax and AUC of voriconazole.
Nortriptyline: (Minor) Voriconazole is associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, voriconazole inhibits CYP2C19 and CYP3A4. CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs. Nortriptyline may be affected by this potential interaction, but specific data are lacking. Monitor for an increased response to nortriptyline if voriconazole is coadministered.
Ofloxacin: (Moderate) Concomitant use of ofloxacin and voriconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Olanzapine: (Moderate) Caution is advised when administering voriconazole with olanzapine as concurrent use may increase the risk of QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Olanzapine; Fluoxetine: (Moderate) Caution is advised when administering voriconazole with olanzapine as concurrent use may increase the risk of QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. (Moderate) Concomitant use of fluoxetine and voriconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Olanzapine; Samidorphan: (Moderate) Caution is advised when administering voriconazole with olanzapine as concurrent use may increase the risk of QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Olaparib: (Major) Avoid coadministration of olaparib with voriconazole due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 100 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after voriconazole is discontinued. Olaparib is a CYP3A substrate and voriconazole is a strong CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with another strong CYP3A inhibitor increased the olaparib Cmax by 42% and the AUC by 170%.
Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and voriconazole is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and voriconazole may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If voriconazole is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with voriconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Voriconazole is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Olopatadine; Mometasone: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and mometasone. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Concomitant administration of another strong CYP3A4 inhibitor increased peak plasma mometasone concentrations to more than 200 pcg/mL (211 to 324 pcg/mL) on day 9 in 4 of 12 subjects. Voriconazole is a strong CYP3A4 inhibitor, and mometasone is a CYP3A4 substrate.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and voriconazole. If concomitant use is necessary, decrease omaveloxolone dose to 50 mg once daily. Concomitant use may increase omaveloxolone exposure and the risk for omaveloxolone-related adverse effects. Omaveloxolone is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased omaveloxolone overall exposure by 4-fold.
Omeprazole: (Moderate) Reduce the omeprazole dose by one-half when initiating voriconazole therapy in patients who are currently receiving omeprazole at doses of 40 mg/day or greater. Levels of omeprazole may increase by up to 2-fold due to CYP2C19 and CYP3A4 inhibition by voriconazole.
Omeprazole; Amoxicillin; Rifabutin: (Contraindicated) Concurrent administration of rifabutin and voriconazole is contraindicated. In one study, the maximum plasma concentration (Cmax) and systemic exposure (AUC) of voriconazole were decreased by an average of 67% and 79%, respectively, when given with rifabutin. Another study, found concurrent administration caused the Cmax and AUC of rifabutin to be increased by an average of 3-times and 4-times, respectively. Rifabutin induces the CYP2C9, CYP2C19 and CYP3A4 metabolism of voriconazole. Voriconazole inhibits the CYP3A4 metabolism of rifabutin. (Moderate) Reduce the omeprazole dose by one-half when initiating voriconazole therapy in patients who are currently receiving omeprazole at doses of 40 mg/day or greater. Levels of omeprazole may increase by up to 2-fold due to CYP2C19 and CYP3A4 inhibition by voriconazole.
Omeprazole; Sodium Bicarbonate: (Moderate) Reduce the omeprazole dose by one-half when initiating voriconazole therapy in patients who are currently receiving omeprazole at doses of 40 mg/day or greater. Levels of omeprazole may increase by up to 2-fold due to CYP2C19 and CYP3A4 inhibition by voriconazole.
Ondansetron: (Major) Caution is advised when administering voriconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as ondansetron. Ondansetron has been associated with QT prolongation and postmarketing reports of torsade de pointes (TdP). Voriconazole has been associated with QT prolongation and rare cases of TdP, cardiac arrest, and sudden death. Use of these drugs together increases the risk for QT prolongation. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. In addition, coadministration of voriconazole (a strong CYP3A4 inhibitor) with ondansetron (a CYP3A4 substrate) may result in elevated ondansetron plasma concentrations and could increase the risk for adverse events, including QT prolongation. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Osilodrostat: (Major) Reduce the dose of osilodrostat by one-half and consider more frequent ECG monitoring during coadministration of voriconazole; concurrent use may increase osilodrostat exposure and the risk of osilodrostat-related adverse reactions, including QT prolongation. Osilodrostat is a CYP3A4 substrate that is associated with dose-dependent QT prolongation; voriconazole is a strong CYP3A4 inhibitor that ha s been associated with QT prolongation and rare cases of torsade de pointes.
Osimertinib: (Major) Avoid coadministration of voriconazole with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Voriconazole has also been associated with QT prolongation and rare cases of TdP.
Ospemifene: (Moderate) Monitor for an increase in ospemifene-related adverse reactions if coadministration with voriconazole is necessary. Ospemifene is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration of another strong inhibitor increased ospemifene systemic exposure by 1.4-fold.
Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of voriconazole with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP); QT prolongation and ventricular arrhythmias including fatal TdP have also been reported with oxaliplatin use in postmarketing experience.
Oxaprozin: (Moderate) The hepatic isoenzyme CYP2C9 is responsible for the metabolism of many NSAIDs. Voriconazole is known to be an inhibitor of CYP2C9 and may lead to increased plasma levels of some NSAIDs, such as oxaprozin. The clinical significance of this potential interaction is unknown. Monitor for NSAID-related side-effects, such as fluid retention or GI irritation, and adjust the dose of the NSAID if needed.
Oxybutynin: (Moderate) Oxybutynin is metabolized by CYP3A4. Inhibitors of the CYP3A4 enzyme, such as voriconazole, may increase the serum concentrations of oxybutynin. The manufacturer recommends caution when oxybutynin is co-administered with CYP3A4 inhibitors.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of voriconazole is necessary. If voriconazole is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like voriconazole can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If voriconazole is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking voriconazole due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Voriconazole has been associated with QT prolongation and rare cases of TdP.
Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration with voriconazole is necessary. Paclitaxel is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor.
Pacritinib: (Contraindicated) Concurrent use of pacritinib with voriconazole is contraindicated due to increased pacritinib exposure which increases the risk of adverse reactions. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de pointes (TdP). Pacritinib is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor.
Palbociclib: (Major) Avoid coadministration of voriconazole with palbociclib; significantly increased plasma exposure of palbociclib may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If voriconazole is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of voriconazole) to the dose used before initiation of voriconazole. Palbociclib is primarily metabolized by CYP3A4 and voriconazole is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Paliperidone: (Major) Avoid coadministration of paliperidone and voriconazole if possible due to the potential for additive effects on the QT interval. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. Voriconazole has been associated with QT prolongation and rare cases of TdP. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Palovarotene: (Major) Avoid concomitant use of palovarotene and voriconazole due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. Palovarotene is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased palovarotene overall exposure by 3-fold.
Panobinostat: (Major) Avoid coadministration of voriconazole and panobinostat due to the potential for additive effects on the QT interval; increased exposure to panobinostat may also occur. If these drugs are administered together, reduce the starting dose of panobinostat to 10 mg. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to 480 milliseconds or higher during therapy; permanently discontinue if QT prolongation does not resolve. Coadministration of voriconazole (a strong CYP3A4 inhibitor) with panobinostat (a CYP3A4 substrate) results in elevated panobinostat plasma concentrations and may increase the risk for adverse events, including QT prolongation. The Cmax and AUC of panobinostat were increased by 62% and 73%, respectively, when administered with a strong CYP3A4 inhibitor. In addition, both panobinostat and voriconazole are associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Paricalcitol: (Moderate) Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with both paricalcitol and voriconazole, or during periods of dose titration. If hypercalcemia occurs, the dose of paricalcitol should be reduced or withheld until these parameters are normalized. Voriconazole is a strong CYP3A4 inhibitor and paricalcitol is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor approximately doubled the exposure of paricalcitol.
Pasireotide: (Moderate) Use caution when using pasireotide in combination with voriconazole as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses. Voriconazole has been associated with QT prolongation and rare cases of torsades de pointes.
Pazopanib: (Major) Avoid concurrent administration of voriconazole and pazopanib due to increased pazopanib exposure and additive QT prolongation. If coadministration is unavoidable, reduce the pazopanib dose to 400 mg PO once daily; further dose adjustments may be necessary if adverse effects occur. Pazopanib is a CYP3A4 substrate that has been reported to prolong the QT interval. Voriconazole is a strong CYP3A4 inhibitor that has also been associated with rare cases of torsade de pointes, cardiac arrest, and sudden death.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and voriconazole due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If voriconazole is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of voriconazole. Pemigatinib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased pemigatinib exposure by 88%.
