Sporanox

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Sporanox

Classes

Azole Antifungals

Administration
Oral Administration

The 65 mg capsule, 100 mg capsule, 200 mg tablet, and the oral solution are NOT interchangeable. [63821]

Oral Solid Formulations

100 mg capsule and 200 mg tablet:
Administer with a full meal to ensure maximal absorption.
Swallow capsules whole; do not crush or chew.
Avoid concurrent administration with drugs that reduce gastric acidity (e.g., proton pump inhibitors, H2-blockers, antacids) as these itraconazole formulations require an acidic environment for absorption. In patients receiving drugs that reduce gastric acidity, administer these formulations with a non-diet cola product to ensure maximal absorption. Administer antacids at least 2 hours before or 2 hours after the 100 mg capsule or 200 mg tablet.[27983] [52489]
 
65 mg capsule:
Administer with food.
Swallow whole; do not crush, chew, or break.[63821]

Oral Liquid Formulations

Oral solution:
If possible, administer without food.
Administer using an oral calibrated measuring device to ensure accurate dosing.
Swish solution vigorously in the mouth (10 mL at a time) for several seconds and swallow.

Adverse Reactions
Severe

hearing loss / Delayed / 0-3.3
visual impairment / Early / 0-2.0
bradycardia / Rapid / 1.0-1.0
pancreatitis / Delayed / Incidence not known
pulmonary edema / Early / Incidence not known
torsade de pointes / Rapid / Incidence not known
heart failure / Delayed / Incidence not known
serum sickness / Delayed / Incidence not known
erythema multiforme / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
vasculitis / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
teratogenesis / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
hyperkalemia / Delayed / Incidence not known

Moderate

hypokalemia / Delayed / 0-8.0
edema / Delayed / 0-4.0
elevated hepatic enzymes / Delayed / 2.9-4.0
stomatitis / Delayed / 0-3.0
constipation / Delayed / 2.0-3.0
hypertension / Early / 2.0-3.0
chest pain (unspecified) / Early / 3.0-3.0
depression / Delayed / 1.0-3.0
hypertriglyceridemia / Delayed / 3.0-3.0
dyspnea / Early / 2.0-3.0
cystitis / Delayed / 3.0-3.0
hemorrhoids / Delayed / 0-2.0
gastritis / Delayed / 2.0-2.0
dysphagia / Delayed / 0-2.0
hot flashes / Early / 0-2.0
dehydration / Delayed / 0-2.0
adrenocortical insufficiency / Delayed / 0-2.0
hematuria / Delayed / 0-2.0
hypotension / Rapid / 1.0-1.0
QT prolongation / Rapid / 0-1.0
orthostatic hypotension / Delayed / 1.0-1.0
impotence (erectile dysfunction) / Delayed / 1.0-1.0
sinus tachycardia / Rapid / Incidence not known
peripheral edema / Delayed / Incidence not known
peripheral neuropathy / Delayed / Incidence not known
confusion / Early / Incidence not known
blurred vision / Early / Incidence not known
leukopenia / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
neutropenia / Delayed / Incidence not known
jaundice / Delayed / Incidence not known
hyperbilirubinemia / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
hypocalcemia / Delayed / Incidence not known
hypophosphatemia / Delayed / Incidence not known
hypomagnesemia / Delayed / Incidence not known
hyperglycemia / Delayed / Incidence not known
dysphonia / Delayed / Incidence not known
urinary incontinence / Early / Incidence not known
secondary malignancy / Delayed / Incidence not known

Mild

nausea / Early / 1.7-11.0
diarrhea / Early / 1.7-11.0
headache / Early / 1.0-10.0
rash / Early / 3.0-9.0
rhinitis / Early / 0-9.0
infection / Delayed / 0-8.0
vomiting / Early / 5.0-7.0
fever / Early / 2.0-7.0
sinusitis / Delayed / 2.0-7.0
abdominal pain / Early / 1.7-6.0
pruritus / Rapid / 0-5.0
flatulence / Early / 0-4.0
dyspepsia / Early / 0-4.0
dizziness / Early / 1.2-4.0
hyperhidrosis / Delayed / 3.0-4.0
cough / Delayed / 1.2-4.0
gingivitis / Delayed / 3.0-3.0
anxiety / Delayed / 3.0-3.0
malaise / Early / 1.0-3.0
fatigue / Early / 1.0-3.0
myalgia / Early / 0-3.0
appetite stimulation / Delayed / 2.0-2.0
weight loss / Delayed / 0-2.0
dysgeusia / Early / 0-2.0
nightmares / Early / 2.0-2.0
insomnia / Early / 0-2.0
tremor / Early / 2.0-2.0
tinnitus / Delayed / 0-2.0
gynecomastia / Delayed / 0-2.0
menstrual irregularity / Delayed / 0-2.0
pharyngitis / Delayed / 0-2.0
asthenia / Delayed / 0-2.0
back pain / Delayed / 0-2.0
anorexia / Delayed / 1.0-1.0
vertigo / Early / 1.0-1.0
drowsiness / Early / 1.0-1.0
libido decrease / Delayed / 1.0-1.0
paresthesias / Delayed / Incidence not known
hypoesthesia / Delayed / Incidence not known
diplopia / Early / Incidence not known
alopecia / Delayed / Incidence not known
urticaria / Rapid / Incidence not known
photosensitivity / Delayed / Incidence not known
chills / Rapid / Incidence not known
arthralgia / Delayed / Incidence not known

Boxed Warning
Chronic obstructive pulmonary disease (COPD), coronary artery disease, dialysis, heart failure, pulmonary disease, pulmonary edema, valvular heart disease, ventricular dysfunction

Itraconazole has been shown to have a negative inotropic effect. Itraconazole is contraindicated for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. For the treatment of life-threatening infections, the drug should be used with caution in patients with ventricular dysfunction as rare cases of CHF and pulmonary edema have been reported in patients treated with itraconazole for onychomycosis and/or systemic fungal infections. If signs or symptoms of CHF occur during administration of the capsules, discontinue treatment. If CHF symptoms occur during administration of the oral solution, continued use of itraconazole should be reassessed. For patients with risk factors for CHF, prescribers should carefully review the risks vs. benefits of therapy. These risk factors include ischemic coronary artery disease or valvular heart disease; significant pulmonary disease [e.g., chronic obstructive pulmonary disease (COPD)], renal disease requiring dialysis, or other edematous disorders. Such patients should be informed of the symptoms of CHF and closely monitored.

Apheresis, AV block, bradycardia, cardiomyopathy, celiac disease, females, fever, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, hypothyroidism, itraconazole coadministration with other drugs, long QT syndrome, myocardial infarction, pheochromocytoma, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, stroke, systemic lupus erythematosus (SLE), ventricular arrhythmias

Due to its potent inhibition of the CYP3A4 enzyme system, itraconazole coadministration with other drugs metabolized by CYP3A4 should be done with extreme caution, if at all. Itraconazole is contraindicated with selected drugs due to the potential for severe, and sometimes fatal, interactions which result from elevated plasma drug concentrations. For example, life-threatening cardiac dysrhythmias (ventricular arrhythmias) and/or sudden death have occurred in patients receiving some of these medications concurrently with itraconazole and/or other CYP3A4 inhibitors. Itraconazole may produce QT prolongation. Use itraconazole with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, people 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus infection (HIV), fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.

Common Brand Names

Sporanox, TOLSURA

Dea Class

Rx

Description

Oral, azole antifungal agent
Used for blastomycosis, histoplasmosis, aspergillosis, onychomycosis, and oropharyngeal or esophageal candidiasis
Dosage forms not interchangeable

Dosage And Indications
For the treatment of invasive aspergillosis. Oral dosage (Sporanox capsule or equivalent) Adults

200 mg PO once daily. If there is no obvious improvement or there is evidence of progressive fungal disease, increase the dose in 100 mg increments to a maximum of 400 mg/day PO. Administer dosages above 200 mg/day in 2 divided doses. For life-threatening cases, 200 mg PO 3 times daily for the first 3 days and continue treatment for at least 3 months until clinical parameters and laboratory tests indicate the active fungal infection has subsided. Guidelines recommend itraconazole solution.

Oral dosage (Tolsura) Adults

130 mg PO once daily. If there is no obvious improvement or there is evidence of progressive fungal disease, increase the dose in 65 mg increments to a maximum of 260 mg/day PO. Administer dosages above 130 mg/day in 2 divided doses. For life-threatening cases, 130 mg PO 3 times daily for the first 3 days and continue treatment for at least 3 months until clinical parameters and laboratory tests indicate the active fungal infection has subsided.

Oral dosage (Sporanox solution† or equivalent) Adults

200 mg PO every 12 hours as salvage therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.

Infants, Children, and Adolescents

5 mg/kg/dose (Max: 200 mg/dose) PO every 12 hours as salvage 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 blastomycosis.
NOTE: For CNS infections, see meningitis.
For the treatment of mild to moderate pulmonary or disseminated extrapulmonary blastomycosis. Oral dosage (Sporanox capsule, solution†, or equivalent) Adults

200 mg PO 3 times daily for 3 days followed by 200 mg PO 1 or 2 times daily for 6 to 12 months. Monitor serum itraconazole trough concentration after at least 2 weeks to ensure adequate drug exposure.[34215] The FDA-approved dose is 200 mg PO once daily with 100 mg increment dose increases to a maximum of 400 mg/day if there is no obvious improvement or there is evidence of progressive fungal disease. Administer doses above 200 mg/day in 2 divided doses.[27983]

Infants†, Children†, and Adolescents†

5 mg/kg/dose (Max: 200 mg/dose) PO twice daily for 6 to 12 months. Monitor serum itraconazole trough concentration after at least 2 weeks to ensure adequate drug exposure.[34215]

Oral dosage (Tolsura) Adults

130 mg PO once daily with 65 mg increment dose increases to a maximum of 260 mg/day if there is no obvious improvement or there is evidence of progressive fungal disease. Administer doses above 130 mg/day in 2 divided doses.[63821]

For step-down therapy of blastomycosis in immunosuppressed patients after initial treatment with amphotericin B. Oral dosage (Sporanox capsule, solution†, or equivalent) Adults

200 mg PO 3 times daily for 3 days followed by 200 mg PO twice daily to complete a total of at least 12 months of therapy. Monitor serum itraconazole trough concentration after at least 2 weeks to ensure adequate drug exposure. Lifelong suppressive therapy may be required.

Infants†, Children†, and Adolescents†

5 mg/kg/dose (Max: 200 mg/dose) PO twice daily to complete a total of at least 12 months of therapy. Monitor serum itraconazole trough concentration after at least 2 weeks to ensure adequate drug exposure. Lifelong suppressive therapy may be required.

For step-down therapy of moderately severe or severe disseminated extrapulmonary blastomycosis, including osteoarticular blastomycosis after initial treatment with amphotericin B. Oral dosage (Sporanox capsule, solution†, or equivalent) Adults

200 mg PO 3 times daily for 3 days followed by 200 mg PO twice daily to complete a total of at least 12 months of therapy. Monitor serum itraconazole trough concentration after at least 2 weeks to ensure adequate drug exposure.[34215]

Infants†, Children†, and Adolescents†

5 mg/kg/dose (Max: 200 mg/dose) PO twice daily to complete a total of 12 months of therapy. Monitor serum itraconazole trough concentration after at least 2 weeks to ensure adequate drug exposure.[34215]

For step-down therapy of moderately severe or severe pulmonary blastomycosis after initial treatment with amphotericin B. Oral dosage (Sporanox capsule, solution†, or equivalent) Adults

200 mg PO 3 times daily for 3 days followed by 200 mg PO twice daily to complete a total of 6 to 12 months of therapy. Monitor serum itraconazole trough concentration after at least 2 weeks to ensure adequate drug exposure.[34215]

Infants†, Children†, and Adolescents†

5 mg/kg/dose (Max: 200 mg/dose) PO twice daily to complete a total of 12 months of therapy. Monitor serum itraconazole trough concentration after at least 2 weeks to ensure adequate drug exposure.[34215]

For the treatment of life-threatening blastomycosis. Oral dosage (Sporanox capsule, solution†, or equivalent) Adults

200 mg PO 3 times daily for 3 days followed by 200 mg PO once daily with 100 mg increment dose increases to a maximum of 400 mg/day if there is no obvious improvement or there is evidence of progressive fungal disease. Administer doses above 200 mg/day in 2 divided doses. Continue treatment for at least 3 months until clinical parameters and laboratory tests indicate the active fungal infection has subsided.[27983]

Oral dosage (Tolsura) Adults

130 mg PO 3 times daily for 3 days followed by 130 mg PO once daily with 65 mg increment dose increases to a maximum of 260 mg/day if there is no obvious improvement or there is evidence of progressive fungal disease. Administer doses above 130 mg/day in 2 divided doses. Continue treatment for at least 3 months until clinical parameters and laboratory tests indicate the active fungal infection has subsided.[63821]

For the treatment of histoplasmosis.
NOTE: For CNS infections, see meningitis.
For the treatment of moderately severe to severe acute pulmonary histoplasmosis. Oral dosage (Sporanox capsule or equivalent) Adults

200 mg PO 3 times daily for 3 days, then 200 mg PO twice daily for 12 weeks. Guidelines recommend itraconazole after 1 to 2 weeks of lipid formulation amphotericin B.[27983] [44326]

Oral dosage (Tolsura) Adults

130 mg PO once daily. If there is no obvious improvement or there is evidence of progressive fungal disease, increase the dose in 65 mg increments to a maximum of 260 mg/day PO. Administer dosages above 130 mg/day in 2 divided doses. For life-threatening cases, 130 mg PO 3 times daily for the first 3 days and continue treatment for at least 3 months until clinical parameters and laboratory tests indicate the active fungal infection has subsided.

For the treatment of chronic cavitary pulmonary histoplasmosis. Oral dosage (Sporanox capsule or equivalent) Adults

200 mg PO 3 times daily for 3 days, then 200 mg PO once or twice daily for at least 12 months and up to 18 to 24 months.

Oral dosage (Tolsura) Adults

130 mg PO once daily. If there is no obvious improvement or there is evidence of progressive fungal disease, increase the dose in 65 mg increments to a maximum of 260 mg/day PO. Administer dosages above 130 mg/day in 2 divided doses. For life-threatening cases, 130 mg PO 3 times daily for the first 3 days and continue treatment for at least 3 months until clinical parameters and laboratory tests indicate the active fungal infection has subsided.

For the treatment of chronic progressive disseminated histoplasmosis. Oral dosage (Sporanox capsule or equivalent) Adults

200 mg PO 3 times daily for 3 days, then 200 mg PO twice daily for at least 12 months. Guidelines recommend itraconazole after 1 to 2 weeks of liposomal amphotericin B for moderately severe to severe disease.

Oral dosage (Tolsura) Adults

130 mg PO once daily. If there is no obvious improvement or there is evidence of progressive fungal disease, increase the dose in 65 mg increments to a maximum of 260 mg/day PO. Administer dosages above 130 mg/day in 2 divided doses. For life-threatening cases, 130 mg PO 3 times daily for the first 3 days and continue treatment for at least 3 months until clinical parameters and laboratory tests indicate the active fungal infection has subsided.

For the treatment of moderately severe to severe disseminated histoplasmosis in HIV-infected patients. Oral dosage (Sporanox capsule, solution†, or equivalent) Adults

200 mg PO 3 times daily for 3 days, then 200 mg PO twice daily for at least 12 months as step-down therapy after the patient has responded to initial therapy with liposomal amphotericin B.[27983] [34362]

Adolescents†

200 mg PO 3 times daily for 3 days, then 200 mg PO twice daily for at least 12 months as step-down therapy after the patient has responded to initial therapy with liposomal amphotericin B.[34362]

Infants† and Children†

2 to 5 mg/kg/dose (Max: 200 mg/dose) PO 3 times daily for 3 days, then 2 to 5 mg/kg/dose (Max: 200 mg/dose) PO twice daily for 12 months as step-down therapy after the patient has responded to initial therapy with liposomal amphotericin B.[34361]

For the treatment of less severe disseminated histoplasmosis in HIV-infected patients. Oral dosage (Sporanox capsule, solution†, or equivalent) Adults

200 mg PO 3 times daily for 3 days, then 200 mg PO twice daily for at least 12 months.[27983] [34362]

Adolescents†

200 mg PO 3 times daily for 3 days, then 200 mg PO twice daily for at least 12 months.[34362]

Infants† and Children†

2 to 5 mg/kg/dose (Max: 200 mg/dose) PO 3 times daily for 3 days, then 2 to 5 mg/kg/dose (Max: 200 mg/dose) PO twice daily for 12 months.[34361]

For the treatment of mild to moderate acute pulmonary histoplasmosis. Oral dosage (Sporanox capsule or equivalent) Adults

200 mg PO once or twice daily for 6 weeks. Treatment is typically not necessary; itraconazole is recommended for patients who continue to have symptoms for more than 1 month.[27983] [44326]

Oral dosage (Tolsura) Adults

130 mg PO once daily. If there is no obvious improvement or there is evidence of progressive fungal disease, increase the dose in 65 mg increments to a maximum of 260 mg/day PO. Administer dosages above 130 mg/day in 2 divided doses.

For the treatment of onychomycosis due to dermatophytes (tinea unguium) in immunocompetent patients.
NOTE: Due to the serious adverse reactions associated with itraconazole, nail specimens should be sent for laboratory testing to confirm the diagnosis prior to beginning itraconazole therapy.
For fingernail involvement only. Oral dosage (Sporanox capsule or equivalent) Adults

200 mg PO twice daily for 1 week, followed by no drug for 3 weeks, then another week of 200 mg PO twice daily.

For toenail involvement with or without fingernail involvement. Oral dosage (Sporanox capsule or equivalent or Onmel) Adults

200 mg PO once daily for 12 weeks.

Children† and Adolescents†

In a small group, itraconazole 5 mg/kg/day PO once daily for one week, followed by no drug for 3 weeks was given for a total of 3 to 5 months to patients aged 3 to 14 years for onychomycosis of the toenails and/or fingernails. Of the 17 patients reported, all but 1 experienced a clinical cure. Seven of the 16 patients with a clinical cure were administered 3 months of itraconazole dosed as noted.

For the treatment of esophageal candidiasis, including fluconazole-refractory disease.
NOTE: Itraconazole oral solution only is FDA-approved for esophageal and/or oral candidiasis. The FDA-approved labeling states that patients with severe neutropenia were not studied. The oral solution is not recommended for treatment of these indications in patients who are at immediate risk for systemic candidiasis.[40233]
Oral dosage (solution) Adults

200 mg PO once daily for 14 to 21 days as an alternative.[34362] [60487] The FDA-approved dosage is 100 to 200 mg PO once daily for a minimum of 3 weeks and for 2 weeks after resolution of symptoms.[40233]

Adolescents†

200 mg PO once daily for 14 to 21 days as an alternative.[34362] [60487]

Infants† and Children†

2.5 mg/kg/dose (Max: 200 mg/dose) PO twice daily for 14 to 21 days.[34361]

For the treatment of oropharyngeal candidiasis (thrush).
NOTE: The oral solution is not recommended for treatment of persons who are at immediate risk for systemic candidiasis; persons with severe neutropenia were not studied.[40233]
For the initial treatment of oropharyngeal candidiasis†. Oral dosage (solution) Adults

200 mg PO once daily for 7 to 14 days as an alternative.[34362] [40233] [60487]

Adolescents

200 mg PO once daily for 7 to 14 days as an alternative.[34362] [60487]

Infants and Children

2.5 mg/kg/dose (Max: 200 mg/dose) PO twice daily for 7 to 14 days as an alternative.[34361] [60487]

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

200 mg PO once daily for up to 28 days. [40233] [60487] The FDA-approved dosage is 100 mg PO twice daily.[40233]

Adolescents†

200 mg PO once daily for up to 28 days. [60487]

Infants† and Children†

2.5 mg/kg/dose (Max: 200 mg/dose) PO twice daily for up to 28 days.[34361] [60487]

For the treatment of CNS infections†, including meningitis†.
NOTE: For CNS infections caused by Cryptococcus, see Cryptococcus meningitis.
For step-down therapy of CNS infections due to Blastomyces dermatitidis† after initial treatment with amphotericin B. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

200 mg PO 2 to 3 times daily for at least 12 months and until resolution of CSF abnormalities. Monitor serum itraconazole trough concentration after at least 2 weeks to ensure adequate drug exposure.[34215]

Infants, Children, and Adolescents

5 mg/kg/dose (Max: 200 mg/dose) PO twice daily for at least 12 months and until resolution of CSF abnormalities. Monitor serum itraconazole trough concentration after at least 2 weeks to ensure adequate drug exposure.[34215]

For the treatment of meningitis due to Coccidioides sp. in persons living with HIV†. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

200 mg PO 2 to 3 times daily as an alternative to fluconazole. Monitor serum itraconazole trough concentration after at least 2 weeks to ensure adequate drug exposure. Continue lifelong suppressive therapy.[34362]

Adolescents

200 mg PO 2 to 3 times daily as an alternative to fluconazole. Monitor serum itraconazole trough concentration after at least 2 weeks to ensure adequate drug exposure. Continue lifelong suppressive therapy.[34362]

For step-down therapy of CNS infections due to Histoplasma capsulatum† after initial treatment with amphotericin B. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

200 mg PO 2 or 3 times daily for at least 12 months and until resolution of abnormal CSF findings.[34362]

Adolescents

200 mg PO 2 or 3 times daily for at least 12 months and until resolution of abnormal CSF findings.[34362]

Infants and Children

2 to 5 mg/kg/dose (Max: 200 mg/dose) PO 3 times daily for 3 days followed by 2 to 5 mg/kg/dose (Max: 200 mg/dose) twice daily for at least 12 months and until resolution of abnormal CSF findings.

For step-down therapy of meningitis due to Sporothrix schenckii† after initial treatment with amphotericin B. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

200 mg PO twice daily to complete a total of at least 12 months of therapy. Monitor serum itraconazole trough concentration after at least 2 weeks to ensure adequate drug exposure.[50784]

For the treatment of meningitis due to Coccidioides sp. in persons without HIV†. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

200 mg PO 2 to 4 times daily. Monitor serum itraconazole trough concentration after at least 2 weeks to ensure adequate drug exposure. Continue lifelong suppressive therapy.[34362]

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

200 mg PO 3 times daily for 3 days, then 200 mg PO twice daily as preferred therapy. Monitor serum itraconazole trough concentration after at least 2 weeks to ensure adequate drug exposure. 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.

Adolescents

200 mg PO 3 times daily for 3 days, then 200 mg PO twice daily as preferred therapy. Monitor serum itraconazole trough concentration after at least 2 weeks to ensure adequate drug exposure. 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.

Infants and Children

2 to 5 mg/kg/dose (Max: 200 mg/dose) PO 3 times daily for 3 days, then 2 to 5 mg/kg/dose (Max: 200 mg/dose) PO twice daily. Consider long-term suppressive therapy if CD4 count is less than 250 cells/mm3 or CD4% is less than 15%.

For treatment of severe pulmonary or nonmeningeal extrapulmonary coccidioidomycosis† in persons living with HIV. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

200 mg PO twice daily after clinical improvement on amphotericin B. Monitor serum itraconazole trough concentration after at least 2 weeks to ensure adequate drug exposure. Continue therapy for at least 12 months, followed by long-term suppressive therapy; discontinuation is dependent on clinical and serological response. Some experts will also add an azole to amphotericin B during the acute phase of treatment.

Adolescents

200 mg PO twice daily after clinical improvement on amphotericin B. Monitor serum itraconazole trough concentration after at least 2 weeks to ensure adequate drug exposure. Continue therapy for at least 12 months, followed by long-term suppressive therapy; discontinuation is dependent on clinical and serological response. Some experts will also add an azole to amphotericin B during the acute phase of treatment.

Infants and Children

2 to 5 mg/kg/dose (Max: 200 mg/dose) PO twice daily after clinical improvement on amphotericin B. Continue therapy for at least 12 months, followed by long-term suppressive therapy. Some experts will also add an azole to amphotericin B during the acute phase of treatment.

For the treatment of pulmonary or nonmeningeal, extrapulmonary coccidioidomycosis† in persons without HIV. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

200 mg PO twice daily. Monitor serum itraconazole trough concentration after at least 2 weeks to ensure adequate drug exposure. Duration of treatment varies with disease location and depends on clinical response; treatment may be necessary for 12 months or longer.

Adolescents

200 mg PO twice daily. Monitor serum itraconazole trough concentration after at least 2 weeks to ensure adequate drug exposure. Duration of treatment varies with disease location and depends on clinical response; treatment may be necessary for 12 months or longer.

Infants and Children

2 to 5 mg/kg/dose (Max: 200 mg/dose) PO twice daily. Duration of treatment varies with disease location and depends on clinical response; treatment may be necessary for 12 months or longer.

