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Prograf
Classes
Calcineurin Inhibitors
Topical Calcineurin Inhibitors
Administration
Hazardous Drugs Classification
NIOSH 2016 List: Group 2
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
INJECTABLES: Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
ORAL TABLETS/CAPSULES/ORAL LIQUID: Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown; may require eye/face protection.
Administer at approximately the same time each day.
Do not administer with grapefruit or grapefruit juice.
Immediate-release formulations (capsules and granules for oral suspension, administered twice daily), extended-release capsules (Astagraf XL; administered once daily), and extended-release tablets (Envarsus XR; administered once daily) are not interchangeable or substitutable.
Conventional immediate-release capsules
To minimize variations in bioavailability, administer consistently with or without food.
Extended-release capsules (Astagraf XL)
Take in the morning, preferably on an empty stomach at least 1 hour before a meal or at least 2 hours after a meal.
Swallow whole; do not chew, divide, or crush capsules.
Do not administer with an alcoholic beverage.
If a dose is missed up to 14 hours from the scheduled time, take the dose. If a dose is missed at more than 14 hours from the scheduled time, skip the dose and take the next dose at the regularly scheduled time.
Extended-release tablets (Envarsus XR)
Take in the morning, preferably on an empty stomach at least 1 hour before a meal or at least 2 hours after a meal.
Swallow whole; do not chew, divide, or crush tablets.
Do not administer with an alcoholic beverage.
If a dose is missed up to 15 hours from the scheduled time, take the dose. If a dose is missed at more than 15 hours from the scheduled time, skip the dose and take the next dose at the regularly scheduled time.
Granules for oral suspension
To minimize variations in bioavailability, administer consistently with or without food.
Use the minimum whole number of packets that corresponds to the required morning or evening dose. If the dose is not covered by the whole number of packets, use 1 additional 0.2 mg packet to round up the dose.
Do not use tubing, syringes, or other equipment (e.g., cups) containing PVC to prepare or administer tacrolimus.
Do not sprinkle the granules on food.
Wearing disposable gloves is recommended when preparing the oral suspension or when wiping spills. Avoid inhalation or direct contact with skin or mucous membranes. If contact occurs, wash the skin thoroughly with soap and water. If ocular contact occurs, rinse the eyes with water. Wipe the surface with a wet paper towel if a spill occurs; throw the paper towel away in the trash and wash your hands well.
To prepare the dose, empty the entire packet contents into a glass cup. Add 15 to 30 mL of room temperature drinking water and mix the entire contents of the cup. The granules will not completely dissolve. Give the suspension immediately after preparation. The suspension can be drawn up via a non-PVC oral syringe that is dispensed with the prescription. Rinse the cup or syringe with 15 to 30 mL of water and administer this to the patient to ensure all the medication is taken.
Extemporaneous compounding preparation†
A 0.5 mg/mL suspension can be made by mixing the contents of six 5-mg immediate-release tacrolimus capsules with equal amounts of Ora-Plus and Simple Syrup, NF to make a final volume of 60 mL. When stored at room temperature in either glass or plastic amber bottles, the suspension is stable for 56 days. Shake well before each use.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Because of the risk of hypersensitivity reactions, IV administration should be reserved for patients who cannot take tacrolimus orally. Oral therapy should replace IV therapy as soon as possible.
Observe patients for 30 minutes after beginning the infusion and frequently thereafter for possible hypersensitivity reactions. Epinephrine and oxygen should be available at the bedside.
Due to chemical instability, tacrolimus should not be mixed or infused with solutions with a pH of 9 or more (e.g., acyclovir or ganciclovir).
Dilution
The concentrate for injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final concentration between 0.004 mg/mL and 0.02 mg/mL.
ASHP Recommended Standard Concentrations for Pediatric Continuous Infusions: 0.02 mg/mL.
Prepare solutions in polyethylene or glass containers to allow storage for 24 hours. Do not use polyvinyl chloride (PVC) containers because stability is decreased and the polyoxyl 60 hydrogenated castor oil in the formulation may leach phthalates from PVC containers.
Continuous IV Infusion
Administer through non-PVC tubing to minimize the potential for drug adsorption onto the tubing.
Infuse the required daily dose of the diluted IV solution over 24 hours.
Apply tacrolimus as a thin layer and rub in gently and completely. Before applying the ointment after a bath or shower, make sure the skin is completely dry.
Avoid the eyes and surrounding area.
Do not use with occlusive dressings. Use of occlusive dressings may promote systemic absorption.
Adverse Reactions
hyperkalemia / Delayed / 0-45.0
pleural effusion / Delayed / 22.0-36.0
oliguria / Early / 0-19.0
renal failure (unspecified) / Delayed / 0-15.0
renal tubular necrosis / Delayed / 0-15.0
anuria / Delayed / 0-15.0
seizures / Delayed / 0-15.0
atrial flutter / Early / 0-15.0
atrial fibrillation / Early / 0-15.0
pericardial effusion / Delayed / 15.0-15.0
thrombotic microangiopathy / Delayed / 0-15.0
hemolytic anemia / Delayed / 0-15.0
anasarca / Delayed / 0-15.0
pulmonary edema / Early / 0-15.0
acute respiratory distress syndrome (ARDS) / Early / 0-15.0
stroke / Early / 3.1-14.9
bradycardia / Rapid / 3.1-14.9
thrombosis / Delayed / 3.1-14.9
heart failure / Delayed / 3.1-14.9
GI perforation / Delayed / 3.1-14.9
GI bleeding / Delayed / 3.1-14.9
esophageal ulceration / Delayed / 3.1-14.9
ileus / Delayed / 3.1-14.9
coagulopathy / Delayed / 3.1-14.9
exfoliative dermatitis / Delayed / 0-14.9
pneumothorax / Early / 3.1-14.9
angioedema / Rapid / 1.0-2.0
cardiomyopathy / Delayed / 0-1.0
anaphylactoid reactions / Rapid / 0-1.0
cardiac valvulopathy / Delayed / 0.2-0.9
nephrotoxicity / Delayed / 10.0
hemorrhagic cystitis / Delayed / Incidence not known
optic atrophy / Delayed / Incidence not known
hearing loss / Delayed / Incidence not known
leukoencephalopathy / Delayed / Incidence not known
ventricular fibrillation / Early / Incidence not known
torsade de pointes / Rapid / Incidence not known
arrhythmia exacerbation / Early / Incidence not known
cardiac arrest / Early / Incidence not known
myocardial infarction / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
hemolytic-uremic syndrome / Delayed / Incidence not known
pancytopenia / Delayed / Incidence not known
disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
red cell aplasia / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
graft-versus-host disease (GVHD) / Delayed / Incidence not known
anaphylactic shock / Rapid / Incidence not known
pulmonary hypertension / Delayed / Incidence not known
bronchiolitis obliterans / Delayed / Incidence not known
pulmonary embolism / Delayed / Incidence not known
rhabdomyolysis / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
cirrhosis / Delayed / Incidence not known
veno-occlusive disease (VOD) / Delayed / Incidence not known
hepatic necrosis / Delayed / Incidence not known
lymphoma / Delayed / Incidence not known
new primary malignancy / Delayed / Incidence not known
post-transplant lymphoproliferative disorder (PTLD) / Delayed / Incidence not known
hypertension / Early / 0-89.0
diabetes mellitus / Delayed / 10.0-75.0
hypertriglyceridemia / Delayed / 65.0-65.0
anemia / Delayed / 0.2-65.0
hypercholesterolemia / Delayed / 0.2-57.0
hypophosphatemia / Delayed / 13.0-49.0
hypomagnesemia / Delayed / 12.0-48.0
leukopenia / Delayed / 13.0-48.0
hyperglycemia / Delayed / 11.0-47.0
constipation / Delayed / 0.2-40.0
elevated hepatic enzymes / Delayed / 0-37.0
peripheral edema / Delayed / 0-36.0
hyperlipidemia / Delayed / 10.0-34.0
hypokalemia / Delayed / 0-29.0
dyspnea / Early / 0-29.0
erythema / Early / 9.0-28.0
ascites / Delayed / 7.0-27.0
thrombocytopenia / Delayed / 0-24.0
chest pain (unspecified) / Early / 0.2-19.0
edema / Delayed / 0.2-18.0
conjunctivitis / Delayed / 0-15.0
proteinuria / Delayed / 0-15.0
hyponatremia / Delayed / 0-15.0
hyperphosphatemia / Delayed / 0-15.0
depression / Delayed / 0-15.0
confusion / Early / 0-15.0
hallucinations / Early / 0-15.0
peripheral neuropathy / Delayed / 0-15.0
blurred vision / Early / 0-15.0
neurotoxicity / Early / 0-15.0
sinus tachycardia / Rapid / 0-15.0
metabolic acidosis / Delayed / 0-15.0
hyperuricemia / Delayed / 0-15.0
stomatitis / Delayed / 0-15.0
gastritis / Delayed / 0-15.0
esophagitis / Delayed / 0-15.0
neutropenia / Delayed / 0-15.0
impaired wound healing / Delayed / 0-15.0
osteopenia / Delayed / 0-15.0
osteoporosis / Delayed / 0-15.0
hepatitis / Delayed / 0-15.0
cholestasis / Delayed / 0-15.0
vaginitis / Delayed / 0-15.0
BK virus-associated nephropathy / Delayed / 0.7-14.9
pyuria / Delayed / 3.1-14.9
hematuria / Delayed / 3.1-14.9
urinary retention / Early / 3.1-14.9
cystitis / Delayed / 3.1-14.9
bladder spasm / Early / 3.1-14.9
dysuria / Early / 3.1-14.9
hypercalcemia / Delayed / 3.1-14.9
hypocalcemia / Delayed / 3.1-14.9
psychosis / Early / 3.1-14.9
encephalopathy / Delayed / 3.1-14.9
amnesia / Delayed / 3.1-14.9
myoclonia / Delayed / 3.1-14.9
amblyopia / Delayed / 3.1-14.9
hypotension / Rapid / 3.1-14.9
phlebitis / Rapid / 3.1-14.9
peripheral vasodilation / Rapid / 0.2-14.9
angina / Early / 3.1-14.9
orthostatic hypotension / Delayed / 3.1-14.9
metabolic alkalosis / Delayed / 3.1-14.9
hypoglycemia / Early / 3.1-14.9
Cushing's syndrome / Delayed / 3.1-14.9
hypervolemia / Delayed / 3.1-14.9
dysphagia / Delayed / 3.1-14.9
polycythemia / Delayed / 3.1-14.9
skin ulcer / Delayed / 0.2-14.9
heat intolerance / Early / 3.1-14.9
dehydration / Delayed / 0.2-14.9
myasthenia / Delayed / 3.1-14.9
gout / Delayed / 3.1-14.9
hyperbilirubinemia / Delayed / 0.2-14.9
cholangitis / Delayed / 3.1-14.9
jaundice / Delayed / 3.1-14.9
hyperesthesia / Delayed / 0-7.0
migraine / Early / 0.2-0.9
cataracts / Delayed / 0.2-0.9
blepharitis / Early / 0.2-0.9
hypothyroidism / Delayed / 0.2-0.9
colitis / Delayed / 0.2-0.9
furunculosis / Delayed / 0.2-0.9
osteomyelitis / Delayed / Incidence not known
urinary incontinence / Early / Incidence not known
delirium / Early / Incidence not known
photophobia / Early / Incidence not known
aphasia / Delayed / Incidence not known
QT prolongation / Rapid / Incidence not known
supraventricular tachycardia (SVT) / Early / Incidence not known
glycosuria / Early / Incidence not known
immunosuppression / Delayed / Incidence not known
diarrhea / Early / 3.0-72.0
insomnia / Early / 1.0-64.0
headache / Early / 9.0-64.0
abdominal pain / Early / 0-59.0
tremor / Early / 15.0-56.0
asthenia / Delayed / 0-52.0
nausea / Early / 1.0-46.0
pruritus / Rapid / 0-46.0
fever / Early / 1.0-46.0
infection / Delayed / 1.0-45.0
paresthesias / Delayed / 0-40.0
anorexia / Delayed / 0-34.0
leukocytosis / Delayed / 0-32.0
cough / Delayed / 1.0-31.0
back pain / Delayed / 1.0-30.0
vomiting / Early / 1.0-29.0
dyspepsia / Early / 0-28.0
arthralgia / Delayed / 0-25.0
rash / Early / 0-24.0
dizziness / Early / 0-19.0
fatigue / Early / 16.0-16.0
anxiety / Delayed / 0-15.0
agitation / Early / 0-15.0
nightmares / Early / 0-15.0
hypoesthesia / Delayed / 0-15.0
tinnitus / Delayed / 0-15.0
flushing / Rapid / 0-15.0
Cushingoid features / Delayed / 0-15.0
gastroesophageal reflux / Delayed / 0-15.0
flatulence / Early / 0-15.0
acne vulgaris / Delayed / 0-15.0
hyperhidrosis / Delayed / 0-15.0
alopecia / Delayed / 0-15.0
pharyngitis / Delayed / 3.0-14.9
rhinitis / Early / 2.0-14.9
sinusitis / Delayed / 2.0-14.9
influenza / Delayed / 3.1-14.9
urinary urgency / Early / 3.1-14.9
nocturia / Early / 3.1-14.9
drowsiness / Early / 3.1-14.9
psychomotor impairment / Early / 3.1-14.9
abnormal dreams / Early / 3.1-14.9
emotional lability / Early / 3.1-14.9
inconsolable crying / Delayed / 3.1-14.9
syncope / Early / 0.2-14.9
vertigo / Early / 0.2-14.9
otalgia / Early / 0-14.9
weight gain / Delayed / 3.1-14.9
appetite stimulation / Delayed / 3.1-14.9
ecchymosis / Delayed / 0.2-14.9
diaphoresis / Early / 0.2-14.9
hirsutism / Delayed / 3.1-14.9
skin discoloration / Delayed / 0.2-14.9
photosensitivity / Delayed / 0.2-14.9
chills / Rapid / 0.2-14.9
hiccups / Early / 3.1-14.9
myalgia / Early / 0-14.9
folliculitis / Delayed / 2.0-6.0
urticaria / Rapid / 1.0-6.0
vesicular rash / Delayed / 1.0-4.0
dysmenorrhea / Delayed / 0-4.0
xerosis / Delayed / 1.0-3.0
maculopapular rash / Early / 0-2.0
laryngitis / Delayed / 0.2-0.9
xerophthalmia / Early / 0.2-0.9
ocular pain / Early / 0.2-0.9
dysgeusia / Early / 0.2-0.9
seborrhea / Delayed / 0.2-0.9
xerostomia / Early / 0.2-0.9
epistaxis / Delayed / 0.2-0.9
arthropathy / Delayed / 0.2-0.9
muscle cramps / Delayed / 0.2-0.9
weight loss / Delayed / Incidence not known
skin hyperpigmentation / Delayed / Incidence not known
Boxed Warning
Increased susceptibility to infection may occur with either systemic or topical use. Bacterial, viral, protozoal, and fungal infection occur commonly during immunosuppressive therapy and can be fatal. Serious viral infections reported include polyoma virus-associated nephropathy (PVAN) mostly due to BK virus infection, JC virus-associated progressive multifocal leukoencephalopathy (PML), and cytomegalovirus (CMV) infections. CMV seronegative transplant patients who receive an organ from a CMV seropositive donor are at higher risk of developing CMV viremia and CMV disease. Reactivation of a latent viral infection, especially herpes infection, can occur with immunosuppressive therapy. Monitor for infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection. Treatment with topical tacrolimus may be associated with an increased risk of varicella zoster (chickenpox or shingles) and herpes simplex infection. In the presence of these infections, the balance of risk and benefits associated with topical therapy should be evaluated. Patients should be instructed to report signs of infection promptly. Therapy requires an experienced clinician, specifically only clinicians experienced in immunosuppressant therapy and organ transplantation should use systemic tacrolimus, and the clinician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. Administration of systemic tacrolimus requires a specialized care setting and should be managed in facilities equipped and staffed with adequate laboratory and supportive medical services.