Pentamidine: (Major) Voriconazole has been associated with QT prolongation and rare cases of torsades de pointes. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with voriconazole include pentamidine. Pentamidine has been associated with QT prolongation. Also, voriconazole is an inhibitor of the CYP 2C19 isoenzyme and interactions are possible with agents that are substrates of this enzyme, such as pentamidine; increased plasma levels of pentamidine may occur.
Pentobarbital: (Major) Coadministration may result in decreased exposure to voriconazole and increased exposure to pentobarbital. Per the manufacturer, voriconazole is contraindicated for use with long-acting barbiturates; caution is advised when coadministering with short-acting barbiturates, such as pentobarbital. Barbiturates are CYP3A4 and CYP2C9 inducers and may increase the metabolism and reduce the effective serum concentrations of voriconazole. Barbiturates are also substrates for CYP2C9, and voriconazole may theoretically increase the serum concentrations of the barbiturates.
Perampanel: (Moderate) Ketoconazole, a potent CYP3A4 inhibitor, can prolong the half-life of perampanel and decrease perampanel metabolism. Administration of a single dose of perampanel 1 mg with ketoconazole 400 mg once daily for 8 days in healthy subjects increased perampanel half-life from 58.4 to 67.8 hours, and increased perampanel AUC by 20%. Patients taking ketoconazole and perampanel should be closely monitored for adverse effects; a perampanel dose adjustment may be necessary. Caution should also be used during concomitant use of perampanel with voriconazole, as it inhibits CYP3A4.
Perindopril; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with voriconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Voriconazole is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Perphenazine: (Minor) Caution is advised when administering voriconazole with perphenazine as concurrent use may increase the risk of QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Perphenazine; Amitriptyline: (Minor) Caution is advised when administering voriconazole with perphenazine as concurrent use may increase the risk of QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering voriconazole with amitriptyline. Voriconazole has been associated with prolongation of the QT interval and rare cases of arrhythmias, including TdP. Tricyclic antidepressants (TCAs), such as amitriptyline, share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, voriconazole inhibits CYP3A4 and amitriptyline is partially metabolized by CYP3A4. Coadministration may result in elevated amitriptyline serum concentrations. Monitor for an increased response to amitriptyline if coadministered with voriconazole.
Pexidartinib: (Major) Avoid concomitant use of pexidartinib and voriconazole due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects; concomitant use may also decrease voriconazole plasma concentrations and reduce its efficacy. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If voriconazole is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of voriconazole. Pexidartinib is a CYP3A substrate and moderate CYP3A inducer; voriconazole is a CYP3A substrate and strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased pexidartinib exposure by 70%. Coadministration with another moderate CYP3A inducer decreased voriconazole exposure by 77%.
Phenobarbital: (Contraindicated) Voriconazole is contraindicated for use with long-acting barbiturates, such as phenobarbital. Phenobarbital is a CYP3A4 and CYP2C9 inducer and may increase the metabolism and reduce the effective serum concentrations of voriconazole. Barbiturates are also substrates for CYP2C9, and voriconazole may theoretically increase the serum concentrations of the barbiturates.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Contraindicated) Voriconazole is contraindicated for use with long-acting barbiturates, such as phenobarbital. Phenobarbital is a CYP3A4 and CYP2C9 inducer and may increase the metabolism and reduce the effective serum concentrations of voriconazole. Barbiturates are also substrates for CYP2C9, and voriconazole may theoretically increase the serum concentrations of the barbiturates.
Pimavanserin: (Major) Avoid concurrent administration of voriconazole and pimavanserin if possible due to the potential for additive effects on the QT interval and increased exposure to pimavanserin. If an alternative to voriconazole is not available and coadministration is unavoidable, the manufacturer recommends reducing the pimavanserin dose to 10 mg once daily. Both drugs have been associated with prolongation of the QT interval and voriconazole has also been associated with rare cases of torsade de pointes, cardiac arrest, and sudden death. In addition, coadministration of voriconazole (a strong CYP3A4 inhibitor) with pimavanserin (a CYP3A4 substrate) may result in elevated pimavanserin plasma concentrations and an increased risk for adverse events, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation. Correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) before initiating concurrent therapy.
Pimozide: (Contraindicated) Concurrent use of pimozide and voriconazole is contraindicated. Pimozide is metabolized primarily through CYP3A4, and voriconazole is a potent CYP3A4 inhibitor. Elevated pimozide concentrations occurring through inhibition of CYP3A4 can lead to QT prolongation, ventricular arrhythmias, and sudden death. The manufacturer of voriconazole contraindicates concurrent use with pimozide due to inhibition of CYP3A4 by voriconazole and the potential for pimozide toxicity. Furthermore, voriconazole is associated with QT prolongation; therefore, use with pimozide is contraindicated.
Pioglitazone; Glimepiride: (Moderate) Voriconazole should be used cautiously with sulfonylureas. The combination of voriconazole and oral antidiabetic agents may result in severe hypoglycemia. Voriconazole may inhibit the metabolism of sulfonylureas. Blood glucose concentrations should be monitored and possible dose adjustments of hypoglycemics may need to be made.
Piroxicam: (Moderate) The hepatic isoenzyme CYP2C9 is responsible for the metabolism of many NSAIDs. Voriconazole is known to be an inhibitor of CYP2C9 and may lead to increased plasma levels of some NSAIDs, such as piroxicam. The clinical significance of this potential interaction is unknown. Monitor for NSAID-related side-effects, such as fluid retention or GI irritation, and adjust the dose of the NSAID, if needed.
Pirtobrutinib: (Major) Avoid concomitant use of pirtobrutinib and voriconazole due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of voriconazole use. Resume the previous dose of pirtobrutinib after voriconazole is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Pitolisant: (Major) Avoid coadministration of pitolisant with voriconazole as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes.
Polatuzumab Vedotin: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of voriconazole due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; voriconazole is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Ponatinib: (Major) Avoid coadministration of ponatinib and voriconazole due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of voriconazole and consider alternative therapy. After voriconazole has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting voriconazole. Ponatinib is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking voriconazole due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Voriconazole has been associated with QT prolongation and rare cases of TdP.
Porfimer: (Major) Avoid coadministration of porfimer with voriconazole due to the risk of increased photosensitivity. All patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like voriconazole may increase the risk of a photosensitivity reaction.
Posaconazole: (Contraindicated) Concomitant use of voriconazole with posaconazole is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Posaconazole causes dose-dependent QT and PR prolongation. Voriconazole has also been associated with prolongation of the QT interval and rare cases of arrhythmias, including TdP. In addition, both drugs are inhibitors and substrates of the hepatic isoenzyme CYP3A4. This complex interaction may ultimately result in altered plasma concentrations of voriconazole and posaconazole. Furthermore, both drugs are azole antifungals and concurrent use would represent duplicate therapy.
Pralsetinib: (Major) Avoid concomitant use of voriconazole with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration is predicted to increase the overall exposure of pralsetinib by 122%.
Prednisolone: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and prednisolone. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. In vivo studies showed no significant effects of voriconazole on prednisolone exposure; no prednisolone dosage adjustment is necessary. Voriconazole (200 mg every 12 hours for 30 days) with prednisolone (60 mg as a single dose) increased prednisolone Cmax and AUC by 11% and 34%, respectively, in healthy subjects. Voriconazole is a strong CYP3A4 inhibitor, and prednisolone is a CYP3A4 substrate.
Prednisone: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and prednisone. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Voriconazole is a strong CYP3A4 inhibitor, and prednisone is a CYP3A4 substrate.
Primaquine: (Moderate) Exercise caution when administering primaquine in combination with voriconazole as concurrent use may increase the risk of QT prolongation. Primaquine is associated with QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes.
Primidone: (Contraindicated) Voriconazole is contraindicated for use with long-acting barbiturates, such as primidone. Primidone is a CYP3A4 inducer and may increase the metabolism and reduce the effective serum concentrations of voriconazole.
Probenecid; Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and voriconazole in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Voriconazole can inhibit colchicine's metabolism via CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken a strong CYP3A4 inhibitor like voriconazole in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
Procainamide: (Major) Voriconazole should be used cautiously and with close clinical monitoring with procainamide. Procainamide is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Voriconazole has been associated with QT prolongation and rare cases of torsades de pointes.
Prochlorperazine: (Minor) Caution is advised when administering voriconazole with prochlorperazine as concurrent use may increase the risk of QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Prochlorperazine is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Progesterone: (Moderate) Use caution if coadministration of voriconazole with progesterone is necessary, as the systemic exposure of progesterone may be increased resulting in an increase in treatment-related adverse reactions. Voriconazole is a strong CYP3A4 inhibitor. Progesterone is metabolized primarily by hydroxylation via a CYP3A4. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Promethazine: (Moderate) Concomitant use of promethazine and voriconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Promethazine; Dextromethorphan: (Moderate) Concomitant use of promethazine and voriconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Promethazine; Phenylephrine: (Moderate) Concomitant use of promethazine and voriconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Propafenone: (Major) Caution is advised when administering voriconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as propafenone. Both drugs are associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. In addition, coadministration of voriconazole (a strong CYP3A4 inhibitor) with propafenone (a CYP3A4 substrate) may result in elevated propafenone plasma concentrations and an increased risk for adverse events, including QT prolongation. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Propranolol: (Moderate) Voriconazole is metabolized by CYP3A4 and, theoretically, inhibitors of CYP3A4, such as propranolol, could lead to increased serum levels of voriconazole.
Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Voriconazole is metabolized by CYP3A4 and, theoretically, inhibitors of CYP3A4, such as propranolol, could lead to increased serum levels of voriconazole.
Protriptyline: (Minor) Voriconazole is associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, voriconazole inhibits CYP2C19 and CYP3A4. CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs. Protriptyline may be affected by this potential interaction, but specific data are lacking. Monitor for an increased response to protriptyline if voriconazole is coadministered.
Quazepam: (Moderate) Monitor for an increase in quazepam-related adverse reactions including sedation and respiratory depression if coadministration with voriconazole is necessary; reduce the dose of quazepam if clinically appropriate. Quazepam is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor.
Quetiapine: (Major) Avoid coadministration of voriconazole with quetiapine due to the potential for additive effects on the QT interval; increased exposure to quetiapine may also occur. Both drugs are associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. In addition, coadministration of voriconazole (a strong CYP3A4 inhibitor) with quetiapine (a CYP3A4 substrate) may result in elevated quetiapine plasma concentrations and could increase the risk for adverse events, including QT prolongation. The manufacturer recommends a quetiapine dose reduction to one-sixth the original dose during concurrent administration of CYP3A4 inhibitors, such as voriconazole. When voriconazole is discontinued, the dose should be increased by 6-fold. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Quinidine: (Contraindicated) Quinidine (including dextromethorphan; quinidine) use is contraindicated with voriconazole according to recommendations made by the manufacturer of voriconazole. Voriconazole inhibits the CYP3A4 enzyme that is responsible for quinidine metabolism; elevated and toxic levels of quinidine may occur potentiating the risk for QT prolongation and cardiac arrhythmias (e.g., torsade de pointes).
Quinine: (Major) Concurrent use of quinine and voriconazole should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Both drugs have been associated with prolongation of the QT interval and rare cases of TdP. Additionally, the systemic exposure of quinine may be increased, resulting in an increase in treatment-related adverse reactions. Voriconazole is a strong CYP3A4 inhibitor. Quinine is a CYP3A4 substrate.
Quizartinib: (Major) Avoid concomitant use of voriconazole with quizartinib due to the risk of increased quizartinib exposure which may increase the risk of adverse reactions. Concomitant use may also increase the risk for torsade de pointes (TdP) and QT/QTc prolongation. If concomitant use is necessary, reduce the dose of quizartinib to 26.5 mg for patients taking a daily dose of 53 mg, and to 17.7 mg for patients taking a daily dose of 35.4 mg or 26.5 mg; interrupt quizartinib therapy for the duration of the strong CYP3A inhibitor use for patients already taking a daily dose of 17.7 mg. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Quizartinib is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of quizartinib by 94%.
Rabeprazole: (Moderate) Rabeprazole is a substrate of CYP2C19. Voriconazole inhibits CYP2C19 and may cause a decrease in the metabolism of rabeprazole if coadministered.
Ramelteon: (Moderate) Monitor for an increase in ramelteon-related adverse reactions if coadministration with voriconazole is necessary. Ramelteon is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ramelteon exposure by 84%.
Ranolazine: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors including voriconazole. Inhibition of ranolazine CYP3A metabolism could lead to increased ranolazine plasma concentrations, QTc prolongation, and possibly torsade de pointes.
Red Yeast Rice: (Contraindicated) Voriconazole inhibits the CYP3A4 metabolism of certain HMG-CoA reductase inhibitors, including lovastatin, increasing the potential for developing myopathy, rhabdomyolysis, and acute renal failure. Since compounds in red yeast rice claim to have HMG-CoA reductase inhibitor activity and have a similar structure and activity as lovastatin, coadministration of red yeast rice and voriconazole should be avoided.
Regorafenib: (Major) Avoid coadministration of regorafenib with voriconazole due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
Relugolix: (Moderate) Administer voriconazole with caution in combination with relugolix due to the risk of additive QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Moderate) Administer voriconazole with caution in combination with relugolix due to the risk of additive QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval. (Moderate) Ethinyl estradiol and norethindrone increases the Cmax and AUC of voriconazole and voriconazole increases the Cmax and AUC of both ethinyl estradiol and norethindrone. (Minor) As voriconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Repaglinide: (Moderate) A dose reduction of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with voriconazole is necessary. Repaglinide is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased repaglinide exposure by up to 1.5-fold.
Retapamulin: (Moderate) Coadministration of retapamulin with strong CYP3A4 inhibitors, such as voriconazole, in patients younger than 24 months is not recommended. Systemic exposure of topically administered retapamulin may be higher in patients younger than 24 months than in patients 2 years and older. Retapamulin is a CYP3A4 substrate.
Ribociclib: (Major) Avoid coadministration of ribociclib with voriconazole due to an increased risk for QT prolongation and torsade de pointes (TdP). Additionally, the systemic exposure of both drugs may be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a CYP3A4 substrate and strong inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Voriconazole is also a CYP3A4 substrate and strong inhibitor that has been associated with QT prolongation and rare cases of TdP. Concomitant use may increase the risk for QT prolongation.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with voriconazole due to an increased risk for QT prolongation and torsade de pointes (TdP). Additionally, the systemic exposure of both drugs may be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a CYP3A4 substrate and strong inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Voriconazole is also a CYP3A4 substrate and strong inhibitor that has been associated with QT prolongation and rare cases of TdP. Concomitant use may increase the risk for QT prolongation.
Rifabutin: (Contraindicated) Concurrent administration of rifabutin and voriconazole is contraindicated. In one study, the maximum plasma concentration (Cmax) and systemic exposure (AUC) of voriconazole were decreased by an average of 67% and 79%, respectively, when given with rifabutin. Another study, found concurrent administration caused the Cmax and AUC of rifabutin to be increased by an average of 3-times and 4-times, respectively. Rifabutin induces the CYP2C9, CYP2C19 and CYP3A4 metabolism of voriconazole. Voriconazole inhibits the CYP3A4 metabolism of rifabutin.
Rifampin: (Contraindicated) Use of rifampin with voriconazole is contraindicated. Induction of CYP3A4, CYP2C9 and CYP2C19 by rifampin could result in increased voriconazole clearance and impaired antifungal activity. Voriconazole AUC and Cmax may be reduced by roughly 95%. Doubling the dose of voriconazole to 400 mg every 12 hours does not restore adequate exposure to voriconazole during rifampin coadministration.
Rifapentine: (Major) Avoid coadministration of voriconazole with rifapentine as concurrent use may decrease voriconazole exposure. Although specific recommendations are unavailable for use with rifapentine, coadministration with other strong CYP3A4 inducers is either contraindicated or requires an increased dose of voriconazole. Voriconazole is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased voriconazole exposure by 96%.
Rilpivirine: (Moderate) Caution is advised when administering voriconazole with rilpivirine due to the potential for additive effects on the QT interval, increased exposure to rilpivirine, and decreased exposure to voriconazole. Monitor for breakthrough fungal infections in patients receiving rilpivirine with an azole antifungal. Rilpivirine, a CYP3A4 substrate, and voriconazole, a strong CYP3A4 inhibitor, are both associated with QT prolongation; rilpivirine dosage adjustments are not recommended. In addition, concurrent use of rilpivirine decreased exposure to another azole antifungal. A similar interaction may occur with voriconazole.
Rimegepant: (Major) Avoid coadministration of rimegepant with voriconazole; concurrent use may significantly increase rimegepant exposure. Rimegepant is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration of rimegepant with another strong CYP3A4 inhibitor increased rimegepant exposure by 4-fold.
Ripretinib: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with voriconazole. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Risperidone: (Moderate) Use risperidone and voriconazole together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting. Voriconazole has also been associated with QT prolongation and rare cases of TdP.
Ritlecitinib: (Moderate) Monitor for increased voriconazole-related adverse effects if coadministered with ritlecitinib as concurrent use may increase voriconazole exposure. Voriconazole is a CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased voriconazole exposure by 79%.
Ritonavir: (Major) Coadministration of voriconazole and ritonavir at doses of 400 mg every 12 hours is contraindicated, and coadministration of voriconazole with ritonavir at doses of 100 mg or less should be avoided unless an assessment of the benefit to risk ratio justifies concurrent use. In 1 study, coadministration of ritonavir 400 mg every 12 hours for 9 days resulted in an 82% decrease in voriconazole AUC. Low dose ritonavir (100 mg every 12 hours) decreased voriconazole AUC concentrations by 39%.
Roflumilast: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if coadministration with voriconazole is necessary; carefully weigh the risk against the benefit. Roflumilast is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased roflumilast exposure by 99%.
Romidepsin: (Major) The concomitant use of romidepsin, a CYP3A4 substrate, and voriconazole, a strong CYP3A4 inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram (ECG) changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops. Additionally, voriconazole has been associated with QT prolongation and rare cases of torsade de pointes and changes in ECGs (including T-wave and ST-segment changes) have been reported with romidepsin use. If romidepsin is administered with agents that may cause significant QT prolongation, such as voriconazole, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and electrocardiograms at baseline and periodically during treatment.