For the treatment of sporotrichosis†. For the treatment of cutaneous or lymphocutaneous sporotrichosis†. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

200 mg PO once daily for 2 to 4 weeks after all lesions have resolved, usually for a total of 3 to 6 months. Increase dose to 200 mg PO twice daily in patients who do not respond to initial dose.[50784]

Infants, Children, and Adolescents

3 to 5 mg/kg/dose (Max: 200 mg/dose) PO twice daily for 2 to 4 weeks after all lesions have resolved, usually for a total of 3 to 6 months. Monitor serum itraconazole trough concentration after at least 2 weeks to ensure adequate drug exposure.[50784]

For the treatment of osteoarticular or less severe pulmonary sporotrichosis†. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

200 mg PO twice daily for at least 12 months. Monitor serum itraconazole trough concentration after at least 2 weeks to ensure adequate drug exposure.[50784]

For step-down therapy† after initial treatment with amphotericin B. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

200 mg PO twice daily to complete a total of at least 12 months of therapy for osteoarticular, pulmonary, or disseminated disease. Monitor serum itraconazole trough concentration after at least 2 weeks to ensure adequate drug exposure.[50784]

Infants, Children, and Adolescents

3 to 5 mg/kg/dose (Max: 200 mg/dose) PO twice daily to complete a total of at least 12 months of therapy for visceral or disseminated disease. Monitor serum itraconazole trough concentration after at least 2 weeks to ensure adequate drug exposure.[50784]

For the treatment of tinea corporis†. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

100 mg PO once daily for 2 weeks or 200 mg PO once daily for 1 week.

Adolescents

100 mg PO once daily for 2 weeks or 200 mg PO once daily for 1 week.

For the treatment of talaromycosis† in HIV-infected patients. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

200 mg PO twice daily for 10 weeks after induction therapy with amphotericin B deoxycholate, liposomal amphotericin B, or voriconazole then chronic suppressive therapy.[34362]

Adolescents

200 mg PO twice daily for 10 weeks after induction therapy with amphotericin B deoxycholate, liposomal amphotericin B, or voriconazole then chronic suppressive therapy.[34362]

For candidiasis prophylaxis† in high-risk patients. For candidiasis prophylaxis† in high-risk cancer patients and those with chemotherapy-induced neutropenia. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

200 mg PO twice daily as alterative therapy; however, itraconazole has no therapeutic advantage over other agents and is less tolerated.

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

200 mg PO once daily as an alternative to fluconazole in patients with frequent or severe recurrences. Discontinuation of secondary prophylaxis is reasonable when the CD4 count is more than 200 cells/mm3 due to antiretroviral therapy. Routine primary candidiasis prophylaxis in HIV-infected patients is not recommended.

Adolescents

200 mg PO once daily as an alternative to fluconazole in patients with frequent or severe recurrences. Discontinuation of secondary prophylaxis is reasonable when the CD4 count is more than 200 cells/mm3 due to antiretroviral therapy. Routine primary candidiasis prophylaxis in HIV-infected patients is not recommended.

Infants and Children

2.5 mg/kg/dose PO twice daily (Max: 200 mg/day) as an alternative to fluconazole in patients with frequent or severe recurrences. Discontinuation of secondary prophylaxis may be considered when CD4 count is at least 750 cells/mm3 (infants), 500 cells/mm3 (children 1 to 5 years), or 200 cells/mm3 (children 6 years and older) or the CD4 percentage has risen to 15% or more (all ages). Routine primary candidiasis prophylaxis in HIV-infected patients is not recommended.

For secondary esophageal candidiasis prophylaxis† (i.e., long-term suppressive therapy) in HIV-infected patients. Oral dosage (solution) Infants and Children

2.5 mg/kg/dose PO twice daily (Max: 200 mg/day) as an alternative to fluconazole in patients with frequent or severe recurrences. Discontinuation of secondary prophylaxis may be considered when CD4 count has risen to at least 750 cells/mm3 (infants), 500 cells/mm3 (children 1 to 5 years), or 200 cells/mm3 (children 6 years and older) or the CD4 percentage has risen to 15% or more (all ages). Routine primary candidiasis prophylaxis in HIV-infected patients is not recommended.

For the treatment or secondary prophylaxis of disseminated (non-ocular) infections associated with microsporidiosis† and attributed to Trachipleistophora or Anncaliia.
NOTE: Initiating antiretroviral therapy (ART) before severe immunosuppression develops is key to preventing chronic microsporidiosis, as infection most commonly occurs in patients with CD4 counts less than 100 cells/mm3. Other preventative measures for patients with CD4 counts less than 200 cells/mm3 include: proper hand washing and personal hygiene; avoid untreated water sources; avoid consuming undercooked meat or seafood; limit exposure to animals known to be infected with microsporidia.[34362]
NOTE: All patients infected with microsporidiosis should be offered ART as part of the initial treatment.[34362]
Oral dosage (Sporanox capsule, solution, or equivalent) Adults

400 mg PO once daily in combination with albendazole 400 mg PO twice daily. Continue treatment until CD4 count exceeds 200 cells/mm3 for at least 6 months after the initiation of antiretroviral therapy.

Adolescents

400 mg PO once daily in combination with albendazole 400 mg PO twice daily. Continue treatment until CD4 count exceeds 200 cells/mm3 for at least 6 months after the initiation of antiretroviral therapy.

For primary or secondary histoplasmosis prophylaxis† (i.e., long-term suppressive therapy) in HIV-infected patients. For primary histoplasmosis prophylaxis† in HIV-infected patients. Oral dosage (Sporanox capsules, solution, or equivalent) Adults

200 mg PO once daily. Consider discontinuation if patients are receiving antiretroviral therapy, have a CD4 count of 150 cells/mm3 or more, and have an undetectable viral load for 6 months. Resume primary prophylaxis if the CD4 count decreases below 150 cells/mm3. Guidelines recommend primary prophylaxis for patients with a CD4 count of less than 150 cells/mm3 and at high risk due to occupational exposure or residence in a hyperendemic community.[34362]

Adolescents

200 mg PO once daily. 200 mg PO once daily. Consider discontinuation if patients are receiving antiretroviral therapy, have a CD4 count of 150 cells/mm3 or more, and have an undetectable viral load for 6 months. Resume primary prophylaxis if the CD4 count decreases below 150 cells/mm3. Guidelines recommend primary prophylaxis for patients with a CD4 count of less than 150 cells/mm3 and at high risk due to occupational exposure or residence in a hyperendemic community.[34362]

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

200 mg PO once daily. 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 more than 150 CD4 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

200 mg PO once daily. 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 more than 150 CD4 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]

For talaromycosis prophylaxis† in HIV-infected patients. For primary talaromycosis prophylaxis in HIV-infected patients residing in endemic areas†. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

200 mg PO once daily. Recommended for patients with CD4 count less than 100 cells/mm3 who are unable to have antiretroviral therapy (ART) or have treatment failure without access to effective ART options and who reside in the highly endemic regions in northern Thailand, Vietnam, or southern China. May discontinue if the CD4 count is more than 100 cells/mm3 for 6 months or more in response to ART or virologic suppression is achieved for 6 months or more on ART. Restart prophylaxis if CD4 count is less than 100 cells/mm3 and patient still resides in high-risk areas.

Adolescents

200 mg PO once daily. Recommended for patients with CD4 count less than 100 cells/mm3 who are unable to have antiretroviral therapy (ART) or have treatment failure without access to effective ART options and who reside in the highly endemic regions in northern Thailand, Vietnam, or southern China. May discontinue if the CD4 count is more than 100 cells/mm3 for 6 months or more in response to ART or virologic suppression is achieved for 6 months or more on ART. Restart prophylaxis if CD4 count is less than 100 cells/mm3 and patient still resides in high-risk areas.

For primary talaromycosis prophylaxis in HIV-infected patients traveling to endemic areas†. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

200 mg PO once daily starting 3 days before travel and continuing for 1 week after leaving the endemic area. Recommended for patients with CD4 count less than 100 cells/mm3 who are unable to have antiretroviral therapy (ART) or have treatment failure without access to effective ART options and who are from countries outside the highly endemic regions in northern Thailand, Vietnam, or southern China and must travel to the region. Restart prophylaxis if CD4 count is less than 100 cells/mm3 and patient still travels to high-risk areas.

Adolescents

200 mg PO once daily starting 3 days before travel and continuing for 1 week after leaving the endemic area. Recommended for patients with CD4 count less than 100 cells/mm3 who are unable to have antiretroviral therapy (ART) or have treatment failure without access to effective ART options and who are from countries outside the highly endemic regions in northern Thailand, Vietnam, or southern China and must travel to the region. Restart prophylaxis if CD4 count is less than 100 cells/mm3 and patient still travels to high-risk areas.

For secondary talaromycosis prophylaxis† (i.e., long-term suppressive therapy) in HIV-infected patients†. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

200 mg PO once daily. May discontinue if the CD4 count is more than 100 cells/mm3 for 6 months or more in response to ART or virologic suppression is achieved for 6 months or more on ART. Restart prophylaxis if CD4 count is less than 100 cells/mm3.

Adolescents

200 mg PO once daily. May discontinue if the CD4 count is more than 100 cells/mm3 for 6 months or more in response to ART or virologic suppression is achieved for 6 months or more on ART. Restart prophylaxis if CD4 count is less than 100 cells/mm3.

For secondary cryptococcosis prophylaxis† (chronic maintenance therapy) for meningitis caused by Cryptococcus sp. in HIV-infected patients . Oral dosage (Sporanox capsule, solution, or equivalent) Infants and Children

As an alternative to fluconazole, the HIV guidelines recommend 5 mg/kg/dose PO every 24 hours (Max: 200 mg) given as the oral solution. Fluconazole is superior to itraconazole in preventing relapse and is considered the preferred agent. Discontinuation of secondary prophylaxis may be considered in patients who are at least 6 years of age with CD4 count 100 cells/mm3 or more, are asymptomatic on at least 12 months of prophylactic therapy, and have an undetectable viral load on more than 3 months of antiretroviral therapy. Restart secondary prophylaxis if CD4 count is less than 100 cells/mm3.[34361]

For aspergillosis prophylaxis†. Oral dosage (solution) Adults

200 mg PO every 12 hours. Guidelines recommend itraconazole as an alternative to posaconazole throughout the duration of immunosuppression for allogeneic hematopoietic stem cell transplant recipients with graft-versus-host disease (GVHD) and neutropenic patients with acute myelogenous leukemia or myelodysplastic syndrome who are at high-risk for invasive aspergillosis. Antifungal prophylaxis is also recommended for 3 to 4 months after lung transplant; reinitiate prophylaxis for lung transplant recipients receiving immunosuppression augmentation with thymoglobulin, alemtuzumab, or high-dose corticosteroids.

Oral dosage (Sporanox capsule or equivalent) Children and Adolescents

5 to 10 mg/kg/day PO was used in an open, prospective study of 32 children with chronic granulomatous disease to prevent Aspergillus infection. During the study period, the percentage of patients infected with Aspergillus was 10% in the itraconazole group vs. 34.4% in the untreated historical control group.

For the treatment of fungal keratitis†. Oral dosage (Sporanox capsule or equivalent) Adults

200 mg PO once daily until epithelial lesion heals, then 100 mg PO once daily for 5 days, then 50 mg PO once daily for 5 days. May be more useful for infections associated with Aspergillus sp. rather than Fusarium sp.

Adolescents

200 mg PO once daily until epithelial lesion heals, then 100 mg PO once daily for 5 days, then 50 mg PO once daily for 5 days. May be more useful for infections associated with Aspergillus sp. rather than Fusarium sp.

Children 5 years and older

100 mg PO once daily until the epithelial lesion heals and for 5 subsequent days then 50 mg PO once daily for 5 days. May be more useful for infections associated with Aspergillus sp. rather than Fusarium sp.

For the treatment of seborrheic dermatitis†. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

Inititally, 100 mg PO twice daily or 200 mg PO once daily for 1 week, then 100 mg PO twice daily or 200 mg PO once daily for the first 2 days of next 2 to 11 months as maintenance therapy. Alternate maintenance regimens include, after 1 week, 100 mg PO twice daily for first 2 days of next 4 weeks, or after 5 weeks, 200 mg PO every 2 weeks for 18 weeks.

For the treatment of tinea capitis†. Oral dosage (Sporanox capsule, solution, or equivalent) Infants, Children, and Adolescents

5 mg/kg/dose PO once daily for 2 weeks, in general; alternately, 50 mg PO once daily for patients weighing less than 20 kg; 100 mg PO once daily for patients weighing 20 to 40 kg; and 200 mg PO once daily for patients weighing more than 40 kg. Treatment was studied up to 12 weeks.

For the treatment of tinea manuum†. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

100 mg PO once daily for 4 weeks or 200 mg PO twice daily for 7 days.

For the treatment of tinea pedis†. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

100 mg PO once daily for 2 to 4 weeks or 200 mg PO twice daily for 1 week.

For the treatment of tinea versicolor†. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

200 mg PO once daily for 7 days or 400 mg PO as single dose.

Children and Adolescents 12 to 17 years

200 mg PO once daily for 7 days or 400 mg PO as single dose.

For the treatment of tinea cruris†. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

100 mg PO once daily for 2 weeks or 200 mg PO once daily for 1 week.

Adolescents

100 mg PO once daily for 2 weeks or 200 mg PO once daily for 1 week.

For the treatment of allergic bronchopulmonary aspergillosis†. Oral dosage (Sporanox solution or equivalent) Adults

200 mg PO every 12 hours as primary treatment in patients with asthma, cystic fibrosis, or bronchiectasis.

Infants, Children, and Adolescents

5 mg/kg/dose (Max: 200 mg/dose) PO every 12 hours as primary treatment in patients with asthma, cystic fibrosis, or bronchiectasis.

For the treatment of vulvovaginal candidiasis† (VVC) and vulvovaginal candidiasis prophylaxis† in patients with recurrent infections. For the treatment of uncomplicated VVC† in persons living with HIV. Oral dosage (oral solution) Adults

200 mg PO once daily for 3 to 7 days as an alternative to fluconazole.[34362]

Adolescents

200 mg PO once daily for 3 to 7 days as an alternative to fluconazole.[34362]

For the treatment of non-Candida albicans VVC†. Oral dosage (oral solution) Adults

200 mg PO once daily for 7 to 14 days.

Adolescents

200 mg PO once daily for 7 to 14 days.

For secondary vulvovaginal candidiasis prophylaxis† (i.e., long-term suppressive therapy) in patients with recurrent infections. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

200 mg PO twice daily for 2 doses given once monthly for 6 months after initial therapy with a topical agent or oral fluconazole for 10 to 14 days.[60487] [63804]

Adolescents

200 mg PO twice daily for 2 doses given once monthly for 6 months after initial therapy with a topical agent or oral fluconazole for 10 to 14 days.[60487] [63804]

For secondary sporotrichosis prophylaxis† (i.e., long-term suppressive therapy) in immunosuppressed patients. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

200 mg PO once daily. Lifelong suppressive therapy is recommended for meningeal or disseminated infections when immunosuppression cannot be reversed.[50784]

Infants, Children, and Adolescents

2.5 mg/kg/dose (Max: 200 mg/dose) PO twice daily. Lifelong suppressive therapy may be required for children living with HIV.[50784]

For secondary blastomycosis prophylaxis† (i.e., long-term suppressive therapy) in immunosuppressed patients. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

200 mg PO once daily. Lifelong suppressive therapy may be required when immunosuppression cannot be reversed.[34215]

Infants, Children, and Adolescents

2.5 mg/kg/dose (Max: 200 mg/dose) PO twice daily. Lifelong suppressive therapy may be required when immunosuppression cannot be reversed.[34215]

For secondary coccidioidomycosis prophylaxis† (long-term suppressive therapy†). For secondary coccidioidomycosis prophylaxis† (long-term suppressive therapy†) in persons living with HIV after treatment for mild to moderate pulmonary coccidioidomycosis. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

200 mg PO twice daily. Discontinue therapy when have clinically responded to 3 months or more of antifungal therapy, 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.

Adolescents

200 mg PO twice daily. Discontinue therapy when have clinically responded to 3 months or more of antifungal therapy, 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.

Infants and Children

2 to 5 mg/kg/dose (Max: 200 mg/dose) PO twice daily. May consider discontinuation of therapy when have clinically responded and have a CD4 count of 250 cells/mm3 or more or CD4% of 15% or more.

For secondary coccidioidomycosis prophylaxis† (long-term suppressive therapy†) in persons living with HIV after treatment for severe pulmonary or nonmeningeal, extrapulmonary disease. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

200 mg PO twice daily. Prophylaxis may be lifelong; discontinuation is dependent on clinical and serological response.

Adolescents

200 mg PO twice daily. Prophylaxis may be lifelong; discontinuation is dependent on clinical and serological response.

Infants and Children

2 to 5 mg/kg/dose (Max: 200 mg/dose) PO twice daily. Prophylaxis is lifelong.

For secondary coccidioidomycosis prophylaxis† (long-term suppressive therapy†) after treatment for meningitis. Oral dosage (Sporanox capsule, solution, or equivalent) Adults

200 mg PO twice daily. Prophylaxis is lifelong.

Adolescents

200 mg PO twice daily. Prophylaxis is lifelong.

Infants and Children

2 to 5 mg/kg/dose (Max: 200 mg/dose) PO twice daily. Prophylaxis is lifelong.

†Indicates off-label use

Dosing Considerations
Hepatic Impairment

The effect of hepatic impairment on itraconazole is not known. The manufacturer recommends these patients be monitored closely; however, no dosage adjustment guidelines are available.

Renal Impairment

There are limited data available on the use of itraconazole in patients with renal dysfunction. The manufacturer recommends caution in these patients; however, no dosage adjustment recommendations are available.
 
Hemodialysis
Itraconazole is not dialyzable.