Patients receiving immunosuppressants, such as oral or injectable tacrolimus, are at increased risk for the development of lymphomas and other malignancies, particularly of the skin. Risk of developing a malignancy appears to be related to the intensity and duration of immunosuppression rather than the specific immunosuppressive agent. Post-transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients and has an association with the Epstein-Barr Virus (EBV). The risk of PTLD appears greatest in those patients who are EBV seronegative; a population that includes young pediatric patients. Monitor EBV serology during tacrolimus therapy. Also, immunosuppression from the use of topical tacrolimus may influence the possible development of a new primary malignancy, especially skin cancer, lymphoma, or other lymphoproliferative disorders; rare cases of malignancy (e.g., skin and lymphoma) have been reported, but a causal relationship has not been established. Some malignant conditions such as cutaneous T-cell lymphoma may mimic atopic dermatitis; avoid the use of topical tacrolimus on premalignant and malignant skin conditions. Discontinue Protopic in the presence of acute infectious mononucleosis, and do not use Protopic in patients who are immunocompromised. Avoid continuous long-term use of topical calcineurin inhibitors such as tacrolimus ointment, and limit application to areas of involvement with atopic dermatitis. Only physicians experienced in immunosuppressant therapy and organ transplantation should use systemic tacrolimus, and the physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. Patients initiating systemic tacrolimus therapy should be managed in facilities equipped and staffed with adequate laboratory and supportive medical services.[28611] [30973] [55401] [60497]
Tacrolimus ointment is not approved for use in neonates, infants, or children younger than 2 years old; only the lower concentration (tacrolimus 0.03%) ointment is recommended for use in non-immunocompromised pediatric patients aged 2 to 15 years. The long-term effect of tacrolimus on the developing immune system in infants and children is not known. Immediate-release capsules and granules for oral suspension are indicated for the prophylaxis of organ rejection in pediatric kidney, liver, and heart transplant patients. In general, pediatric patients require higher tacrolimus doses compared to adults; these requirements may decrease as the child grows older. If pediatric patients are converted between immediate-release formulations, perform therapeutic drug monitoring and adjust the dosage as necessary to ensure adequate tacrolimus exposure is maintained. Astagraf XL is approved in pediatric patients 4 years of age and older. The safety and efficacy of Envarsus XR have not been established in patients less than 18 years of age.
Common Brand Names
ASTAGRAF XL, ENVARSUS, HECORIA, Prograf, Protopic
Dea Class
Rx
Description
Immunosuppressant; more potent than cyclosporine
Used for graft rejection prophylaxis and treatment of acute or refractory graft rejection; considered an alternative to cyclosporine; topical formulation used for atopic dermatitis
Increased susceptibility to infections and secondary malignancy possible
Dosage And Indications
0.1 to 0.15 mg/kg/day PO in 2 divided doses, every 12 hours. Adjust dose as needed based on tacrolimus trough whole blood concentrations. Administer the initial dose of tacrolimus no sooner than 6 hours after transplantation.
0.15 to 0.2 mg/kg/day PO in 2 divided doses, every 12 hours. Adjust dose as needed based on tacrolimus trough whole blood concentrations. Administer the initial dose of tacrolimus no sooner than 6 hours after transplantation. For conversion from capsules to granules, the total daily dose should remain the same; therapeutic drug monitoring is recommended after conversion.
0.2 mg/kg/day PO in 2 divided doses, every 12 hours. Adjust dose as needed based on tacrolimus trough whole blood concentrations. Administer the initial dose of tacrolimus no sooner than 6 hours after transplantation. For conversion from granules to capsules, the total daily dose should remain the same; therapeutic drug monitoring is recommended after conversion.
NOTE: In patients unable to take oral tacrolimus, therapy may be initiated with tacrolimus injection. Continue continuous IV infusion only until the patient can tolerate oral administration. Give the first oral dose 8 to 12 hours after the IV infusion is stopped.
0.03 to 0.05 mg/kg/day continuous IV infusion, beginning no sooner than 6 hours after transplantation. Adjust dose as needed based on tacrolimus trough whole blood concentrations.
0.03 to 0.05 mg/kg/day continuous IV infusion, beginning no sooner than 6 hours after transplantation. Adjust dose as needed based on tacrolimus trough whole blood concentrations.
NOTE: Do not administer concomitantly with cyclosporine. Additionally, use with sirolimus is not recommended in kidney transplant recipients.
NOTE: According to renal transplant guidelines, tacrolimus is the suggested first-line calcineurin inhibitor (CNI) to be used for initial maintenance immunosuppression with an antiproliferative agent such as mycophenolate plus or minus corticosteroids. The CNI is suggested to be started before or at the time of transplantation rather than delayed until graft function onset. Further, the CNI is suggested to be continued rather than withdrawn during long-term maintenance therapy. In combination with azathioprine. Oral dosage (immediate-release capsules)
NOTE: Tacrolimus immediate-release capsules (administered twice daily), immediate-release oral suspension (administered twice daily), extended-release capsules (Astagraf XL; administered once daily), and extended-release tablets (Envarsus XR; administered once daily) are not interchangeable or substitutable.
0.2 mg/kg/day PO in 2 divided doses given 12 hours apart in combination with azathioprine; adjunct therapy with corticosteroids recommended early post-transplant. The first dose may be administered within 24 hours of transplantation but should be delayed until renal function has recovered. Titrate dose based on clinical assessment of rejection and tolerability; monitor trough concentrations to ensure therapeutic concentrations. Lower than the recommended initial tacrolimus doses may be adequate as maintenance therapy.[28611]
NOTE: Tacrolimus immediate-release capsules (administered twice daily), immediate-release oral suspension (administered twice daily), extended-release capsules (Astagraf XL; administered once daily), and extended-release tablets (Envarsus XR; administered once daily) are not interchangeable or substitutable.
0.1 mg/kg/day PO in 2 divided doses given 12 hours apart in combination with mycophenolate mofetil and induction therapy with an interleukin-2 (IL-2) inhibitor, such as basiliximab or daclizumab; adjunct therapy with corticosteroids recommended early post-transplant. The first dose may be administered within 24 hours of transplantation but should be delayed until renal function has recovered. Titrate dose based on clinical assessment of rejection and tolerability; monitor trough concentrations to ensure therapeutic concentrations. Lower than the recommended initial tacrolimus doses may be adequate as maintenance therapy.[28611]
NOTE: Tacrolimus immediate-release capsules (administered twice daily), immediate-release oral suspension (administered twice daily), extended-release capsules (Astagraf XL; administered once daily), and extended-release tablets (Envarsus XR; administered once daily) are not interchangeable or substitutable.
0.1 mg/kg/dose PO once daily (on an empty stomach) pre-operatively (first dose given 12 hours prior to reperfusion) and 0.2 mg/kg/dose PO once daily post-operatively (first dose given within 12 hours after reperfusion but at least 4 hours after the pre-operative dose) in combination with mycophenolate mofetil and corticosteroids. Titrate dose based on clinical assessment of rejection and tolerability; monitor trough concentrations to ensure therapeutic concentrations.[55401]
NOTE: Tacrolimus immediate-release capsules (administered twice daily), immediate-release oral suspension (administered twice daily), extended-release capsules (Astagraf XL; administered once daily,) and extended-release tablets (Envarsus XR; administered once daily) are not interchangeable or substitutable.
Oral dosage (extended-release tablets; Envarsus XR) Adults
Initial dose is 0.14 mg/kg/day as a once daily dose taken on an empty stomach at the same time of day, preferably in the morning, in combination with other immunosuppressants. Titrate dose based on clinical assessment of rejection and tolerability; monitor trough concentrations to ensure therapeutic concentrations.[60497]
NOTE: Tacrolimus immediate-release capsules (administered twice daily), immediate-release oral suspension (administered twice daily), extended-release capsules (Astagraf XL; administered once daily,) and extended-release tablets (Envarsus XR; administered once daily) are not interchangeable or substitutable.
Oral dosage (extended-release tablets; Envarsus XR) Adults
Initially, administer at a dose that is 80% of the total daily dose of the tacrolimus immediate-release product. Tacrolimus extended-release tablet is administered PO once daily on an empty stomach, preferably in the morning, in combination with other immunosuppressants. Titrate dose based on clinical assessment of rejection and tolerability; monitor trough concentrations to ensure therapeutic concentrations.[60497]
NOTE: Tacrolimus immediate-release capsules (administered twice daily), immediate-release oral suspension (administered twice daily), extended-release capsules (Astagraf XL; administered once daily), and extended-release tablets (Envarsus XR; administered once daily) are not interchangeable or substitutable.
0.15 to 0.2 mg/kg/dose PO once daily (on an empty stomach) in the morning in combination with mycophenolate mofetil, corticosteroids, and basiliximab induction therapy. The first dose should be given prior to or within 48 hours after transplant completion. Titrate dose based on clinical assessment of rejection and tolerability; monitor trough concentrations to ensure therapeutic concentrations.[55401]
0.3 mg/kg/dose PO once daily (on an empty stomach) in the morning in combination with mycophenolate mofetil, corticosteroids, and basiliximab induction therapy. The first dose should be given within 24 hours after reperfusion. Titrate dose based on clinical assessment of rejection and tolerability; monitor trough concentrations to ensure therapeutic concentrations.[55401]
NOTE: In patients unable to take oral tacrolimus, therapy may be initiated with tacrolimus injection. Continue continuous IV infusion only until the patient can tolerate oral administration.
0.03 to 0.05 mg/kg/day as a continuous IV infusion. The infusion may begin within 24 hours of transplantation but should be delayed until renal function has recovered. Adjust the dose based on tacrolimus trough whole blood concentrations. Concomitant corticosteroid therapy is recommended during the early post-transplantation period. When the patient is able to tolerate oral therapy, give the first oral dose 8 to 12 hours after discontinuing the infusion.
Experience in pediatric renal transplantation patients is limited. In a prospective study comparing tacrolimus and cyclosporine, pediatric patients received tacrolimus 0.1 mg/kg/day IV as an infusion over 24 hours, then 0.3 mg/kg/day PO in divided doses. At 1 year, patient and graft survival rates were 100% and 96%, respectively.[24938] In another study, 0.3 mg/kg/day PO was given as 2 divided doses (every 12 hours); doses were adjusted to achieve whole blood trough concentrations of 10 to 20 ng/mL for the first 30 days and 5 to 10 ng/mL thereafter. Continuous IV infusion of 0.06 mg/kg/day was required initially in 36 patients; the mean duration of IV receipt was 4.1 +/- 2.9 days.[35708]
0.3 mg/kg/day PO in 2 divided doses, every 12 hours. Adjust dose as needed based on tacrolimus trough whole blood concentrations. Administer the initial dose within 24 hours of transplantation, but delay until renal function has recovered. For conversion from capsules to granules or vice versa, the total daily dose should remain the same; therapeutic drug monitoring is recommended after conversion.
NOTE: Tacrolimus is recommended to be used in conjunction with azathioprine or mycophenolate mofetil. Adjunct therapy with adrenal corticosteroids is recommended early post transplant.
Oral dosage (immediate-release capsules) Adults
0.075 mg/kg/day PO in 2 divided doses, every 12 hours. The initial dose should be administered no sooner than 6 hours after transplantation. Adjust dose as needed based on tacrolimus trough whole blood concentrations. According to guidelines, lower concentrations should be sought when used with mycophenolate mofetil as compared with azathioprine because use of lower tacrolimus concentrations with mycophenolate mofetil is safe and is associated with lower rejection rates and improved renal function. Trial data suggest that tacrolimus-based regimens may be associated with lower rejection rates but not with superior survival as compared with cyclosporine-based regimens. Conversion from cyclosporine to tacrolimus 0.05 to 0.15 mg/kg/day PO in 2 divided doses titrated to troughs of 5 to 12 ng/mL led to reductions in rejection episodes among patients with refractory or persistent rejection. After conversion to tacrolimus, the number of treated episodes of rejection decreased from 1.2 +/- 1 to 0.3 +/- 0.5 episodes per patient per year. In another study, replacement of cyclosporine with tacrolimus led to a mean number of rejection episodes Grade 3A or higher of 0.7 +/- 0.8 as compared with 3.2 +/- 0.4 before the switch to tacrolimus.