Rosiglitazone: (Moderate) Because rosiglitazone is metabolized by CYP2C9, exaggerated therapeutic effect or hypoglycemia is possible if rosiglitazone is coadministered with voriconazole.
Rucaparib: (Moderate) Monitor for an increase in voriconazole-related adverse reactions if coadministration with rucaparib is necessary. Voriconazole is a CYP2C19 substrate and rucaparib is a weak CYP2C19 inhibitor. Concomitant use may increase plasma concentrations of voriconazole.
Ruxolitinib: (Major) Reduce the ruxolitinib dosage when coadministered with voriconazole in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur. No dose adjustments are necessary for patients with graft-versus-host disease; however, monitor blood counts more frequently for toxicity and adjust ruxolitinib dosage for adverse reactions. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Avoid the use of voriconazole in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily; alternatively, ruxolitinib therapy may be interrupted for the duration of voriconazole use. Ruxolitinib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor.
Saccharomyces boulardii: (Major) Because Saccharomyces boulardii is an active yeast, it would be expected to be inactivated by any antifungals. The manufacturer does not recommend taking in conjunction with any antifungal agents. Patients should avoid use of this probiotic yeast until the fungal or yeast infection is completely treated.
Salmeterol: (Major) Avoid concomitant use of salmeterol with voriconazole. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
Saquinavir: (Contraindicated) Concurrent use of voriconazole and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Both saquinavir boosted with ritonavir and voriconazole are inhibitors and substrates of the hepatic isoenzyme CYP3A4. This complex interaction may ultimately result in altered plasma concentrations of both voriconazole and saquinavir. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; avoid use with other drugs that may prolong the QT interval, such as voriconazole.
Saxagliptin: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with voriconazole due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively.
Segesterone Acetate; Ethinyl Estradiol: (Moderate) Voriconazole may increase plasma concentrations of ethinyl estradiol by inhibiting CYP3A4 , resulting in estrogen-related side effects such as nausea and breast tenderness. Ethinyl estradiol, when combined with norethindrone, may also increase the Cmax and AUC of voriconazole. (Minor) Coadministration of segesterone, a CYP3A4 substrate and voriconazole, a strong CYP3A4 inhibitor may increase the serum concentration of segesterone.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and voriconazole due to the risk of additive QT prolongation and increased selpercatinib exposure resulting in increased treatment-related adverse effects. If coadministration is unavoidable, reduce the dose of selpercatinib to 40 mg PO twice daily if original dose was 120 mg twice daily, and to 80 mg PO twice daily if original dose was 160 mg twice daily. Monitor ECGs for QT prolongation more frequently. If voriconazole is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of voriconazole. Selpercatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; voriconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes. Coadministration with another strong CYP3A4 inhibitor increased selpercatinib exposure by 133%.
Selumetinib: (Major) Avoid coadministration of selumetinib and voriconazole due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If voriconazole is discontinued, resume the original selumetinib dose after 3 elimination half-lives of voriconazole. Selumetinib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Sertraline: (Moderate) Concomitant use of sertraline and voriconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
Sevoflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with voriconazole. Halogenated anesthetics can prolong the QT interval. Voriconazole has been associated with QT prolongation and rare cases of torsades de pointes.
Sildenafil: (Major) Coadministration of voriconazole is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving voriconazole. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Voriconazole is a strong CYP3A4 inhibitor; sildenafil is a sensitive CYP3A4 substrate. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
Silodosin: (Contraindicated) Concurrent use of silodosin and voriconazole is contraindicated due to increased plasma concentrations of silodosin resulting in an increase of treatment-related adverse reactions. Silodosin is extensively metabolized by CYP3A4 and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased silodosin exposure by 2.9-fold to 3.2-fold.
Simvastatin: (Contraindicated) Concurrent use of simvastatin and voriconazole is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if simvastatin is administered concomitantly with potent CYP3A4 inhibitors such as voriconazole. If therapy with voriconazole is unavoidable, simvastatin therapy must be suspended during voriconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
Siponimod: (Major) Concomitant use of siponimod and voriconazole is not recommended due to a significant increase in siponimod exposure. Additionally, both drugs are associated with QT prolongation. Siponimod is a CYP2C9 and CYP3A4 substrate; voriconazole is a moderate CYP2C9/strong CYP3A4 dual inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Sirolimus: (Contraindicated) Concomitant use of voriconazole with sirolimus is contraindicated; use may increase sirolimus exposure and risk for adverse effects. Sirolimus is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration has been observed to increase sirolimus peak and overall exposure by 7- and 11-fold, respectively
Sodium Stibogluconate: (Moderate) Concomitant use of sodium stibogluconate and voriconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with voriconazole. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Voriconazole is a CYP3A4 inhibitor; velpatasvir is a substrate of CYP3A4.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with voriconazole. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Voriconazole is a CYP3A4 inhibitor; velpatasvir is a substrate of CYP3A4.
Solifenacin: (Major) When possible, avoid administering voriconazole with solifenacin due to the potential for additive effects on the QT interval and increased exposure to solifenacin. If these drugs must be administered together, do not exceed a 5 mg daily dose of solifenacin in adults; do not exceed the initial starting dose in pediatric patients. Voriconazole is a strong CYP3A4 inhibitor. Solifenacin is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the systemic exposure of solifenacin by 2.7-fold. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP), cardiac arrest, and sudden death. Solifenacin may cause dose-dependent prolongation of the QT interval; TdP has been reported with postmarketing use, although causality was not determined.
Sonidegib: (Major) Avoid the concomitant use of sonidegib and voriconazole; sonidegib exposure may be significantly increased resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Sorafenib: (Major) Avoid coadministration of sorafenib with voriconazole due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Sorafenib is also associated with QTc prolongation.
Sotalol: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering voriconazole with sotalol. Voriconazole has been associated with prolongation of the QT interval and rare cases of arrhythmias, including TdP. Sotalol is also associated with QT prolongation and TdP. Proarrhythmic events should be anticipated after initiation of sotalol therapy and after each upward dosage adjustment.
Sparsentan: (Major) Avoid concomitant use of sparsentan and voriconazole. Concomitant use may increase sparsentan exposure and the risk for sparsentan-related adverse effects. Sparsentan is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased sparsentan overall exposure by 174%.
St. John's Wort, Hypericum perforatum: (Contraindicated) Concomitant use of voriconazole with St. John's Wort is contraindicated. Voriconazole is metabolized by the CYP3A4 and CYP2C9 isoenzymes, and St. John's wort is known to be an inducer of CYP3A4 and CYP2C9; coadministration results in significantly reduced plasma levels of voriconazole. A study in healthy volunteers who were given multiple oral doses of St. John's wort for 15 days followed by a single 400 mg oral dose of voriconazole, showed a 59% decrease in mean voriconazole exposure. However, coadministration of single oral doses of St. John's wort and voriconazole had no appreciable effect on voriconazole AUC. Long-term use of St. John's wort could lead to reduced voriconazole exposure.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if voriconazole must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of voriconazole is necessary. If voriconazole is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like voriconazole can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If voriconazole is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Sulfacetamide: (Moderate) Voriconazole is metabolized by the CYP2C9 isoenzyme, and drugs that are known to be inhibitors of CYP2C9 may theoretically lead to elevated plasma levels of voriconazole when coadministered. Drugs that are known to be inhibitors of CYP2C9 include sulfonamides.
Sulfacetamide; Sulfur: (Moderate) Voriconazole is metabolized by the CYP2C9 isoenzyme, and drugs that are known to be inhibitors of CYP2C9 may theoretically lead to elevated plasma levels of voriconazole when coadministered. Drugs that are known to be inhibitors of CYP2C9 include sulfonamides.
Sulfadiazine: (Moderate) Voriconazole is metabolized by the CYP2C9 isoenzyme, and drugs that are known to be inhibitors of CYP2C9 may theoretically lead to elevated plasma levels of voriconazole when co-administered. Sulfonamides are known to be inhibitors of CYP2C9.
Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Monitor for increased voriconazole-related adverse reactions if coadministered with sulfamethoxazole. Elevated voriconazole concentrations and, thus, adverse reactions may result. Voriconazole is a CYP2C9 substrate and sulfamethoxazole is a CYP2C9 inhibitor.
Sulfasalazine: (Moderate) Voriconazole is metabolized by the CYP2C9 isoenzyme, and drugs that are known to be inhibitors of CYP2C9 may theoretically lead to elevated plasma levels of voriconazole when coadministered. Drugs that are known to be inhibitors of CYP2C9 include sulfonamides.
Sulfonylureas: (Moderate) Voriconazole should be used cautiously with sulfonylureas. The combination of voriconazole and oral antidiabetic agents may result in severe hypoglycemia. Voriconazole may inhibit the metabolism of sulfonylureas. Blood glucose concentrations should be monitored and possible dose adjustments of hypoglycemics may need to be made.
Sulindac: (Moderate) The hepatic isoenzyme CYP2C9 is responsible for the metabolism of many NSAIDs. Voriconazole is known to be an inhibitor of CYP2C9 and may lead to increased plasma levels of some NSAIDs. The clinical significance of this potential interaction is unknown. Monitor for NSAID-related side-effects, such as fluid retention or GI irritation, and adjust the dose of the NSAID if needed.