Drug Interactions

Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministered with itraconazole. Concomitant use may increase dolutegravir plasma concentrations. Dolutegravir is an in vitro substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); itraconazole inhibits both P-gp and BCRP.
Abemaciclib: (Major) If coadministration with itraconazole 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 itraconazole is discontinued, increase the dose of abemaciclib to the original dose after 3 to 5 half-lives of itraconazole. Abemaciclib is a CYP3A4 substrate and itraconazole 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 itraconazole; significantly increased acalabrutinib exposure occurred in a drug interaction study. If short-term itraconazole use is unavoidable, interrupt acalabrutinib therapy. Wait at least 24 hours after itraconazole is discontinued before resuming acalabrutinib at the previous dosage. Acalabrutinib is a CYP3A4 substrate; itraconazole 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 itraconazole 200 mg/day for 5 days.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with itraconazole 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 itraconazole could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If itraconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Itraconazole is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with itraconazole 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 itraconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If itraconazole 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. Itraconazole 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 itraconazole 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 itraconazole 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 itraconazole 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; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of itraconazole is necessary. If itraconazole 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 itraconazole 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 itraconazole 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.
Aclidinium; Formoterol: (Moderate) Use itraconazole with caution in combination with beta-agonists as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Adagrasib: (Contraindicated) Avoid concomitant use of adagrasib and itraconazole. 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 itraconazole with a CYP3A substrate that causes QT prolongation, such as adagrasib, is contraindicated per the manufacturer of itraconazole. If use is necessary, wait for adagrasib levels to reach steady state (approximately 8 days after initiation), monitor for itraconazole-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, itraconazole 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 itraconazole 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 itraconazole 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 itraconazole has cleared from the circulation (approximately 3 half-lives of itraconazole) 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; itraconazole is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
Afatinib: (Moderate) If the concomitant use of itraconazole and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of itraconazole. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and itraconazole is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
Albuterol; Budesonide: (Moderate) Avoid coadministration of oral budesonide and itraconazole due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of itraconazole is necessary. If itraconazole is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like itraconazole can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If itraconazole is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
Alfuzosin: (Contraindicated) Use of alfuzosin with itraconazole is contraindicated as potentially increased alfuzosin concentrations can result in hypotension, and potentially life-threatening cardiac arrhythmia. Use is not recommended for 2 weeks after completion of itraconazole therapy. Alfuzosin is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor.
Aliskiren: (Major) Avoid use of aliskiren during and for 2 weeks after discontinuation of itraconazole treatment due to increased aliskiren exposure. Coadministration of 100 mg itraconazole with 150 mg aliskiren resulted in an approximate 5.8-fold increase in Cmax and 6.5-fold increase in AUC of aliskiren.
Aliskiren; Hydrochlorothiazide, HCTZ: (Major) Avoid use of aliskiren during and for 2 weeks after discontinuation of itraconazole treatment due to increased aliskiren exposure. Coadministration of 100 mg itraconazole with 150 mg aliskiren resulted in an approximate 5.8-fold increase in Cmax and 6.5-fold increase in AUC of aliskiren.
Almotriptan: (Moderate) The maximum recommended starting dose of almotriptan is 6.25 mg if coadministration with itraconazole is necessary; do not exceed 12.5 mg within a 24-hour period. Concomitant use of almotriptan and itraconazole should be avoided in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased almotriptan exposure by approximately 60%.
Alogliptin; Pioglitazone: (Moderate) Itraconazole should be used cautiously with oral antidiabetic agents. The combination of itraconazole and oral antidiabetic agents has resulted in severe hypoglycemia. Blood glucose concentrations should be monitored and possible dose adjustments of hypoglycemics may need to be made.
Alosetron: (Moderate) Concomitant use of alosetron with itraconazole 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; itraconazole is a strong inhibitor of this enzyme. In a study of healthy female subjects, another strong CYP3A4 inhibitor increased mean alosetron AUC by 29%.
Alpelisib: (Major) Avoid coadministration of alpelisib with itraconazole due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and itraconazole is a BCRP inhibitor.
Alprazolam: (Contraindicated) Coadministration of itraconazole and alprazolam is contraindicated. Itraconazole significantly impairs the CYP3A4 metabolism of alprazolam, resulting in significantly elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. When a single dose of alprazolam was administered to healthy patients receiving itraconazole, the mean AUC and half-live of alprazolam were increased 2.7 fold. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with itraconazole, as these benzodiazepines are not oxidatively metabolized.
Alvimopan: (Moderate) Alvimopan is a substrate of P-glycoprotein (P-gp). Although the concomitant use of mild to moderate inhibitors of P-gp did not influence the pharmacokinetics of alvimopan, the concomitant use of strong P-gp inhibitors, such as itraconazole has not been studied. Coadministration of itraconazole and alvimopan may result in elevated concentrations of alvimopan. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect of alvimopan.
Amiodarone: (Major) Avoid coadministration of amiodarone and itraconazole due to the potential for increased amiodarone concentrations and additive effects on the QT interval. There have been reports of prolonged QT, with or without torsade de pointes (TdP) with the concomitant use of amiodarone and azole antifungals. Both itraconazole and amiodarone are associated with QT prolongation. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with amiodarone (a CYP3A4 substrate) may result in elevated amiodarone plasma concentrations and an increased risk for adverse events, including QT prolongation. According to the manufacturer, the need to administer amiodarone with drugs known to prolong the QT interval should be done with a careful assessment of risks versus benefits, especially when the coadministered agent might decrease the metabolism of amiodarone. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Further, it takes approximately 7 to 14 days after discontinuing itraconazole before the plasma concentrations are undetectable. The decline in itraconazole plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with itraconazole. Amisulpride causes dose- and concentration- dependent QT prolongation. Itraconazole has been associated with prolongation of the QT interval.
Amitriptyline: (Minor) Use itraconazole with caution in combination with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. 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). CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs; itraconazole may increase TCA concentrations via inhibition of CYP3A4. In at least one case, an increased incidence of TCA-related side effects, such as dizziness and syncope has occurred in combination with an azole antifungal. In another case, QT-prolongation and torsades de pointes occurred.
Amlodipine: (Moderate) Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. In addition, itraconazole may increase amlodipine serum concentrations via inhibition of CYP3A4 with the potential for amlodipine toxicity. Edema has been reported in patients receiving concomitantly itraconazole and amlodipine, therefore, caution is recommended when administering these medications in combination. A dosage reduction of the calcium-channel blocker may be appropriate.
Amlodipine; Atorvastatin: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with itraconazole is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. 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. Itraconazole inhibits the CYP3A4 metabolism of atorvastatin. Itraconazole increases the AUC of atorvastatin by 2.5 to 3.3-fold, which is substantially less than the effect of itraconazole on the AUC of simvastatin and lovastatin (increased 19-fold and 20-fold, respectively). (Moderate) Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. In addition, itraconazole may increase amlodipine serum concentrations via inhibition of CYP3A4 with the potential for amlodipine toxicity. Edema has been reported in patients receiving concomitantly itraconazole and amlodipine, therefore, caution is recommended when administering these medications in combination. A dosage reduction of the calcium-channel blocker may be appropriate.
Amlodipine; Benazepril: (Moderate) Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. In addition, itraconazole may increase amlodipine serum concentrations via inhibition of CYP3A4 with the potential for amlodipine toxicity. Edema has been reported in patients receiving concomitantly itraconazole and amlodipine, therefore, caution is recommended when administering these medications in combination. A dosage reduction of the calcium-channel blocker may be appropriate.
Amlodipine; Celecoxib: (Moderate) Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. In addition, itraconazole may increase amlodipine serum concentrations via inhibition of CYP3A4 with the potential for amlodipine toxicity. Edema has been reported in patients receiving concomitantly itraconazole and amlodipine, therefore, caution is recommended when administering these medications in combination. A dosage reduction of the calcium-channel blocker may be appropriate.
Amlodipine; Olmesartan: (Moderate) Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. In addition, itraconazole may increase amlodipine serum concentrations via inhibition of CYP3A4 with the potential for amlodipine toxicity. Edema has been reported in patients receiving concomitantly itraconazole and amlodipine, therefore, caution is recommended when administering these medications in combination. A dosage reduction of the calcium-channel blocker may be appropriate.
Amlodipine; Valsartan: (Moderate) Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. In addition, itraconazole may increase amlodipine serum concentrations via inhibition of CYP3A4 with the potential for amlodipine toxicity. Edema has been reported in patients receiving concomitantly itraconazole and amlodipine, therefore, caution is recommended when administering these medications in combination. A dosage reduction of the calcium-channel blocker may be appropriate.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. In addition, itraconazole may increase amlodipine serum concentrations via inhibition of CYP3A4 with the potential for amlodipine toxicity. Edema has been reported in patients receiving concomitantly itraconazole and amlodipine, therefore, caution is recommended when administering these medications in combination. A dosage reduction of the calcium-channel blocker may be appropriate.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Caution is advised when administering itraconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as clarithromycin. Consider use of azithromycin in place of clarithromycin. Both clarithromycin and itraconazole are associated with QT prolongation; coadministration may increase this risk. 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. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors. Azithromycin can be considered as an alternative macrolide antimicrobial if appropriate for the clinical circumstance, due to its lack of metabolism via CYP3A4.
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) Itraconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with itraconazole include anagrelide.
Antacids: (Moderate) When administering antacids with the 100 mg itraconazole capsule and 200 mg itraconazole tablet formulations, systemic exposure to itraconazole is decreased. Conversely, exposure to itraconazole is increased when antacids are administered with the 65 mg itraconazole capsule. Administer antacids at least 2 hours before or 2 hours after the 100 mg capsule or 200 mg tablet. Monitor for increased itraconazole-related adverse effects if antacids are administered with itraconazole 65 mg capsules.
Apalutamide: (Major) The use of apalutamide within 2 weeks of itraconazole therapy is not recommended. If coadministration cannot be avoided, monitor for decreased efficacy of itraconazole and increase the dose of itraconazole as necessary. Exposure to apalutamide may also increase; monitor for apalutamide-related adverse reactions. Consider reducing the dose of apalutamide if necessary based on tolerability in patients experiencing grade 3 or higher adverse reactions or intolerable toxicities. Itraconazole is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer. Coadministration with itraconazole decreased the Cmax of single-dose apalutamide by 22% and the AUC remained similar.
Apixaban: (Major) Use of apixaban is not recommended during and for 2 weeks after discontinuation of itraconazole. If itraconazole therapy is necessary in a patient receiving apixaban 5 mg or 10 mg twice daily, reduce the apixaban dose by 50%. Avoid coadministration in patients already receiving apixaban 2.5 mg twice daily. Apixaban is a CYP3A4 and P-glycoprotein substrate; itraconazole is a strong CYP3A4 and P-gp inhibitor. Concomitant administration of itraconazole and apixaban results in increased exposure to apixaban and an increase in the risk of bleeding.
Apomorphine: (Moderate) Exercise caution when administering apomorphine concomitantly with itraconazole since concurrent use may increase the risk of QT prolongation. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure. Itraconazole has been associated with prolongation of the QT interval.
Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use of itraconazole with aprepitant, fosaprepitant due to substantially increased exposure of aprepitant; increased itraconazole exposure may also occur. If coadministration cannot be avoided, use caution and monitor for an increase in itraconazole- and aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. Itraconazole is a strong CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of a single oral dose of aprepitant (125 mg) on day 5 of a 10-day ketoconazole regimen (strong CYP3A4 inhibitor) increased the aprepitant AUC approximately 5-fold, and increased the mean terminal half-life by approximately 3-fold. Itraconazole 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 and inducer and may additionally increase plasma concentrations of itraconazole. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Arformoterol: (Moderate) Use itraconazole with caution in combination with beta-agonists as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Aripiprazole: (Contraindicated) Avoid concomitant use of aripiprazole and itraconazole 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, itraconazole is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. (Contraindicated) Avoid concomitant use of aripiprazole and itraconazole 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, itraconazole is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation.
Armodafinil: (Moderate) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as itraconazole 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) Avoid coadministration of itraconazole and arsenic trioxide. Itraconazole has been associated with prolongation of the QT interval. If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. If concomitant drug use is unavoidable, frequently monitor electrocardiograms. QT prolongation should be expected with the administration of arsenic trioxide.
Artemether; Lumefantrine: (Major) Caution is advised when administering itraconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as lumefantrine. Both lumefantrine and itraconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with lumefantrine (a CYP3A4 substrate) may result in elevated lumefantrine plasma concentrations. No dosage adjustments are required by the manufacturer, but patients should be monitored for adverse events, including QT prolongation. (Major) Caution is advised when administering itraconazole with drugs that are known to prolong the QT interval and are metabolized by CYP3A4, such as artemether. Both artemether and itraconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with artemether (a CYP3A4 substrate) may result in elevated artemether plasma concentrations. No dosage adjustments are required by the manufacturer, but patients should be monitored for adverse events, including QT prolongation.
Asciminib: (Major) Avoid concurrent use of asciminib with itraconazole oral solution containing hydroxypropyl-beta-cyclodextrin as asciminib exposure may decrease which may reduce its efficacy; an interaction is not expected with other formulations of itraconazole. Coadministration of multiple doses of itraconazole oral solution containing hydroxypropyl-beta-cyclodextrin with a single 40-mg asciminib dose decreased asciminib exposure by 40%.
Asenapine: (Major) Avoid coadministration of asenapine and itraconazole due to the potential for additive effects on the QT interval; increased exposure to asenapine is also possible. Both asenapine and itraconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with asenapine (a CYP3A4 substrate) may result in elevated asenapine plasma concentrations and an increased risk for adverse events, including QT prolongation. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with itraconazole 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 itraconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If itraconazole 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. Itraconazole is a strong inhibitor of CYP3A4.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Administer antacids at least 2 hours before or 2 hours after oral itraconazole to minimize the potential for an interaction. Because itraconazole oral bioavailability requires an acidic environment for solubility, its absorption may be decreased with concomitant administration of antacids.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of itraconazole is necessary. If itraconazole 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 itraconazole 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 itraconazole 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) Coadministration of atazanavir and itraconazole may result in increased serum concentrations of itraconazole. While clinically significant interactions are not expected with atazanavir monotherapy, the addition of cobicistat to atazanavir may cause a significant interaction and therefore, atazanavir; cobicistat should be avoided in combination with itraconazole. Atazanavir is a CYP3A4 inhibitor and itraconazole is a CYP3A4 substrate. Caution and close monitoring of the anticipated responses are recommended when coadministered.
Atazanavir; Cobicistat: (Major) Avoid concurrent use of itraconazole with regimens containing cobicistat and atazanavir or darunavir. Use of these drugs together may result in increased plasma concentrations of itraconazole, cobicistat, atazanavir, and darunavir. Specific dosage recommendations have not been determined. (Major) Coadministration of atazanavir and itraconazole may result in increased serum concentrations of itraconazole. While clinically significant interactions are not expected with atazanavir monotherapy, the addition of cobicistat to atazanavir may cause a significant interaction and therefore, atazanavir; cobicistat should be avoided in combination with itraconazole. Atazanavir is a CYP3A4 inhibitor and itraconazole is a CYP3A4 substrate. Caution and close monitoring of the anticipated responses are recommended when coadministered.
Atogepant: (Major) Avoid use of atogepant and itraconazole when atogepant is used for chronic migraine. Limit the dose of atogepant to 10 mg PO once daily for episodic migraine if coadministered with itraconazole. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of CYP3A and itraconazole is a strong CYP3A inhibitor. Coadministration 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 itraconazole 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) Do not exceed 20 mg/day of atorvastatin if coadministration with itraconazole is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. 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. Itraconazole inhibits the CYP3A4 metabolism of atorvastatin. Itraconazole increases the AUC of atorvastatin by 2.5 to 3.3-fold, which is substantially less than the effect of itraconazole on the AUC of simvastatin and lovastatin (increased 19-fold and 20-fold, respectively).
Atorvastatin; Ezetimibe: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with itraconazole is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. 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. Itraconazole inhibits the CYP3A4 metabolism of atorvastatin. Itraconazole increases the AUC of atorvastatin by 2.5 to 3.3-fold, which is substantially less than the effect of itraconazole on the AUC of simvastatin and lovastatin (increased 19-fold and 20-fold, respectively).
Atropine: (Moderate) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole.
Atropine; Difenoxin: (Moderate) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole.
Avacopan: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of itraconazole is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and itraconazole is a strong CYP3A inhibitor. Concomitant use increased avacopan overall exposure 2.19-fold.
Avanafil: (Contraindicated) Avanafil is contraindicated for use during and for 2 weeks after itraconazole therapy. Use of these drugs together increases avanafil serum concentrations and may result in serious adverse reactions. Avanafil is a substrate of and primarily metabolized by CYP3A4; itraconazole is a strong inhibitor of CYP3A4. Coadministration of avanafil with other strong inhibitors of CYP3A4 has resulted in significantly increased exposure to avanafil; itraconazole would be expected to have similar effects.
Avapritinib: (Major) Avoid coadministration of avapritinib with itraconazole due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole is predicted to increase the AUC of avapritinib by 600% at steady-state.
Axitinib: (Major) Avoid axitinib during and for 2 weeks after discontinuation of itraconazole treatment. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; 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 itraconazole is discontinued. Axitinib is a CYP3A4/5 substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Azelastine; Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and itraconazole is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Azithromycin: (Major) Concomitant use of itraconazole and azithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. 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.
Barbiturates: (Major) Use of barbiturates is not recommended for 2 weeks before or during itraconazole therapy. Barbiturates induce hepatic CYP enzymes including 3A4, 2C19 and 2C9 and may reduce effective serum concentrations of itraconazole. Monitor for breakthrough fungal infections.
Bedaquiline: (Major) Concurrent use of itraconazole is not recommended for more than 2 weeks at any time during bedaquiline treatment. Both bedaquiline and itraconazole are associated with QT prolongation; coadministration increases this risk. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with bedaquiline (a CYP3A4 substrate) may result in elevated bedaquiline plasma concentrations and could increase the risk for adverse events, including QT prolongation. Monitor ECGs if bedaquiline is coadministered to patients receiving itraconazole; discontinue bedaquiline if evidence of serious ventricular arrhythmia or QT interval greater than 500 msec.
Belladonna; Opium: (Moderate) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with itraconazole 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 itraconazole 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 itraconazole 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. Itraconazole is a strong inhibitor of CYP3A4.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole.
Benztropine: (Moderate) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole.
Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking itraconazole. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Berotralstat is a P-gp and BCRP substrate and itraconazole is a P-gp and BCRP inhibitor. Coadministration with another P-gp and BCRP inhibitor increased berotralstat exposure by 69%.
Betamethasone: (Moderate) Monitor for corticosteroid-related adverse effects if coadministration is necessary. Itraconazole is a strong CYP3A4 inhibitor and betamethasone is a CYP3A4 substrate. Another strong CYP3A4 inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving itraconazole. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving itraconazole. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; itraconazole inhibits P-gp.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and itraconazole 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 itraconazole 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 patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with itraconazole. Bortezomib is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Coadminsitration or another strong CYP3A4 inhibitor increased the exposure of bortezomib by 35%.
Bosentan: (Moderate) Bosentan is metabolized by CYP2C9 and CYP3A4. Inhibition of these isoenzymes may increase the plasma concentration of bosentan. Coadministration of bosentan with ketoconazole, a potent CYP3A4 inhibitor, has been shown to increase the plasma concentrations of bosentan by approximately 2-fold. No dosage adjustment of bosentan is needed; however, the potential for increased bosentan effects should be monitored. Although data are lacking, itraconazole could also increase bosentan plasma concentrations via CYP3A4 inhibition.
Bosutinib: (Major) Avoid bosutinib use during and for 2 weeks after discontinuation of itraconazole treatment due to the potential for increased bosutinib plasma exposure resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. In a cross-over trial in 24 healthy volunteers, 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 adverse reactions if coadminsitration of itraconazole and brentuximab vedotin is necessary. Concurrent use may result in increased exposure to monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. MMAE is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Coadminsitration of another strong inhibitor increased exposure to MMAE by approximately 34%.
Brexpiprazole: (Major) Because brexpiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the brexpiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as itraconazole. If these agents are used in combination, the patient should be carefully monitored for brexpiprazole-related adverse reactions. Because brexpiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a moderate to strong CYP3A4 inhibitor and moderate to strong CYP2D6 inhibitor should have their brexpiprazole dose reduced to one-quarter (25%) of the usual dose. If the co-administered CYP inhibitor is discontinued, adjust the brexpiprazole dose to its original level.
Brigatinib: (Major) Avoid coadministration of brigatinib with itraconazole 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 itraconazole, resume the brigatinib dose that was tolerated prior to initiation of itraconazole. Brigatinib is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
Bromocriptine: (Major) When bromocriptine is used for diabetes, avoid coadministration with itraconazole 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; itraconazole is a strong inhibitor of CYP3A4.
Budesonide: (Moderate) Avoid coadministration of oral budesonide and itraconazole due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Budesonide; Formoterol: (Moderate) Avoid coadministration of oral budesonide and itraconazole due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. (Moderate) Use itraconazole with caution in combination with beta-agonists as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole. (Moderate) Avoid coadministration of oral budesonide and itraconazole due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. (Moderate) Use itraconazole with caution in combination with beta-agonists as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Bupivacaine Liposomal: (Moderate) Itraconazole causes a modest increase in bupivacaine serum concentrations. It is unclear if this increase is due to CYP3A4 inhibition by itraconazole or if other mechanisms are involved.
Bupivacaine: (Moderate) Itraconazole causes a modest increase in bupivacaine serum concentrations. It is unclear if this increase is due to CYP3A4 inhibition by itraconazole or if other mechanisms are involved.
Bupivacaine; Epinephrine: (Moderate) Itraconazole causes a modest increase in bupivacaine serum concentrations. It is unclear if this increase is due to CYP3A4 inhibition by itraconazole or if other mechanisms are involved.
Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and itraconazole may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; itraconazole inhibits CYP3A4. (Moderate) Itraconazole causes a modest increase in bupivacaine serum concentrations. It is unclear if this increase is due to CYP3A4 inhibition by itraconazole or if other mechanisms are involved.
Bupivacaine; Meloxicam: (Major) Concomitant use of itraconazole and meloxicam may result in decreased plasma concentrations of meloxicam. Caution should be used when meloxicam is used concurrently with itraconazole and its effects should be monitored; dosage adjustment of meloxicam may be required. (Moderate) Itraconazole causes a modest increase in bupivacaine serum concentrations. It is unclear if this increase is due to CYP3A4 inhibition by itraconazole or if other mechanisms are involved.
Buprenorphine: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of itraconazole and buprenorphine is necessary. Buprenorphine and itraconazole have been associated with QT prolongation and torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, coadministration of a strong CYP3A4 inhibitor such as itraconazole may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
Buprenorphine; Naloxone: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of itraconazole and buprenorphine is necessary. Buprenorphine and itraconazole have been associated with QT prolongation and torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, coadministration of a strong CYP3A4 inhibitor such as itraconazole may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
Buspirone: (Major) A low dose of buspirone is recommended (e.g., 2.5 mg daily) if used in combination with itraconazole. Subsequent dose adjustment of either drug should be based on clinical assessment. Buspirone is a sensitive CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. In a study in healthy volunteers, coadministration of buspirone with itraconazole increased the AUC and Cmax of buspirone by 19-fold and 13-fold, respectively. These pharmacokinetic interactions were accompanied by an increased incidence of side effects attributable to buspirone.
Busulfan: (Moderate) Monitor for evidence of busulfan toxicity if coadminsitration of itraconazole is necessary. Itraconazole reduced busulfan clearance by up to 25% in patients receiving itraconazole compared to patients who did not receive itraconazole. Higher busulfan exposure due to concomitant itraconazole could lead to toxic plasma levels in some patients.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with itraconazole 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 itraconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If itraconazole 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. Itraconazole is a strong inhibitor of CYP3A4.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of codeine with itraconazole 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 itraconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If itraconazole 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. Itraconazole is a strong inhibitor of CYP3A4.
Cabazitaxel: (Major) Avoid use of cabazitaxel during and for 2 weeks after discontinuation of itraconazole 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 itraconazole is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Cabotegravir; Rilpivirine: (Moderate) Caution is advised when administering itraconazole with rilpivirine due to the potential for additive effects on the QT interval, increased exposure to rilpivirine, and decreased exposure to itraconazole. Monitor for breakthrough fungal infections in patients receiving rilpivirine with an azole antifungal. Rilpivirine, a CYP3A4 substrate, and itraconazole, 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 itraconazole.
Cabozantinib: (Major) Avoid concomitant use of cabozantinib and itraconazole 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 itraconazole 2 to 3 days after discontinuation of itraconazole. Cabozantinib is a CYP3A substrate and itraconazole 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 itraconazole. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with itraconazole. Itraconazole, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
Calcium Carbonate: (Moderate) When administering antacids with the 100 mg itraconazole capsule and 200 mg itraconazole tablet formulations, systemic exposure to itraconazole is decreased. Conversely, exposure to itraconazole is increased when antacids are administered with the 65 mg itraconazole capsule. Administer antacids at least 2 hours before or 2 hours after the 100 mg capsule or 200 mg tablet. Monitor for increased itraconazole-related adverse effects if antacids are administered with itraconazole 65 mg capsules.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) When administering antacids with the 100 mg itraconazole capsule and 200 mg itraconazole tablet formulations, systemic exposure to itraconazole is decreased. Conversely, exposure to itraconazole is increased when antacids are administered with the 65 mg itraconazole capsule. Administer antacids at least 2 hours before or 2 hours after the 100 mg capsule or 200 mg tablet. Monitor for increased itraconazole-related adverse effects if antacids are administered with itraconazole 65 mg capsules. (Moderate) When administering H2-blockers with the 100 mg itraconazole capsule and 200 mg itraconazole tablet formulations, systemic exposure to itraconazole is decreased. Conversely, exposure to itraconazole is increased when H2-blockers are administered with the 65 mg itraconazole capsule. Administer H2-blockers at least 2 hours before or 2 hours after the 100 mg capsule or 200 mg tablet. Monitor for increased itraconazole-related adverse effects if H2-blockers are administered with itraconazole 65 mg capsules.
Calcium Carbonate; Magnesium Hydroxide: (Moderate) When administering antacids with the 100 mg itraconazole capsule and 200 mg itraconazole tablet formulations, systemic exposure to itraconazole is decreased. Conversely, exposure to itraconazole is increased when antacids are administered with the 65 mg itraconazole capsule. Administer antacids at least 2 hours before or 2 hours after the 100 mg capsule or 200 mg tablet. Monitor for increased itraconazole-related adverse effects if antacids are administered with itraconazole 65 mg capsules.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Moderate) When administering antacids with the 100 mg itraconazole capsule and 200 mg itraconazole tablet formulations, systemic exposure to itraconazole is decreased. Conversely, exposure to itraconazole is increased when antacids are administered with the 65 mg itraconazole capsule. Administer antacids at least 2 hours before or 2 hours after the 100 mg capsule or 200 mg tablet. Monitor for increased itraconazole-related adverse effects if antacids are administered with itraconazole 65 mg capsules.
Calcium Carbonate; Simethicone: (Moderate) When administering antacids with the 100 mg itraconazole capsule and 200 mg itraconazole tablet formulations, systemic exposure to itraconazole is decreased. Conversely, exposure to itraconazole is increased when antacids are administered with the 65 mg itraconazole capsule. Administer antacids at least 2 hours before or 2 hours after the 100 mg capsule or 200 mg tablet. Monitor for increased itraconazole-related adverse effects if antacids are administered with itraconazole 65 mg capsules.
Calcium; Vitamin D: (Moderate) When administering antacids with the 100 mg itraconazole capsule and 200 mg itraconazole tablet formulations, systemic exposure to itraconazole is decreased. Conversely, exposure to itraconazole is increased when antacids are administered with the 65 mg itraconazole capsule. Administer antacids at least 2 hours before or 2 hours after the 100 mg capsule or 200 mg tablet. Monitor for increased itraconazole-related adverse effects if antacids are administered with itraconazole 65 mg capsules.
Capmatinib: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with itraconazole is necessary. Capmatinib is a CYP3A substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole increased capmatinib exposure by 42%.
Carbamazepine: (Major) Use of carbamazepine is not recommended for 2 weeks before, during, or for 2 weeks after itraconazole therapy due to the potential for increased carbamazepine and decreased itraconazole exposure. If concurrent use is unavoidable, an increased dose of itraconazole and a decreased dose of carbamazepine may be necessary. Itraconazole is a strong CYP3A4 inhibitor and substrate; carbamazepine is a strong CYP3A4 inducer and substrate.
Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. When a strong CYP3A4 inhibitor, such as itraconazole, 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 adult patients taking cariprazine 1.5 mg daily, the dosing frequency should be adjusted to every other day. When the CYP3A4 inhibitor is withdrawn, the cariprazine dosage may need to be increased. When initiating cariprazine in a patient who is stable on a strong CYP3A4 inhibitor, 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, then increased to a maximum dose of 3 mg daily. When the CYP3A4 inhibitor is withdrawn, the cariprazine dosage may need to be increased.
Carvedilol: (Moderate) Altered concentrations of itraconazole and/or carvedilol may occur during coadministration. Carvedilol and itraconazole are both substrates and inhibitors of P-glycoprotein (P-gp). Use caution if concomitant use is necessary and monitor for increased side effects.
Ceritinib: (Major) Avoid concomitant use of ceritinib during and for 2 weeks after itraconazole due to increased exposure to ceritinib which may increase the incidence and severity of adverse reactions as well as an additive risk of QT prolongation; itraconazole exposure 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; monitor for treatment-related adverse reactions. Periodically monitor electrolytes and ECGs; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. After itraconazole is discontinued, resume the dose of ceritinib taken prior to initiating itraconazole. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Ceritinib also causes concentration-dependent prolongation of the QT interval and itraconazole is associated with QT prolongation. Coadministration with a strong CYP3A inhibitor increased ceritinib exposure by 2.9-fold.
Chlordiazepoxide: (Moderate) CYP3A4 inhibitors, such as itraconazole, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
Chlordiazepoxide; Amitriptyline: (Moderate) CYP3A4 inhibitors, such as itraconazole, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. (Minor) Use itraconazole with caution in combination with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. 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). CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs; itraconazole may increase TCA concentrations via inhibition of CYP3A4. In at least one case, an increased incidence of TCA-related side effects, such as dizziness and syncope has occurred in combination with an azole antifungal. In another case, QT-prolongation and torsades de pointes occurred.
Chlordiazepoxide; Clidinium: (Moderate) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole. (Moderate) CYP3A4 inhibitors, such as itraconazole, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