0.3 mg/kg/day PO in 2 divided doses, every 12 hours. If cell depleting induction treatment is administered, initiate tacrolimus at 0.1 mg/kg/day PO. Adjust dose as needed based on tacrolimus trough whole blood concentrations. Administer the initial dose no sooner than 6 hours after transplantation. For conversion from capsules to granules, the total daily dose should remain the same; therapeutic drug monitoring is recommended after conversion.
0.3 mg/kg/day PO in 2 divided doses, every 12 hours. If cell depleting induction treatment is administered, initiate tacrolimus at 0.1 mg/kg/day PO. Adjust dose as needed based on tacrolimus trough whole blood concentrations. Administer the initial dose no sooner than 6 hours after transplantation. For conversion from granules to capsules, the total daily dose should remain the same; therapeutic drug monitoring is recommended after conversion.
NOTE: In patients unable to take oral tacrolimus, therapy may be initiated with tacrolimus injection. Continue continuous IV infusion only until the patient can tolerate oral tacrolimus administration. Give the first oral dose 8 to 12 hours after the IV infusion is stopped.
0.01 mg/kg/day as a continuous IV infusion, beginning no sooner than 6 hours after transplantation. Adjust the dose based on tacrolimus trough whole blood concentrations. According to guidelines, monotherapy with early corticosteroid withdrawal may be considered in highly selected patients. Lower tacrolimus concentrations should be sought when used with mycophenolate mofetil as compared with azathioprine because use of lower tacrolimus concentrations with mycophenolate mofetil is safe and is associated with lower rejection rates and improved renal function. Trial data suggest that tacrolimus-based regimens may be associated with lower rejection rates but not with superior survival as compared with cyclosporine-based regimens.
Experience in pediatric heart transplantation patients is limited. Tacrolimus dosage 0.03 to 0.05 mg/kg/day continuous IV infusion to achieve whole blood concentrations of 15 to 20 ng/mL has been studied. In a retrospective review, doses less than 0.05 mg/kg/day IV may have resulted in a clinically important delay in reaching therapeutic concentrations. Frequent monitoring of whole blood concentrations is recommended during the first 48 hours, especially when the initial concentration is more than 10 ng/mL to avoid toxicity. According to heart transplant guidelines, maintenance therapy for all pediatric heart transplant recipients should include a calcineurin inhibitor (CNI) such as tacrolimus, and tacrolimus monotherapy is acceptable for patients with a benign rejection history. Tacrolimus is the preferred CNI for those considered to be at high immunologic risk such as sensitized recipients with evidence of donor-specific antibody. Also, patients with preformed alloantibodies and a positive donor-specific cross-match should get tacrolimus, corticosteroids, and either mycophenolate mofetil or a mTOR inhibitor such as sirolimus or everolimus.
NOTE: In patients unable to take oral tacrolimus, therapy may be initiated with tacrolimus injection. Continue continuous IV infusion only until the patient can tolerate oral tacrolimus administration. Give the first oral dose 8 to 12 hours after the IV infusion is stopped.
Oral dosage (immediate-release capsules) Adults
0.075 mg/kg/day PO in 2 divided doses, every 12 hours. Administer the initial dose no sooner than 6 hours after transplantation. Adjust dose as needed based on tacrolimus trough whole blood concentrations. Administer in combination with azathioprine or mycophenolate. Due to lower bioavailability, patients with cystic fibrosis may require higher doses of tacrolimus.
0.3 mg/kg/day PO in 2 divided doses, every 12 hours. If cell depleting induction treatment is administered, initiate tacrolimus at 0.1 mg/kg/day PO. Administer the initial dose no sooner than 6 hours after transplantation. Adjust dose as needed based on tacrolimus trough whole blood concentrations. Due to lower bioavailability, patients with cystic fibrosis may require higher doses of tacrolimus. For conversion from granules to capsules, the total daily dose should remain the same; therapeutic drug monitoring is recommended after conversion.
0.3 mg/kg/day PO in 2 divided doses, every 12 hours. If cell depleting induction treatment is administered, initiate tacrolimus at 0.1 mg/kg/day PO. Administer the initial dose no sooner than 6 hours after transplantation. Adjust dose as needed based on tacrolimus trough whole blood concentrations. Due to lower bioavailability, patients with cystic fibrosis may require higher doses of tacrolimus. For conversion from granules to capsules, the total daily dose should remain the same; therapeutic drug monitoring is recommended after conversion.
0.01 to 0.03 mg/kg/day continuous IV infusion, beginning no sooner than 6 hours after transplantation. Adjust dose as needed based on tacrolimus trough whole blood concentrations.
NOTE: Topical tacrolimus is indicated as a second-line therapy for short-term and non-continuous chronic treatment in non-immunocompromised persons who have failed to respond adequately to other topical treatments or when those treatments are not advisable.
Topical dosage (0.03% ointment) Adults
Apply a thin layer topically to the affected skin area(s) 2 times daily until symptoms resolve. If no improvement within 6 weeks, reassess diagnosis. Avoid continuous long-term use. Proactive, intermittent application of topical calcineurin inhibitors 2 to 3 times weekly to recurrent sites of disease has also been shown to be effective in reducing relapses.
Apply a thin layer topically to the affected skin area(s) 2 times daily until symptoms resolve. If no improvement within 6 weeks, reassess diagnosis. Avoid continuous long-term use. Proactive, intermittent application of topical calcineurin inhibitors 2 to 3 times weekly to recurrent sites of disease has also been shown to be effective in reducing relapses.
Apply a thin layer topically to the affected skin area(s) 2 times daily until symptoms resolve. Proactive, intermittent application of topical calcineurin inhibitors 2 to 3 times weekly to recurrent sites of disease has also been shown to be effective in reducing relapses.
Apply a thin layer topically to the affected skin area(s) 2 times daily until symptoms resolve. If no improvement within 6 weeks, reassess diagnosis. Avoid continuous long-term use. Proactive, intermittent application of topical calcineurin inhibitors 2 to 3 times weekly to recurrent sites of disease has also been shown to be effective in reducing relapses.
Apply a thin layer topically to the affected skin area(s) 2 times daily until symptoms resolve. If no improvement within 6 weeks, reassess diagnosis. Avoid continuous long-term use. Proactive, intermittent application of topical calcineurin inhibitors 2 to 3 times weekly to recurrent sites of disease has also been shown to be effective in reducing relapses.
Tacrolimus has been widely studied for rescue therapy in patients who do not tolerate cyclosporine, have cyclosporine-refractory rejection or chronic rejection. Doses studied include 0.075—0.15 mg/kg/day continuous IV infusion, then 0.3 mg/kg/day PO in divided doses. In one study, patients with uncontrolled rejection or complications related to cyclosporine were given tacrolimus 0.15 mg/kg/day IV as a continuous infusion over 24 hours, followed by 0.3 mg/kg/day PO in 2 divided doses every 12 hours. Of the 39 patients meeting criteria for tacrolimus rescue therapy, all but 12 responded to therapy as demonstrated by histopathologic findings and liver function. In a follow-up report, patients receiving cyclosporine were changed to tacrolimus because of failure of the conventional immunosuppressive therapy. The tacrolimus dosage was 0.075—0.15 mg/kg IV given over 4 hours, followed by 0.3 mg/kg/day PO in divided doses.
Dosages studied include tacrolimus 0.15 mg/kg/day continuous IV infusion, then 0.15—0.33 mg/kg/day PO in divided doses. In children whose immunosuppressive therapy was changed to tacrolimus therapy after early or late graft rejection on conventional immunosuppression, the tacrolimus dosage was 0.15 mg/kg/day IV as a slow infusion, followed by 0.15 mg/kg PO every 12 hours. After a mean follow-up of 150 days, 3 patients had died and 7 patients had retransplantations. In another study, patients were changed from cyclosporine to tacrolimus because of uncontrollable acute rejection, chronic rejection, or nonspecific hepatitis. Patients received a dosage of 0.15 mg/kg IV as a continuous infusion for 4—19 days, then 0.2—0.33 mg/kg/day PO in divided doses or oral therapy starting on day 4. Of the 18 patients with acute rejection, 11 had a complete response and 7 did not respond. Five patients developed a lymphoproliferative syndrome.
Tacrolimus has been widely studied for rescue therapy in patients who do not tolerate cyclosporine, have cyclosporine-refractory rejection, or chronic rejection. Tacrolimus dosages studied include 0.02—0.1 mg/kg/day IV, followed by 0.3 mg/kg/day PO in 2 divided doses to maintain tacrolimus 12-hour whole blood trough levels of 1—2 ng/ml. In one study, 57 of 77 patients (74%) were successfully rescued with tacrolimus therapy and still had functioning allografts with a mean follow-up of 14 months. Renal transplant guidelines mention consideration of a switch from cyclosporine to tacrolimus for severe or steroid-resistant acute rejection, if applicable.
Numerous trials have studied the use of tacrolimus in patients receiving pancreas transplant alone, simultaneous pancreas/kidney transplant, and pancreas transplant after kidney transplant. These studies have shown that tacrolimus is effective both as part of primary immunosuppressive therapy and in patients who do not tolerate cyclosporine or develop refractory rejection. For rejection prophylaxis dosages of 4—10 mg/day PO in divided doses have been used to maintain tacrolimus whole blood concentrations at an average of 12 ng/ml. In patients who switched to tacrolimus for rejection or rescue therapy the median dose was 10 mg/day PO in divided doses with a median whole blood concentration of 11 ng/ml.
In seven patients, immunosuppression with daclizumab, sirolimus, and low-dose tacrolimus 1 mg PO twice daily was begun immediately prior to islet transplantation. The tacrolimus dose was adjusted to maintain a whole blood trough concentration at 12 hours of 3—6 ng/ml. No corticosteroids were used as immunosuppression. All patients remain free of the need for exogenous insulin and no episodes of acute rejection have been observed with median follow-up of 11.9 months.
Conversion from cyclosporine to tacrolimus may reduce the severity of a rejection episode. For example, 14 of 15 patients who got oral tacrolimus rescue therapy (target 12-hour trough of 10—20 ng/ml) for grade 3A or higher refractory rejection converted from at least grade 3A to grade 2 or lower rejection.]
In one report, adults and children received tacrolimus 0.1—0.15 mg/kg/day IV, followed by 0.3 mg/kg/day PO in divided doses for either small-bowel, small-bowel and liver, or multivisceral transplantation. In a subsequent report of 15 patients who received tacrolimus 0.1—0.15 mg/kg/day IV, followed by 0.3 mg/kg/day PO in divided doses for small-bowel, with or without the colon, transplantation, actuarial patient survival rates at 6, 12, and 18 months were 100%, 88%, and 70%, respectively. The overall incidence of rejection was 94%.
NOTE: Tacrolimus has been designated an orphan drug by the FDA for this indication.
For the treatment of acute GVHD†. Topical dosage (0.03% ointment) Adults
Apply a thin layer topically to the affected skin area(s) 2 to 3 times daily. The 0.03% ointment may be beneficial in weaning if skin flares after resolution with and discontinuation of the 0.1% ointment. Guidelines suggest topical tacrolimus may be useful in resistant grade I acute cutaneous GVHD.
Apply a thin layer topically to the affected skin area(s) 2 times daily. The 0.03% ointment may be beneficial in weaning if skin flares after resolution with and discontinuation of the 0.1% ointment. Guidelines suggest topical tacrolimus may be useful in resistant grade I acute cutaneous GVHD.
Apply a thin layer topically to the affected skin area(s) 2 times daily. Guidelines suggest topical tacrolimus may be useful in resistant grade I acute cutaneous GVHD.
Apply a thin layer topically to the affected skin area(s) 2 to 3 times daily. Guidelines suggest topical tacrolimus may be useful in resistant grade I acute cutaneous GVHD.
Apply a thin layer topically to the affected skin area(s) 2 times daily. Guidelines suggest topical tacrolimus may be useful in resistant grade I acute cutaneous GVHD.
0.15 mg/kg/dose PO twice daily, initially. Adjust dose based on serum tacrolimus trough concentration to target 15 to 25 ng/mL. Guidelines suggest calcineurin inhibitors may be useful in the initial treatment of chronic GVHD as a steroid sparer.
0.15 mg/kg/dose PO twice daily, initially. Adjust dose based on serum tacrolimus trough concentration to target 15 to 25 ng/mL. Guidelines suggest calcineurin inhibitors may be useful in the initial treatment of chronic GVHD as a steroid sparer.
0.05 mg/kg/dose IV twice daily. Adjust dose based on serum tacrolimus trough concentration to target 15 to 25 ng/mL. Guidelines suggest calcineurin inhibitors may be useful in the initial treatment of chronic GVHD as a steroid sparer.
0.05 mg/kg/dose IV twice daily. Adjust dose based on serum tacrolimus trough concentration to target 15 to 25 ng/mL. Guidelines suggest calcineurin inhibitors may be useful in the initial treatment of chronic GVHD as a steroid sparer.
Apply a thin layer topically to the affected skin area(s) 2 to 3 times daily. Guidelines suggest topical therapy, including calcineurin inhibitors, as first-line therapy for chronic cutaneous GVHD.
Apply a thin layer topically to the affected skin area(s) 2 times daily. Guidelines suggest topical therapy, including calcineurin inhibitors, as first-line therapy for chronic cutaneous GVHD.
Doses of 0.03 mg/kg/day continuous IV infusion, starting 1—2 days prior to bone marrow transplantation (day -1 or -2) have been recommended. Beginning tacrolimus on day -2 may be of benefit in pediatric patients. The dose should be adjusted based on tacrolimus trough whole blood concentrations. Usually given in combination with methotrexate.