Sumatriptan; Naproxen: (Moderate) The hepatic isoenzyme CYP2C9 is responsible for the metabolism of many NSAIDs. Voriconazole is known to be an inhibitor of CYP2C9 and may lead to increased plasma levels of some NSAIDs, such as naproxen. The clinical significance of this potential interaction is unknown. Monitor for NSAID-related side-effects, such as fluid retention or GI irritation, and adjust the dose of the NSAID if needed.
Sunitinib: (Major) Avoid coadministration of voriconazole with sunitinib if possible due to increased sunitinib exposure, which may increase the risk of QT prolongation. If concomitant use is unavoidable, monitor the QT interval more frequently and consider reducing the daily dose of sunitinib to a minimum of 37.5 mg for patients with GIST or RCC, and to a minimum of 25 mg for patients with pNET. Sunitinib is a CYP3A4 substrate that can prolong the QT interval. Voriconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased exposure to sunitinib and its primary active metabolite by 51%.
Suvorexant: (Major) Coadministration of suvorexant and voriconazole is not recommended due to the potential for significantly increased suvorexant exposure. Suvorexant is a CYP3A4 substrate. Voriconazole is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the suvorexant AUC by 2.8-fold.
Tacrolimus: (Major) A reduction in tacrolimus dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring of QT prolongation is recommended if coadministered with voriconazole as concurrent use may result in an increase tacrolimus exposure and additive QT prolongation. When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose by two-thirds (i.e., administer one-third of the pre-voriconazole dose) and make subsequent tacrolimus dose adjustments based on the tacrolimus whole blood concentrations. Use of these drugs together has resulted in a 2-fold and 3-fold increase in the maximum plasma concentrations and systemic exposure of tacrolimus, respectively. Tacrolimus concentrations should be frequently assessed. When voriconazole is discontinued, tacrolimus concentrations should be carefully monitored, and the dose increased as needed. In all cases, renal function in these patients should be carefully monitored. In addition, both drugs are associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range that may prolong the QT interval and cause torsade de pointes (TdP). Posaconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation and TdP.
Tadalafil: (Major) Avoid coadministration of voriconazole and tadalafil for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of voriconazole for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the tadalafil AUC after a 20-mg single dose by 312% and Cmax by 22%, relative to the values for tadalafil alone. The same strong inhibitor increased the tadalafil AUC after a 10-mg single dose by 107% and Cmax by 15%, relative to the values for tadalafil alone. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension, syncope, visual changes, and prolonged erection.
Tamoxifen: (Moderate) Concomitant use of tamoxifen and voriconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Tamsulosin: (Major) Concurrent use of tamsulosin and voriconazole is not recommended due to the potential for elevated tamsulosin concentrations. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension, dizziness, and vertigo. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes, and strong inhibitors of CYP3A4 are expected to significantly raise tamsulosin concentrations. Concomitant treatment with another strong CYP3A4 inhibitor increased the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively.
Tasimelteon: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as voriconazole, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with voriconazole as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. Tazemetostat is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
Telavancin: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering voriconazole with telavancin. Voriconazole has been associated with prolongation of the QT interval and rare cases of arrhythmias, including TdP. Telavancin has also been associated with QT prolongation.
Telmisartan; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with voriconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Voriconazole is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Temsirolimus: (Major) Avoid coadministration of voriconazole with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of voriconazole before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering voriconazole. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C9, CYP2C19, and CYP3A4; voriconazole is an inhibitor of these enzymes. Monitor patients for adverse reactions if these drugs are coadministered.
Tetrabenazine: (Major) Concurrent use of tetrabenazine and voriconazole should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Voriconazole has been associated with prolongation of the QT interval and rare cases of arrhythmias, including TdP. Tetrabenazine causes a small increase in the corrected QT interval (QTc).
Tezacaftor; Ivacaftor: (Major) If voriconazole and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with voriconazole; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); voriconazole is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
Thioridazine: (Contraindicated) Thioridazine is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Thioridazine is considered contraindicated for use along with voriconazole which, when combined with thioridazine, may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension.
Thiotepa: (Major) Avoid the concomitant use of thiotepa and voriconazole if possible; reduced metabolism to the active thiotepa metabolite may result in decreased thiotepa efficacy. Consider an alternative agent with no or minimal potential to inhibit CYP3A4. If coadministration is necessary, monitor patients for signs of reduced thiotepa efficacy. In vitro, thiotepa is metabolized via CYP3A4 to the active metabolite, TEPA; voriconazole is a strong CYP3A4 inhibitor.
Tiagabine: (Moderate) Voriconazole is an inhibitor of CYP3A4 isoenzyme and tiagabine is a substrate for CYP3A4. Reduced metabolism of tiagabine may occur when voriconazole is administered concomitantly. The clinical significance of this potential interaction is not known.
Ticagrelor: (Major) Avoid coadministration of ticagrelor with voriconazole due to increased plasma concentrations of ticagrelor resulting in an increased risk of dyspnea, bleeding, and other treatment-related adverse reactions. Ticagrelor is a sensitive CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ticagrelor exposure by 7.32-fold.
Tinidazole: (Moderate) Monitor for an increase in tinidazole-related adverse reactions if coadministration with voriconazole is necessary. Tinidazole is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor.
Tipranavir: (Major) There is a potential for a bi-directional inhibition between voriconazole and protease inhibitors, such as tipranavir. Coadministration of tipranavir boosted with ritonavir and voriconazole has not been studied; however, their concurrent use is not recommended unless the benefit outweighs the risk.
Tisotumab Vedotin: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with voriconazole is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Tofacitinib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with voriconazole. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with voriconazole. Voriconazole is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
Tolazamide: (Moderate) Voriconazole should be used cautiously with sulfonylureas. The combination of voriconazole and oral antidiabetic agents may result in severe hypoglycemia. Voriconazole may inhibit the metabolism of sulfonylureas. Blood glucose concentrations should be monitored and possible dose adjustments of hypoglycemics may need to be made.
Tolbutamide: (Moderate) Voriconazole should be used cautiously with sulfonylureas. The combination of voriconazole and oral antidiabetic agents may result in severe hypoglycemia. Voriconazole may inhibit the metabolism of sulfonylureas. Blood glucose concentrations should be monitored and possible dose adjustments of hypoglycemics may need to be made.
Tolmetin: (Moderate) The hepatic isoenzyme CYP2C9 is responsible for the metabolism of many NSAIDs. Voriconazole is known to be an inhibitor of CYP2C9 and may lead to increased plasma levels of some NSAIDs, such as tolmetin. The clinical significance of this potential interaction is unknown. Monitor for NSAID-related side-effects, such as fluid retention or GI irritation, and adjust the dose of the NSAID if needed.
Tolterodine: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily and monitor for evidence of QT prolongation if coadministered with voriconazole. Concurrent use may increase tolterodine exposure. Voriconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Tolvaptan: (Contraindicated) The concomitant use of tolvaptan and voriconazole is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; voriconazole is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
Toremifene: (Major) Avoid coadministration of voriconazole with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner. Voriconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
Trabectedin: (Major) Avoid the concomitant use of trabectedin with voriconazole due to the risk of increased trabectedin exposure. If short-term voriconazole (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with voriconazole is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of voriconazole, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Tramadol; Acetaminophen: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with voriconazole is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of voriconazole, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Trandolapril; Verapamil: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with voriconazole is necessary. Concurrent use may result in elevated verapamil concentrations. Verapamil is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor.
Trazodone: (Major) Avoid coadministration of voriconazole with trazodone due to the potential for additive effects on the QT interval; increased exposure to trazodone may also occur. Both drugs are associated with QT prolongation; there are also postmarketing reports of torsade de pointes (TdP) with trazodone. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. In addition, coadministration of voriconazole (a strong CYP3A4 inhibitor) with trazodone (a CYP3A4 substrate) may result in elevated trazodone plasma concentrations and an increased risk for adverse events, including QT prolongation. If these drugs are given together, consider decreasing the dose of trazodone and closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Tretinoin, ATRA: (Moderate) Monitor frequently for signs of pseudotumor cerebri or hypercalcemia during coadministration of voriconazole and tretinoin. Although this interaction has not been studied, voriconazole may increase tretinoin concentrations and increase the risk of adverse reactions. Voriconazole is a strong CYP3A4 inhibitor, and tretinoin is a CYP3A4 substrate. Administration of tretinoin with another strong CYP3A4 inhibitor resulted in a 72% increase in the mean tretinoin plasma AUC.