Chloroquine: (Major) Avoid coadministration of chloroquine with itraconazole 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. Itraconazole has also been associated with prolongation of the QT interval.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with itraconazole 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 itraconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If itraconazole 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. Itraconazole is a strong inhibitor of CYP3A4.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with itraconazole 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 itraconazole could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If itraconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Itraconazole 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 itraconazole 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 itraconazole 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 itraconazole 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.
Chlorpromazine: (Major) Itraconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with itraconazole include chlorpromazine.
Ciclesonide: (Moderate) Monitor for steroid-related adverse effects if coadministration of ciclesonide and itraconazole is necessary. Ciclesonide is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of the active metabolite of ciclesonide, des-ciclesonide, by approximately 3.6-fold at steady state, while levels of ciclesonide remained unchanged.
Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with itraconazole and monitor for an increase in cilostazol-related adverse reactions. Concurrent use may increase cilostazol exposure. Cilostazol is a CYP3A substrate; itraconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the cilostazol AUC by 117%.
Cimetidine: (Moderate) When administering H2-blockers with the 100 mg itraconazole capsule and 200 mg itraconazole tablet formulations, systemic exposure to itraconazole is decreased. Conversely, exposure to itraconazole is increased when H2-blockers are administered with the 65 mg itraconazole capsule. Administer H2-blockers at least 2 hours before or 2 hours after the 100 mg capsule or 200 mg tablet. Monitor for increased itraconazole-related adverse effects if H2-blockers are administered with itraconazole 65 mg capsules.
Cinacalcet: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of itraconazole and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and itraconazole 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 itraconazole 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) Cisapride is contraindicated for use during and for 2 weeks after itraconazole therapy. Serious cardiovascular events including EKG changes (i.e., QT prolongation), cardiac arrhythmias, including ventricular arrhythmias and torsade de pointes, cardiac arrest, and sudden death have occurred when cisapride and itraconazole were administered together. Itraconazole is an inhibitor of cytochrome P450 3A4, which may cause increased plasma concentrations of cisapride resulting in potentially serious and life-threatening side effects, including EKG changes (i.e., QT prolongation), cardiac arrhythmias, including ventricular arrhythmias and torsade de pointes, cardiac arrest, and sudden death have occurred when cisapride and itraconazole were administered together. Itraconazole is an inhibitor of cytochrome P450 3A4, which may cause increased plasma concentrations of cisapride resulting in potentially serious and life-threatening side effects.
Citalopram: (Major) Avoid coadministration of citalopram and itraconazole due to the potential for additive effects on the QT interval; increased exposure to citalopram is also possible. Both citalopram and itraconazole are associated with QT prolongation; coadministration may increase this risk. If concurrent therapy is considered essential, ECG monitoring is recommended. In addition, because CYP3A4 is one of the primary enzymes involved in the metabolism of citalopram, coadministration of a strong CYP3A4 inhibitor like itraconazole might be expected to decrease the metabolism of citalopram. However, coadministration of another strong CYP3A4 inhibitor did not significantly affect the pharmacokinetics of citalopram.
Clarithromycin: (Major) Caution is advised when administering itraconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as clarithromycin. Consider use of azithromycin in place of clarithromycin. Both clarithromycin and itraconazole are associated with QT prolongation; coadministration may increase this risk. 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. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors. Azithromycin can be considered as an alternative macrolide antimicrobial if appropriate for the clinical circumstance, due to its lack of metabolism via CYP3A4.
Clindamycin: (Moderate) Monitor for an increase in clindamycin-related adverse reactions with coadministration of itraconazole as concurrent use may increase clindamycin exposure. Clindamycin is a CYP3A4 substrate; itraconazole is a strong inhibitor of CYP3A4.
Clofazimine: (Moderate) Concomitant use of clofazimine and itraconazole 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) Use itraconazole with caution in combination with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. 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). CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs; itraconazole may increase TCA concentrations via inhibition of CYP3A4. In at least one case, an increased incidence of TCA-related side effects, such as dizziness and syncope has occurred in combination with an azole antifungal. In another case, QT-prolongation and torsades de pointes occurred.
Clonazepam: (Moderate) Use itraconazole 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. Itraconazole is a strong CYP3A4 inhibitor.
Clorazepate: (Moderate) Itraconazole is a CYP3A4 inhibitor and may reduce the metabolism of clorazepate and increase the potential for benzodiazepine toxicity. Monitor patients closely who receive concurrent therapy.
Clozapine: (Major) Caution is advised when administering itraconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as clozapine. Both clozapine and itraconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with clozapine (a CYP3A4 substrate) may result in elevated clozapine plasma concentrations and an increased risk for adverse events, including QT prolongation. Consider a clozapine dose reduction if necessary. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
Cobicistat: (Major) Avoid concurrent use of itraconazole with regimens containing cobicistat and atazanavir or darunavir. Use of these drugs together may result in increased plasma concentrations of itraconazole, cobicistat, atazanavir, and darunavir. Specific dosage recommendations have not been determined.
Cobimetinib: (Major) Avoid cobimetinib use during and for 2 weeks after discontinuation of itraconazole due to increased cobimetinib exposure. Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate; itraconazole is a P-gp inhibitor and a strong CYP3A inhibitor. In healthy subjects, coadministration of itraconazole increased the mean cobimetinib AUC by 6.7-fold and the mean Cmax by 3.2-fold.
Codeine: (Moderate) Concomitant use of codeine with itraconazole 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 itraconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If itraconazole 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. Itraconazole is a strong inhibitor of CYP3A4.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with itraconazole 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 itraconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If itraconazole 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. Itraconazole is a strong inhibitor of CYP3A4.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with itraconazole 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 itraconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If itraconazole 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. Itraconazole is a strong inhibitor of CYP3A4.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with itraconazole 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 itraconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If itraconazole 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. Itraconazole is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of promethazine and itraconazole 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 itraconazole 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 itraconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If itraconazole 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. Itraconazole is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of promethazine and itraconazole 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) Avoid concomitant use of colchicine and itraconazole due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a CYP3A and P-gp substrate and itraconazole is a dual strong CYP3A and P-gp inhibitor. Concomitant use with other dual strong CYP3A and P-gp inhibitors has been observed to increase colchicine overall exposure by 3- to 4-fold.
Conivaptan: (Contraindicated) Coadministration of conivaptan and itraconazole is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a sensitive CYP3A substrate; itraconazole is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
Conjugated Estrogens: (Minor) In vitro and in vivo studies have shown that estrogens are metabolized partially by CYP3A4. Therefore, inhibitors of CYP3A4 may affect estrogen drug metabolism. Inhibitors of CYP3A4, such as itraconazole, may increase the exposure of conjugated estrogens resulting in an increased risk of endometrial hyperplasia. Therefore, for chronically administered CYP3A4 inhibitors ( > 30 days) concurrently administered with conjugated estrogens, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
Conjugated Estrogens; Bazedoxifene: (Minor) In vitro and in vivo studies have shown that estrogens are metabolized partially by CYP3A4. Therefore, inhibitors of CYP3A4 may affect estrogen drug metabolism. Inhibitors of CYP3A4, such as itraconazole, may increase the exposure of conjugated estrogens resulting in an increased risk of endometrial hyperplasia. Therefore, for chronically administered CYP3A4 inhibitors ( > 30 days) concurrently administered with conjugated estrogens, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
Conjugated Estrogens; Medroxyprogesterone: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with itraconazole, 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. (Minor) In vitro and in vivo studies have shown that estrogens are metabolized partially by CYP3A4. Therefore, inhibitors of CYP3A4 may affect estrogen drug metabolism. Inhibitors of CYP3A4, such as itraconazole, may increase the exposure of conjugated estrogens resulting in an increased risk of endometrial hyperplasia. Therefore, for chronically administered CYP3A4 inhibitors ( > 30 days) concurrently administered with conjugated estrogens, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
Copanlisib: (Major) Avoid the concomitant use of copanlisib and itraconazole if possible; increased copanlisib exposure occurred in a drug interaction study. 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 substrate of CYP3A, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP); itraconazole is a strong CYP3A inhibitor and also inhibits P-gp and BCRP. The AUC of copanlisib increased by 53% when a single IV dose of copanlisib 60 mg was administered following 10 days of itraconazole 200 mg/day in a drug interaction study in patients with cancer; the Cmax of copanlisib was not significantly increased.
Crizotinib: (Major) Avoid crizotinib use during and for 2 weeks after discontinuation of itraconazole due to increased plasma concentrations of crizotinib, which may increase the incidence and severity of adverse reactions; QT prolongation may also occur. 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. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Resume the original crizotinib dose after discontinuation of itraconazole. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation. Itraconazole is a strong CYP3A4 inhibitor that is also associated with QT prolongation. Concomitant use with itraconazole increased the steady-state AUC of crizotinib by 57% compared to crizotinib alone.
Cyclosporine: (Major) Monitor cyclosporine serum concentrations and adjust dose as needed if coadministration of itraconazole is necessary. Cyclosporine concentrations may be significantly increased in the presence of itraconazole. Itraconazole is a strong CYP3A4 and P-glycoprotein(P-gp) inhibitor; cyclosporine is a CYP3A4/P-gp substrate.
Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with itraconazole, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like itraconazole in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with itraconazole, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
Dabrafenib: (Major) Avoid dabrafenib use during and for 2 weeks after discontinuation of itraconazole treatment. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity and for loss of itraconazole efficacy. The concomitant use of dabrafenib, a CYP3A4 substrate and moderate CYP3A4 inducer, and itraconazole, a strong CYP3A4 inhibitor and a CYP3A4 substrate, may result in altered levels of either agent.
Daclatasvir: (Major) 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 itraconazole. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects. In addition, the therapeutic effects of itraconazole, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor.
Dapagliflozin; Saxagliptin: (Major) Do not exceed 2.5 mg PO daily of saxagliptin when combined with itraconazole; monitor for evidence of hypoglycemia. Itraconazole is a strong CYP3A4 inhibitor; saxagliptin is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the saxagliptin AUC up to 3.7-fold.
Daridorexant: (Major) Avoid concomitant use of daridorexant and itraconazole. Daridorexant is a CYP3A substrate and itraconazole is a strong CYP3A inhibitor. In drug interaction studies, concomitant use of itraconazole increased daridorexant overall exposure by over 400%, increasing the risk for daridorexant-related adverse effects.
Darifenacin: (Major) Avoid use of darifenacin during and for 2 weeks after discontinuation of itraconazole treatment due to the potential for increased darifenacin exposure. If concurrent use cannot be avoided, do not exceed 7.5 mg/day PO darifenacin. Darifenacin is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Additionally, antimuscarinic drugs can raise intragastric pH, which can decrease the oral bioavailability of itraconazole.
Darolutamide: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with itraconazole is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Itraconazole is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with itraconazole increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Darunavir: (Major) If darunavir monotherapy is coadministered with itraconazole, high doses (i.e., more than 200 mg) of itraconazole should be avoided. When cobicistat is added to darunavir as in the darunavir; cobicistat combination product, avoid coadministration with itraconazole. Additionally, plasma concentrations of itraconazole may be increased when coadministered with darunavir (in the FDA approved dosage regimen). Both darunavir and itraconazole are strong inhibitors and substrates of CYP3A.
Darunavir; Cobicistat: (Major) Avoid concurrent use of itraconazole with regimens containing cobicistat and atazanavir or darunavir. Use of these drugs together may result in increased plasma concentrations of itraconazole, cobicistat, atazanavir, and darunavir. Specific dosage recommendations have not been determined. (Major) If darunavir monotherapy is coadministered with itraconazole, high doses (i.e., more than 200 mg) of itraconazole should be avoided. When cobicistat is added to darunavir as in the darunavir; cobicistat combination product, avoid coadministration with itraconazole. Additionally, plasma concentrations of itraconazole may be increased when coadministered with darunavir (in the FDA approved dosage regimen). Both darunavir and itraconazole are strong inhibitors and substrates of CYP3A.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concurrent use of itraconazole with regimens containing cobicistat and atazanavir or darunavir. Use of these drugs together may result in increased plasma concentrations of itraconazole, cobicistat, atazanavir, and darunavir. Specific dosage recommendations have not been determined. (Major) If darunavir monotherapy is coadministered with itraconazole, high doses (i.e., more than 200 mg) of itraconazole should be avoided. When cobicistat is added to darunavir as in the darunavir; cobicistat combination product, avoid coadministration with itraconazole. Additionally, plasma concentrations of itraconazole may be increased when coadministered with darunavir (in the FDA approved dosage regimen). Both darunavir and itraconazole are strong inhibitors and substrates of CYP3A.
Dasatinib: (Major) Avoid dasatinib use during and for 2 weeks after discontinuation of itraconazole treatment due to the potential for increased dasatinib exposure and subsequent toxicity including QT prolongation and torsade de pointes (TdP). An alternative to itraconazole 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 itraconazole in patients receiving dasatinib 60 mg or 40 mg PO daily. If dasatinib is not tolerated after dose reduction, either discontinue itraconazole or stop dasatinib until itraconazole is discontinued. Allow a washout of approximately 2 weeks after itraconazole is stopped before increasing the dasatinib dose or reinitiating dasatinib. Dasatinib is a CYP3A4 substrate that has the potential to prolong the QT interval; itraconazole is a strong CYP3A4 inhibitor that is associated with QT prolongation. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of dasatinib by 4-fold and 5-fold, respectively.
Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with itraconazole. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; itraconazole is a strong inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
Degarelix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving itraconazole as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Itraconazole has also been associated with prolongation of the QT interval.
Delavirdine: (Minor) Trough plasma concentrations of delavirdine may be increased in patients receiving itraconazole concurrently with delavirdine.
Desflurane: (Major) Itraconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with itraconazole include halogenated anesthetics.
Desipramine: (Minor) Use itraconazole with caution in combination with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. 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). CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs; itraconazole may increase TCA concentrations via inhibition of CYP3A4. In at least one case, an increased incidence of TCA-related side effects, such as dizziness and syncope has occurred in combination with an azole antifungal. In another case, QT-prolongation and torsades de pointes occurred.
Desogestrel; Ethinyl Estradiol: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as itraconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Deutetrabenazine: (Moderate) Use itraconazole with caution in combination with deutetrabenazine. Itraconazole has been associated with prolongation of the QT interval. 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 itraconazole 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 itraconazole 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.
Dexmedetomidine: (Moderate) Concomitant use of dexmedetomidine and itraconazole 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 is contraindicated for use during and for 2 weeks after itraconazole therapy. Serious cardiovascular events including EKG changes (i.e., QT prolongation) and cardiac arrhythmias, including ventricular arrhythmias and torsade de pointes, cardiac arrest, and/or sudden death have occurred when these drugs were administered together. Reports have documented cases in which substantial elevations in serum quinidine concentrations occurred after the addition of itraconazole. Quinidine is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Transient or permanent hearing loss has also been reported in elderly patients receiving quinidine in combination with itraconazole.
Diazepam: (Moderate) Monitor for increased and prolonged sedation if coadministration of itraconazole and diazepam is necessary. A dose reduction of diazepam may be necessary. Diazepam is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor.
Dichlorphenamide: (Moderate) Use dichlorphenamide and itraconazole 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.
Dicyclomine: (Moderate) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole.
Didanosine, ddI: (Major) Administer itraconazole at least 2 hours before or several hours after didanosine chewable tablets and powder for oral solution. Didanosine chewable tablets and powder for oral solution contain acid buffers to enhance the bioavailability of didanosine. These buffers, however, may decrease the absorption of itraconazole, which requires an acid environment for absorption. The delayed-release didanosine capsules do not contain a buffering agent and would not be expected to interact with itraconazole.
Dienogest; Estradiol valerate: (Minor) As itraconazole 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, ketoconazole, 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.
Digoxin: (Major) Measure serum digoxin concentrations before initiating itraconazole. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring. Concomitant use of digoxin with itraconazole has resulted in an 80% increase in digoxin serum concentrations. Itraconazole is an inhibitor of P-glycoprotein (P-gp); digoxin is a substrate for P-gp.
Dihydroergotamine: (Contraindicated) Coadministration of ergot alkaloids with inhibitors of CYP3A4, such as itraconazole, or administration for 2 weeks after discontinuation of itraconazole treatment is contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
Diltiazem: (Moderate) Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. In addition, itraconazole may increase diltiazem serum concentrations via inhibition of CYP3A4 with the potential for diltiazem toxicity. Caution is recommended when administering these medications in combination. A dosage reduction of the calcium-channel blocker may be appropriate.
Diphenoxylate; Atropine: (Moderate) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole.
Disopyramide: (Contraindicated) Use of disopyramide during and for 2 weeks after discontinuation of itraconazole treatment is contraindicated due to the potential for elevated disopyramide concentrations and QT prolongation. Serious cardiovascular events including ECG changes (i.e., QT prolongation) and cardiac arrhythmias, including ventricular arrhythmias and torsade de pointes, may occur when these drugs are administered together. Itraconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation. Disopyramide is a CYP3A4 substrate that is associated with QT prolongation and torsade de pointes (TdP).
Docetaxel: (Major) Administration of docetaxel is not recommended during or for 2 weeks after discontinuation of itraconazole treatment 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 itraconazole is a strong CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased docetaxel exposure by 2.2-fold.
Dofetilide: (Contraindicated) Use of dofetilide during and for 2 weeks after discontinuation of itraconazole treatment is contraindicated due to the potential elevated dofetilide concentrations and QT prolongation. Serious cardiovascular events including EKG changes (i.e., QT prolongation), cardiac arrhythmias, including ventricular arrhythmias and torsade de pointes, cardiac arrest, and sudden death may occur when these drugs are administered together. Itraconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation. Dofetilide is a CYP3A4 substrate that is associated with QT prolongation and torsade de pointes (TdP).
Dolasetron: (Moderate) Administer dolasetron with caution in combination with itraconazole as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
Dolutegravir: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministered with itraconazole. Concomitant use may increase dolutegravir plasma concentrations. Dolutegravir is an in vitro substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); itraconazole inhibits both P-gp and BCRP.
Dolutegravir; Lamivudine: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministered with itraconazole. Concomitant use may increase dolutegravir plasma concentrations. Dolutegravir is an in vitro substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); itraconazole inhibits both P-gp and BCRP.
Dolutegravir; Rilpivirine: (Moderate) Caution is advised when administering itraconazole with rilpivirine due to the potential for additive effects on the QT interval, increased exposure to rilpivirine, and decreased exposure to itraconazole. Monitor for breakthrough fungal infections in patients receiving rilpivirine with an azole antifungal. Rilpivirine, a CYP3A4 substrate, and itraconazole, 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 itraconazole. (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministered with itraconazole. Concomitant use may increase dolutegravir plasma concentrations. Dolutegravir is an in vitro substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); itraconazole inhibits both P-gp and BCRP.
Donepezil: (Moderate) Use donepezil with caution in combination with itraconazole 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 itraconazole. Itraconazole 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 itraconazole 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 itraconazole. Itraconazole 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 itraconazole may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; itraconazole 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: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, concurrently with inhibitors of P-gp and BCRP, such as itraconazole. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (Minor) Coadministration of doravirine and itraconazole may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; itraconazole 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 itraconazole. Itraconazole 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: (Minor) Use itraconazole with caution in combination with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. 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). CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs; itraconazole may increase TCA concentrations via inhibition of CYP3A4. In at least one case, an increased incidence of TCA-related side effects, such as dizziness and syncope has occurred in combination with an azole antifungal. In another case, QT-prolongation and torsades de pointes occurred.
Doxercalciferol: (Moderate) Cytochrome P450 enzyme inhibitors, such as itraconazole, 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 itraconazole with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Itraconazole is a strong CYP3A4 inhibitor and an inhibitor of P-glycoprotein (P-gp). Doxorubicin is a major substrate of CYP3A4 and P-gp. Concurrent use of CYP3A4 or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of itraconazole with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Itraconazole is a strong CYP3A4 inhibitor and an inhibitor of P-glycoprotein (P-gp). Doxorubicin is a major substrate of CYP3A4 and P-gp. Concurrent use of CYP3A4 or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Dronabinol: (Major) Use caution if coadministration of dronabinol with itraconazole 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; itraconazole is a strong inhibitor of CYP3A4. Concomitant use may result in elevated plasma concentrations of dronabinol.
Dronedarone: (Contraindicated) Use of dronedarone during and for 2 weeks after discontinuation of itraconazole treatment is contraindicated due to the potential for elevated dronedarone concentrations and QT prolongation. Serious cardiovascular events such as EKG changes (i.e., QT prolongation) and cardiac arrhythmias, including ventricular arrhythmias and torsade de pointes, may occur. Dronedarone is a CYP3A4 substrate that is associated with a dose-related increase in the QTc interval. Itraconazole is a strong CYP3A4 substrate that is also associated with QT prolongation. Repeated doses of another strong CYP3A4 inhibitor increased dronedarone exposure 17-fold and increased dronedarone Cmax 9-fold.
Droperidol: (Major) Caution is advised when administering itraconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as droperidol. Both droperidol and itraconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with droperidol (a CYP3A4 substrate) may result in elevated droperidol plasma concentrations and an increased risk for adverse e vents, including QT prolongation. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
Drospirenone: (Moderate) Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Itraconazole is a strong CYP3A4 inhibitor 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. Itraconazole is a strong CYP3A4 inhibitor 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. Itraconazole is a strong CYP3A4 inhibitor 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 itraconazole 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. Itraconazole is a strong CYP3A4 inhibitor 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) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as itraconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Itraconazole is a strong CYP3A4 inhibitor 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) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as itraconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Dutasteride: (Moderate) Monitor for increased dutasteride adverse effects if coadministration of itraconazole is necessary. No clinical drug interaction trials have been performed to evaluate the impact of CYP3A enzyme inhibitors on dutasteride pharmacokinetics. However, based on in vitro data, blood concentrations of dutasteride may increase in the presence of inhibitors of CYP3A4 such as itraconazole.
Dutasteride; Tamsulosin: (Major) Use of tamsulosin is not recommended during and for 2 weeks after itraconazole therapy 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. 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 resulted in an increase in the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively. (Moderate) Monitor for increased dutasteride adverse effects if coadministration of itraconazole is necessary. No clinical drug interaction trials have been performed to evaluate the impact of CYP3A enzyme inhibitors on dutasteride pharmacokinetics. However, based on in vitro data, blood concentrations of dutasteride may increase in the presence of inhibitors of CYP3A4 such as itraconazole.
Duvelisib: (Major) Reduce duvelisib dose to 15 mg PO twice daily and monitor for increased toxicity when coadministered with itraconazole. Coadministration may increase the exposure of duvelisib. Duvelisib is a CYP3A substrate; itraconazole 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 itraconazole.
Edoxaban: (Major) Reduce the dose of edoxaban to 30 mg/day PO in patients being treated for deep venous thrombosis (DVT) or pulmonary embolism and receiving concomitant therapy with oral itraconazole. No dosage adjustment is required in patients with atrial fibrillation. Edoxaban is a P-glycoprotein (P-gp) substrate and oral itraconazole is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of itraconazole; monitor for increased adverse effects of edoxaban.
Efavirenz: (Major) Use of efavirenz is not recommended for 2 weeks before or during itraconazole therapy. Consider an alternative antifungal medication. Administering itraconazole with inducers of CYP3A4, such as efavirenz, may decrease the bioavailability of itraconazole and hydroxy-itraconazole to such an extent that efficacy could be reduced. Efavirenz is also partially metabolized by CYP3A4; taking efavirenz with itraconazole (a potent CYP3A4 inhibitor) may increase exposure to efavirenz. In addition, both drugs are associated with QT prolongation; coadministration may increase this risk.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Use of efavirenz is not recommended for 2 weeks before or during itraconazole therapy. Consider an alternative antifungal medication. Administering itraconazole with inducers of CYP3A4, such as efavirenz, may decrease the bioavailability of itraconazole and hydroxy-itraconazole to such an extent that efficacy could be reduced. Efavirenz is also partially metabolized by CYP3A4; taking efavirenz with itraconazole (a potent CYP3A4 inhibitor) may increase exposure to efavirenz. In addition, both drugs are associated with QT prolongation; coadministration may increase this risk. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, concurrently with inhibitors of P-gp and BCRP, such as itraconazole. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Use of efavirenz is not recommended for 2 weeks before or during itraconazole therapy. Consider an alternative antifungal medication. Administering itraconazole with inducers of CYP3A4, such as efavirenz, may decrease the bioavailability of itraconazole and hydroxy-itraconazole to such an extent that efficacy could be reduced. Efavirenz is also partially metabolized by CYP3A4; taking efavirenz with itraconazole (a potent CYP3A4 inhibitor) may increase exposure to efavirenz. In addition, both drugs are associated with QT prolongation; coadministration may increase this risk. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, concurrently with inhibitors of P-gp and BCRP, such as itraconazole. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Elacestrant: (Major) Avoid concomitant use of elacestrant and itraconazole due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and itraconazole is a strong CYP3A inhibitor. Concomitant use with itraconazole increased elacestrant overall exposure by 5.3-fold.
Elagolix: (Major) Concomitant use of elagolix 200 mg twice daily and itraconazole for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and itraconazole to 6 months. Monitor for elagolix-related side effects and reduced response to itraconazole. Elagolix is a CYP3A substrate and a weak to moderate CYP3A4 inducer; itraconazole is a strong inhibitor of CYP3A and a CYP3A4 substrate. Coadministration may increase elagolix plasma concentrations and decrease itraconazole 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 itraconazole for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and itraconazole to 6 months. Monitor for elagolix-related side effects and reduced response to itraconazole. Elagolix is a CYP3A substrate and a weak to moderate CYP3A4 inducer; itraconazole is a strong inhibitor of CYP3A and a CYP3A4 substrate. Coadministration may increase elagolix plasma concentrations and decrease itraconazole 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. (Minor) As itraconazole 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: (Major) Elbasvir is not recommended for use during and for 2 weeks after itraconazole therapy. Inhibition of CYP3A4 by itraconazole may significantly increase the plasma concentrations of elbasvir, resulting in adverse effects. Itraconazole is a strong inhibitor of CYP3A4; elbasvir is a CYP3A4 substrate. (Major) Grazoprevir is not recommended for use during and for 2 weeks after itraconazole therapy. Inhibition of CYP3A4 by itraconazole may significantly increase the plasma concentrations of grazoprevir, resulting in adverse effects. Itraconazole is a strong inhibitor of CYP3A4; grazoprevir is a CYP3A4 substrate.
Eletriptan: (Contraindicated) Eletriptan is contraindicated with recent use (i.e., within 72 hours) of itraconazole due to the potential for increased eletriptan exposure. Eletriptan is a sensitive substrate of CYP3A4; itraconazole 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 itraconazole 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 itraconazole 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 itraconazole; omit the evening dose of ivacaftor. Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; itraconazole is a strong CYP3A inhibitor. Coadministration 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 itraconazole; 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); itraconazole is a strong CYP3A inhibitor. Coadministration of itraconazole increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
Eliglustat: (Contraindicated) In intermediate or poor CYP2D6 metabolizers (IMs or PMs), eliglustat is contraindicated for use during and for 2 weeks after itraconazole therapy; recommendations for extensive CYP2D6 metabolizers (EMs) is less clear. In addition, use of eliglustat with a moderate or strong CYP2D6 inhibitor is contraindicated for use during and for 2 weeks after itraconazole therapy in all patients (i.e., IMs, PMs, and EMs). Both eliglustat and itraconazole can independently prolong the QT interval. Itraconazole is a strong CYP3A inhibitor and P-glycoprotein (P-gp) substrate; eliglustat is a CYP3A and CYP2D6 substrate and P-gp inhibitor. Both drugs have the potential to increase each other's blood concentrations, and therefore, further increase the risk of QT prolongation. Itraconazole's product labeling contraindicates coadministration of a number of other drugs that prolong the QT interval and are metabolized by CYP3A4. The product labeling of ketoconazole (another systemic azole and strong CYP3A inhibitor) carries the same contraindication, but pharmacokinetic data examining the interaction between ketoconazole and eliglustat support a dose reduction of eliglustat to 84 mg PO once daily in EMs rather than contraindication. However, extrapolation of this data to itraconazole must be undertaken with extreme caution because itraconazole is a P-gp substrate (ketoconazole is not), and eliglustat is a P-gp inhibitor. The additional risk that increased itraconazole exposure could pose is not known.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concurrent use of itraconazole with regimens containing cobicistat and atazanavir or darunavir. Use of these drugs together may result in increased plasma concentrations of itraconazole, cobicistat, atazanavir, and darunavir. Specific dosage recommendations have not been determined. (Moderate) Monitor for evidence of elvitegravir-related adverse reactions if coadministration is necessary. Itraconazole is a strong CYP3A4 inhibitor; elvitegravir is a CYP3A4 substrate.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concurrent use of itraconazole with regimens containing cobicistat and atazanavir or darunavir. Use of these drugs together may result in increased plasma concentrations of itraconazole, cobicistat, atazanavir, and darunavir. Specific dosage recommendations have not been determined. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, concurrently with inhibitors of P-gp and BCRP, such as itraconazole. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (Moderate) Monitor for evidence of elvitegravir-related adverse reactions if coadministration is necessary. Itraconazole is a strong CYP3A4 inhibitor; elvitegravir is a CYP3A4 substrate.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Caution is advised when administering itraconazole with rilpivirine due to the potential for additive effects on the QT interval, increased exposure to rilpivirine, and decreased exposure to itraconazole. Monitor for breakthrough fungal infections in patients receiving rilpivirine with an azole antifungal. Rilpivirine, a CYP3A4 substrate, and itraconazole, 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 itraconazole.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering itraconazole with rilpivirine due to the potential for additive effects on the QT interval, increased exposure to rilpivirine, and decreased exposure to itraconazole. Monitor for breakthrough fungal infections in patients receiving rilpivirine with an azole antifungal. Rilpivirine, a CYP3A4 substrate, and itraconazole, 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 itraconazole. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, concurrently with inhibitors of P-gp and BCRP, such as itraconazole. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, concurrently with inhibitors of P-gp and BCRP, such as itraconazole. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Encorafenib: (Major) Avoid coadministration of encorafenib and itraconazole due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of itraconazole. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If itraconazole is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of itraconazole. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; itraconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Enfortumab vedotin: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with itraconazole is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; itraconazole is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Entrectinib: (Major) Avoid coadministration of entrectinib with itraconazole 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 itraconazole is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of itraconazole. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; itraconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. Coadministration of itraconazole increased the AUC of entrectinib by 6-fold in a drug interaction study.