Doses of 0.12 mg/kg/day PO in 2 divided doses, starting when the patient is able to tolerate oral medications have been recommended. The dose should be adjusted based on tacrolimus trough whole blood concentrations. Usually given in combination with methotrexate. Children may require higher doses to maintain therapeutic whole blood trough concentrations of tacrolimus.
A randomized, double-blind, vehicle-controlled trial was conducted using daily exposure to nickel allergen as a model. Patients applied nickel patches to each arm for 4 to 8 hours daily, and were then randomly assigned to apply 0.1% tacrolimus ointment to the patch site of one arm and a vehicle to the patch site of the other arm twice daily for 8 weeks. After 8 weeks, 45% of patients achieved clear or almost clear dermatitis with tacrolimus compared to 1% with vehicle; 31% of patients achieved success as early as day 8 with tacrolimus. There was no statistical difference in the occurrence of adverse events between the treatments. Adverse events occurred in 2% or fewer of the patients and were reported as application site reactions including edema, pruritus, erythema, pain, burning and bruising.
0.05 to 0.15 mg/kg/day PO in 2 divided doses.
Apply a thin layer topically to the affected skin area(s) twice daily. Guidelines recommend tacrolimus 0.1% for psoriasis involving the face as well as inverse (intertriginous) psoriasis.
Apply a thin layer topically to the affected skin area(s) twice daily. Guidelines recommend tacrolimus 0.1% for psoriasis involving the face and genital region.
In patients with refractory uveitis, a dose of 0.1—0.15 mg/kg/day PO in 2 divided doses given for 12 weeks was effective in 60—83% of patients. Higher doses of 0.2 mg/kg/day PO have also been used; however, an increase in adverse effects has been reported with these dosages. A tacrolimus whole blood trough concentration of 15—25 ng/ml has been recommended.
In a pilot study, 7 patients with steroid-resistant nephrotic syndrome received a dose of 0.1 mg/kg/day PO for at least 3 months. This dose was effective in decreasing proteinuria to 50% to normal protein levels. In the management of cyclosporine- and steroid- resistant nephrotic syndrome after renal transplantation, the use of tacrolimus may only be useful in a small group of patients (i.e., patients with de novo nephrotic syndrome following transplantation). Patients with chronic rejection should not be changed from cyclosporine to tacrolimus to treat post-transplantation nephrotic syndrome.
0.025 mg/kg PO twice daily initially, with dose titration to an optimal target tacrolimus serum trough level of 10 to 15 ng/mL, given for 2 weeks, has been used. Median dose at week 2 was 0.2 mg/kg/day (dose range 0.08 to 0.30 mg/kg/day), given in divided doses. Tacrolimus may be effective for short-term clinical improvement; guidelines do not routinely recommend use at this time due to the small numbers of patients studied and the lack of prospective long-term outcome data. Cyclosporine or infliximab are often recommended for rescue therapy. In a double-blind placebo-controlled trial of adult patients with steroid-refractory UC, the clinical response rate at week 2 was 50% with tacrolimus vs. 13% with placebo (p = 0.003). Rates of mucosal healing were also superior with tacrolimus (44%) vs. placebo (13%); the rate of clinical remission observed was 9.4% (3/32) in the tacrolimus group and 0% in the placebo group (p = 0.238).
In a pilot study, 16 women with biopsy-proven lichen sclerosus were treated with twice daily applications of 0.1% tacrolimus ointment for three months; responders then received twice daily applications of 0.03% tacrolimus ointment. Sixty percent of patients reported a partial response, and two had a complete response. Further investigation is needed.
0.05 mg/kg/day PO in 2 divided doses titrated to achieve a trough of 5—10 ng/ml plus prednisone for induction led to a complete response in 22 of 42 patients. In contrast, 15 of 39 recipients of cyclophosphamide 750 mg/m2 IV adjusted to 500—1000 mg/m2 every 4 weeks for a total of 6 doses plus prednisone met the endpoint. Data are limited by the small sample size and follow-up duration of 6 months. Tacrolimus is not a recommended induction agent, and consensus was not reached regarding the use of calcineurin inhibitors in patients whose nephritis fails to improve or worsens after 6 months of induction with cyclophosphamide, mycophenolate mofetil, or both. Tacrolimus may be a consideration if nephritis is worsening in patients treated for 3 months with glucocorticoids plus either cyclophosphamide or mycophenolate mofetil.]
0.075 mg/kg/day PO divided twice daily, initially. Adjust dosage to maintain a serum trough concentration of 5 to 10 ng/mL.
Apply a thin layer topically to the affected area(s) twice daily.
Apply a thin layer topically to the affected area(s) twice daily.
0.075 mg/kg/day PO divided twice daily, initially. Adjust dosage to maintain a serum trough concentration of 5 to 10 ng/mL.
0.1 mg/kg PO twice daily, initially. Adjust dose to maintain tacrolimus whole blood concentration of 10 to 20 ng/mL. Tacrolimus has been shown to be effective for fistula improvement, but not fistula remission, in persons with perianal Crohn's disease. Guidelines suggest tacrolimus for short-term treatment of perianal and cutaneous fistulas in Crohn's disease; however, tacrolimus has not been shown to be effective and is not recommended for active luminal Crohn's disease.
†Indicates off-label use
Dosing Considerations
A lower dosage may be necessary in patients with severe hepatic impairment (Child-Pugh class C score greater than 10) due to reduced tacrolimus clearance and a prolonged half-life in these patients.
Renal ImpairmentConsider starting at the lower end of the dosing range in patients who received a liver, lung, or heart transplant and have pre-existing renal impairment; further dosage reduction below the targeted range may be necessary. Consider dosage reductions in patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range. For immediate-release capsules, initiation of therapy may be delayed until renal function shows evidence of recovery after renal transplant.[28611]
Drug Interactions
Acarbose: (Moderate) Tacrolimus has been reported to cause hyperglycemia. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Acetaminophen; Aspirin: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Acetaminophen; Ibuprofen: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Acyclovir: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including acyclovir. Assessment of renal function in patients who have received tacrolimus is recommended, as the tacrolimus dosage may need to be reduced.
Adagrasib: (Major) Avoid concomitant use of adagrasib and tacrolimus due to the potential for increased tacrolimus exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, decrease tacrolimus dose and adjust dose based on tacrolimus serum concentrations. Additionally, consider taking steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation.
Adefovir: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including adefovir. Assessment of renal function in patients who have received tacrolimus is recommended, as the tacrolimus dosage may need to be reduced.
Afatinib: (Moderate) If the concomitant use of tacrolimus and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of tacrolimus. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro. While data is conflicting, tacrolimus may be a weak P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir 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 ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. 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.
Aldesleukin, IL-2: (Moderate) Aldesleukin may cause nephrotoxicity. Concurrent administration of drugs possessing nephrotoxic effects with Aldesleukin, such as tacrolimus, may increase the risk of kidney dysfunction. In addition, reduced kidney function secondary to Aldesleukin treatment may delay elimination of concomitant medications and increase the risk of adverse events from those drugs.
Alfuzosin: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with alfuzosin as concurrent use may increase the risk of QT prolongation. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Alfuzosin may prolong the QT interval in a dose-dependent manner.
Alogliptin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Alogliptin; Metformin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Alogliptin; Pioglitazone: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Alpelisib: (Major) Avoid coadministration of alpelisib with tacrolimus 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 tacrolimus is a BCRP inhibitor.
Alpha-glucosidase Inhibitors: (Moderate) Tacrolimus has been reported to cause hyperglycemia. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Aluminum Hydroxide: (Major) Monitor tacrolimus whole blood trough concentration and reduce tacrolimus dose if needed during concurrent use of antacids. Magnesium and aluminum hydroxide antacids may increase the blood concentration of tacrolimus. In a single-dose crossover study in healthy volunteers, coadministration of tacrolimus and magnesium-aluminum-hydroxide resulted in a mean AUC increase of 21% and a 10% decrease in the mean tacrolimus Cmax, compared to tacrolimus administration alone.
Aluminum Hydroxide; Magnesium Carbonate: (Major) Monitor tacrolimus whole blood trough concentration and reduce tacrolimus dose if needed during concurrent use of antacids. Magnesium and aluminum hydroxide antacids may increase the blood concentration of tacrolimus. In a single-dose crossover study in healthy volunteers, coadministration of tacrolimus and magnesium-aluminum-hydroxide resulted in a mean AUC increase of 21% and a 10% decrease in the mean tacrolimus Cmax, compared to tacrolimus administration alone.
Aluminum Hydroxide; Magnesium Hydroxide: (Major) Monitor tacrolimus whole blood trough concentration and reduce tacrolimus dose if needed during concurrent use of antacids. Magnesium and aluminum hydroxide antacids may increase the blood concentration of tacrolimus. In a single-dose crossover study in healthy volunteers, coadministration of tacrolimus and magnesium-aluminum-hydroxide resulted in a mean AUC increase of 21% and a 10% decrease in the mean tacrolimus Cmax, compared to tacrolimus administration alone.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Major) Monitor tacrolimus whole blood trough concentration and reduce tacrolimus dose if needed during concurrent use of antacids. Magnesium and aluminum hydroxide antacids may increase the blood concentration of tacrolimus. In a single-dose crossover study in healthy volunteers, coadministration of tacrolimus and magnesium-aluminum-hydroxide resulted in a mean AUC increase of 21% and a 10% decrease in the mean tacrolimus Cmax, compared to tacrolimus administration alone.
Aluminum Hydroxide; Magnesium Trisilicate: (Major) Monitor tacrolimus whole blood trough concentration and reduce tacrolimus dose if needed during concurrent use of antacids. Magnesium and aluminum hydroxide antacids may increase the blood concentration of tacrolimus. In a single-dose crossover study in healthy volunteers, coadministration of tacrolimus and magnesium-aluminum-hydroxide resulted in a mean AUC increase of 21% and a 10% decrease in the mean tacrolimus Cmax, compared to tacrolimus administration alone.
Amikacin: (Moderate) Additive nephrotoxicity is possible if aminoglycosides are used with tacrolimus. Care should be taken in using tacrolimus with other nephrotoxic drugs. Assessment of renal function in patients who have received tacrolimus is recommended as the tacrolimus dosage may need to be reduced.
Amiloride: (Major) Avoid concomitant use of tacrolimus and potassium-sparing diuretics, such as amiloride, due to the risk of hyperkalemia. If concomitant use is necessary, closely monitor serum potassium concentrations.
Amiloride; Hydrochlorothiazide, HCTZ: (Major) Avoid concomitant use of tacrolimus and potassium-sparing diuretics, such as amiloride, due to the risk of hyperkalemia. If concomitant use is necessary, closely monitor serum potassium concentrations.
Aminoglycosides: (Moderate) Additive nephrotoxicity is possible if aminoglycosides are used with tacrolimus. Care should be taken in using tacrolimus with other nephrotoxic drugs. Assessment of renal function in patients who have received tacrolimus is recommended as the tacrolimus dosage may need to be reduced.
Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Amiodarone: (Major) Amiodarone and tacrolimus both prolong the QT interval; also, both drugs are metabolized by CYP3A4, and amiodarone is also a CYP3A4 inhibitor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Although the manufacturer recommends dose adjustment and close monitoring when tacrolimus is coadminsitered with other drugs that prolong the QT interval and are subtrates or inhibitors of CYP3A4, it may be prudent to avoid coadministration as the risk of torsade de pointes may be increased.
Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with tacrolimus. Amisulpride causes dose- and concentration- dependent QT prolongation. Tacrolimus causes QT prolongation.
Amlodipine: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
Amlodipine; Atorvastatin: (Moderate) Carefully weigh the benefits of combined use of tacrolimus and atorvastatin against the potential risk of statin-induced myopathy/rhabdomyolysis. Guidelines recommend lower doses of statins in combination with tacrolimus. Atorvastatin doses above 10 mg/day are not recommended without close monitoring of creatinine kinase and symptoms of muscle-related toxicity. (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
Amlodipine; Benazepril: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index. (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including ACE inhibitors.
Amlodipine; Celecoxib: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index. (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Amlodipine; Olmesartan: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
Amlodipine; Valsartan: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
Amobarbital: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
Amoxicillin; Clarithromycin; Omeprazole: (Major) A reduction in tacrolimus dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended if coadministered with clarithromycin as concurrent use may result in increased tacrolimus exposure and additive QT prolongation. Additional tacrolimus dosage reductions may be required. Despite an initial reduction in tacrolimus dose, a rapid, sharp increase in tacrolimus levels has been reported during coadministration with clarithromycin. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; clarithromycin is a strong CYP3A4 inhibitor. Both tacrolimus and clarithromycin are associated with an established risk of QT prolongation and torsade de pointes (TdP). Use this combination with caution. (Moderate) Concomitant administration of omeprazole and tacrolimus may increase tacrolimus serum concentrations possibly leading to increased risk of serious adverse reactions (e.g., neurotoxicity, infection, QT prolongation), especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. Monitor tacrolimus whole blood concentrations; reduce tacrolimus dose if needed to maintain therapeutic concentrations.
Amphotericin B lipid complex (ABLC): (Moderate) Additive nephrotoxicity can occur if amphotericin B is given concomitantly with tacrolimus. Amphotericin B and/or tacrolimus dosage reduction may be necessary if renal impairment occurs.
Amphotericin B liposomal (LAmB): (Moderate) Additive nephrotoxicity can occur if amphotericin B is given concomitantly with tacrolimus. Amphotericin B and/or tacrolimus dosage reduction may be necessary if renal impairment occurs.
Amphotericin B: (Moderate) Additive nephrotoxicity can occur if amphotericin B is given concomitantly with tacrolimus. Amphotericin B and/or tacrolimus dosage reduction may be necessary if renal impairment occurs.
Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include tacrolimus.