Triamcinolone: (Moderate) Monitor for potential adrenal dysfunction with concomitant use of voriconazole and triamcinolone. In patients taking corticosteroids, voriconazole-associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Corticosteroid exposure is likely to be increased. Voriconazole is a strong CYP3A4 inhibitor, and triamcinolone is a CYP3A4 substrate.
Triazolam: (Contraindicated) Coadministration of triazolam, a primary CYP3A4 substrate, with strong CYP3A4 inhibitors, such as voriconazole, is contraindicated by the manufacturer of triazolam due to the risk for increased and prolonged sedation and respiratory depression. Concurrent use is expected to produce large increases in systemic exposure to triazolam, with the potential for serious adverse effects.
Triclabendazole: (Moderate) Concomitant use of triclabendazole and voriconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Trifluoperazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering voriconazole with trifluoperazine. Voriconazole has been associated with prolongation of the QT interval and rare cases of arrhythmias, including TdP. Trifluoperazine, a phenothiazine, is associated with a possible risk for QT prolongation.
Trimipramine: (Minor) Voriconazole is associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, voriconazole inhibits CYP2C19 and CYP3A4. CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs. Trimipramine may be affected by this potential interaction, but specific data are lacking. Monitor for an increased response to trimipramine if voriconazole is coadministered.
Triptorelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., triptorelin) outweigh the potential risks of QT prolongation in patients receiving voriconazole as concurrent use may increase the risk of QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Androgen deprivation therapy may also prolong the QT/QTc interval.
Tucatinib: (Moderate) Monitor for increased voriconazole-related adverse effects if coadministered with tucatinib as concurrent use may increase voriconazole exposure. Voriconazole is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased voriconazole exposure by 79%.
Ubrogepant: (Contraindicated) Coadministration of ubrogepant and voriconazole is contraindicated as concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor resulted in a 9.7-fold increase in the exposure of ubrogepant.
Ulipristal: (Minor) Concomitant use of ulipristal and voriconazole may increase the plasma concentration of ulipristal resulting in an increased risk for ulipristal-related adverse events; however, this is not likely to be significant for single-dose emergency contraceptive use. Ulipristal is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ulipristal overall exposure by 5.9-fold and increased the overall exposure if ulipristal's active metabolite, monodemethyl-ulipristal acetate, by 2.4-fold.
Upadacitinib: (Major) During concomitant use of upadacitinib and voriconazole reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Valbenazine: (Major) Reduce the dose of valbenazine to 40 mg once daily if coadministration with voriconazole is necessary. Prolongation of the QT interval is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant. Valbenazine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased both valbenazine and NBI-98782 exposure by approximately 2-fold.
Valproic Acid, Divalproex Sodium: (Moderate) Voriconazole is an inhibitor of the cytochrome P450 2C19 and 2C9 isoenzymes and interactions are possible with drugs that are substrates of these enzymes, like valproic acid. Increased valproic acid plasma levels may occur.
Vandetanib: (Major) Avoid coadministration of vandetanib with voriconazole due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Voriconazole has also been associated with QT prolongation and rare cases of TdP.
Vardenafil: (Major) Do not use vardenafil orally disintegrating tablets with voriconazole due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; voriconazole is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10- to 16-fold. In addition, voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval.
Vemurafenib: (Major) Avoid vemurafenib in patients receiving medications known to prolong the QT interval such as ceritinib. Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first month of treatment. Voriconazole may cause additive QT prolongation; it has also been associated with rare cases of torsade de pointes, cardiac arrest, and sudden death. Additionally, coadministration may result in increased vemurafenib exposure and an increased risk of adverse events, including QT prolongation. Vemurafenib is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Venetoclax: (Major) Coadministration of voriconazole with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of voriconazole. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
Venlafaxine: (Major) Caution is advised when administering voriconazole with venlafaxine due to the potential for additive effects on the QT interval and increased exposure to venlafaxine. Both drugs are associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. In addition, venlafaxine is a substrate of CYP2D6 (major) and CYP3A4 (minor). In patients who are poor CYP2D6 metabolizers, the CYP3A4 pathway for venlafaxine may become more important. Administration of venlafaxine and voriconazole (a strong CYP3A4 inhibitor) to patients identified as CYP2D6 poor metabolizers may significantly increase venlafaxine plasma concentrations. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Verapamil: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with voriconazole is necessary. Concurrent use may result in elevated verapamil concentrations. Verapamil is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with voriconazole is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like voriconazole may increase the risk of a photosensitivity reaction.
Vilazodone: (Major) Do not exceed a vilazodone dose of 20 mg once daily if coadministration with voriconazole is necessary; the original dose of vilazodone can be resumed if voriconazole is discontinued. Vilazodone is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vilazodone exposure by 50%.
Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with voriconazole is necessary. Vinblastine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor.
Vincristine Liposomal: (Major) Avoid coadministration of voriconazole with vincristine due to increased plasma concentrations of vinorelbine. Vincristine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Although no studies have been conducted, vincristine exposure is likely to be increased.
Vincristine: (Major) Avoid coadministration of voriconazole with vincristine due to increased plasma concentrations of vinorelbine. Vincristine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Although no studies have been conducted, vincristine exposure is likely to be increased.
Vinorelbine: (Major) Avoid coadministration of voriconazole with vinorelbine if possible due to increased plasma concentrations of vinorelbine. If concomitant use is unavoidable and alternative antifungal options are not available, frequently monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy. Vinorelbine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Concomitant administration of azole antifungals with another vinca alkaloid has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus.
Voclosporin: (Contraindicated) Concomitant use of voclosporin and voriconazole is contraindicated; concomitant use may increase the exposure of voclosporin and the risk of voclosporin-related adverse effects such as nephrotoxicity, hypertension, and QT prolongation. Additive QT prolongation may also occur. Voclosporin is a sensitive CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased voclosporin exposure by approximately 19-fold.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Caution is advised when administering voriconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as clarithromycin. Both drugs have been associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. In addition, both drugs are substrates and inhibitors of CYP3A4. Coadministration may result in increased plasma concentrations of both drugs, thereby further increasing the risk for adverse events. Azithromycin can be considered as an alternative macrolide antimicrobial if appropriate for the clinical circumstance, due to its lack of metabolism via CYP3A4. If these drugs are given together, closely monitor for prolongation of the QT interval and other adverse effects such as drowsiness, fatigue, dry mouth, nausea, or insomnia. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Vorapaxar: (Major) Avoid coadministration of vorapaxar with voriconazole due to increased plasma concentrations of vorapaxar and the risk of treatment-related adverse reactions. Vorapaxar is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vorapaxar exposure by 2-fold; the bleeding risk for a change in exposure of this magnitude is not known.
Vorinostat: (Moderate) Caution is advised when administering voriconazole with vorinostat as concurrent use may increase the risk of QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Vorinostat therapy is also associated with a risk of QT prolongation.
Voxelotor: (Moderate) Monitor for increased voriconazole-related adverse effects if coadministered with voxelotor as concurrent use may increase voriconazole exposure. Voriconazole is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased voriconazole exposure by 79%.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with voriconazole is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Voriconazole is a strong CYP3A4 and moderate CYP2C9 inhibitor and warfarin is a CYP3A4/CYP2C9 substrate.
Zafirlukast: (Moderate) In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4 and CYP2C9, such as voriconazole.
Zaleplon: (Moderate) Monitor for an increase in zaleplon-related adverse reactions if coadministration with voriconazole is necessary. Dosage adjustments should be made on an individual basis according to efficacy and tolerability. Zaleplon is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased zaleplon exposure by 20%.
Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO once daily if coadministered with voriconazole. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Interrupt zanubrutinib therapy as recommended for adverse reactions. After discontinuation of voriconazole, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. The AUC of zanubrutinib was increased by 278% when coadministered with another strong CYP3A4 inhibitor.
Zidovudine, ZDV: (Minor) Concomitant administration of voriconazole and zidovudine may result in a reduction in the clearance of zidovudine.
Ziprasidone: (Contraindicated) The concurrent use of voriconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as ziprasidone, is considered contraindicated. Voriconazole has been associated with QT prolongation as well as rare cases of torsade de pointes (TdP) and is a strong CYP3A4 inhibitor. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors.
Zolpidem: (Moderate) Consider decreasing the dose of zolpidem if coadministration with voriconazole is necessary. Zolpidem is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.