Enzalutamide: (Major) The use of enzalutamide within 2 weeks of itraconazole therapy is not recommended. If coadministration cannot be avoided, monitor for decreased efficacy of itraconazole; increase the dose of itraconazole as necessary. Itraconazole is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
Eplerenone: (Contraindicated) Eplerenone is contraindicated for use during and for 2 weeks after itraconazole therapy due to increased eplerenone exposure which increases the risk of developing hyperkalemia and hypotension. Itraconazole is a strong CYP3A4 inhibitor; eplerenone is a sensitive CYP3A4 substrate. Another strong CYP3A4 inhibitor increased serum eplerenone concentrations by roughly 5-fold.
Erdafitinib: (Major) Avoid the concomitant use of erdafitinib and itraconazole 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 itraconazole is discontinued, the dose of erdafitinib may be increased in the absence of drug-related toxicity. Erdafitinib is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. The mean ratios for the Cmax and AUC of erdafitinib were 105% and 134%, respectively, when coadministered with itraconazole.
Ergoloid Mesylates: (Contraindicated) Coadministration of ergot alkaloids with inhibitors of CYP3A4, such as itraconazole, or administration for 2 weeks after discontinuation of itraconazole treatment is contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
Ergot alkaloids: (Contraindicated) Coadministration of ergot alkaloids with inhibitors of CYP3A4, such as itraconazole, or administration for 2 weeks after discontinuation of itraconazole treatment is contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
Ergotamine: (Contraindicated) Coadministration of ergot alkaloids with inhibitors of CYP3A4, such as itraconazole, or administration for 2 weeks after discontinuation of itraconazole treatment is contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
Ergotamine; Caffeine: (Contraindicated) Coadministration of ergot alkaloids with inhibitors of CYP3A4, such as itraconazole, or administration for 2 weeks after discontinuation of itraconazole treatment is contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
Eribulin: (Major) Itraconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with itraconazole include eribulin.
Erlotinib: (Major) Avoid coadministration of erlotinib with itraconazole 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 itraconazole is a strong CYP3A4 inhibitor. Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment; the decline in plasma concentrations may be more gradual In patients with cirrhosis or receiving other CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
Erythromycin: (Major) Caution is advised when administering itraconazole with drugs that are known to prolong that QT interval, such as erythromycin. Both erythromycin and itraconazole are associated with QT prolongation; coadministration may increase this risk. In addition, itraconazole is a substrate of CYP3A4 and erythromycin is an inhibitor of CYP3A4. Coadministration may result in increased plasma concentrations of itraconazole, thereby further increasing the risk for adverse events.
Escitalopram: (Moderate) Concomitant use of escitalopram and itraconazole 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.
Estazolam: (Major) In theory, CYP3A4 inhibitors, such as itraconazole, may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity. Although one study using single oral doses of estazolam suggests that itraconazole has no effect on the pharmacokinetics or pharmacodynamics of estazolam, the manufacturer for Prosom recommends that estazolam should be avoided in patients receiving itraconazole.
Esterified Estrogens: (Minor) Monitor for estrogen-related side effects. Drugs that potently inhibit CYP3A4 such as certain systemic azole antifungals (e.g., itraconazole) may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Esterified estrogens contain a mixture of estrogenic substances, including estrone and . Estrogens are partially metabolized by CYP3A4.
Esterified Estrogens; Methyltestosterone: (Minor) Monitor for estrogen-related side effects. Drugs that potently inhibit CYP3A4 such as certain systemic azole antifungals (e.g., itraconazole) may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Esterified estrogens contain a mixture of estrogenic substances, including estrone and . Estrogens are partially metabolized by CYP3A4.
Estradiol: (Minor) As itraconazole 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 itraconazole 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: (Minor) As itraconazole 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 itraconazole 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 itraconazole with progesterone is necessary, as the systemic exposure of progesterone may be increased resulting in an increase in treatment-related adverse reactions. Itraconazole 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 itraconazole 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 adult dose of eszopiclone should not exceed 2 mg/day during coadministration of potent CYP3A4 inhibitors, such as ketoconazole or itraconazole. CYP3A4 is a primary metabolic pathway for eszopiclone, and increased systemic exposure to eszopiclone increases the risk of next-day psychomotor or memory impairment, which may decrease the ability to perform tasks requiring full mental alertness such as driving. A pharmacokinetic study of ketoconazole coadministered with eszopiclone resulted in a 2.2-fold increase in eszopiclone AUC. Although other azole antifungals (e.g., fluconazole, voriconazole) inhibit CYP3A4 to a lesser extent than ketoconazole or itraconazole, a clinically relevant interaction is possible, and dose adjustments of eszopiclone may be necessary.
Ethinyl Estradiol; Norelgestromin: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as itraconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Ethinyl Estradiol; Norethindrone Acetate: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as itraconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Ethinyl Estradiol; Norgestrel: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as itraconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Ethosuximide: (Moderate) Itraconazole may inhibit the metabolism of ethosuximide and may necessitate up to a 50% dose reduction of ethosuximide.
Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as itraconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Etonogestrel: (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as itraconazole may increase the serum concentration of etonogestrel.
Etonogestrel; Ethinyl Estradiol: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as itraconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as itraconazole may increase the serum concentration of etonogestrel.
Etravirine: (Moderate) Itraconazole is a potent inhibitor and a substrate of CYP3A4. Etravirine is a substrate and an inducer of CYP3A4. Coadministration with itraconazole may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole may be decreased by etravirine. Dose adjustments for itraconazole may be necessary when coadministered with etravirine. Monitor patients closely for etravirine-related adverse effects and for efficacy of itraconazole.
Everolimus: (Major) Avoid coadministration of everolimus with itraconazole 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 a P-glycoprotein (P-gp) substrate. Itraconazole is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
Ezetimibe; Simvastatin: (Contraindicated) Simvastatin is contraindicated for use during and for 2 weeks after itraconazole therapy. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if simvastatin is administered concomitantly with potent CYP3A4 inhibitors such as itraconazole. If therapy with itraconazole is unavoidable, simvastatin therapy must be suspended during the course of itraconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
Famotidine: (Moderate) When administering H2-blockers with the 100 mg itraconazole capsule and 200 mg itraconazole tablet formulations, systemic exposure to itraconazole is decreased. Conversely, exposure to itraconazole is increased when H2-blockers are administered with the 65 mg itraconazole capsule. Administer H2-blockers at least 2 hours before or 2 hours after the 100 mg capsule or 200 mg tablet. Monitor for increased itraconazole-related adverse effects if H2-blockers are administered with itraconazole 65 mg capsules.
Fedratinib: (Major) Avoid coadministration of fedratinib with itraconazole as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If itraconazole 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. Fedratinib is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
Felodipine: (Contraindicated) Felodipine is contraindicated for use during and for 2 weeks after itraconazole therapy. Itraconazole is an inhibitor of CYP3A4, which increases the plasma concentrations (AUC) and Cmax of felodipine by 6- and 8-fold, respectively. Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. Edema has been reported in patients receiving itraconazole and dihydropyridine calcium-channel blockers concomitantly.
Fentanyl: (Major) Avoid use of fentanyl during and for 2 weeks after itraconazole therapy. Concomitant use may increase fentanyl plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of fentanyl until stable drug effects are achieved. Discontinuation of itraconazole could decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to fentanyl. If itraconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Fentanyl is a substrate for CYP3A4. Itraconazole is a potent inhibitor of CYP3A4.
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 itraconazole. Avoid use of fesoterodine and itraconazole in pediatric patients weighing 25 to 35 kg. Concurrent use may increase fesoterodine exposure. Fesoterodine is a CYP3A4 substrate and itraconazole 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 use of tadalafil for the treatment of pulmonary hypertension during and for 2 weeks after discontinuation of itraconazole treatment. For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of itraconazole for the as needed dose or 2.5 mg daily for the once-daily dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as itraconazole, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Finerenone: (Contraindicated) Concomitant use of finerenone and itraconazole is contraindicated. Concomitant use may increase finerenone exposure and the risk for finerenone-related adverse reactions. Finerenone is a CYP3A substrate and itraconazole is a strong CYP3A inhibitor. Coadministration with itraconazole increased overall exposure to finerenone by more than 400%.
Fingolimod: (Moderate) Exercise caution when administering fingolimod concomitantly with itraconazole 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 torsade de pointes (TdP) in patients with bradycardia. Itraconazole has been associated with prolongation of the QT interval.
Flavoxate: (Moderate) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole.
Flecainide: (Major) Itraconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with itraconazole include flecainide.
Flibanserin: (Contraindicated) The concomitant use of flibanserin and strong CYP3A4 inhibitors, such as itraconazole, 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: (Major) Typically fluconazole and itraconazole would not be used in combination due to similar mechanisms of action and indications for use (duplicate therapies). Fluconazole may inhibit the CYP3A4 metabolism of itraconazole, resulting in increased itraconazole serum concentrations. Furthermore, all systemic azole antifungal agents have been associated with prolongation of the QT interval. Coadministration would increase the risk of QT prolongation.
Fluoxetine: (Moderate) Concomitant use of fluoxetine and itraconazole 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) Use itraconazole with caution in combination with fluphenazine as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Flurazepam: (Moderate) CYP3A4 inhibitors, such as itraconazole, may reduce the metabolism of flurazepam and increase the potential for benzodiazepine toxicity. Monitor patients closely who receive concurrent therapy. Reduced flurazepam dosages or avoidance of benzodiazepine use may be recommended in selected situations.
Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and itraconazole is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Salmeterol: (Major) Avoid concomitant use of salmeterol with itraconazole. 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 itraconazole 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. (Major) Coadministration of inhaled fluticasone propionate and itraconazole is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Umeclidinium; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and itraconazole is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Moderate) Use itraconazole with caution in combination with beta-agonists as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Fluticasone; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and itraconazole is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Moderate) Use itraconazole with caution in combination with beta-agonists as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Fluvoxamine: (Moderate) Use caution as there may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and itraconazole. Itraconazole has been associated with prolongation of the QT interval. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Food: (Major) Advise patients to avoid cannabis use during itraconazole 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 substrates and itraconazole is a strong CYP3A 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. (Moderate) Oral bioavailability of itraconazole from the capsules is increased if administered with a meal or cola beverage. Administration with orange juice should be avoided.
Formoterol: (Moderate) Use itraconazole with caution in combination with beta-agonists as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Formoterol; Mometasone: (Moderate) Concomitant administration of itraconazole and mometasone may increase systemic exposure to mometasone, increasing the risk of corticosteroid-related adverse events. Exercise caution when administering mometasone with itraconazole long-term and monitor closely for hypercorticism and adrenal suppression. Mometasone is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. (Moderate) Use itraconazole with caution in combination with beta-agonists as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Fosamprenavir: (Moderate) Monitor for increased toxicity of both drugs if fosamprenavir is coadministered with itraconazole; an itraconazole dose reduction may be needed for patients receiving more than 400 mg/day. Concurrent use may increase the plasma concentrations of both drugs. Fosamprenavir is a CYP3A substrate and moderate CYP3A inhibitor; itraconazole is a CYP3A substrate and strong CYP3A inhibitor.
Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as itraconazole. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Itraconazole has also been associated with prolongation of the QT interval. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
Fosphenytoin: (Major) Phenytoin has been shown to reduce itraconazole AUC and half-life. The mechanism appears to be enhanced first-pass and CYP3A4 hepatic enzyme metabolism of itraconazole. Additionally, itraconazole may increase phenytoin AUC. In general, this drug combination should be avoided, as the serum concentrations of the azole antifungal may be drastically subtherapeutic.
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; itraconazole is a strong CYP3A4 inhibitor. Coadministration of fostamatinib with another strong CYP3A4 inhibitor increased R406 AUC by 102% and Cmax by 37%.
Fostemsavir: (Moderate) Use itraconazole with caution in combination with fostemsavir. Itraconazole has been associated with prolongation of the QT interval. 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.
Futibatinib: (Major) Avoid concurrent use of futibatinib and itraconazole. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; itraconazole is a dual P-gp and strong CYP3A inhibitor. Coadministration with itraconazole increased futibatinib exposure by 41%.
Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with itraconazole is necessary. Gefitinib is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole increased gefitinib exposure by 80%.
Gemifloxacin: (Moderate) Gemifloxacin should be used cautiously with itraconazole as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Gemifloxacin may 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 itraconazole 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. Itraconazole has been associated with prolongation of the QT interval.
Gilteritinib: (Major) Consider an alternative to itraconazole 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; itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation.
Glasdegib: (Major) Avoid use of glasdegib during and for 2 weeks after discontinuation of itraconazole therapy due to the potential for increased glasdegib exposure and additive effects on the QT interval. 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. Itraconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and itraconazole as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Glecaprevir and itraconazole are both substrates and inhibitors of P-glycoprotein (P-gp). In addition, itraconazole inhibits breast cancer resistance protein (BCRP); glecaprevir is a BCRP substrate. (Moderate) Caution is advised with the coadministration of pibrentasvir and itraconazole as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Both pibrentasvir and itraconazole are substrates and inhibitors of P-glycoprotein (P-gp). In addition, itraconazole inhibits breast cancer resistance protein (BCRP); pibrentasvir is a BCRP substrate.
Glycopyrrolate: (Moderate) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole.
Glycopyrrolate; Formoterol: (Moderate) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole. (Moderate) Use itraconazole with caution in combination with beta-agonists as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Goserelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., goserelin) outweigh the potential risks of QT prolongation in patients receiving itraconazole as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Androgen deprivation therapy may also prolong the QT/QTc interval.
Granisetron: (Moderate) Use itraconazole with caution in combination with granisetron as concurrent use may increase the risk of QT prolongation. Itraconazole and granisetron have been associated with prolongation of the QT interval.
Grapefruit juice: (Minor) Grapefruit juice reduced the mean peak itraconazole concentration by 35 percent when itraconazole capsules were administered with grapefruit juice in healthy volunteers; the AUC was reduced by an average of 43 percent compared to administration with water. Conversely, another study reported that grapefruit juice did not significantly affect the bioavailability of itraconazole capsules.
Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of itraconazole 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 itraconazole 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 itraconazole 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) Itraconazole may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased 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. Upon itraconazole discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and itraconazole is a strong CYP3A4 inhibitor.
H2-blockers: (Moderate) When administering H2-blockers with the 100 mg itraconazole capsule and 200 mg itraconazole tablet formulations, systemic exposure to itraconazole is decreased. Conversely, exposure to itraconazole is increased when H2-blockers are administered with the 65 mg itraconazole capsule. Administer H2-blockers at least 2 hours before or 2 hours after the 100 mg capsule or 200 mg tablet. Monitor for increased itraconazole-related adverse effects if H2-blockers are administered with itraconazole 65 mg capsules.
Halogenated Anesthetics: (Major) Itraconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with itraconazole include halogenated anesthetics.
Haloperidol: (Moderate) Use itraconazole 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. Itraconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. 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 itraconazole as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. 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 itraconazole 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 itraconazole 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 itraconazole 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: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of itraconazole 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 itraconazole 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 itraconazole 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 itraconazole 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 itraconazole 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 itraconazole 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.
Hy drocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of itraconazole 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 itraconazole 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 itraconazole 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.
Hydroxychloroquine: (Major) Concomitant use of itraconazole and hydroxychloroquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. 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.
Hydroxyzine: (Moderate) Concomitant use of hydroxyzine and itraconazole 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.
Hyoscyamine: (Moderate) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole.
Ibrexafungerp: (Major) Decrease the ibrexafungerp dose to 150 mg PO every 12 hours for 1 day if administered concurrently with itraconazole. Coadministration may result in increased ibrexafungerp exposure and toxicity. Ibrexafungerp is a CYP3A substrate and itraconazole 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) Avoid ibrutinib use during and for 2 weeks after discontinuation of itraconazole treatment. If short-term use of itraconazole is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when itraconazole is discontinued. Taking these drugs together may result in increased ibrutinib plasma concentrations, resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Ibuprofen; Famotidine: (Moderate) When administering H2-blockers with the 100 mg itraconazole capsule and 200 mg itraconazole tablet formulations, systemic exposure to itraconazole is decreased. Conversely, exposure to itraconazole is increased when H2-blockers are administered with the 65 mg itraconazole capsule. Administer H2-blockers at least 2 hours before or 2 hours after the 100 mg capsule or 200 mg tablet. Monitor for increased itraconazole-related adverse effects if H2-blockers are administered with itraconazole 65 mg capsules.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of itraconazole is necessary. If itraconazole 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 itraconazole 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 itraconazole 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.
Ibutilide: (Major) Itraconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with itraconazole include ibutilide.
Idelalisib: (Moderate) Monitor for increased idelalisib and itraconazole adverse reactions if coadministration is necessary. A dose reduction of either agent may be necessary. Both itraconazole and idelalisib are strong CYP3A4 inhibitors and substrates.
Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with itraconazole is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Itraconazole 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 itraconazole and iloperidone. If concurrent use is necessary, the iloperidone dose should be reduced by one-half. Coadministration of itraconazole (a strong CYP3A4 inhibitor) with iloperidone (a CYP3A4 substrate) may result in elevated iloperidone plasma concentrations and could increase the risk for adverse events, including QT prolongation. If itraconazole is subsequently withdrawn, the iloperidone dose should be returned to the previous amount. In addition, both iloperidone and itraconazole are associated with QT prolongation; coadministration may increase this risk.
Imatinib: (Moderate) Use caution if coadministration of itraconazole and imatinib is necessary due to increased imatinib exposure and adverse effects. Imatinib is a CYP3A4 and breast cancer resistance protein (BCRP) substrate; and itraconazole is a BCRP inhibitor and strong CYP3A4 inhibitor. Coadminsitration of another CYP3A4 inhibitor increased imatinib exposure by 40%.
Imipramine: (Minor) Use itraconazole with caution in combination with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. 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). CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs; itraconazole may increase TCA concentrations via inhibition of CYP3A4. In at least one case, an increased incidence of TCA-related side effects, such as dizziness and syncope has occurred in combination with an azole antifungal. In another case, QT-prolongation and torsades de pointes occurred.
Indacaterol: (Major) Although no dosage adjustment of the 75 mcg/day indacaterol dose is needed, avoid use if possible. Consider alternatives. By inhibiting CYP3A4 and P-gp, itraconazole inhibits indacaterol metabolism. In drug interaction studies, coadministration of indacaterol inhalation powder 300 mcg (single dose) with another systemic azole antifungal with similar CYP3A4/P-gp activity caused a 1.9-fold increase in indacaterol exposure (AUC), and a 1.3-fold increase in indacaterol maximal concentration (Cmax). This may result in indacaterol side effects like tremor, nervousness, or a fast, irregular heart rate. Itraconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with itraconazole include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
Indacaterol; Glycopyrrolate: (Major) Although no dosage adjustment of the 75 mcg/day indacaterol dose is needed, avoid use if possible. Consider alternatives. By inhibiting CYP3A4 and P-gp, itraconazole inhibits indacaterol metabolism. In drug interaction studies, coadministration of indacaterol inhalation powder 300 mcg (single dose) with another systemic azole antifungal with similar CYP3A4/P-gp activity caused a 1.9-fold increase in indacaterol exposure (AUC), and a 1.3-fold increase in indacaterol maximal concentration (Cmax). This may result in indacaterol side effects like tremor, nervousness, or a fast, irregular heart rate. Itraconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with itraconazole include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. (Moderate) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole.
Indinavir: (Major) Monitor for increased indinavir and itraconazole adverse reactions if coadministration is necessary. Dose reduction of indinavir to 600 mg every 8 hours is recommended when administering itraconazole 200 mg twice daily concurrently. An itraconazole dose reduction may also be necessary. Both itraconazole and indinavir are strong CYP3A4 inhibitors and substrates.
Infigratinib: (Major) Avoid concomitant use of infigratinib and itraconazole. Coadministration may increase infigratinib exposure, increasing the risk for adverse effects. Infigratinib is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration increased the AUC of infigratinib by 622%.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with itraconazole due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Both inotuzumab and itraconazole have been associated with QT prolongation.
Irinotecan Liposomal: (Contraindicated) According to the manufacturer of itraconazole, the use of irinotecan is contraindicated for use during and for 2 weeks after discontinuation of itraconazole therapy. The manufacturer of irinotecan recommends that any strong CYP3A4 inhibitor be discontinued at least 1 week prior to starting irinotecan liposomal therapy. Itraconazole is a strong CYP3A4 inhibitor; irinotecan is metabolized extensively by CYP3A4 and UGT1A1. Exposure to irinotecan and to the active metabolite, SN-38, is increased when the drugs are used together, which can cause severe toxicity, including neutropenia and severe and life-threatening diarrhea.
Irinotecan: (Contraindicated) According to the manufacturer of itraconazole, the use of irinotecan is contraindicated for use during and for 2 weeks after discontinuation of itraconazole therapy. The manufacturer of irinotecan recommends that any strong CYP3A4 inhibitor be discontinued at least 1 week prior to starting irinotecan liposomal therapy. Itraconazole is a strong CYP3A4 inhibitor; irinotecan is metabolized extensively by CYP3A4 and UGT1A1. Exposure to irinotecan and to the active metabolite, SN-38, is increased when the drugs are used together, which can cause severe toxicity, including neutropenia and severe and life-threatening diarrhea.
Isavuconazonium: (Contraindicated) Isavuconazonium is contraindicated for use with and for 2 weeks after itraconazole therapy, due to the risk for increased isavuconazole serum concentrations and serious adverse reactions, such as hepatic toxicity. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of hepatic isoenzyme CYP3A4; itraconazole is a strong inhibitor of this enzyme. Isavuconazole serum concentrations were increased 5-fold when coadministered with another strong CYP3A4 inhibitor. Elevated itraconazole concentrations would also be expected with coadministration, as itraconazole is a substrate and isavuconazole is an inhibitor of CYP3A4 and the drug transporter P-glycoprotein (P-gp).
Isoflurane: (Major) Itraconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with itraconazole include halogenated anesthetics.
Isoniazid, INH: (Major) Use of isoniazid is not recommended for 2 weeks before or during itraconazole therapy. Isoniazid may reduce itraconazole serum concentrations resulting in antifungal treatment failure.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) The use of rifampin within 2 weeks of itraconazole therapy is not recommended. If coadministration cannot be avoided, monitor for decreased efficacy of itraconazole and increase the dose of itraconazole as necessary. Itraconazole is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. (Major) Use of isoniazid is not recommended for 2 weeks before or during itraconazole therapy. Isoniazid may reduce itraconazole serum concentrations resulting in antifungal treatment failure.
Isoniazid, INH; Rifampin: (Major) The use of rifampin within 2 weeks of itraconazole therapy is not recommended. If coadministration cannot be avoided, monitor for decreased efficacy of itraconazole and increase the dose of itraconazole as necessary. Itraconazole is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. (Major) Use of isoniazid is not recommended for 2 weeks before or during itraconazole therapy. Isoniazid may reduce itraconazole serum concentrations resulting in antifungal treatment failure.
Isradipine: (Moderate) Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. In addition, itraconazole may increase isradipine serum concentrations via inhibition of CYP3A4 with the potential for isradipine toxicity. Edema has been reported in patients receiving concomitantly itraconazole and dihydropyridine calcium-channel blockers; therefore, caution is recommended when administering these medications in combination. A dosage reduction of the calcium-channel blocker may be appropriate.
Istradefylline: (Major) Do not exceed 20 mg once daily of istradefylline if administered with itraconazole as istradefylline exposure and adverse effects may increase. Itraconazole 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) Ivabradine is contraindicated for use during and for 2 weeks after itraconazole therapy. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances. Ivabradine is primarily metabolized by CYP3A4; itraconazole is a strong CYP3A4 inhibitor.
Ivacaftor: (Major) If itraconazole 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 itraconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Ivosidenib: (Major) Do not coadminister ivosidenib with itraconazole due to decreased exposure to itraconazole and loss of antifungal efficacy. Additionally, ivosidenib exposure may increase which increases the risk of QT prolongation. If a patient has received itraconazole, reduce the initial dose of ivosidenib to 250 mg PO once daily and wait at least 5 half-lives of itraconazole after stopping therapy before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and inducer, and has been associated with QTc prolongation as well as ventricular arrhythmias. Itraconazole is a CYP3A4 substrate and strong inhibitor that has also been associated with QT prolongation. Coadministration with itraconazole 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 itraconazole, to a clinically relevant extent.
Ixabepilone: (Major) Avoid concurrent use of ixabepilone and itraconazole 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 itraconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ixabepilone exposure by 79%.
Ketoconazole: (Major) Typically ketoconazole and itraconazole would not be used in combination due to similar mechanisms of action and indications for use (duplicate therapies). Both itraconazole and ketoconazole are substrates and inhibitors of CYP3A4; taking these drugs together may increase the serum concentrations of both drugs. Furthermore, all systemic azole antifungal agents have been associated with prolongation of the QT interval. Coadministration would increase the risk of QT prolongation.
Lacosamide: (Moderate) Use caution during concurrent use of lacosamide and itraconazole, particularly in patients with renal or hepatic impairment. Lacosamide is a CYP3A4 substrate; itraconazole is a potent inhibitor of CYP3A4. Patients with renal or hepatic impairment may have significantly increased exposure to lacosamide if coadministered with a strong CYP3A4 inhibitor. Dosage reduction of lacosamide may be necessary in this population.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, concurrently with inhibitors of P-gp and BCRP, such as itraconazole. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Caution is advised when administering itraconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as clarithromycin. Consider use of azithromycin in place of clarithromycin. Both clarithromycin and itraconazole are associated with QT prolongation; coadministration may increase this risk. 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. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors. Azithromycin can be considered as an alternative macrolide antimicrobial if appropriate for the clinical circumstance, due to its lack of metabolism via CYP3A4.
Lapatinib: (Major) Avoid administration of lapatinib during and for 2 weeks after discontinuation of itraconazole therapy. If concurrent use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. Monitor for an increase in lapatinib-related adverse reactions and for evidence of QT prolongation. If itraconazole 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. Itraconazole is a strong CYP3A4 inhibitor that has also been associated with prolongation of the QT interval. 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 Itraconazole due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If itraconazole is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of itraconazole. Larotrectinib is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Ledipasvir; Sofosbuvir: (Minor) Itraconazole and ledipasvir may be given together with caution and close monitoring. Taking these drugs together may increase plasma concentrations of ledipasvir. Ledipasvir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor; itraconazole is a P-gp and BCRP inhibitor. (Minor) Itraconazole and sofosbuvir may be given together with caution. Taking these drugs together may increase plasma concentrations of sofosbuvir, without increasing GS-331007 plasma concentrations. Sofosbuvir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor; itraconazole is a P-gp and BCRP inhibitor.
Lefamulin: (Major) Avoid coadministration of lefamulin with itraconazole 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 and P-gp 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. Itraconazole is a P-gp and strong CYP3A4 inhibitor that is also associated with QT prolongation. Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Leflunomide: (Moderate) A pharmacodynamic interaction may occur when leflunomide is given concomitantly with other hepatotoxic drugs including itraconazole. The potential for hepatotoxicity should also be considered when such medications would be prescribed after leflunomide administration has ceased, if the patient has not received the leflunomide elimination procedure.
Lemborexant: (Major) Avoid coadministration of lemborexant and itraconazole as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. In a drug interaction study, itraconazole increased the lemborexant AUC by up to 4.5-fold.
Leniolisib: (Major) Avoid concomitant use of leniolisib and itraconazole due to the risk for increased leniolisib exposure which may increase the risk for adverse effects. Leniolisib is a CYP3A substrate and itraconazole is a strong CYP3A inhibitor. Concomitant use increased leniolisib overall exposure by 2-fold.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with itraconazole due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Itraconazole has also been associated with prolongation of the QT interval.
Leuprolide: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving itraconazole as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. 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 itraconazole as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Androgen deprivation therapy may also prolong the QT/QTc interval.
Levamlodipine: (Moderate) Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. In addition, itraconazole may increase amlodipine serum concentrations via inhibition of CYP3A4 with the potential for amlodipine toxicity. Edema has been reported in patients receiving concomitantly itraconazole and amlodipine, therefore, caution is recommended when administering these medications in combination. A dosage reduction of the calcium-channel blocker may be appropriate.
Levofloxacin: (Moderate) Concomitant use of levofloxacin and itraconazole 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.
Levoketoconazole: (Major) Typically ketoconazole and itraconazole would not be used in combination due to similar mechanisms of action and indications for use (duplicate therapies). Both itraconazole and ketoconazole are substrates and inhibitors of CYP3A4; taking these drugs together may increase the serum concentrations of both drugs. Furthermore, all systemic azole antifungal agents have been associated with prolongation of the QT interval. Coadministration would increase the risk of QT prolongation.
Levomilnacipran: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors. Itraconazole is considered a strong inhibitor of CYP3A4. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention.
Levonorgestrel; Ethinyl Estradiol: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as itraconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as itraconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as itraconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Lidocaine: (Moderate) Concomitant use of systemic lidocaine and itraconazole may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; itraconazole inhibits CYP3A4.
Lidocaine; Epinephrine: (Moderate) Concomitant use of systemic lidocaine and itraconazole may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; itraconazole inhibits CYP3A4.
Lidocaine; Prilocaine: (Moderate) Concomitant use of systemic lidocaine and itraconazole may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; itraconazole inhibits CYP3A4.
Lithium: (Moderate) Concomitant use of lithium and itraconazole 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 itraconazole due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Itraconazole has been associated with prolongation of the QT interval.
Lomitapide: (Contraindicated) Lomitapide is contraindicated for use during and for 2 weeks after itraconazole therapy. Itraconazole is a strong CYP3A4 inhibitor; exposure to lomitapide was increased 27-fold in the presence of another strong CYP3A4 inhibitor.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and itraconazole is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Loperamide: (Contraindicated) Avoid concomitant use of loperamide and itraconazole 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 and P-gp substrate and itraconazole is a strong CYP3A and P-gp inhibitor. Coadministration with itraconazole increased loperamide exposure by 3.8-fold.
Loperamide; Simethicone: (Contraindicated) Avoid concomitant use of loperamide and itraconazole 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 and P-gp substrate and itraconazole is a strong CYP3A and P-gp inhibitor. Coadministration with itraconazole increased loperamide exposure by 3.8-fold.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with itraconazole 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. Both drugs have been associated with QT prolongation. (Major) When administering itraconazole with ritonavir or ritonavir-containing drugs, do not exceed the maximum recommended itraconazole dose of 200 mg per day. Concurrent administration may result in increased exposure to both drugs. Monitor patients for itraconazole and ritonavir-associated adverse effects. Both itraconazole and ritonavir are strong CYP3A4 inhibitors and substrates.