Angiotensin-converting enzyme inhibitors: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including ACE inhibitors.
Apalutamide: (Moderate) Measure tacrolimus whole blood trough concentrations and adjust the dose as clinically appropriate if coadministration with apalutamide is necessary. Tacrolimus is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly increased tacrolimus clearance.
Apomorphine: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with apomorphine. Tacrolimus may prolong the QT interval and cause torsade de pointes. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
Aprepitant, Fosaprepitant: (Major) Use caution if tacrolimus and aprepitant, fosaprepitant are used concurrently and monitor tacrolimus levels and for an increase in tacrolimus-related adverse effects for several days after administration of a multi-day aprepitant regimen. Tacrolimus is 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 increase plasma concentrations of tacrolimus. 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. Use caution if tacrolimus and aprepitant, fosaprepitant are used concurrently and monitor tacrolimus levels and for an increase in tacrolimus-related adverse effects for several days after administration of a multi-day aprepitant regimen. Tacrolimus is 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 increase plasma concentrations of tacrolimus. 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.
Aripiprazole: (Moderate) Concomitant use of aripiprazole and tacrolimus 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.
Arsenic Trioxide: (Major) If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with arsenic trioxide include tacrolimus.
Artemether; Lumefantrine: (Major) Concurrent use of tacrolimus and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If tacrolimus must be coadministered with substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval, such as artemether; lumefantrine, consider reducing the tacrolimus dose, closely monitor tacrolimus whole blood concentrations, and monitor for QT prolongation. Consider ECG monitoring if tacrolimus must be used with or after artemether; lumefantrine treatment.
Asciminib: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with asciminib is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; asciminib is a weak CYP3A inhibitor.
Asenapine: (Major) Asenapine has been associated with QT prolongation. Tacrolimus causes QT prolongation. Reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended when coadministrating tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval, such as asenapine. However, according to the manufacturer of asenapine, the drug should be avoided in combination with other agents also known to prolong the QT interval.
Aspirin, ASA: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Aspirin, ASA; Butalbital; Caffeine: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended. (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Aspirin, ASA; Caffeine: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Administration of oral tacrolimus at the same time as sodium bicarbonate may result in pH-dependent degradation of tacrolimus. Administer oral Tacrolimus 1 hour before or 2 hours after the Sodium Bicarbonate dose to help limit an interaction. Separation of the oral tacrolimus and sodium bicarbonate doses by at least 2 hours may not be necessary, but more data are needed. Tacrolimus concentrations can be maintained with appropriate monitoring and dosage adjustment. Intravenous and topical forms of tacrolimus do not interact. (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Aspirin, ASA; Dipyridamole: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Aspirin, ASA; Omeprazole: (Moderate) Concomitant administration of omeprazole and tacrolimus may increase tacrolimus serum concentrations possibly leading to increased risk of serious adverse reactions (e.g., neurotoxicity, infection, QT prolongation), especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. Monitor tacrolimus whole blood concentrations; reduce tacrolimus dose if needed to maintain therapeutic concentrations. (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Aspirin, ASA; Oxycodone: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Atazanavir: (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration with atazanavir is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Consider a tacrolimus dose reduction to 0.5 mg to 1 mg once per week when coadministered with a protease inhibitor. In one study, the tacrolimus half-life increased to 10.6 days in one patient and 20.6 days in another following coadministration of tacrolimus and lopinavir; ritonavir. Up to 80% reductions in tacrolimus dosages and 7-fold increase in dosage intervals were needed when tacrolimus was coadministered with protease inhibitors in studies. Tacrolimus is a sensitive CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor.
Atazanavir; Cobicistat: (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration with atazanavir is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Consider a tacrolimus dose reduction to 0.5 mg to 1 mg once per week when coadministered with a protease inhibitor. In one study, the tacrolimus half-life increased to 10.6 days in one patient and 20.6 days in another following coadministration of tacrolimus and lopinavir; ritonavir. Up to 80% reductions in tacrolimus dosages and 7-fold increase in dosage intervals were needed when tacrolimus was coadministered with protease inhibitors in studies. Tacrolimus is a sensitive CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration with cobicistat is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; cobicistat is a strong CYP3A4 inhibitor.
Atomoxetine: (Moderate) Concomitant use of atomoxetine and tacrolimus 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: (Moderate) Carefully weigh the benefits of combined use of tacrolimus and atorvastatin against the potential risk of statin-induced myopathy/rhabdomyolysis. Guidelines recommend lower doses of statins in combination with tacrolimus. Atorvastatin doses above 10 mg/day are not recommended without close monitoring of creatinine kinase and symptoms of muscle-related toxicity.
Avacopan: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with avacopan is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; avacopan is a weak CYP3A inhibitor.
Azathioprine: (Minor) Because azathioprine is an immunosuppressant with myelosuppressive actions, additive effects may be seen with other immunosuppressants. While therapy is designed to take advantage of this effect, patients may be predisposed to increased immunosuppression and myelosuppression, resulting in an increased risk of infection or other side effects. The risk is typically related to the intensity and duration of immunosuppression.
Azithromycin: (Major) Concomitant use of tacrolimus 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.
Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Do not administer live vaccines to tacrolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving tacrolimus. At least 2 weeks before initiation of tacrolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Tacrolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Bacitracin: (Minor) Additive nephrotoxicity may occur with concurrent use of these medicines. When possible, avoid concomitant administration of systemic bacitracin and other nephrotoxic drugs such as tacrolimus. Use of topically administrated preparations containing bacitracin, especially when applied to large surface areas, may have additive nephrotoxic potential.
Barbiturates: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
Basiliximab: (Major) Basiliximab acts as an IL-2 receptor antagonist. Binding of basiliximab to the IL-2 receptors on activated T cells may allow circulating IL-2 to bind to IL-2 receptors on hepatic and intestinal cells, which may cause a down-regulation of CYP3A4 enzyme activity. Reduced CYP3A4 activity may increase concentrations of CYP3A4 substrates such as tacrolimus. In a retrospective evaluation, the tacrolimus dose needed to achieve a trough concentration of 15 to 20 ng/ml was lower among basiliximab recipients as compared with antithymocyte globulin recipients. Over the 60 days after transplantation, tacrolimus dose requirements were 0.16 mg/kg/day for basiliximab recipients and 0.24 mg/kg/day for antithymocyte globulin recipients. All patients initially received oral tacrolimus 0.075 to 0.15 mg/kg with the dose titrated to achieve the desired trough concentration. On day 3 after transplantation, tacrolimus trough concentrations were higher than 20 ng/ml in 6 of 12 adults who also got basiliximab 20 mg on the day of transplantation and 4 days later; three patients with an elevated trough concentration had acute tubular necrosis and underwent hemodialysis. In contrast, 2 of 8 patients who got antithymocyte globulin daily for the first 7 days had a tacrolimus trough concentration higher than 20 ng/ml - no significant adverse effects were noted. The half-life of basiliximab is 7.2 days, so the tacrolimus dose may need upward adjustment as the effects of basiliximab on IL-2 dissipate. For example, one month after transplantation, 6 of the 12 basiliximab recipients had tacrolimus trough concentrations below the targeted range of 15 to 20 ng/ml.
Bedaquiline: (Major) Bedaquiline and tacrolimus can cause QT prolongation, and both drugs are CYP3A4 substrates. The manufacturer of tacrolimus recommends reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation when coadministering with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval. The manufacturer of bedaquiline recommends obtaining obtain serum electrolyte concentrations and a baseline ECG prior to initiation of therapy. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Belumosudil: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with belumosudil is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; belumosudil is a weak CYP3A inhibitor.
Belzutifan: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with belzutifan is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; belzutifan is a weak CYP3A inducer.
Benazepril: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including ACE inhibitors.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including ACE inhibitors.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Berotralstat: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with berotralstat is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; berotralstat is a moderate CYP3A inhibitor.
Bicalutamide: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with bicalutamide is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; bicalutamide is a weak CYP3A4 inhibitor.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered with tacrolimus. Consider the potential for drug interaction prior to and during concurrent use of these medications. Medications that decrease renal function, such as tacrolimus, may increase concentrations of emtricitabine; as emtricitabine is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. (Moderate) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Use of these medications together may result in elevated tacrolimus serum concentrations. Additionally, monitoring for changes in renal function is advised if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as tacrolimus. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and tacrolimus 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: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and tacrolimus 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) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Blinatumomab: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as tacrolimus. The dose of the concomitant drug may need to be adjusted.
Bortezomib: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like tacrolimus; the risk of peripheral neuropathy may be additive.
Bosentan: (Moderate) Drugs such as bosentan, which can induce cytochrome P-450 3A4, can decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations is recommended if any of the hepatic enzyme inducing agents are used concurrently with tacrolimus.
Brigatinib: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with brigatinib is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; brigatinib is a weak CYP3A4 inducer.
Brodalumab: (Moderate) If brodalumab is initiated or discontinued in a patient taking tacrolimus, monitor tacrolimus concentrations; tacrolimus dose adjustments may be needed. The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during brodalumab administration. In theory, clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as tacrolimus.
Bromocriptine: (Minor) Bromocriptine may decrease the clearance of tacrolimus with the potential to either reduce immunosuppressant dosage requirements or cause drug-related toxicity. Close monitoring of tacrolimus concentrations is recommended if bromocriptine is coadministered.
Bupivacaine; Meloxicam: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Buprenorphine: (Major) Both buprenorphine and tacrolimus have been associated with QTc prolongation, and both are CYP3A4 substrates. The manufacturer of tacrolimus recommends reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation when co-administering tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval. 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.
Buprenorphine; Naloxone: (Major) Both buprenorphine and tacrolimus have been associated with QTc prolongation, and both are CYP3A4 substrates. The manufacturer of tacrolimus recommends reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation when co-administering tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval. 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.
Butalbital; Acetaminophen: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
Butalbital; Acetaminophen; Caffeine: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended. (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Cabotegravir; Rilpivirine: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with rilpivirine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Canagliflozin: (Moderate) Tacrolimus has been reported to cause hyperglycemia, and may contribute to insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Monitor for changes in glycemic control if therapy with tacrolimus is initiated.
Canagliflozin; Metformin: (Moderate) Tacrolimus has been reported to cause hyperglycemia, and may contribute to insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Monitor for changes in glycemic control if therapy with tacrolimus is initiated. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents.
Cannabidiol: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with cannabidiol is necessary. The dose of tacrolimus may need to be reduced. Concomitant use is expected to increase tacrolimus overall exposure.
Capivasertib: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with capivasertib is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; capivasertib is a weak CYP3A inhibitor.
Capreomycin: (Major) Since capreomycin is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including tacrolimus, may increase serum concentrations of either drug. Theoretically, the chronic coadministration of these drugs may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered.
Captopril: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including ACE inhibitors.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including ACE inhibitors.
Carbamazepine: (Moderate) Carbamazepine induces CYP3A enzymes and may decrease tacrolimus whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when carbamazepine and tacrolimus are used concomitantly.
Carboplatin: (Moderate) Concurrent use of carboplatin with other agents that cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Caspofungin: (Moderate) Tacrolimus concentrations are reduced approximately 25% in those patients receiving concurrent caspofungin. The mechanism of this interaction has not been identified; monitor tacrolimus blood concentrations. Increased dosage of tacrolimus may be required. The pharmacokinetic parameters of caspofungin are not altered by tacrolimus.
Celecoxib: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Celecoxib; Tramadol: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Cenobamate: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with cenobamate is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; cenobamate is a moderate CYP3A4 inducer.
Ceritinib: (Major) Avoid coadministration of ceritinib with tacrolimus if possible due to the risk of QT prolongation; plasma concentrations of tacrolimus may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range that can cause QT prolongation. Ceritinib is a strong CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor significantly increased oral bioavailability of tacrolimus (14% vs. 30%) and decreased oral clearance (0.43 L/hour/kg vs. 0.148 L/hour/kg) compared to tacrolimus alone. Overall, intravenous clearance of tacrolimus was not significantly changed by coadministration with a strong CYP3A4 inhibitor, although it was highly variable between patients.
Chikungunya Vaccine, Live: (Contraindicated) Do not administer live vaccines to tacrolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving tacrolimus. At least 2 weeks before initiation of tacrolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Tacrolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Chlorambucil: (Minor) Chlorambucil is known to cause myelosuppression, which may lead to neutropenia related side effects. Concurrent use of chlorambucil with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects.
Chloramphenicol: (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration with chloramphenicol is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentration and increase the risk of toxicity. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; chloramphenicol is a strong CYP3A4 inhibitor.
Chloroquine: (Major) Avoid coadministration of chloroquine with tacrolimus 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. Tacrolimus may prolong the QT interval and cause TdP.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Chlorpromazine: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and chlorpromazine should be used together cautiously. Tacrolimus causes QT prolongation. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and TdP.
Chlorpropamide: (Moderate) Tacrolimus has been reported to cause hyperglycemia and has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Choline Salicylate; Magnesium Salicylate: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Cidofovir: (Contraindicated) The administration of cidofovir with another potentially nephrotoxic agent, such as tacrolimus is contraindicated. Tacrolimus should be discontinued at least 7 days prior to beginning cidofovir.
Cimetidine: (Major) Tacrolimus is metabolized via the hepatic cytochrome P-450 system. Drugs that inhibit this enzyme system, including cimetidine, may decrease the metabolism of tacrolimus. Subsequent increased plasma concentrations of tacrolimus may lead to nephrotoxicity.
Ciprofloxacin: (Moderate) Concomitant use of ciprofloxacin and tacrolimus 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) Tacrolimus prolongs the QTc interval. Because of the potential for torsades de pointes (TdP), use of cisapride with tacrolimus is contraindicated.
Cisplatin: (Moderate) Closely monitor renal function and tacrolimus concentrations if concomitant use with cisplatin and tacrolimus is necessary; adjust the dose of tacrolimus if necessary. Both cisplatin and tacrolimus can cause nephrotoxicity, which may be additive.