How Supplied

VFEND/Voriconazole Intravenous Inj Pwd F/Sol: 200mg
VFEND/Voriconazole Oral Pwd F/Recon: 1mL, 40mg
VFEND/Voriconazole Oral Tab: 50mg, 200mg

Maximum Dosage

Adults

weighing 40 kg or more: 12 mg/kg/day IV; 600 mg/day PO is FDA-approved maximum; however, doses up to 800 mg/day PO have been used off-label.
weighing less than 40 kg: 12 mg/kg/day IV; 300 mg/day PO is FDA-approved maximum; however, doses up to 800 mg/day PO have been used off-label.

Geriatric

Adolescents

15 to 17 years weighing 40 kg or more: 12 mg/kg/day IV; 600 mg/day PO is FDA-approved maximum; however, doses up to 800 mg/day PO have been used off-label.
15 to 17 years weighing less than 40 kg: 12 mg/kg/day IV; 300 mg/day PO is FDA-approved maximum; however, doses up to 800 mg/day PO have been used off-label.
13 to 14 years weighing 50 kg or more: 12 mg/kg/day IV; 600 mg/day PO is FDA-approved maximum; however, doses up to 800 mg/day PO have been used off-label.
13 to 14 years weighing less than 50 kg: 18 mg/kg/day IV; 18 mg/kg/day PO (Max: 700 mg/day) is FDA-approved maximum; however, doses up to 800 mg/day PO have been used off-label.

Children

12 years weighing 50 kg or more: 12 mg/kg/day IV; 600 mg/day PO.
12 years weighing less than 50 kg: 18 mg/kg/day IV; 18 mg/kg/day PO (Max: 700 mg/day).
2 to 11 years: 18 mg/kg/day IV; 18 mg/kg/day PO (Max: 700 mg/day).
younger than 2 years: Safety and efficacy have not been established; however, doses up to 18 mg/kg/day IV/PO have been used off-label.

Infants

Safety and efficacy have not been established; however, doses up to 18 mg/kg/day IV/PO have been used off-label.

Neonates

Safety and efficacy have not been established; however, doses up to 18 mg/kg/day IV and 8 mg/kg/day PO have been used off-label.