Lorlatinib: (Major) Avoid coadministration of lorlatinib with itraconazole if possible due to the increased risk of lorlatinib-related adverse reactions; itraconazole exposure may also decrease. 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 itraconazole is discontinued, resume the original dose of lorlatinib after 3 half-lives of itraconazole. Lorlatinib is a CYP3A substrate and moderate inducer. Itraconazole is a CYP3A substrate and strong inhibitor. Coadministration with itraconazole increased lorlatinib exposure by 42%.
Lovastatin: (Contraindicated) Lovastatin is contraindicated for use during and for 2 weeks after itraconazole therapy due to the substantial increased risk of developing myopathy, rhabdomyolysis, and acute renal failure. In a small, double-blind study in healthy volunteers, lovastatin mean peak concentrations and lovastatin AUC increased by more than 20-fold when subjects were pretreated with itraconazole. Although side effects were not reported, one patient experienced a 10-fold increase in creatine kinase. One other case is noted of a patient who developed rhabdomyolysis when itraconazole was added to a stable regimen of lovastatin and niacin. Because pravastatin does not significantly rely on the CYP3A4 isoenzyme for metabolism, it is less likely to exhibit an interaction with the azole antifungals. Compared to a 19 to 20-fold increase in lovastatin AUC with concurrent itraconazole, the AUC of pravastatin is increased 1.7-fold when coadministered with itraconazole. The relatively small increase in pravastatin AUC during itraconazole therapy is postulated by the manufacturer to be due to inhibition of P-glycoprotein transport.
Lumacaftor; Ivacaftor: (Major) Avoid lumacaftor; ivacaftor use during and for up to 2 weeks before and after itraconazole treatment. Lumacaftor; ivacaftor may decrease the therapeutic efficacy of itraconazole. Consider alternative antifungals such as fluconazole. If concomitant use of itraconazole is necessary, monitor for antifungal efficacy and adjust the dosage as appropriate. Lumacaftor; ivacaftor dosage adjustment is not required when itraconazole is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking itraconazole, 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 itraconazole. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Itraconazole is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of itraconazole and decrease its therapeutic efficacy. Although itraconazole 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 itraconazole increased ivacaftor exposure by 4.3-fold. Lastly, itraconazole is also a substrate for P-glycoprotein (P-gp) efflux, and lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect on P-gp substrates is not clear, but their exposure may be affected.
Lumacaftor; Ivacaftor: (Major) If itraconazole 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 itraconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Lumateperone: (Major) Reduce the dose of lumateperone to 10.5 mg once daily if concomitant use of itraconazole is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole increased the lumateperone AUC by approximately 4-fold.
Lurasidone: (Contraindicated) Lurasidone is contraindicated for use during and for 2 weeks after itraconazole therapy due to the potential for significantly increased lurasidone exposure. Lurasidone is primarily metabolized by CYP3A4; itraconazole is a strong CYP3A4 inhibitor.
Lurbinectedin: (Major) Avoid concomitant use of lurbinectedin and itraconazole 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 itraconazole is a strong CYP3A inhibitor. Coadministration 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 itraconazole. 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. Itraconazole has been associated with prolongation of the QT interval.
Macitentan: (Major) Avoid concurrent use of macitentan and itraconazole. Itraconazole is a strong inhibitor of CYP3A4. Coadministration of macitentan with another strong CYP3A4 inhibitor (ketoconazole) approximately doubles macitentan exposure. Consider alternative treatment options for pulmonary hypertension if treatment with itraconazole is necessary.
Maprotiline: (Moderate) Use itraconazole with caution in combination with maprotiline as concurrent use may increase the risk of QT prolongation. The plasma concentration of maprotiline may also be increased; a maprotiline dosage adjustment may be necessary. Itraconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. Maprotiline is a CYP3A4 substrate that 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 torsade de pointes (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.
Maraviroc: (Major) Reduce the dose of maraviroc when coadministered with itraconazole; coadministration is contraindicated in patients with CrCl less than 30 mL/min. Coadministration of maraviroc, a CYP3A/P-gp substrate, with itraconazole, a strong CYP3A4 inhibitor and P-gp inhibitor, may result in increased maraviroc concentrations. Maraviroc dosage adjustments are as follows when administered with itraconazole (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 itraconazole due to risk of heart failure due to systolic dysfunction. Concomitant use increases mavacamten exposure. Mavacamten is a CYP3A substrate and itraconazole is a strong CYP3A inhibitor. Concomitant use with a strong CYP3A inhibitor is predicted to increase mavacamten overall exposure up to 130%.
Medroxyprogesterone: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with itraconazole, 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.
Mefloquine: (Major) Caution is advised when administering itraconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as mefloquine. Both mefloquine and itraconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with mefloquine (a CYP3A4 substrate) may result in elevated mefloquine plasma concentrations and an increased risk for adverse events, including QT prolongation. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
Meloxicam: (Major) Concomitant use of itraconazole and meloxicam may result in decreased plasma concentrations of meloxicam. Caution should be used when meloxicam is used concurrently with itraconazole and its effects should be monitored; dosage adjustment of meloxicam may be required.
Metformin; Repaglinide: (Major) Coadministration of itraconazole and repaglinide increases the AUC of repaglinide by 1.4-fold; if coadministration is necessary, consider a dose reduction of repaglinide and increased frequency of glucose monitoring. Itraconazole is a CYP3A4 inhibitor and repaglinide is a CYP3A4 substrate. The possibility of an increased risk of hypoglycemia should be considered during concomitant use of itraconazole and repaglinide.
Metformin; Saxagliptin: (Major) Do not exceed 2.5 mg PO daily of saxagliptin when combined with itraconazole; monitor for evidence of hypoglycemia. Itraconazole is a strong CYP3A4 inhibitor; saxagliptin is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the saxagliptin AUC up to 3.7-fold.
Methadone: (Contraindicated) Methadone is contraindicated for use during and for 2 weeks after itraconazole therapy. Serious cardiovascular events including EKG changes (i.e., QT prolongation) and cardiac arrhythmias, including ventricular arrhythmias and torsade de pointes, cardiac arrest, and/or sudden death have occurred when these drugs were administered together. Methadone is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole.
Methotrexate: (Moderate) Systemic exposure of methotrexate, a substrate of the drug transporter breast cancer resistance protein (BCRP), may be increased when administered concurrently with itraconazole, a BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of methotrexate; monitor patients for potential adverse effects.
Methscopolamine: (Major) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole.
Methylergonovine: (Contraindicated) Coadministration of ergot alkaloids with inhibitors of CYP3A4, such as itraconazole, or administration for 2 weeks after discontinuation of itraconazole treatment is contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
Methylprednisolone: (Moderate) Itraconazole may inhibit the metabolism of methylprednisolone via hepatic CYP3A4 inhibition. Several published reports note that itraconazole decreases the clearance and increases the elimination half-life of methylprednisolone, resulting in increased exposure to methylprednisolone. The interaction can result in enhanced adrenal suppression.
Metronidazole: (Moderate) Concomitant use of metronidazole and itraconazole 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.
Micafungin: (Moderate) Micafungin was shown to increase the systemic exposure (AUC) of itraconazole by 22% in a pharmacokinetic study. The mechanism of this interaction has not been identified, as micafungin does not significantly affect CYP450 enzymes or P-glycoprotein (P-gp). Itraconazole is not known to alter the pharmacokinetic parameters of micafungin. Patients should be evaluated for itraconazole-related side effects during concurrent therapy; itraconazole dosage adjustment may be necessary.
Midazolam: (Contraindicated) Oral midazolam is contraindicated for use during and for 2 weeks after itraconazole therapy due to significantly increased exposure to midazolam. The significance of an interaction between itraconazole and IV midazolam is uncertain, but may be less significant due to absence of an effect on pre-systemic midazolam clearance. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with itraconazole, as these benzodiazepines are not oxidatively metabolized. A study using single oral doses of estazolam showed that itraconazole had no effect on the pharmacokinetics or pharmacodynamics of estazolam. Itraconazole is a strong CYP3A4 inhibitor; midazolam is a sensitive CYP3A4 substrate.
Midostaurin: (Major) Avoid the concomitant use of midostaurin and itraconazole 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 itraconazole is a strong CYP3A4 inhibitor. Coadministration of itraconazole 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 itraconazole 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 itraconazole, initiate mifepristone at a dose of 300 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with itraconazole is initiated in a patient already receiving mifepristone 300 mg, dosage adjustments are not required. If therapy with itraconazole 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 itraconazole 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 itraconazole is initiated in a patient already receiving 1,200 mg, reduce the mifepristone dose to 900 mg. Both mifepristone and itraconazole are substrates and strong inhibitors of CYP3A4 that are associated with QT prolongation.
Mirtazapine: (Moderate) Use itraconazole with caution in combination with mirtazapine as concurrent use may increase the risk of QT prolongation; mirtazapine exposure may also increase. Itraconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. Mirtazapine is a CYP3A4 substrate that has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
Mirvetuximab Soravtansine: (Moderate) Closely monitor for mirvetuximab soravtansine-related adverse reactions if concomitant use of itraconazole is necessary. DM4, the cytotoxic component of mirvetuximab soravtansine, is a CYP3A substrate and itraconazole is a strong CYP3A inhibitor. Concomitant use may increase unconjugated DM4 exposure.
Mitapivat: (Major) Avoid coadministration of mitapivat with itraconazole due to increased risk of adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and itraconazole is a strong CYP3A inhibitor. Itraconazole increased mitapivat overall and peak exposure by 4.9-fold and 1.7-fold, respectively, after a single mitapivat 20 mg dose. Itraconazole increased mitapivat overall and peak exposure by 3.6-fold and 2.2-fold, respectively, after mitapivat 50 mg twice daily.
Mitotane: (Major) The use of mitotane within 2 weeks of itraconazole therapy is not recommended; if coadministration cannot be avoided, monitor for decreased efficacy of itraconazole. Mitotane is a strong CYP3A4 inducer and itraconazole is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of itraconazole.
Mitoxantrone: (Moderate) Systemic exposure of mitoxantrone, a substrate of the drug transporter breast cancer resistance protein (BCRP), may be increased when administered concurrently with itraconazole, a BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of mitoxantrone; monitor patients for potential adverse effects.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and itraconazole. 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 itraconazole 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: (Moderate) Modafinil is extensively metabolized by the CYP3A4 hepatic isoenzyme and inhibitors of CYP3A4, such as itraconazole, may decrease modafinil clearance. Observation of the patient for increased effects from modafinil may be needed.
Mometasone: (Moderate) Concomitant administration of itraconazole and mometasone may increase systemic exposure to mometasone, increasing the risk of corticosteroid-related adverse events. Exercise caution when administering mometasone with itraconazole long-term and monitor closely for hypercorticism and adrenal suppression. Mometasone is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor.
Moxifloxacin: (Major) Itraconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with itraconazole include moxifloxacin.
Nadolol: (Moderate) Careful monitoring is recommended when itraconazole is coadministered with nadolol. If these drugs are administered together, monitor patient for signs or symptoms of increased or prolonged nadolol-related side effects.
Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with itraconazole. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; itraconazole is a moderate P-gp inhibitor and a strong CYP3A4 inhibitor.
Naloxegol: (Contraindicated) Concomitant use of naloxegol with itraconazole is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as itraconazole, 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 itraconazole is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and itraconazole 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: (Major) Avoid concomitant use of sirolimus and itraconazole. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and itraconazole is a strong CYP3A and P-gp inhibitor.
Neostigmine; Glycopyrrolate: (Moderate) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole.
Neratinib: (Major) Avoid concomitant use of itraconazole with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and itraconazole 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 increased netupitant and itraconazole adverse effects if coadminsitration is necessary. No dosage adjustment of netupitant is necessary for single dose administration of netupitant; palonosetron. Netupitant is a moderate CYP3A4 inhibitor and substrate; itraconazole is a strong CYP3A4 inhibitor and substrate.
Nevirapine: (Major) Avoid coadministration of nevirapine and itraconazole. Concurrent use may result in decreases in itraconazole plasma concentrations that may reduce efficacy of the drug. If concurrent use cannot be avoided, monitor for decreased efficacy of itraconazole and increase the dose of itraconazole as necessary. Additionally, monitor for an increase in nevirapine-related adverse reactions if coadministration with itraconazole is necessary. Itraconazole is a CYP3A substrate and strong CYP3A inhibitor; nevirapine is a CYP3A substrate and CYP3A inducer.
Niacin; Simvastatin: (Contraindicated) Simvastatin is contraindicated for use during and for 2 weeks after itraconazole therapy. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if simvastatin is administered concomitantly with potent CYP3A4 inhibitors such as itraconazole. If therapy with itraconazole is unavoidable, simvastatin therapy must be suspended during the course of itraconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
Nicardipine: (Moderate) Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. In addition, itraconazole may increase nicardipine serum concentrations via inhibition of CYP3A4 with the potential for nicardipine toxicity. Edema has been reported in patients receiving concomitantly itraconazole and dihydropyridine calcium-channel blockers; therefore, caution is recommended when administering these medications in combination. A dosage reduction of the calcium-channel blocker may be appropriate.
Nifedipine: (Moderate) Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. In addition, itraconazole may increase nifedipine serum concentrations via inhibition of CYP3A4 with the potential for nifedipine toxicity. Edema has been reported in patients receiving concomitantly itraconazole and dihydropyridine calcium-channel blockers; therefore, caution is recommended when administering these medication in combination. A dosage reduction of the calcium-channel blocker may be appropriate.
Nilotinib: (Major) Avoid nilotinib use during and for 2 weeks after discontinuation of itraconazole. If use of itraconazole is necessary, hold nilotinib therapy. Consider a nilotinib dose reduction (to nilotinib 200 mg PO once daily in adult patients with newly diagnosed Ph+ CML or to nilotinib 300 mg PO once daily in adult patients with resistant or intolerant Ph+ CML); close monitoring of the QT interval is recommended. If itraconazole is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period. Taking these drugs together may increase concentrations of nilotinib and itraconazole and could result in additive effects on the QT interval. Nilotinib is a substrate and moderate inhibitor of CYP3A4. Itraconazole is a substrate and strong inhibitor of CYP3A4.
Nimodipine: (Moderate) Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. In addition, itraconazole may increase nimodipine serum concentrations via inhibition of CYP3A4 with the potential for nimodipine toxicity. Edema has been reported in patients receiving concomitantly itraconazole and dihydropyridine calcium-channel blockers; therefore, caution is recommended when administering these medications in combination. A dosage reduction of the calcium-channel blocker may be appropriate.
Nintedanib: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as itraconazole, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Itraconazole is a potent inhibitor of CYP3A4 and a moderate P-gp inhibitor; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
Nirmatrelvir; Ritonavir: (Major) When administering itraconazole with ritonavir or ritonavir-containing drugs, do not exceed the maximum recommended itraconazole dose of 200 mg per day. Concurrent administration may result in increased exposure to both drugs. Monitor patients for itraconazole and ritonavir-associated adverse effects. Both itraconazole and ritonavir are strong CYP3A4 inhibitors and substrates.
Nisoldipine: (Contraindicated) Nisoldipine is contraindicated for use during and for 2 weeks after itraconazole therapy. Itraconazole is an inhibitor of cytochrome P450 3A4, which significantly increases nisoldipine exposure. Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. Edema has been reported in patients receiving itraconazole and dihydropyridine calcium-channel blockers concomitantly.
Nizatidine: (Moderate) When administering H2-blockers with the 100 mg itraconazole capsule and 200 mg itraconazole tablet formulations, systemic exposure to itraconazole is decreased. Conversely, exposure to itraconazole is increased when H2-blockers are administered with the 65 mg itraconazole capsule. Administer H2-blockers at least 2 hours before or 2 hours after the 100 mg capsule or 200 mg tablet. Monitor for increased itraconazole-related adverse effects if H2-blockers are administered with itraconazole 65 mg capsules.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as itraconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Norethindrone; Ethinyl Estradiol: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as itraconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as itraconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. > Norgestimate; Ethinyl Estradiol: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as itraconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Nortriptyline: (Minor) Use itraconazole with caution in combination with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. 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). CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs; itraconazole may increase TCA concentrations via inhibition of CYP3A4. In at least one case, an increased incidence of TCA-related side effects, such as dizziness and syncope has occurred in combination with an azole antifungal. In another case, QT-prolongation and torsades de pointes occurred.
Ofloxacin: (Moderate) Concomitant use of ofloxacin and itraconazole 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) Use itraconazole with caution in combination with olanzapine as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Olanzapine; Fluoxetine: (Moderate) Concomitant use of fluoxetine and itraconazole 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. (Moderate) Use itraconazole with caution in combination with olanzapine as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Olanzapine; Samidorphan: (Moderate) Use itraconazole with caution in combination with olanzapine as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. 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 itraconazole 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 itraconazole is discontinued. Olaparib is a CYP3A substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole 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 itraconazole is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and itraconazole may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If itraconazole 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 itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole increased the oliceridine exposure by approximately 80% in healthy CYP2D6 poor metabolizers.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. In addition, itraconazole may increase amlodipine serum concentrations via inhibition of CYP3A4 with the potential for amlodipine toxicity. Edema has been reported in patients receiving concomitantly itraconazole and amlodipine, therefore, caution is recommended when administering these medications in combination. A dosage reduction of the calcium-channel blocker may be appropriate.
Olopatadine; Mometasone: (Moderate) Concomitant administration of itraconazole and mometasone may increase systemic exposure to mometasone, increasing the risk of corticosteroid-related adverse events. Exercise caution when administering mometasone with itraconazole long-term and monitor closely for hypercorticism and adrenal suppression. Mometasone is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and itraconazole. 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 itraconazole is a strong CYP3A inhibitor. Concomitant use increased omaveloxolone overall exposure by 4-fold.
Omeprazole; Sodium Bicarbonate: (Moderate) Administer antacids at least 2 hours before or 2 hours after oral itraconazole to minimize the potential for an interaction. Because itraconazole oral bioavailability requires an acidic environment for solubility, its absorption may be decreased with concomitant administration of antacids.
Ondansetron: (Major) Caution is advised when administering itraconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as ondansetron. Both ondansetron and itraconazole are associated with QT prolongation; coadministration may increase this risk. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with ondansetron (a CYP3A4 substrate) may result in elevated ondansetron plasma concentrations and an increased risk for adverse events, including QT prolongation. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
Oritavancin: (Moderate) Itraconazole is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of itraconazole may be reduced if these drugs are administered concurrently.
Osilodrostat: (Major) Reduce the dose of osilodrostat by one-half and consider more frequent ECG monitoring during coadministration of itraconazole; 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; itraconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval.
Osimertinib: (Major) Avoid coadministration of itraconazole with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor for an increase in itraconazole-related adverse reactions, 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. Itraconazole has also been associated with prolongation of the QT interval. Additionally, itraconazole is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor.
Ospemifene: (Moderate) Coadministration of itraconazole and ospemifene may increase ospemifene systemic concentrations and increase the risk of ospemifene-related adverse reactions. Itraconazole is a strong CYP3A4 inhibitor, and ospemifene is a CYP3A4 substrate. Another azole antifungal that is a strong CYP3A4 inhibitor increased the systemic exposure of ospemifene by 1.4-fold.
Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of itraconazole with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. Itraconazole has been associated with prolongation of the QT interval. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
Oxybutynin: (Moderate) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole. In addition, oxybutynin is metabolized by CYP3A4. Anticholinergic side effects may be increased when oxybutynin is used in combination with itraconazole. In healthy subjects receiving both itraconazole and oxybutynin, serum concentrations of oxybutynin were doubled; however, the serum concentrations of the active metabolite, N-desethoxybutynin, were not significantly changed. Since the pharmacologic effects of oxybutynin are mainly due to the active metabolite, adverse reactions associated with this interaction should be minimal.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of itraconazole is necessary. If itraconazole 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 itraconazole 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 itraconazole 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) Concomitant use of ozanimod and itraconazole increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. 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. Ozanimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
Paclitaxel: (Minor) Due to itraconazole-induced inhibition of cytochrome P450 3A4, interactions are possible with agents that are substrates of this enzyme including paclitaxel.
Pacritinib: (Contraindicated) Concurrent use of pacritinib with itraconazole 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 itraconazole is a strong CYP3A inhibitor.
Palbociclib: (Major) Avoid coadministration of itraconazole 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 itraconazole is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of itraconazole) to the dose used before initiation of itraconazole. Palbociclib is primarily metabolized by CYP3A4 and itraconazole is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with itraconazole increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Paliperidone: (Major) Avoid coadministration of paliperidone and itraconazole if possible due to the potential for additive effects on the QT interval. Both paliperidone and itraconazole are associated with QT prolongation. Torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of paliperidone overdose. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Palovarotene: (Major) Avoid concomitant use of palovarotene and itraconazole due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. Palovarotene is a CYP3A substrate and itraconazole is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased palovarotene overall exposure by 3-fold.
Panobinostat: (Major) Avoid coadministration of itraconazole 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 itraconazole (a potent 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 itraconazole are associated with QT prolongation; coadministration may increase this risk. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
Paricalcitol: (Moderate) Paricalcitol is partially metabolized by CYP3A4. Care should be taken when dosing paricalcitol with strong CYP3A4 inhibitors, such as itraconazole. Dose adjustments of paricalcitol may be required. Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with this combination.
Pasireotide: (Moderate) Use caution when using pasireotide in combination with itraconazole as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses. Itraconazole has been associated with prolongation of the QT interval.
Pazopanib: (Major) Avoid pazopanib use during and for 2 weeks after discontinuation of itraconazole treatment due the potential for increased pazopanib exposure and QT prolongation. If coadministration is unavoidable, reduce the pazopanib dose to 400 mg PO once daily and closely monitor for QT prolongation. Both pazopanib and itraconazole are associated with QT prolongation; coadministration may increase this risk. Pazopanib is a CYP3A4 and breast cancer resistance protein (BCRP) substrate; itraconazole is a strong CYP3A4 and BCRP inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased the Cmax and AUC of pazopanib by 1.5-fold and 1.7-fold, respectively.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and itraconazole 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 itraconazole is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of itraconazole. Pemigatinib is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole increased pemigatinib exposure by 88%.
Pentamidine: (Major) Itraconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with itraconazole include pentamidine.
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 itraconazole, as it inhibits CYP3A4.
Perindopril; Amlodipine: (Moderate) Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. In addition, itraconazole may increase amlodipine serum concentrations via inhibition of CYP3A4 with the potential for amlodipine toxicity. Edema has been reported in patients receiving concomitantly itraconazole and amlodipine, therefore, caution is recommended when administering these medications in combination. A dosage reduction of the calcium-channel blocker may be appropriate.
Perphenazine: (Minor) Use itraconazole with caution in combination with perphenazine as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Perphenazine; Amitriptyline: (Minor) Use itraconazole with caution in combination with perphenazine as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. (Minor) Use itraconazole with caution in combination with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. 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). CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs; itraconazole may increase TCA concentrations via inhibition of CYP3A4. In at least one case, an increased incidence of TCA-related side effects, such as dizziness and syncope has occurred in combination with an azole antifungal. In another case, QT-prolongation and torsades de pointes occurred.
Pexidartinib: (Major) Avoid concomitant use of pexidartinib and itraconazole due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects. 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 itraconazole is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of itraconazole. Pexidartinib is a CYP3A substrate; itraconazole is a strong CYP3A inhibitor. Coadministration with itraconazole increased pexidartinib exposure by 70%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole.
Phenytoin: (Major) Use of phenytoin is not recommended for 2 weeks before or during itraconazole therapy. Phenytoin has been shown to significantly reduce itraconazole AUC and half-life. Itraconazole, in turn, modestly increased phenytoin AUC.
Pimavanserin: (Major) Avoid concurrent administration of itraconazole and pimavanserin if possible due to the potential for additive effects on the QT interval and increased exposure to pimavanserin. If an alternative to itraconazole is not available and coadministration is unavoidable, the manufacturer recommends reducing the pimavanserin dose to 10 mg once daily. In addition, coadministration of itraconazole (a 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. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks while itraconazole plasma concentrations decrease. The decline in itraconazole plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
Pimozide: (Contraindicated) Pimozide is contraindicated for use during and for 2 weeks after itraconazole therapy. Serious cardiovascular events including EKG changes (i.e., QT prolongation), cardiac arrhythmias, including ventricular arrhythmias and torsade de pointes, cardiac arrest, and sudden death have occurred when these drugs were administered together. Itraconazole is an inhibitor of CYP3A4, which may cause increased plasma concentrations of pimozide resulting in potentially serious and life threatening side effects.
Pioglitazone: (Moderate) Itraconazole should be used cautiously with oral antidiabetic agents. The combination of itraconazole and oral antidiabetic agents has resulted in severe hypoglycemia. Blood glucose concentrations should be monitored and possible dose adjustments of hypoglycemics may need to be made.
Pioglitazone; Glimepiride: (Moderate) Itraconazole should be used cautiously with oral antidiabetic agents. The combination of itraconazole and oral antidiabetic agents has resulted in severe hypoglycemia. Blood glucose concentrations should be monitored and possible dose adjustments of hypoglycemics may need to be made.
Pioglitazone; Metformin: (Moderate) Itraconazole should be used cautiously with oral antidiabetic agents. The combination of itraconazole and oral antidiabetic agents has resulted in severe hypoglycemia. Blood glucose concentrations should be monitored and possible dose adjustments of hypoglycemics may need to be made.
Pirtobrutinib: (Major) Avoid concomitant use of pirtobrutinib and itraconazole 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 itraconazole use. Resume the previous dose of pirtobrutinib after itraconazole is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and itraconazole is a strong CYP3A inhibitor. Concomitant increased pirtobrutinib overall exposure by 49%.
Pitolisant: (Major) Avoid coadministration of pitolisant with itraconazole as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Itraconazole has been associated with prolongation of the QT interval.
Polatuzumab Vedotin: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of itraconazole due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; itraconazole 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 itraconazole 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 itraconazole and consider alternative therapy. After itraconazole has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting itraconazole. Ponatinib is a CYP3A4 substrate; itraconazole 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 itraconazole 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. Itraconazole has been associated with prolongation of the QT interval.
Posaconazole: (Major) Typically posaconazole and itraconazole would not be used in combination due to similar mechanisms of action and indications for use (duplicate therapies). Posaconazole may inhibit the CYP3A4 metabolism of itraconazole, resulting in increased itraconazole serum concentrations. Furthermore, all systemic azole antifungal agents have been associated with prolongation of the QT interval. Coadministration would increase the risk of QT prolongation.
Pralsetinib: (Major) Avoid concomitant use of itraconazole and pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of pralsetinib to 200 mg once daily for patients taking a daily dose of 400 mg or 300 mg, and to 100 mg once daily for patients taking a daily dose of 200 mg. Pralsetinib is a CYP3A and P-gp substrate and itraconazole is a combined strong CYP3A and P-gp inhibitor. Coadministration is predicted to increase the overall exposure of pralsetinib by 251%.
Praziquantel: (Moderate) Itraconazole inhibits CYP3A4 and may reduce metabolism of praziquantel. This interaction may be beneficial. The combination may prolong the exposure of the parasites to praziquantel and may not result in an increased risk of side effects.
Prednisolone: (Moderate) Itraconazole is a potent inhibitor of CYP3A4, and prednisolone is a CYP3A4 substrate. Monitor patients for corticosteroid-related side effects if both prednisolone and itraconazole are taken.
Prednisone: (Moderate) Prednisone is metabolized by the liver to the active metabolite prednisolone. Itraconazole is a potent inhibitor of CYP3A4, and prednisolone is a CYP3A4 substrate. Monitor patients for corticosteroid-related side effects if both prednisone and itraconazole are taken.
Primaquine: (Moderate) Caution is advised during concurrent use of itraconazole and primaquine as both drugs may cause QT prolongation.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and itraconazole due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a CYP3A and P-gp substrate and itraconazole is a dual strong CYP3A and P-gp inhibitor. Concomitant use with other dual strong CYP3A and P-gp inhibitors has been observed to increase colchicine overall exposure by 3- to 4-fold.
Procainamide: (Major) Itraconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with itraconazole include procainamide.
Prochlorperazine: (Minor) Use itraconazole with caution in combination with prochlorperazine as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. 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 itraconazole with progesterone is necessary, as the systemic exposure of progesterone may be increased resulting in an increase in treatment-related adverse reactions. Itraconazole 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 itraconazole 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 itraconazole 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 itraconazole 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) Use caution during coadministration of itraconazole and propafenone due to the potential for additive effects on the QT interval and increased exposure to propafenone. Both propafenone and itraconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with propafenone (a CYP3A4 substrate) may result in elevated propafenone plasma concentrations and an increased risk for adverse events, including QT prolongation. It may be prudent to avoid use of propafenone for up to 2 weeks after discontinuing itraconazole, unless benefits of treatment outweigh the potential risk for side effects. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
Propantheline: (Moderate) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole.
Proton pump inhibitors: (Moderate) When administering proton pump inhibitors with the 100 mg itraconazole capsule and 200 mg itraconazole tablet formulations, systemic exposure to itraconazole is decreased. Conversely, exposure to itraconazole is increased when proton pump inhibitors are administered with the 65 mg itraconazole capsule. Administer proton pump inhibitors at least 2 hours before or 2 hours after the 100 mg capsule or 200 mg tablet. Monitor for increased itraconazole-related adverse effects if proton pump inhibitors are administered with itraconazole 65 mg capsules.
Protriptyline: (Minor) Use itraconazole with caution in combination with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. 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). CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs; itraconazole may increase TCA concentrations via inhibition of CYP3A4. In at least one case, an increased incidence of TCA-related side effects, such as dizziness and syncope has occurred in combination with an azole antifungal. In another case, QT-prolongation and torsades de pointes occurred.
Quazepam: (Moderate) CYP3A4 inhibitors, such as itraconazole, may reduce the metabolism of quazepam and increase the potential for benzodiazepine toxicity.
Quetiapine: (Major) Avoid coadministration of itraconazole with quetiapine due to the potential for additive effects on the QT interval; increased exposure to quetiapine may also occur. Both quetiapine and itraconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of itraconazole (a potent 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 itraconazole. When itraconazole is discontinued, the dose should be increased by 6-fold. Of note, once itraconazole is discontinued, plasma concentrations decrease to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
Quinidine: (Contraindicated) Quinidine is contraindicated for use during and for 2 weeks after itraconazole therapy. Serious cardiovascular events including EKG changes (i.e., QT prolongation) and cardiac arrhythmias, including ventricular arrhythmias and torsade de pointes, cardiac arrest, and/or sudden death have occurred when these drugs were administered together. Reports have documented cases in which substantial elevations in serum quinidine concentrations occurred after the addition of itraconazole. Quinidine is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Transient or permanent hearing loss has also been reported in elderly patients receiving quinidine in combination with itraconazole.
Quinine: (Moderate) Monitor patients for increased quinine-related adverse effects if coadministration of itraconazole is necessary. Quinine is a substrate of P-glycoprotein (P-gp) and CYP3A4, and itraconazole is a P-gp and CYP3A4 inhibitor. Therefore, quinine concentrations could be increased with coadministration.