Citalopram: (Major) Concomitant use of tacrolimus and citalopram 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.
Citric Acid; Potassium Citrate; Sodium Citrate: (Moderate) Monitor serum potassium concentrations closely if potassium supplements and tacrolimus are used together. Concomitant use may increase the risk of hyperkalemia.
Clarithromycin: (Major) A reduction in tacrolimus dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended if coadministered with clarithromycin as concurrent use may result in increased tacrolimus exposure and additive QT prolongation. Additional tacrolimus dosage reductions may be required. Despite an initial reduction in tacrolimus dose, a rapid, sharp increase in tacrolimus levels has been reported during coadministration with clarithromycin. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; clarithromycin is a strong CYP3A4 inhibitor. Both tacrolimus and clarithromycin are associated with an established risk of QT prolongation and torsade de pointes (TdP). Use this combination with caution.
Clindamycin: (Moderate) Concomitant use of tacrolimus and clindamycin may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required.
Clofazimine: (Moderate) Concomitant use of clofazimine and tacrolimus 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) Tacrolimus has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and tricyclic antidepressants (TCAs) should be used together cautiously.
Clozapine: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with clozapine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation.
Cobicistat: (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration with cobicistat is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; cobicistat is a strong CYP3A4 inhibitor.
Cobimetinib: (Minor) If concurrent use of cobimetinib and tacrolimus is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and tacrolimus is a P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of promethazine and tacrolimus 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 promethazine and tacrolimus 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: (Minor) Monitor for colchicine-related adverse effects during concomitant use of tacrolimus. Concomitant use may increase colchicine exposure.
Colistimethate, Colistin, Polymyxin E: (Major) Theoretically, the chronic coadministration of these drugs may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered. Since colistimethate sodium is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including tacrolimus, may increase serum concentrations of either drug.
Colistin: (Major) Theoretically, the chronic coadministration of these drugs may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered. Since colistimethate sodium is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including tacrolimus, may increase serum concentrations of either drug.
Conivaptan: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with conivaptan is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; conivaptan is a moderate CYP3A inhibitor.
Crizotinib: (Major) Avoid coadministration of crizotinib with tacrolimus due to the risk of QT prolongation; exposure to tacrolimus may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. Frequently monitor tacrolimus whole blood concentrations; adjust the dose of tacrolimus as clinically appropriate. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Tacrolimus is a sensitive CYP3A4 substrate that also causes QT prolongation.
Cyclosporine: (Contraindicated) Concurrent use of cyclosporine and tacrolimus may increase the risk of nephrotoxicity due to synergistic or additive effects. Concomitant tacrolimus and cyclosporine usage is not recommended. When switching patients from cyclosporine to tacrolimus, wait at least 24 hours after the last dose of cyclosporine before beginning tacrolimus therapy. In the presence of elevated tacrolimus or cyclosporine concentrations, dosing with the other drug usually should be delayed until the concentration falls into the normal
Dabrafenib: (Major) The concomitant use of dabrafenib and tacrolimus may lead to decreased tacrolimus concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor tacrolimus levels and for loss of tacrolimus efficacy. Dabrafenib is a moderate CYP3A4 inducer and tacrolimus is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 65%.
Daclatasvir: (Moderate) Closely monitor tacrolimus serum concentrations if coadministration with a direct acting antiviral (DAA) agent, such as daclatasvir, is necessary; dosage adjustments may be required. Changes in liver function due to clearance of the hepatitis C virus by DAA therapy may alter tacrolimus serum concentrations.
Dalfopristin; Quinupristin: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with dalfopristin; quinupristin. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Dalfopristin; quinupristin is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
Danazol: (Moderate) Danazol has been reported to increase tacrolimus whole blood concentrations. Patients receiving tacrolimus should be closely monitored for toxicity if danazol is added to therapy. Conversely, a dose adjustment of tacrolimus may be necessary if danazol therapy is discontinued.
Dapagliflozin: (Moderate) Both cyclosporine and tacrolimus have been reported to cause hyperglycemia. Tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Both of these drugs may have direct beta-cell toxicity; the effects from cyclosporine may be dose-related. Patients should be monitored for changes in glycemic control if therapy with either of these immunosuppressant drugs is initiated in patients receiving dapagliflozin.
Dapagliflozin; Metformin: (Moderate) Both cyclosporine and tacrolimus have been reported to cause hyperglycemia. Tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Both of these drugs may have direct beta-cell toxicity; the effects from cyclosporine may be dose-related. Patients should be monitored for changes in glycemic control if therapy with either of these immunosuppressant drugs is initiated in patients receiving dapagliflozin. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents.
Dapagliflozin; Saxagliptin: (Moderate) Both cyclosporine and tacrolimus have been reported to cause hyperglycemia. Tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Both of these drugs may have direct beta-cell toxicity; the effects from cyclosporine may be dose-related. Patients should be monitored for changes in glycemic control if therapy with either of these immunosuppressant drugs is initiated in patients receiving dapagliflozin. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Monitor for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Daridorexant: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with daridorexant is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; daridorexant is a weak CYP3A inhibitor.
Darunavir: (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentration if coadministration with darunavir is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Consider a tacrolimus dose reduction to 0.5 mg to 1 mg once per week when coadministered with a protease inhibitor. In one study, the tacrolimus half-life increased to 10.6 days in one patient and 20.6 days in another following coadministration of tacrolimus and another protease inhibitor combination. Up to 80% reductions in tacrolimus dosages and 7-fold increase in dosage intervals were needed when tacrolimus was coadministered with protease inhibitors in studies. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; darunavir is a strong CYP3A4 inhibitor.
Darunavir; Cobicistat: (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentration if coadministration with darunavir is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Consider a tacrolimus dose reduction to 0.5 mg to 1 mg once per week when coadministered with a protease inhibitor. In one study, the tacrolimus half-life increased to 10.6 days in one patient and 20.6 days in another following coadministration of tacrolimus and another protease inhibitor combination. Up to 80% reductions in tacrolimus dosages and 7-fold increase in dosage intervals were needed when tacrolimus was coadministered with protease inhibitors in studies. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; darunavir is a strong CYP3A4 inhibitor. (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration with cobicistat is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; cobicistat is a strong CYP3A4 inhibitor.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentration if coadministration with darunavir is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Consider a tacrolimus dose reduction to 0.5 mg to 1 mg once per week when coadministered with a protease inhibitor. In one study, the tacrolimus half-life increased to 10.6 days in one patient and 20.6 days in another following coadministration of tacrolimus and another protease inhibitor combination. Up to 80% reductions in tacrolimus dosages and 7-fold increase in dosage intervals were needed when tacrolimus was coadministered with protease inhibitors in studies. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; darunavir is a strong CYP3A4 inhibitor. (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration with cobicistat is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; cobicistat is a strong CYP3A4 inhibitor. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered with tacrolimus. Consider the potential for drug interaction prior to and during concurrent use of these medications. Medications that decrease renal function, such as tacrolimus, may increase concentrations of emtricitabine; as emtricitabine is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. (Moderate) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Use of these medications together may result in elevated tacrolimus serum concentrations. Additionally, monitoring for changes in renal function is advised if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as tacrolimus. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions.
Dasatinib: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with dasatinib. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). In vitro studies have shown that dasatinib also has the potential to prolong the QT interval.
Deferasirox: (Moderate) Acute renal failure has been reported during treatment with deferasirox. Coadministration of deferasirox with other potentially nephrotoxic drugs, including tacrolimus, may increase the risk of this toxicity. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly.
Degarelix: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with degarelix as concurrent use may increase the risk of QT prolongation. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval.
Delavirdine: (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration with delavirdine is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; delavirdine is a strong CYP3A4 inhibitor.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Desflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with tacrolimus. Halogenated anesthetics and tacrolimus can prolong the QT interval.
Desipramine: (Minor) Tacrolimus has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and tricyclic antidepressants (TCAs) should be used together cautiously.
Desogestrel; Ethinyl Estradiol: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
Deutetrabenazine: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with deutetrabenazine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
Dexamethasone: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with dexamethasone is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; dexamethasone is a weak CYP3A inducer.
Dexlansoprazole: (Moderate) Monitor tacrolimus whole blood concentrations and adjust tacrolimus dose as needed to maintain therapeutic concentrations during concomitant use of dexlansoprazole. Coadministration may increase serum concentrations of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Dexmedetomidine: (Moderate) Concomitant use of dexmedetomidine and tacrolimus 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: (Major) Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). As the risk of TdP is increased with greater QT prolongation, avoid use of quinidine with another drug that prolongs the QT interval such as tacrolimus. It should be noted that the manufacturer of tacrolimus recommends reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation when coadministrating tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval such as quinidine. Tacrolimus and quinidine are both metabolized by cytochrome P450 3A4.
Diclofenac: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Diclofenac; Misoprostol: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Diflunisal: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Diltiazem: (Moderate) Diltiazem inhibits tacrolimus metabolism via the CYP3A pathway. Tacrolimus blood concentrations should be monitored during concurrent diltiazem therapy as dosage adjustments of tacrolimus may be needed to avoid tacrolimus-induced toxicity.
Diphenhydramine; Ibuprofen: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Diphenhydramine; Naproxen: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Disopyramide: (Major) Disopyramide and tacrolimus both prolong the QT interval; also, both drugs are metabolized by CYP3A4. Although the manufacturer recommends dose adjustment and close monitoring when tacrolimus is coadminsitered with other drugs that prolong the QT interval and are subtrates or inhibitors of CYP3A4, it may be prudent to avoid coadministration as the risk of torsade de pointes may be increased.
Dofetilide: (Major) Coadministration of dofetilide and tacrolimus is not recommended as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG and electrolytes periodically during treatment. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Tacrolimus may prolong the QT interval and cause TdP.
Dolasetron: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with dolasetron. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
Dolutegravir; Rilpivirine: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with rilpivirine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Donepezil: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with donepezil as concurrent use may increase the risk of QT prolongation. Both tacrolimus and donepezil may prolong the QT interval and cause torsade de pointes (TdP).
Donepezil; Memantine: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with donepezil as concurrent use may increase the risk of QT prolongation. Both tacrolimus and donepezil may prolong the QT interval and cause torsade de pointes (TdP).
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent, including tacrolimus.
Dronabinol: (Major) Use caution if coadministration of dronabinol with tacrolimus is necessary, and monitor for an increase in tacrolimus concentrations as well as tacrolimus-related adverse effects. Dronabinol is highly bound to plasma proteins, and may displace and increase the free fraction of other concomitantly administered protein-bound drugs; caution is recommended with other drugs with a narrow therapeutic index.
Dronedarone: (Contraindicated) Concomitant use of dronedarone and tacrolimus is contraindicated. Tacrolimus prolongs the QTc interval. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Droperidol: (Major) Droperidol and tacrolimus both prolong the QT interval; also, both drugs are metabolized by CYP3A4. Droperidol is also associated with torsade de pointes. Although the manufacturer recommends dose adjustment and close monitoring when tacrolimus is coadminsitered with other drugs that prolong the QT interval and are substrates or inhibitors of CYP3A4, it may be prudent to avoid coadministration as the risk of torsade de pointes may be increased.
Drospirenone; Ethinyl Estradiol: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
Dulaglutide: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents, including dulaglutide. Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity.
Dupilumab: (Moderate) Coadministration of dupilumab may result in altered exposure to tacrolimus. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP450 enzymes could be normalized during dupilumab administration. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as tacrolimus. Monitor tacrolimus concentrations if dupilumab is initiated or discontinued in a patient taking tacrolimus; tacrolimus dose adjustments may be needed.
Duvelisib: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with duvelisib is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range. Duvelisib is a moderate CYP3A inhibitor.
Efavirenz: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with efavirenz. Monitoring of serum tacrolimus concentrations for at least 2 weeks is recommended when starting or stopping treatment with efavirenz. Tacrolimus is a CYP3A4 substrate that may prolong the QT interval and cause torsade de pointes (TdP). Efavirenz induces CYP3A4; QTc prolongation has been observed with the use of efavirenz.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent, including tacrolimus. (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with efavirenz. Monitoring of serum tacrolimus concentrations for at least 2 weeks is recommended when starting or stopping treatment with efavirenz. Tacrolimus is a CYP3A4 substrate that may prolong the QT interval and cause torsade de pointes (TdP). Efavirenz induces CYP3A4; QTc prolongation has been observed with the use of efavirenz. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered with tacrolimus. Consider the potential for drug interaction prior to and during concurrent use of these medications. Medications that decrease renal function, such as tacrolimus, may increase concentrations of emtricitabine; as emtricitabine is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent, including tacrolimus. (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with efavirenz. Monitoring of serum tacrolimus concentrations for at least 2 weeks is recommended when starting or stopping treatment with efavirenz. Tacrolimus is a CYP3A4 substrate that may prolong the QT interval and cause torsade de pointes (TdP). Efavirenz induces CYP3A4; QTc prolongation has been observed with the use of efavirenz.
Elagolix: (Moderate) Monitor tacrolimus whole blood trough concentrations when tacrolimus is administered with elagolix; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus whole blood concentrations. Tacrolimus is metabolized mainly by CYP3A enzymes; elagolix is a weak to moderate CYP3A4 inducer.
Elagolix; Estradiol; Norethindrone acetate: (Moderate) Monitor tacrolimus whole blood trough concentrations when tacrolimus is administered with elagolix; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus whole blood concentrations. Tacrolimus is metabolized mainly by CYP3A enzymes; elagolix is a weak to moderate CYP3A4 inducer.
Elbasvir; Grazoprevir: (Moderate) Closely monitor tacrolimus serum concentrations if coadministration with a direct acting antiviral (DAA) agent, such as elbasvir, is necessary; dosage adjustments may be required. Changes in liver function due to clearance of the hepatitis C virus by DAA therapy may alter tacrolimus serum concentrations. (Moderate) Studies have shown plasma concentrations of tacrolimus are increased when administered concurrently with elbasvir; grazoprevir. If these drugs are use together, frequently monitor for changes in tacrolimus whole blood concentrations, renal function, and for tacrolimus-associated adverse events. Tacrolimus is a substrate for the hepatic enzymes CYP3A; grazoprevir is a weak CYP3A inhibitor.