Mechanism Of Action

Like other azole antifungals, voriconazole exerts its effect by altering the fungal cell membrane. Voriconazole inhibits ergosterol synthesis by interacting with 14-alpha demethylase, a cytochrome P450 enzyme that is needed to convert lanosterol to ergosterol, an essential component of the membrane. Inhibition of ergosterol synthesis results in increased cellular permeability causing leakage of cellular contents. In contrast, amphotericin B binds to ergosterol after it is synthesized. Compared to fluconazole, voriconazole has an enhanced antifungal spectrum that includes filamentous fungi. Voriconazole also inhibits 24-methylene dihydrolanasterol demethylation in certain yeast and filamentous fungi. Other antifungal effects of azole compounds have been proposed and include: inhibition of endogenous respiration, interaction with membrane phospholipids, and inhibition of the transformation of yeasts to mycelial forms. Other mechanisms may involve inhibition of purine uptake and impairment of triglyceride and/or phospholipid biosynthesis. Cross-resistance of voriconazole with other azole antifungals has been demonstrated, probably due to common modes of action. Due to the potential for cross-resistance, specific organism susceptibility data should be reviewed before selecting an antifungal for the treatment of infections.

Voriconazole, like all azole antifungals, exhibits concentration-independent killing in which there is saturation of the bacterial killing rate once the drug concentrations approach the minimum inhibitory concentration (MIC). Experiment murine models have demonstrated that the 24 hour AUC:MIC ratio is the pharmacodynamic parameter most associated with treatment efficacy for the azole antifungal agents. These experimental models have also suggested that a 24-hour free AUC:MIC ratio of more than 20 to 25 is associated with efficacy in Candida sp. As AUC:MIC appears to be the major pharmacodynamic predictor for voriconazole efficacy, total antibiotic exposure is the key to a successful regimen.

Mechanisms of resistance to voriconazole may include mutations at the ERG11 gene (encodes for the target enzyme, lanosterol 14-alpha-demethylase), upregulation of genes encoding the ATP-binding cassette efflux transporters (i.e. Candida drug resistance (CDR) pumps), and reduced access of the drug to the target, or some combination of these mechanisms.

In vitro activity for voriconazole against most yeast is 60-fold higher than for fluconazole. Cross-resistance has been noted with voriconazole in some Candida species. In vitro, voriconazole has been shown to be active against fluconazole-resistant isolates of Candida albicans. Voriconazole was more active than amphotericin B or 5-flucytosine against all species of Candida except for C. glabrata. Voriconazole has shown activity against both fluconazole-susceptible and resistant strains of C. neoformans, but higher MICs were noted in fluconazole-resistant strains. Voriconazole's activity against Aspergillus fumigatus and Fusarium sp. has exceeded that of itraconazole. Voriconazole exhibits fungicidal activity against Aspergillus fumigatus and has been shown to be fungistatic against most yeasts. Voriconazole has shown poor in vitro activity against Zygomycetes and Sporothrix schenckii.

The Clinical and Laboratory Standards Institute (CLSI) delineates susceptibility interpretive criteria for voriconazole by pathogen. Currently, there are no established interpretive criteria for Aspergillus sp. or other filamentous fungi. The MICs for most Candida sp. (i.e., C. albicans, C. parapsilosis, C. tropicalis) are defined as susceptible if 0.12 mcg/mL or less, intermediate if 0.25 to 0.5 mcg/mL, and resistant if 1 mcg/mL or more. For C. krusei, MICs are defined as susceptible if 0.5 mcg/mL or less, intermediate if 1 mcg/mL, and resistant if 2 mcg/mL or more.

Pharmacokinetics

Voriconazole is administered orally, intravenously, and ophthalmically†. The volume of distribution is 4.6 L/kg, suggesting widespread distribution in the body. Human data indicate voriconazole vitreal and CSF concentrations are 38% and 60%, respectively, of the concentrations in the plasma.[26832] [50584] [60487] Plasma protein binding is roughly 58%.[28158] [50584] Voriconazole is extensively metabolized in the liver and displays nonlinear pharmacokinetics due to saturation of its metabolism. Eight metabolites have been identified, of which 3 are major N-oxide metabolites. The N-oxide metabolites do not exhibit antifungal activity. Voriconazole metabolites are primarily excreted renally. Roughly 85% of a dose appears in the urine with less than 2% as unchanged drug. The elimination half-life has been reported as 6 hours, but in patients receiving prolonged therapy, up to 6 days have been required to recover 90% of the drug in the urine and feces. Because the half-life is dose-dependent, it is not useful in predicting the accumulation or elimination of voriconazole in adult patients. There is significant interpatient variability for voriconazole serum concentrations mainly due to polymorphisms in the gene encoding the CYP2C19 isoenzyme that results in differing rates of voriconazole metabolism. An approximately 4-fold higher voriconazole exposure has been observed in poor metabolizers vs. extensive metabolizers. Homozygous extensive metabolizers at CYP2C19 have serum concentrations generally less than half that of homozygous poor metabolizers. These polymorphisms are generally related to ethnic groups but may occur in individual patients. The potentially significant interpatient variability for the metabolism of voriconazole warrants the consideration of therapeutic drug monitoring in certain patients. [26827] [28158]

Affected cytochrome P450 isoenzymes and drug transporters: CYP2C19, CYP2C9, CYP3A4
Voriconazole is a substrate for and is extensively metabolized by cytochrome P450 enzymes 2C19, 2C9, and 3A4. The affinity of voriconazole appears to be highest for CYP2C19, followed by CYP2C9, and is appreciably lower for CYP3A4. In vitro, voriconazole is also an inhibitor of CYP2C19, CYP2C9, and CYP3A4. Voriconazole inhibits CYP2C9 and CYP3A4 to a greater extent than CYP2C19. There is the potential for voriconazole to increase systemic exposure to other drugs metabolized by these enzymes.[28158] [34447]

Oral Route

Bioavailability is up to 96% with peak plasma concentrations occurring 1 to 2 hours after dosing. Oral steady state plasma concentrations range from 2.31 to 4.74 mg/L (peak) and 0.46 to 1.63 mg/L (trough). Increasing the oral dose from 200 mg to 300 mg twice daily results in roughly a 2.5-fold increase in the AUC (12.4 mcg x hour/mL to 34 mcg x hour/mL) in adult patients. Administration with a high-fat meal decreases the mean Cmax and AUC of the oral suspension by 58% and 37%, respectively; the mean Cmax and AUC of the tablet formulation are reduced by 34% and 24%, respectively, after a high-fat meal. Absorption is not affected by increases in gastric pH. Combined oral and topical administration produces concentrations in aqueous humor above the MICs for most fungi.[32798] [28158]

Intravenous Route

With administration of the recommended IV loading dose of voriconazole, steady state concentrations are reached within 24 hours; without the loading dose, accumulation must occur for 6 days to reach steady state. Increasing the IV dose from 3 mg/kg to 4 mg/kg twice daily results in roughly a 2.5-fold increase in the AUC (13.7 mcg x hour/mL to 33.9 mcg x hour/mL) in adult patients.[28158]

Other Route(s)

Ophthalmic Route
Distribution into aqueous humor after topical administration results in concentrations above MIC values for Candida albicans and Aspergillus fumigatus; combined oral and topical administration of voriconazole produces concentrations in aqueous humor above the MICs for most fungi.

Pregnancy And Lactation

Pregnancy

Voriconazole may cause fetal harm when administered to a pregnant woman. No adequate or well controlled studies have been conducted in human pregnancy; however, teratogenicity, embryotoxicity, reduced fetal weight, and multiple skeletal abnormalities have been observed in animals at doses ranging from 0.3- to 6-times the recommended human maintenance dose. If voriconazole is used in pregnancy or if the patient becomes pregnant while using this drug, inform the patient of the potential hazard to the fetus. Opportunistic infection guidelines recommend that oral azole antifungals not be started during pregnancy and to discontinue these agents in women living with HIV who become pregnant.

There are no data available regarding the presence of voriconazole in breast milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for voriconazole and any potential adverse effects from voriconazole or the mother's underlying condition. Previous American Academy of Pediatrics (AAP) recommendations considered fluconazole and ketoconazole as usually compatible with breast-feeding. However, site of infection, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative agent.