Quizartinib: (Major) Avoid concomitant use of itraconazole 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 itraconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of quizartinib by 94%.
Ramelteon: (Moderate) Monitor for adverse reactions related to ramelteon if coadministration of itraconazole is necessary. A reduced dose of ramelteon may be necessary. Ramelteon is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC and Cmax of ramelteon by approximately 84% and 36%.
Ranitidine: (Moderate) When administering H2-blockers with the 100 mg itraconazole capsule and 200 mg itraconazole tablet formulations, systemic exposure to itraconazole is decreased. Conversely, exposure to itraconazole is increased when H2-blockers are administered with the 65 mg itraconazole capsule. Administer H2-blockers at least 2 hours before or 2 hours after the 100 mg capsule or 200 mg tablet. Monitor for increased itraconazole-related adverse effects if H2-blockers are administered with itraconazole 65 mg capsules.
Ranolazine: (Contraindicated) Ranolazine is contraindicated for use during and for 2 weeks after itraconazole therapy. Inhibition of ranolazine CYP3A metabolism by itraconazole could lead to increased ranolazine plasma concentrations, prolonged QTc prolongation, and possibly torsade de pointes.
Red Yeast Rice: (Contraindicated) The risk of myopathy, including rhabdomyolysis, may be increased when CYP3A4 inhibitors, like itraconazole, are given with HMG-CoA reductase inhibitors. Since compounds in went yeast, Monascus purpureus/red yeast rice claim to have HMG-CoA reductase inhibitor activity, went yeast/red yeast rice should not be used in combination with itraconazole.
Regorafenib: (Major) Avoid coadministration of regorafenib with itraconazole 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. Do not initiate treatment with regorafenib for 2 weeks after discontinuation of itraconazole. Regorafenib is a CYP3A4 substrate and itraconazole 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: (Major) Avoid concomitant use of relugolix and oral itraconazole. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer itraconazole at least 6 hours after relugolix and monitor for adverse reactions. Alternatively, relugolix therapy may be interrupted for up to 14 days if a short course of itraconazole is required; if treatment is interrupted for more than 7 days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval. Itraconazole has been associated with prolongation of the QT interval. Relugolix is a P-gp substrate and itraconazole is a P-gp inhibitor.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral itraconazole. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer itraconazole at least 6 hours after relugolix and monitor for adverse reactions. Alternatively, relugolix therapy may be interrupted for up to 14 days if a short course of itraconazole is required; if treatment is interrupted for more than 7 days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval. Itraconazole has been associated with prolongation of the QT interval. Relugolix is a P-gp substrate and itraconazole is a P-gp inhibitor. (Minor) As itraconazole 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: (Major) Coadministration of itraconazole and repaglinide increases the AUC of repaglinide by 1.4-fold; if coadministration is necessary, consider a dose reduction of repaglinide and increased frequency of glucose monitoring. Itraconazole is a CYP3A4 inhibitor and repaglinide is a CYP3A4 substrate. The possibility of an increased risk of hypoglycemia should be considered during concomitant use of itraconazole and repaglinide.
Retapamulin: (Moderate) Coadministration of retapamulin with strong CYP3A4 inhibitors, such as itraconazole, 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 itraconazole due to the risk of QT prolongation; plasma concentrations of both drugs may increase. Ribociclib is a CYP3A4 substrate and strong inhibitor that is associated with concentration-dependent QT prolongation. Itraconazole is also a CYP3A4 substrate and strong inhibitor that is associated with QT prolongation.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with itraconazole due to the risk of QT prolongation; plasma concentrations of both drugs may increase. Ribociclib is a CYP3A4 substrate and strong inhibitor that is associated with concentration-dependent QT prolongation. Itraconazole is also a CYP3A4 substrate and strong inhibitor that is associated with QT prolongation.
Rifampin: (Major) The use of rifampin within 2 weeks of itraconazole therapy is not recommended. If coadministration cannot be avoided, monitor for decreased efficacy of itraconazole and increase the dose of itraconazole as necessary. Itraconazole is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer.
Rifapentine: (Major) The use of rifapentine within 2 weeks of itraconazole therapy is not recommended. If coadministration cannot be avoided, monitor for decreased efficacy of itraconazole and increase the dose of itraconazole as necessary. Itraconazole is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with itraconazole is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and itraconazole is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Rilpivirine: (Moderate) Caution is advised when administering itraconazole with rilpivirine due to the potential for additive effects on the QT interval, increased exposure to rilpivirine, and decreased exposure to itraconazole. Monitor for breakthrough fungal infections in patients receiving rilpivirine with an azole antifungal. Rilpivirine, a CYP3A4 substrate, and itraconazole, 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 itraconazole.
Rimegepant: (Major) Avoid coadministration of rimegepant with itraconazole; concurrent use may significantly increase rimegepant exposure. Rimegepant is a CYP3A4 and P-gp substrate and itraconazole is a strong CYP3A4 inhibitor and a P-gp inhibitor. Coadministration of rimegepant with itraconazole increased rimegepant exposure by 4-fold.
Riociguat: (Major) Avoid riociguat use during and for up to 2 weeks after discontinuation of itraconazole treatment unless benefits of treatment outweigh the potentially increased risk of side effects. Concomitant use of riociguat with strong cytochrome CYP inhibitors and P-gp/BCRP inhibitors such as itraconazole, increases riociguat exposure and may result in hypotension. Consider a starting dose of 0.5 mg three times a day when initiating riociguat in patients receiving strong CYP and P-gp/BCRP inhibitors. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat.
Ripretinib: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with itraconazole. 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 itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole increased ripretinib and DP-5439 exposure by 99%.
Risperidone: (Moderate) Use risperidone and itraconazole 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. Itraconazole has also been associated with prolongation of the QT interval.
Ritonavir: (Major) When administering itraconazole with ritonavir or ritonavir-containing drugs, do not exceed the maximum recommended itraconazole dose of 200 mg per day. Concurrent administration may result in increased exposure to both drugs. Monitor patients for itraconazole and ritonavir-associated adverse effects. Both itraconazole and ritonavir are strong CYP3A4 inhibitors and substrates.
Rivaroxaban: (Major) Avoid use of rivaroxaban during and for 2 weeks after discontinuation of itraconazole treatment. Itraconazole is a combined P-glycoprotein (P-gp) and strong CYP3A4 inhibitor while rivaroxaban is a substrate of CYP3A4/5 and the P-gp transporter. Concurrent use of rivaroxaban and ketoconazole, another combined P-gp and strong CYP3A4 inhibitor, led to an increase in the steady-state rivaroxaban AUC by 160% and Cmax by 70%. Increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed. Significant increases in rivaroxaban exposure may increase bleeding risk. Similar effects may be expected with concurrent itraconazole use.
Roflumilast: (Moderate) Coadminister itraconazole and roflumilast cautiously as this may lead to increased systemic exposure to roflumilast; roflumilast-induced adverse effects may occur. Itraconazole is a strong inhibitor of CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inhibitor resulted in variably increased roflumilast Cmax and AUC, as well as decreased Cmax and increased AUC of the active metabolite roflumilast N-oxide.
Romidepsin: (Major) The concomitant use of romidepsin, a CYP3A4 substrate, and itraconazole, 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, itraconazole 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 itraconazole, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and electrocardiograms at baseline and periodically during treatment. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
Rosuvastatin: (Moderate) Itraconazole modestly increases the AUC of rosuvastatin by 28% and 39% in healthy volunteers receiving 80 mg and 10 mg rosuvastatin, respectively. A potential mechanism for this interaction is inhibition of the breast cancer resistance protein (BCRP) by itraconazole; rosuvastatin is a BCRP substrate.
Rosuvastatin; Ezetimibe: (Moderate) Itraconazole modestly increases the AUC of rosuvastatin by 28% and 39% in healthy volunteers receiving 80 mg and 10 mg rosuvastatin, respectively. A potential mechanism for this interaction is inhibition of the breast cancer resistance protein (BCRP) by itraconazole; rosuvastatin is a BCRP substrate.
Ruxolitinib: (Major) Reduce the ruxolitinib dosage when coadministered with itraconazole 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 itraconazole 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 itraconazole use. Ruxolitinib is a CYP3A4 substrate and itraconazole 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 itraconazole. 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 itraconazole 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: (Major) Monitor for adverse effects (i.e.,cardiac arrhythmias, hepatotoxicity) with administering itraconazole with saquinavir boosted with ritonavir. Serum concentrations of both itraconazole and saquinavir are expected to increase if these drugs are given together, as both itraconazole and saquinavir are substrates and inhibitors of CYP3A4.
Saxagliptin: (Major) Do not exceed 2.5 mg PO daily of saxagliptin when combined with itraconazole; monitor for evidence of hypoglycemia. Itraconazole is a strong CYP3A4 inhibitor; saxagliptin is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the saxagliptin AUC up to 3.7-fold.
Scopolamine: (Moderate) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole.
Segesterone Acetate; Ethinyl Estradiol: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as itraconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. (Minor) Coadministration of segesterone, a CYP3A4 substrate and a strong CYP3A4 inhibitor, such as itraconazole may increase the serum concentration of segesterone.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and itraconazole 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 itraconazole is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of itraconazole. Selpercatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; itraconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. Coadministration with itraconazole increased selpercatinib exposure by 133%.
Selumetinib: (Major) Avoid coadministration of selumetinib and itraconazole 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 itraconazole is discontinued, resume the original selumetinib dose after 3 elimination half-lives of itraconazole. Selumetinib is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole increased selumetinib exposure by 49%.
Sertraline: (Moderate) Concomitant use of sertraline and itraconazole 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) Itraconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with itraconazole include halogenated anesthetics.
Sildenafil: (Major) Avoid use of sildenafil for the treatment of pulmonary hypertension during and for 2 weeks after discontinuation of itraconazole treatment. When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving itraconazole. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Itraconazole 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) Silodosin is contraindicated for use during itraconazole therapy and is not recommended for 2 weeks after completion of itraconazole therapy. Concurrent use may significantly increase silodosin plasma concentrations. Silodosin is extensively metabolized by CYP3A4; itraconazole is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the Cmax and AUC of silodosin by 3.8-fold and 3.2-fold, respectively.
Simvastatin: (Contraindicated) Simvastatin is contraindicated for use during and for 2 weeks after itraconazole therapy. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if simvastatin is administered concomitantly with potent CYP3A4 inhibitors such as itraconazole. If therapy with itraconazole is unavoidable, simvastatin therapy must be suspended during the course of itraconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving itraconazole due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Itraconazole has also been associated with prolongation of the QT interval. Additionally, concomitant use of siponimod and itraconazole may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Sirolimus: (Major) Avoid concomitant use of sirolimus and itraconazole. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and itraconazole is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
Sodium Bicarbonate: (Moderate) Administer antacids at least 2 hours before or 2 hours after oral itraconazole to minimize the potential for an interaction. Because itraconazole oral bioavailability requires an acidic environment for solubility, its absorption may be decreased with concomitant administration of antacids.
Sodium Stibogluconate: (Moderate) Concomitant use of sodium stibogluconate and itraconazole 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: (Minor) Itraconazole and sofosbuvir may be given together with caution. Taking these drugs together may increase plasma concentrations of sofosbuvir, without increasing GS-331007 plasma concentrations. Sofosbuvir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor; itraconazole is a P-gp and BCRP inhibitor.
Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with itraconazole. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). In addition, itraconazole is a potent inhibitor of the hepatic enzyme CYP3A4 and the breast cancer resistance protein (BCRP) transporter. Velpatasvir is a CYP3A4 and BCRP substrate. (Minor) Itraconazole and sofosbuvir may be given together with caution. Taking these drugs together may increase plasma concentrations of sofosbuvir, without increasing GS-331007 plasma concentrations. Sofosbuvir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor; itraconazole is a P-gp and BCRP inhibitor.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Plasma concentrations of itraconazole, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with voxilaprevir, a P-gp inhibitor. Monitor patients for increased side effects if these drugs are administered concurrently. (Moderate) Use caution when administering velpatasvir with itraconazole. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). In addition, itraconazole is a potent inhibitor of the hepatic enzyme CYP3A4 and the breast cancer resistance protein (BCRP) transporter. Velpatasvir is a CYP3A4 and BCRP substrate. (Minor) Itraconazole and sofosbuvir may be given together with caution. Taking these drugs together may increase plasma concentrations of sofosbuvir, without increasing GS-331007 plasma concentrations. Sofosbuvir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor; itraconazole is a P-gp and BCRP inhibitor.
Solifenacin: (Major) Coadministration of solifenacin and itraconazole is contraindicated in patients with severe renal dysfunction or moderate/severe hepatic dysfunction due to the risk for QT prolongation. Further, solifenacin should not be administered within 2 weeks of itraconazole discontinuation in patients with renal or hepatic dysfunction. In patients with normal renal and hepatic function, do not exceed solifenacin 5 mg per day in adults; do not exceed the initial solifenacin starting dose in pediatric patients during use of itraconazole concurrently. Solifenacin is significantly metabolized by CYP3A4 and itraconazole is a potent CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased solifenacin exposure by 2.7-fold. Both drugs have been associated with dose- or concentration-dependent QT prolongation, and torsade de pointes (TdP) was reported in postmarketing experience with solifenacin although causality was not determined.
Sonidegib: (Major) Avoid the concomitant use of sonidegib and itraconazole; sonidegib exposure may be significantly increased resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration of another 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 itraconazole 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. Both drugs have been associated with prolongation of the QT interval.
Sotalol: (Major) Concomitant use of sotalol and itraconazole increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. 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.
Sparsentan: (Major) Avoid concomitant use of sparsentan and itraconazole. Concomitant use may increase sparsentan exposure and the risk for sparsentan-related adverse effects. Sparsentan is a CYP3A substrate and itraconazole is a strong CYP3A inhibitor. Concomitant use increased sparsentan overall exposure by 174%.
St. John's Wort, Hypericum perforatum: (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system. Co-administration of St. John's wort could decrease the efficacy of some medications metabolized by these enzymes including itraconazole.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if itraconazole must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of itraconazole is necessary. If itraconazole 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 itraconazole 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 itraconazole 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.
Sulfasalazine: (Moderate) Administering sulfasalazine with itraconazole may increase sulfasalazine plasma concentrations, potentially resulting in adverse events. Sulfasalazine is a substrate of the drug transporter breast cancer resistance protein (BCRP) transporter; itraconazole is a BCRP inhibitor.
Sulfonylureas: (Moderate) Itraconazole should be used cautiously with oral antidiabetic agents like sulfonylureas. The combination of itraconazole and oral antidiabetic agents has resulted in severe hypoglycemia. Blood glucose concentrations should be monitored and possible dose adjustments of hypoglycemics may need to be made.
Sunitinib: (Major) Avoid sunitinib use during and for 2 weeks after discontinuation of itraconazole treatment due to increased sunitinib exposure, which may increase the risk of QT prolongation. Sunitinib is a CYP3A4 substrate that can prolong the QT interval. Itraconazole is a strong CYP3A4 inhibitor that has also been associated with prolongation of the QT interval. Coadministration with another strong CYP3A4 inhibitor increased exposure to sunitinib and its primary active metabolite by 51%.
Suvorexant: (Major) Coadministration of suvorexant and itraconazole is not recommended due to the potential for significantly increased suvorexant exposure. Suvorexant is a CYP3A4 substrate. Itraconazole 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 for QT prolongation is recommended if coadministered with itraconazole as concurrent use may result in increased tacrolimus exposure and additive QT prolongation. Additional tacrolimus dosage reductions may be required. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic index that may prolong the QT interval and cause torsade de pointes (TdP). Itraconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval.
Tadalafil: (Major) Avoid use of tadalafil for the treatment of pulmonary hypertension during and for 2 weeks after discontinuation of itraconazole treatment. For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of itraconazole for the as needed dose or 2.5 mg daily for the once-daily dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as itraconazole, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Talazoparib: (Major) Avoid coadministration of itraconazole with talazoparib when used for the treatment of breast cancer due to increased talazoparib exposure. If concomitant use is unavoidable, reduce the dose of talazoparib to 0.75 mg PO once daily. If itraconazole is discontinued, wait at least 3 to 5 half-lives of itraconazole before increasing the dose of talazoparib to the prior dose used before itraconazole therapy. A talazoparib dose reduction is not necessary for patients with prostate cancer; monitor for an increase in talazoparib-related adverse reactions. Talazoparib is a P-gp substrate and itraconazole is a P-gp inhibitor. In clinical trials, coadministration with itraconazole increased talazoparib exposure by 56%.
Tamoxifen: (Moderate) Concomitant use of tamoxifen and itraconazole 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) Use of tamsulosin is not recommended during and for 2 weeks after itraconazole therapy 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. 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 resulted in an increase in 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 itraconazole, 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 itraconazole as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. Tazemetostat is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
Telavancin: (Moderate) Use itraconazole with caution in combination with telavancin as concurrent use may increase the risk of QT prolongation. Itraconazole and telavancin have been associated with prolongation of the QT interval.
Telmisartan; Amlodipine: (Moderate) Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. In addition, itraconazole may increase amlodipine serum concentrations via inhibition of CYP3A4 with the potential for amlodipine toxicity. Edema has been reported in patients receiving concomitantly itraconazole and amlodipine, therefore, caution is recommended when administering these medications in combination. A dosage reduction of the calcium-channel blocker may be appropriate.
Temsirolimus: (Major) Avoid use of temsirolimus during and for 2 weeks after discontinuation of itraconazole treatment. If coadministration cannot be avoided, consider a dose reduction of temsirolimus to 12.5 mg per week. If itraconazole is discontinued, a washout period of approximately 1 week should be allowed before the temsirolimus dose is adjusted back to the dose used prior to initiation of itraconazole. Concomitant use of temsirolimus with strong CYP3A4 inhibitors such as itraconazole may increase blood concentrations of the temsirolimus active metabolite, sirolimus. Although coadministration of another strong CYP3A4 inhibitor did not have a significant effect on temsirolimus Cmax and AUC, the Cmax and AUC of sirolimus increased by 2.2-fold and 3.1-fold, respectively.
Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, concurrently with inhibitors of P-gp and BCRP, such as itraconazole. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering itraconazole. 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 CYP3A4; itraconazole is an inhibitor of this enzyme. Taking these drugs together may increase the risk for terbinafine related adverse effects. However, in vitro studies suggest that use of terbinafine in combination with itraconazole may have synergistic activity against certain fungal species, including Candida sp. Clinical study is needed to elucidate the potential utility of terbinafine combinations with other antifungal agents.
Tetrabenazine: (Major) Itraconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with itraconazole include tetrabenazine.
Tezacaftor; Ivacaftor: (Major) If itraconazole 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 itraconazole 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 itraconazole; 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); itraconazole is a strong CYP3A inhibitor. Coadministration of itraconazole increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
Thioridazine: (Contraindicated) Thioridazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP). Itraconazole has also been associated with QT prolongation. Thioridazine is contraindicated for use with other drugs that are known to prolong the QT interval.
Thiotepa: (Major) Avoid the concomitant use of thiotepa and itraconazole 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; itraconazole is a strong CYP3A4 inhibitor.
Ticagrelor: (Contraindicated) Ticagrelor is contraindicated for use during and for up to 2 weeks after discontinuation of itraconazole treatment. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp) and concomitant use with itraconazole substantially increases ticagrelor exposure which may increase the bleeding risk.
Tipranavir: (Major) Both tipranavir boosted with ritonavir and itraconazole are inhibitors of CYP3A4. Additionally, both drugs are CYP3A4 substrates. Based on expected CYP drug interactions, tipranavir (in the FDA approved dosage regimen) should be used cautiously with itraconazole; high doses (i.e., > 200 mg) of itraconazole should be avoided.
Tisotumab Vedotin: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with itraconazole 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 itraconazole 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 itraconazole. 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 itraconazole. Itraconazole is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
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 itraconazole. Concurrent use may increase tolterodine exposure. Itraconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. 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) Tolvaptan is contraindicated for use during and for 2 weeks after itraconazole therapy due to increased exposure to tolvaptan. Tolvaptan is a sensitive CYP3A4 substrate; itraconazole 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.
Topotecan: (Major) Avoid coadministration of itraconazole with oral topotecan due to increased topotecan exposure; itraconazole may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); itraconazole is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
Toremifene: (Major) Avoid coadministration of itraconazole with toremifene if possible due to the risk of additive 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. Itraconazole is a strong CYP3A4 inhibitor that has also been associated with prolongation of the QT interval.
Trabectedin: (Major) Avoid the concomitant use of trabectedin with itraconazole due to the risk of increased trabectedin exposure. Avoid trabectedin use during and for 2 weeks after discontinuation of itraconazole treatment. If short-term itraconazole (less than 14 days) cannot be avoided during trabectedin therapy, 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 itraconazole 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.
Trandolapril; Verapamil: (Moderate) Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. In addition, itraconazole may increase verapamil serum concentrations via inhibition of CYP3A4 with the potential for verapamil toxicity. Edema has been reported in patients receiving concomitantly itraconazole and dihydropyridine calcium-channel blockers; therefore, caution is recommended when administering these medications in combination. A dosage reduction of the calcium-channel blocker may be appropriate.
Trazodone: (Major) Avoid coadministration of itraconazole with trazodone due to the potential for additive effects on the QT interval; increased exposure to trazodone may also occur. Both trazodone and itraconazole are associated with QT prolongation; there are also postmarketing reports of torsade de pointes (TdP) with trazodone. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with trazodone (a CYP3A4 substrate) may result in elevated trazodone plasma concentrations and an increased risk for adverse events, including QT prolongation. Consider decreasing the dose of trazodone during coadministration with itraconazole. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
Triamcinolone: (Moderate) Itraconazole may inhibit the CYP3A4 metabolism of triamcinolone, resulting in increased plasma triamcinolone concentrations and reduced serum cortisol concentrations. There have been reports of clinically significant drug interactions in patients receiving another strong CYP3A4 inhibitor with triamcinolone, resulting in systemic corticosteroid effects including, but not limited to, Cushing syndrome and adrenal suppression. Consider the benefit-risk of concomitant use and monitor for systemic corticosteroid side effects. Consider using an alternative treatment to triamcinolone, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone or prednisolone). In some patients, a corticosteroid dose adjustment may be needed. If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal.
Triazolam: (Contraindicated) Triazolam is contraindicated for use during and for 2 weeks after itraconazole therapy. Coadministration of itraconazole with triazolam may result in prolonged sedation and respiratory depression due to inhibition of CYP3A by itraconazole. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with itraconazole, as these benzodiazepines are not oxidatively metabolized. A study using single oral doses of estazolam showed that itraconazole had no effect on the pharmacokinetics or pharmacodynamics of estazolam.
Triclabendazole: (Moderate) Concomitant use of triclabendazole and itraconazole 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.
Tricyclic antidepressants: (Minor) Use itraconazole with caution in combination with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. 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). CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs; itraconazole may increase TCA concentrations via inhibition of CYP3A4. In at least one case, an increased incidence of TCA-related side effects, such as dizziness and syncope has occurred in combination with an azole antifungal. In another case, QT-prolongation and torsades de pointes occurred.
Trifluoperazine: (Minor) Use itraconazole with caution in combination with trifluoperazine as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Trihexyphenidyl: (Moderate) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole.
Trimipramine: (Minor) Use itraconazole with caution in combination with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. 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). CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs; itraconazole may increase TCA concentrations via inhibition of CYP3A4. In at least one case, an increased incidence of TCA-related side effects, such as dizziness and syncope has occurred in combination with an azole antifungal. In another case, QT-prolongation and torsades de pointes occurred.
Triptorelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., triptorelin) outweigh the potential risks of QT prolongation in patients receiving itraconazole as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Androgen deprivation therapy may also prolong the QT/QTc interval.
Trospium: (Moderate) Antimuscarinic drugs including trospium can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole. Trospium should be used cautiously in patients receiving itraconazole.
Tucatinib: (Moderate) Monitor for itraconazole-related adverse reactions during coadministration with tucatinib; an itraconazole dose reduction may be necessary. Concurrent use may increase itraconazole exposure. Itraconazole is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Ubrogepant: (Contraindicated) Coadministration of ubrogepant and itraconazole is contraindicated as concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; itraconazole 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) Ulipristal is a substrate of CYP3A4 and itraconazole is a CYP3A4 inhibitor. Concomitant use may increase the plasma concentration of ulipristal resulting in an increased risk for adverse events.
Umeclidinium; Vilanterol: (Moderate) Use itraconazole with caution in combination with beta-agonists as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Upadacitinib: (Major) During concomitant use of upadacitinib and itraconazole 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) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as itraconazole. QT prolongation 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.
Vandetanib: (Major) Avoid coadministration of vandetanib with itraconazole 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. Itraconazole has also been associated with prolongation of the QT interval.
Vardenafil: (Major) Do not use vardenafil orally disintegrating tablets with itraconazole due to increased vardenafil exposure. Vardenafil is primarily metabolized by CYP3A4/5; itraconazole is a strong CYP3A4 inhibitor. If coadministration of itraconazole and vardenafil oral tablets is required, the maximum single vardenafil dose is 5 mg every 24 hours in patients receiving itraconazole 200 mg daily; for patients receiving itraconazole 400 mg daily, the maximum single vardenafil dose is 2.5 mg every 24 hours. In addition, both itraconazole and vardenafil have been associated with QT prolongation; coadministration may increase this risk.
Vemurafenib: (Major) Avoid vemurafenib in patients receiving medications known to prolong the QT interval such as itraconazole. Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first month of treatment. Itraconazole has been associated with prolongation of the QT interval. Additionally, coadministration may result in increased vemurafenib exposure and an increased risk of adverse events, including QT prolongation. Vemurafenib is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. In a drug interaction study, the steady-state AUC value of vemurafenib was increased by 40% when vemurafenib 960 mg twice daily was administered with itraconazole 200 mg once daily. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
Venetoclax: (Major) Coadministration of itraconazole 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 itraconazole. 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 and P-glycoprotein (P-gp) substrate; itraconazole is a CYP3A4 (strong) and P-gp inhibitor Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies, while coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
Venlafaxine: (Moderate) Caution is advised when administering itraconazole with venlafaxine due to the potential for additive effects on the QT interval and increased exposure to venlafaxine. Both venlafaxine and itraconazole are associated with QT prolongation; coadministration may increase this risk. 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 itraconazole (a potent CYP3A4 inhibitor) to patients identified as CYP2D6 poor metabolizers may significantly increase venlafaxine plasma concentrations.
Verapamil: (Moderate) Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. In addition, itraconazole may increase verapamil serum concentrations via inhibition of CYP3A4 with the potential for verapamil toxicity. Edema has been reported in patients receiving concomitantly itraconazole and dihydropyridine calcium-channel blockers; therefore, caution is recommended when administering these medications in combination. A dosage reduction of the calcium-channel blocker may be appropriate.
Vilazodone: (Major) Because CYP3A4 is the primary isoenzyme involved in the metabolism of vilazodone, the manufacturer of vilazodone recommends that the daily dose not exceed 20 mg/day during concurrent use of a strong CYP3A4 inhibitor, such as itraconazole. The original vilazodone dose can be resumed when the CYP3A4 inhibitor is discontinued.
Vinblastine: (Major) Avoid the use of vinblastine during and for 2 weeks after discontinuation of itraconazole due to the risk of an earlier onset and/or increased severity of vinblastine-related adverse reactions including severe myelosuppression. Vinblastine is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Concomitant administration of another vinca alkaloid with itraconazole has resulted in an increased incidence of neurotoxicity.
Vincristine Liposomal: (Major) Avoid the use of vincristine during and for 2 weeks after discontinuation of itraconazole due to the risk of an earlier onset and/or increased severity of vincristine-related adverse reactions, including constipation and peripheral neuropathy. Vincristine is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Concomitant administration of vincristine and itraconazole has resulted in an increased incidence of neurotoxicity.
Vincristine: (Major) Avoid the use of vincristine during and for 2 weeks after discontinuation of itraconazole due to the risk of an earlier onset and/or increased severity of vincristine-related adverse reactions, including constipation and peripheral neuropathy. Vincristine is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Concomitant administration of vincristine and itraconazole has resulted in an increased incidence of neurotoxicity.
Vinorelbine: (Major) Avoid the use of vinorelbine during and for 2 weeks after discontinuation of itraconazole due to the risk of an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy. Vinorelbine is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Concomitant administration of another vinca alkaloid with itraconazole has resulted in an increased incidence of neurotoxicity.
Voclosporin: (Contraindicated) Concomitant use of voclosporin and itraconazole 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 itraconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased voclosporin exposure by approximately 19-fold.
Vonoprazan; Amoxicillin: (Moderate) Administer vonoprazan at least 2 hours before or 2 hours after itraconazole 100 mg capsules. Monitor for increased itraconazole-related adverse effects if vonoprazan is administered with itraconazole 65 mg capsules; a dose reduction may be needed. Drugs that reduce gastric acidity, such as vonoprazan, may decrease the systemic exposure of the 100 mg itraconazole capsule formulation. Conversely, exposure to itraconazole is increased when gastric acid reducers are administered with the 65 mg itraconazole capsule.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Caution is advised when administering itraconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as clarithromycin. Consider use of azithromycin in place of clarithromycin. Both clarithromycin and itraconazole are associated with QT prolongation; coadministration may increase this risk. 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. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors. Azithromycin can be considered as an alternative macrolide antimicrobial if appropriate for the clinical circumstance, due to its lack of metabolism via CYP3A4. (Moderate) Administer vonoprazan at least 2 hours before or 2 hours after itraconazole 100 mg capsules. Monitor for increased itraconazole-related adverse effects if vonoprazan is administered with itraconazole 65 mg capsules; a dose reduction may be needed. Drugs that reduce gastric acidity, such as vonoprazan, may decrease the systemic exposure of the 100 mg itraconazole capsule formulation. Conversely, exposure to itraconazole is increased when gastric acid reducers are administered with the 65 mg itraconazole capsule.
Vorapaxar: (Major) Avoid vorapaxar during and for 2 weeks after discontinuation of itraconazole treatment due to increase vorapaxar exposure and bleeding risk. Vorapaxar is a CYP3A4 substrate; itraconazole is a strong CYP3A inhibitor.
Vorinostat: (Moderate) Use itraconazole with caution in combination with vorinostat as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Vorinostat therapy is associated with a risk of QT prolongation.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with itraconazole is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Itraconazole is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zaleplon: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as itraconazole, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO once daily if coadministered with itraconazole. 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 itraconazole, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. The AUC of zanubrutinib was increased by 278% when coadministered with itraconazole.
Ziprasidone: (Major) Concomitant use of ziprasidone and itraconazole should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Itraconazole has been associated with prolongation of the QT interval. In addition, ziprasidone is partially metabolized by CYP3A4 and itraconazole is a potent CYP3A4 inhibitor. Concurrent use may increase systemic exposure to ziprasidone. Patients receiving this combination should be monitored for ziprasidone-induced adverse effects such as drowsiness, dizziness, anticholinergic effects, orthostasis, extrapyramidal symptoms, QT prolongation, neuroleptic malignant syndrome, and seizures.
Zolpidem: (Moderate) Consider decreasing the dose of zolpidem if coadministration with itraconazole is necessary. Zolpidem is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole increased the AUC of zolpidem by 34%.
Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and itraconazole is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