Elexacaftor; tezacaftor; ivacaftor: (Major) Use caution when administering ivacaftor and tacrolimus concurrently; careful tacrolimus blood concentrations is warranted. Ivacaftor is an inhibitor of CYP3A, and tacrolimus is a CYP3A substrate. Co-administration can increase tacrolimus exposure leading to increased or prolonged therapeutic effects and adverse events. (Moderate) Administration of tezacaftor; ivacaftor may increase the systemic exposure of tacrolimus. Appropriate monitoring should be used; adjust tacrolimus dosage as necessary. Tacrolimus is a P-gp substrate; ivacaftor is a weak inhibitor of P-gp.
Eliglustat: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with eliglustat. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration with cobicistat is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; cobicistat is a strong CYP3A4 inhibitor. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered with tacrolimus. Consider the potential for drug interaction prior to and during concurrent use of these medications. Medications that decrease renal function, such as tacrolimus, may increase concentrations of emtricitabine; as emtricitabine is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. (Moderate) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Use of these medications together may result in elevated tacrolimus serum concentrations. Additionally, monitoring for changes in renal function is advised if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as tacrolimus. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration with cobicistat is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; cobicistat is a strong CYP3A4 inhibitor. (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent, including tacrolimus. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered with tacrolimus. Consider the potential for drug interaction prior to and during concurrent use of these medications. Medications that decrease renal function, such as tacrolimus, may increase concentrations of emtricitabine; as emtricitabine is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion.
Emapalumab: (Moderate) Monitor for decreased efficacy of tacrolimus and adjust the dose as needed during coadministration with emapalumab. Tacrolimus is a CYP3A4 substrate with a narrow therapeutic index. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
Empagliflozin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Empagliflozin; Linagliptin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. This drug may have direct beta-cell toxicity. Patients should be monitored for changes in glycemic control if therapy with immunosuppressant drugs is initiated in patients receiving linagliptin.
Empagliflozin; Linagliptin; Metformin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. This drug may have direct beta-cell toxicity. Patients should be monitored for changes in glycemic control if therapy with immunosuppressant drugs is initiated in patients receiving linagliptin.
Empagliflozin; Metformin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Emtricitabine: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered with tacrolimus. Consider the potential for drug interaction prior to and during concurrent use of these medications. Medications that decrease renal function, such as tacrolimus, may increase concentrations of emtricitabine; as emtricitabine is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with rilpivirine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered with tacrolimus. Consider the potential for drug interaction prior to and during concurrent use of these medications. Medications that decrease renal function, such as tacrolimus, may increase concentrations of emtricitabine; as emtricitabine is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. (Moderate) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Use of these medications together may result in elevated tacrolimus serum concentrations. Additionally, monitoring for changes in renal function is advised if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as tacrolimus. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent, including tacrolimus. (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with rilpivirine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered with tacrolimus. Consider the potential for drug interaction prior to and during concurrent use of these medications. Medications that decrease renal function, such as tacrolimus, may increase concentrations of emtricitabine; as emtricitabine is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion.
Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered with tacrolimus. Consider the potential for drug interaction prior to and during concurrent use of these medications. Medications that decrease renal function, such as tacrolimus, may increase concentrations of emtricitabine; as emtricitabine is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. (Moderate) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Use of these medications together may result in elevated tacrolimus serum concentrations. Additionally, monitoring for changes in renal function is advised if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as tacrolimus. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent, including tacrolimus. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered with tacrolimus. Consider the potential for drug interaction prior to and during concurrent use of these medications. Medications that decrease renal function, such as tacrolimus, may increase concentrations of emtricitabine; as emtricitabine is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion.
Enalapril, Enalaprilat: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including ACE inhibitors.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including ACE inhibitors.
Encorafenib: (Major) Avoid concurrent use of encorafenib with tacrolimus due to the risk for decreased tacrolimus exposure and efficacy and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, monitor tacrolimus serum concentrations and increase tacrolimus dose as appropriate. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Tacrolimus is a sensitive CYP3A substrate; encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation.
Entecavir: (Moderate) In a small pilot study of entecavir in HBV-infected liver transplant recipients on stable doses of tacrolimus, entecavir exposure was approximately 2-fold the exposure in healthy subjects with normal renal function. Altered renal function contributed to the increase in entecavir exposure in these patients. Monitor renal function.
Entrectinib: (Major) Avoid coadministration of entrectinib with tacrolimus due to the risk of QT prolongation. If coadministration is necessary, consider ECG and electrolyte monitoring periodically during treatment. Entrectinib has been associated with QT prolongation. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP).
Enzalutamide: (Major) Measure tacrolimus whole blood trough concentrations and adjust the dose as clinically appropriate if coadministration with enzalutamide is necessary. Tacrolimus is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly increased tacrolimus clearance.
Erdafitinib: (Major) Avoid coadministration of erdafitinib with tacrolimus due to the potential for altered plasma concentrations of tacrolimus which may lead to loss of activity or increased toxicity of tacrolimus. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range. Erdafitinib is a time dependent inhibitor and inducer of CYP3A4; the effect of erdafitinib on a sensitive CYP3A4 substrate is unknown.
Eribulin: (Major) Eribulin has been associated with QT prolongation. Tacrolimus causes QT prolongation. Reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended when coadministrating tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval such as eribulin.
Ertugliflozin; Metformin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents.
Ertugliflozin; Sitagliptin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Monitor for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Erythromycin: (Major) When possible avoid concurrent erythromycin and tacrolimus therapy. However, if concomitant therapy is necessary, close monitoring of tacrolimus blood concentrations and of the QT interval is warranted. Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP such as tacrolimus should be used cautiously with erythromycin. In addition, the concurrent administration of erythromycin and tacrolimus may result in elevated tacrolimus levels resulting in nephrotoxicity. In one case, the whole blood tacrolimus concentration was > 60 ng/ml following 3 days of therapy with erythromycin (prior tacrolimus level 9.8 ng/ml).
Escitalopram: (Moderate) Concomitant use of escitalopram and tacrolimus 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.
Eslicarbazepine: (Moderate) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Tacrolimus is a CYP3A4 substrate. Eslicarbazepine may potentially accelerate the hepatic metabolism of tacrolimus. Clinicians should be alert to decreased effectiveness of tacrolimus; dosage adjustments may be necessary, and closer monitoring of clinical and/or adverse effects is warranted.
Esomeprazole: (Moderate) Esomeprazole may increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, nephrotoxicity, QT prolongation). Monitor tacrolimus whole blood trough concentrations and reduce the tacrolimus dose if needed. Tacrolimus is metabolized primarily by CYP3A4; esomeprazole inhibits CYP3A4 and thus may decrease CYP3A4-mediated metabolism of tacrolimus.
Ethanol: (Major) Alcohol-containing beverages should not be consumed while taking the extended-release tacrolimus capsules (Astagraf XL). Concomitant alcohol use may increase the rate of release of tacrolimus and/or adversely alter the pharmacokinetic properties and effectiveness and safety. A flushing syndrome (alcohol intolerance) has been reported in patients treated with topical tacrolimus or pimecrolimus upon ingestion of alcohol. The flushing occurred in the face or at the sites of medication application, usually within 5-15 minutes of alcohol ingestion, and lasted for an average duration of 1 hour. Patients describe redness and warm sensations, which sometimes result in discomfort. The reaction does not appear to occur in all patients; roughly 3-7% report a notable effect. The possible mechanism of the effect is the inhibition of acetaldehyde dehydrogenase, leading to increased acetaldehyde dehydrogenase concentrations in the skin. Aspirin appears useful in attenuation of the reaction in those patients for whom the reaction is bothersome. (Major) Alcohol-containing beverages should not be consumed while taking the extended-release tacrolimus capsules (Astagraf XL). Concomitant alcohol use may increase the rate of release of tacrolimus and/or adversely alter the pharmacokinetic properties and effectiveness and safety. A flushing syndrome (alcohol intolerance) has been reported in patients treated with topical tacrolimus upon ingestion of alcohol. The flushing occurred in the face or at the sites of medication application, usually within 5 to 15 minutes of alcohol ingestion, and lasted for an average duration of 1 hour. Patients describe redness and warm sensations, which sometimes result in discomfort. The reaction does not appear to occur in all patients; roughly 3% to 7% report a notable effect. The possible mechanism of the effect is the inhibition of acetaldehyde dehydrogenase, leading to increased acetaldehyde dehydrogenase concentrations in the skin.
Ethinyl Estradiol; Norelgestromin: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
Ethinyl Estradiol; Norgestrel: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
Etodolac: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Etonogestrel; Ethinyl Estradiol: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
Etrasimod: (Moderate) Concomitant use of etrasimod and tacrolimus 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. Etrasimod 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.
Etravirine: (Major) Coadministration with etravirine may result in altered tacrolimus concentrations. Coadminister these drugs with caution, carefully monitoring tacrolimus concentrations and making dosage adjustments as needed.
Everolimus: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with everolimus is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; everolimus is a weak CYP3A4 inhibitor.
Exenatide: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents, including exenatide. Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity.
Ezetimibe; Simvastatin: (Major) Guidelines recommend avoiding coadministration of simvastatin with tacrolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving tacrolimus.
Fedratinib: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with fedratinib is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range. Fedratinib is a moderate CYP3A inhibitor.
Felodipine: (Moderate) Felodipine may increase the blood concentration of tacrolimus. When given concomitantly with felodipine, tacrolimus blood concentration should be monitored and the tacrolimus dose adjusted as necessary.
Fenofibrate: (Moderate) Coadministration of fenofibrate and tacrolimus may result in deterioration of renal function. Tacrolimus can produce nephrotoxicity with decreases in creatinine clearance and increaess in serum creatinine. Because the primary elimination route of fenofibrate is renal excretion, the benefits and risks of using fenofibrate with tacrolimus should be carefully considered, and the lowest effective dose employed with monitoring of renal function.
Fenoprofen: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Fexinidazole: (Major) Concomitant use of fexinidazole and tacrolimus 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. Additionally, monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; fexinidazole is a weak CYP3A inhibitor.
Fingolimod: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with fingolimod. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Flecainide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tacrolimus with flecainide. Tacrolimus causes QT prolongation. Flecainide, a Class IC antiarrhythmic, is also associated with a possible risk for QT prolongation and/or TdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
Fluconazole: (Contraindicated) Concurrent use of fluconazole and tacrolimus is contraindicated. Both drugs can cause QT/QTc prolongation and their use together increases the risk of life-threatening arrhythmias such as torsade de pointes (TdP). Additionally, concomitant use may increase tacrolimus exposure and the risk for tacrolimus-related adverse effects. If concomitant use is unavoidable, monitor tacrolimus serum concentrations more frequently and reduce the dose of tacrolimus if needed. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Tacrolimus is a CYP3A substrate, and fluconazole is a moderate CYP3A inhibitor.
Fluoxetine: (Moderate) Concomitant use of fluoxetine and tacrolimus 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) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with fluphenazine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Fluphenazine is associated witha possible risk for QT prolongation.
Flurbiprofen: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Fluvastatin: (Moderate) Carefully weigh the benefits of combined use of tacrolimus and fluvastatin against the potential risk of statin-induced myopathy/rhabdomyolysis. Guidelines recommend lower doses of statins in combination with tacrolimus. A maximum dose of fluvastatin of 40 mg/day is recommended.
Fluvoxamine: (Moderate) Use fluvoxamine with caution in combination with tacrolimus as concurrent use may increase the risk of QT prolongation; exposure to tacrolimus may also increase. Frequently monitor tacrolimus whole blood concentrations; adjust the dose of tacrolimus as clinically appropriate. Fluvoxamine is a moderate CYP3A4 inhibitor; QT prolongation and torsade de pointes (TdP) has been reported during fluvoxamine post-marketing use. Tacrolimus is a sensitive CYP3A4 substrate that also causes QT prolongation.
Food: (Contraindicated) The extent of absorption of tacrolimus when given orally with high-fat food is reduced as compared with administration in the fasted state. The systemic exposure (mean AUC) of tacrolimus was decreased by 37% when given with a high-fat meal. The systemic exposure was reduced to a similar extent when tacrolimus was given immediately after or 1.5 hours after meal ingestion as compared with the fasted state. While patients may take tacrolimus with food, it is critical that they always take tacrolimus consistently with or without food to ensure consistent whole blood concentrations.
Fosamprenavir: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with fosamprenavir is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; fosamprenavir is a moderate CYP3A inhibitor.
Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as tacrolimus. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Tacrolimus also causes QT prolongation. Also, concurrent use may result in additive nephrotoxicity. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
Fosinopril: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including ACE inhibitors.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including ACE inhibitors.
Fosphenytoin: (Moderate) Fosphenytoin can induce the hepatic cytochrome P-450 enzyme system, thus decreasing plasma concentrations of tacrolimus. If fosphenytoin is added to tacrolimus, the levels of tacrolimus should be closely monitored and adjusted as needed until a new steady-state is achieved. Conversely, if fosphenytoin is discontinued, levels of tacrolimus could increase and result in toxicity.
Fostamatinib: (Moderate) Monitor for tacrolimus toxicities that may require tacrolimus dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a sensitive CYP3A4 substrate may increase the concentration of the CYP3A4 substrate. The active metabolite of fostamatinib, R406, is a CYP3A4 inhibitor; tacrolimus is a sensitive substrate for CYP3A4. Coadministration of fostamatinib with another sensitive CYP3A4 substrate increased the substrate AUC by 64% and Cmax by 113%.
Fostemsavir: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with fostemsavir. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). 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.