How Supplied

Itraconazole/Sporanox Oral Sol: 1mL, 10mg
Itraconazole/Sporanox/TOLSURA Oral Cap: 65mg, 100mg

Maximum Dosage
Adults

200 mg/day PO for the tablets and oral solution. 400 mg/day PO for the 100 mg capsule formulation; however, 600 mg/day PO for 3-day loading dose may be used in life-threatening infections. 260 mg/day PO for the 65 mg capsule formulation; however, 390 mg/day PO for 3-day loading dose may be used in life-threatening infections.

Geriatric

200 mg/day PO for the tablets and oral solution. 400 mg/day PO for the 100 mg capsule formulation; however, 600 mg/day PO for 3-day loading dose may be used in life-threatening infections. 260 mg/day PO for the 65 mg capsule formulation; however, 390 mg/day PO for 3-day loading dose may be used in life-threatening infections.

Adolescents

Safety and efficacy have not been established. However, doses up to 400 mg/day PO have been used off-label; 600 mg/day PO for 3-day loading dose has been used in life-threatening infections.

Children

Safety and efficacy have not been established. However, doses up to 10 mg/kg/day PO (Max: 400 mg/day) have been used off-label; 15 mg/kg/day PO (Max: 600 mg/day) for 3-day loading dose has been used in life-threatening infections.

Infants

Safety and efficacy have not been established. However, doses up to 10 mg/kg/day PO have been used off-label; 15 mg/kg/day PO for 3-day loading dose has been used in life-threatening infections.

Neonates

Safety and efficacy have not been established.

Mechanism Of Action

Like other azole antifungals, itraconazole exerts its effect by altering the fungal cell membrane. Itraconazole inhibits ergosterol synthesis by interacting with 14-alpha demethylase, a cytochrome P-450 (CYP450) enzyme that is necessary for the conversion of lanosterol to ergosterol, an essential component of the membrane. In contrast, amphotericin B binds to ergosterol after it is synthesized. Inhibition of ergosterol synthesis results in increased cellular permeability, which causes leakage of cellular contents. Itraconazole does not appear to have the same effects on human cholesterol synthesis. Other antifungal effects of azole compounds have been proposed and include: inhibition of endogenous respiration, interaction with membrane phospholipids, and inhibition of yeast transformation to mycelial forms. Other mechanisms may involve inhibition of purine uptake and impairment of triglyceride and/or phospholipid biosynthesis.

Pharmacokinetics

Itraconazole is administered orally. Both itraconazole and its major metabolite are highly bound to plasma protein (more than 99%), mainly to albumin. There is extensive distribution into lipophilic tissues, but aqueous tissues contain negligible amounts. Drug concentrations in the lung, kidney, liver, bone, stomach, spleen, and muscle are 2- to 3-times higher than in the plasma; concentrations in keratinous tissues (skin) are up to 4-times higher. Itraconazole accumulates in the stratum corneum and concentrations tend to increase with pulse dosing. Therapeutic concentrations may be detected in the nail for 6 to 9 months. Compared to plasma, drug concentrations in the cerebrospinal fluid are much lower.
 
Itraconazole is metabolized predominately by hepatic CYP3A4 to at least 30 metabolites; the major metabolite, hydroxy-itraconazole, has in vitro antifungal activity that is comparable to the parent compound. It appears itraconazole undergoes saturable metabolism with multiple dosing. The elimination half-life after single oral dose ranges from 16 to 28 hours; however, repeated dosing increases the half-life to 34 to 42 hours. Between 3% to 18% of the administered dose is excreted unchanged in the feces. There is minimal renal excretion of unchanged drug; however, about 35% is excreted in urine as inactive metabolites. Hydroxypropyl-beta-cyclodextrin is eliminated through the kidneys with little accumulation in body tissues.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, BCRP, P-gp
Itraconazole is a substrate of the CYP3A4 isoenzyme and drug transporter P-glycoprotein (P-gp). In addition, itraconazole is a strong CYP3A4 inhibitor and also inhibits P-gp and breast cancer resistance protein (BCRP).[27983] [29036] [34447] [40233] [50364]

Oral Route

After oral administration, peak plasma itraconazole concentrations (Cmax) are achieved within 2 to 6 hours; however, steady-state concentrations are not reached until approximately treatment day 15. Due to pharmacokinetic differences, do not use oral formulations of itraconazole interchangeably. Itraconazole oral bioavailability is susceptible to drug and food interactions that reduce gastric acidity; however, the effects of gastric acidity vary with the different itraconazole formulations.
Oral solution: The absolute bioavailability for the oral solution is reported to be about 72% under fasting conditions and decreases to about 55% under fed conditions. To ensure maximal absorption, administer the oral solution without food. Due to high insolubility in water, itraconazole oral solution is solubilized with a molecular inclusion complex with hydroxypropyl-beta-cyclodextrin. Cyclodextrins are cyclic oligosaccharides whose molecular structures form a hydrophilic exterior surface and a nonpolar cavity interior. These complexes increase water solubility and solution stability. The bioavailability of the hydroxypropyl-beta-cyclodextrin vehicle used in the oral solution is less than 0.5%.[40233]
100 mg capsule and 200 mg tablet: The 100 mg capsule and 200 mg tablet must be administered with a full meal to ensure maximal absorption. Oral bioavailability of the 100 mg itraconazole capsule is roughly 40% to 55% if administered on an empty stomach; food significantly increases the oral bioavailability of itraconazole from the 100 mg capsule and 200 mg tablet. In patients with relative or absolute achlorhydria (e.g., AIDS patients or volunteers on H2-blockers), absorption of itraconazole was significantly increased when administered with a non-diet cola beverage.[27983] [31784] [40233] In a study comparing the bioavailability of the 200 mg tablet with the 100 mg capsules, equivalent doses administered after a moderate-fat meal resulted in similar Cmax and a tablet AUC that was 15% higher than the capsule. When both formulations were administered after a high-fat meal, the Cmax and AUC of the capsules were 20% and 30% higher, respectively, than the tablets. Intersubject variability was high in both studies.[52489]
65 mg capsule: In contrast to the 100 mg capsule, administration of the 65 mg capsule with a high-fat meal decreases itraconazole Cmax and AUC. However, steady-state pharmacokinetic parameters of itraconazole 130 mg (two 65 mg capsules) twice daily were similar to 200 mg (two 100 mg capsules) twice daily when administered immediately after a meal for 14.5 days. Therefore, administer the 65 mg capsule with food.[63821]

Pregnancy And Lactation
Pregnancy

Use of itraconazole to treat onychomycosis is contraindicated during pregnancy and in females contemplating pregnancy. Use itraconazole for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk. There are no data on exposure to itraconazole during pregnancy for the approved indications. Epidemiologic studies of women exposed to short courses of itraconazole in the first trimester of pregnancy have reported no risk of major birth defects overall and inconclusive findings on the risk of miscarriage. However, postmarketing reports for itraconazole have included cases of congenital abnormalities. Teratogenic effects have been demonstrated in animals.[27983] Guidelines for prevention of opportunistic infections in HIV-infected patients recommend that oral azole antifungals, including itraconazole, not be started during pregnancy and that these agents be discontinued in HIV-positive women who become pregnant.[24842]

Itraconazole is distributed into breast milk. Weigh the expected benefits of itraconazole therapy for the mother against the potential risk from exposure of itraconazole to the breast-feeding infant. Fluconazole and ketoconazole may be potential alternatives to consider during breast-feeding. However, assess site of infection, local susceptibility patterns, and specific microbial susceptibility before choosing an alternative agent. Additionally, itraconazole may be used to treat infections in patients with HIV, and guidelines advise against HIV-infected women breast-feeding to avoid postnatal transmission of HIV.