Ganciclovir: (Moderate) Use ganciclovir and tacrolimus together only if the potential benefits outweigh the risks. Monitor renal function when ganciclovir is coadministered with tacrolimus because of the potential increase in serum creatinine. Acute renal failure may occur in patients concomitantly receiving potential nephrotoxic drugs.
Gemifloxacin: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with gemifloxacin as concurrent use may increase the risk of QT prolongation. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). 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 tacrolimus 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. Tacrolimus may cause QT prolongation.
Gentamicin: (Moderate) Additive nephrotoxicity is possible if aminoglycosides are used with tacrolimus. Care should be taken in using tacrolimus with other nephrotoxic drugs. Assessment of renal function in patients who have received tacrolimus is recommended as the tacrolimus dosage may need to be reduced.
Gilteritinib: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with gilteritinib. Gilteritinib has been associated with QT prolongation. Tacrolimus may also prolong the QT interval and cause torsade de pointes.
Glasdegib: (Major) Avoid coadministration of glasdegib with tacrolimus due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Tacrolimus also causes QT prolongation.
Glecaprevir; Pibrentasvir: (Moderate) Closely monitor tacrolimus serum concentrations if coadministration with a direct acting antiviral (DAA) agent, such as glecaprevir, is necessary; dosage adjustments may be required. Changes in liver function due to clearance of the hepatitis C virus by DAA therapy may alter tacrolimus serum concentrations. (Moderate) Closely monitor tacrolim us serum concentrations if coadministration with a direct acting antiviral (DAA) agent, such as pibrentasvir, is necessary; dosage adjustments may be required. Changes in liver function due to clearance of the hepatitis C virus by DAA therapy may alter tacrolimus serum concentrations.
Glimepiride: (Moderate) Tacrolimus has been reported to cause hyperglycemia and has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Glipizide: (Moderate) Tacrolimus has been reported to cause hyperglycemia and has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Glipizide; Metformin: (Moderate) Tacrolimus has been reported to cause hyperglycemia and has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents.
Glyburide: (Moderate) Tacrolimus has been reported to cause hyperglycemia and has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Glyburide; Metformin: (Moderate) Tacrolimus has been reported to cause hyperglycemia and has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents.
Glycerol Phenylbutyrate: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with glycerol phenylbutyrate is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; glycerol phenylbutyrate is a weak CYP3A inducer.
Goserelin: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with goserelin. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Androgen deprivation therapy (i.e., goserelin) may prolong the QT/QTc interval.
Granisetron: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with granisetron as concurrent use may increase the risk of QT prolongation. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Granisetron has been associated with QT prolongation.
Grapefruit juice: (Contraindicated) Grapefruit and grapefruit juice consumption by patients receiving tacrolimus should be avoided; concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic index; grapefruit juice is a strong CYP3A4 inhibitor.
Halogenated Anesthetics: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with tacrolimus. Halogenated anesthetics and tacrolimus can prolong the QT interval.
Haloperidol: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with haloperidol as concurrent use may increase the risk of QT prolongation. 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. Tacrolimus may prolong the QT interval and cause TdP.
Histrelin: (Moderate) Consider the benefits of androgen deprivation therapy and monitor ECG and electrolytes periodically during treatment if tacrolimus is administered with histrelin as concurrent use may increase the risk of QT prolongation. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
Hyaluronidase, Recombinant; Immune Globulin: (Moderate) Immune Globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like tacrolimus. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function.
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including ACE inhibitors.
Hydrocodone; Ibuprofen: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Hydroxychloroquine: (Major) Concomitant use of tacrolimus 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 tacrolimus 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; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Ibandronate: (Moderate) Theoretically, coadministration of intravenous ibandronate with other potentially nephrotoxic drugs like tacrolimus may increase the risk of developing nephrotoxicity.
Ibritumomab Tiuxetan: (Major) Avoid coadministration of potassium phosphate and tacrolimus as concurrent use may increase the risk of severe and potentially fatal hyperkalemia, particularly in high-risk patients (renal impairment, cardiac disease, adrenal insufficiency). If concomitant use is necessary, closely monitor serum potassium concentrations. (Moderate) Monitor serum potassium concentrations closely if potassium supplements and tacrolimus are used together. Concomitant use may increase the risk of hyperkalemia.
Ibuprofen: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Ibuprofen; Famotidine: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Ibuprofen; Oxycodone: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Ibuprofen; Pseudoephedrine: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Ibutilide: (Major) Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval. Tacrolimus causes QT prolongation and should be used cautiously with ibutilide.
Idelalisib: (Major) The manufacturer of idelalisib recommends avoiding concomitant use with sensitive 3A4 substrates such as tacrolimus. If coadministration is unavoidable, decrease tacrolimus dose and closely monitor tacrolimus serum concentrations; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic index; idelalisib is a strong CYP3A4 inhibitor. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
Iloperidone: (Major) Iloperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since iloperidone may prolong the QT interval, it should not be used with other agents also known to have this effect, such as tacrolimus. If coadministration is necessary, reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended.
Imatinib: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with imatinib is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; imatinib is a moderate CYP3A4 inhibitor.
Imipramine: (Minor) Tacrolimus has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and tricyclic antidepressants (TCAs) should be used together cautiously.
Immune Globulin IV, IVIG, IGIV: (Moderate) Immune Globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like tacrolimus. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function.
Indinavir: (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration with indinavir is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Consider a tacrolimus dose reduction to 0.5 mg to 1 mg once per week when coadministered with a protease inhibitor. In one study, the tacrolimus half-life increased to 10.6 days in one patient and 20.6 days in another following coadministration of tacrolimus and a protease inhibitor combination. Up to 80% reductions in tacrolimus dosages and 7-fold increase in dosage intervals were needed when tacrolimus was coadministered with protease inhibitors in studies. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic index; indinavir is a strong CYP3A4 inhibitor.
Indomethacin: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Infliximab: (Moderate) Many serious infections during infliximab therapy have occurred in patients who received concurrent immunosuppressives that, in addition to their underlying Crohn's disease or rheumatoid arthritis, predisposed patients to infections. The impact of concurrent infliximab therapy and immunosuppression on the development of malignancies is unknown. In clinical trials, the use of concomitant immunosuppressant agents appeared to reduce the frequency of antibodies to infliximab and appeared to reduce infusion reactions.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with tacrolimus 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 tacrolimus have been associated with QT interval prolongation.
Insulin Aspart: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Insulin Aspart; Insulin Aspart Protamine: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Insulin Degludec: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Insulin Degludec; Liraglutide: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents, including liraglutide. Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Insulin Detemir: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Insulin Glargine: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Insulin Glargine; Lixisenatide: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents, including lixisenatide. Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Insulin Glulisine: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Insulin Lispro: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Insulin Lispro; Insulin Lispro Protamine: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Insulin, Inhaled: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Insulins: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Intranasal Influenza Vaccine: (Contraindicated) Do not administer live vaccines to tacrolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving tacrolimus. At least 2 weeks before initiation of tacrolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Tacrolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Iodine; Potassium Iodide, KI: (Moderate) Monitor serum potassium concentrations closely if potassium supplements and tacrolimus are used together. Concomitant use may increase the risk of hyperkalemia.
Isavuconazonium: (Moderate) Use caution and closely monitor tacrolimus serum concentrations when administered concurrently with isavuconazonium. Use of these drugs together results in elevated tacrolimus serum concentrations and an increased risk for adverse reactions. Tacrolimus dose adjustments may be necessary and should be guided by serum concentrations during coadministration. Isavuconazole, the active moiety of isavuconazonium, is a inhibitor of hepatic isoenzyme CYP3A4; tacrolimus is metabolized by this enzyme.
Isoflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with tacrolimus. Halogenated anesthetics and tacrolimus can prolong the QT interval.
Isoniazid, INH: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with isoniazid. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Isoniazid is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Coadministration with strong CYP3A4-inducers such as rifampin is not recommended without adjustments in the dosing regimen of tacrolimus and subsequent close monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions. Strong CYP3A4-inducers can decrease whole blood concentrations of tacrolimus. In a study of 6 normal volunteers, a significant decrease in tacrolimus oral bioavailability (14 +/- 6% vs. 7 +/- 3%) was observed with concomitant rifampin administration (600 mg). In addition, there was a significant increase in tacrolimus clearance with concomitant rifampin administration. (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with isoniazid. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Isoniazid is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
Isoniazid, INH; Rifampin: (Major) Coadministration with strong CYP3A4-inducers such as rifampin is not recommended without adjustments in the dosing regimen of tacrolimus and subsequent close monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions. Strong CYP3A4-inducers can decrease whole blood concentrations of tacrolimus. In a study of 6 normal volunteers, a significant decrease in tacrolimus oral bioavailability (14 +/- 6% vs. 7 +/- 3%) was observed with concomitant rifampin administration (600 mg). In addition, there was a significant increase in tacrolimus clearance with concomitant rifampin administration. (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with isoniazid. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Isoniazid is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
Isophane Insulin (NPH): (Moderate) Tacrolimus has been reported to cause hyperglycemia. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Istradefylline: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with istradefylline 40 mg daily is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Itraconazole: (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.
Ivacaftor: (Major) Use caution when administering ivacaftor and tacrolimus concurrently; careful tacrolimus blood concentrations is warranted. Ivacaftor is an inhibitor of CYP3A, and tacrolimus is a CYP3A substrate. Co-administration can increase tacrolimus exposure leading to increased or prolonged therapeutic effects and adverse events.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with tacrolimus due to an increased risk of QT prolongation; tacrolimus exposure may also decrease. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Monitor for loss of efficacy of tacrolimus. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Ivosidenib is a CYP3A4 inducer that has been associated with prolongation of the QTc interval and ventricular arrhythmias. Tacrolimus also causes QT prolongation and is a sensitive CYP3A4 substrate.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and tacrolimus due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of tacrolimus, further increasing the risk for adverse effects. If concomitant use is unavoidable, decrease tacrolimus dose and closely monitor tacrolimus serum concentrations. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased exposure to tacrolimus and its primary active metabolite by 51%.
Ketoprofen: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Ketorolac: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent, including tacrolimus.
Lansoprazole: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 (CYP) 3A4. Lansoprazole may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations. In addition to being a CYP3A4 substrate, lansoprazole is also a CYP2C19 substrate. Patients who are intermediate or poor CYP2C19 metabolizers as compared to those patients who are efficient CYP2C19 metabolizers may have more dramatic increases in their tacrolimus whole blood concentrations. Increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) A reduction in tacrolimus dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended if coadministered with clarithromycin as concurrent use may result in increased tacrolimus exposure and additive QT prolongation. Additional tacrolimus dosage reductions may be required. Despite an initial reduction in tacrolimus dose, a rapid, sharp increase in tacrolimus levels has been reported during coadministration with clarithromycin. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; clarithromycin is a strong CYP3A4 inhibitor. Both tacrolimus and clarithromycin are associated with an established risk of QT prolongation and torsade de pointes (TdP). Use this combination with caution. (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 (CYP) 3A4. Lansoprazole may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations. In addition to being a CYP3A4 substrate, lansoprazole is also a CYP2C19 substrate. Patients who are intermediate or poor CYP2C19 metabolizers as compared to those patients who are efficient CYP2C19 metabolizers may have more dramatic increases in their tacrolimus whole blood concentrations. Increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
Lapatinib: (Major) Measure tacrolimus whole blood trough concentrations and adjust the dose as clinically appropriate if coadministration with lapatinib is necessary. Tacrolimus is a CYP3A4 substrate that can cause QT prolongation. Lapatinib is a weak CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
Larotrectinib: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with larotrectinib. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Larotrectinib is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
Ledipasvir; Sofosbuvir: (Moderate) Closely monitor tacrolimus serum concentrations if coadministration with a direct acting antiviral (DAA) agent, such as ledipasvir, is necessary; dosage adjustments may be required. Changes in liver function due to clearance of the hepatitis C virus by DAA therapy may alter tacrolimus serum concentrations. (Moderate) Closely monitor tacrolimus serum concentrations if coadministration with a direct acting antiviral (DAA) agent, such as sofosbuvir, is necessary; dosage adjustments may be required. Changes in liver function due to clearance of the hepatitis C virus by DAA therapy may alter tacrolimus serum concentrations.
Lefamulin: (Major) Coadministration of lefamulin tablets is contraindicated with tacrolimus due to increased tacrolimus exposure which may result in QT prolongation and torsade de pointes (TdP). Avoid use of lefamulin injection with tacrolimus. If coadministration of lefamulin injection cannot be avoided, ECG monitoring is recommended during treatment. Tacrolimus is a sensitive CYP3A4 substrate that may prolong the QT interval and cause torsade de pointes (TdP). Lefamulin is a CYP3A4 inhibitor 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.
Lenacapavir: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with lenacapavir is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; lenacapavir is a moderate CYP3A inhibitor.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with tacrolimus due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Tacrolimus also causes QT prolongation.
Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of tacrolimus; monitor for potential reduction in efficacy. Tacrolimus is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of tacrolimus; monitor for potential reduction in efficacy. Tacrolimus is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Letermovir: (Moderate) Frequently monitor tacrolimus whole blood concentrations during concurrent treatment and after discontinuation of letermovir, and adjust the tacrolimus dose accordingly. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Concurrent use of letermovir increased the AUC and Cmax of tacrolimus by 2.42-fold and 1.57-fold, respectively. Tacrolimus is a sensitive CYP3A4 substrate; letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Leuprolide: (Moderate) Consider the benefits of androgen deprivation therapy and monitor ECG and electrolytes periodically during treatment if tacrolimus is administered with leuprolide. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Moderate) Consider the benefits of androgen deprivation therapy and monitor ECG and electrolytes periodically during treatment if tacrolimus is administered with leuprolide. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
Levamlodipine: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
Levofloxacin: (Moderate) Concomitant use of levofloxacin and tacrolimus 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: (Contraindicated) Avoid concomitant use of ketoconazole and tacrolimus due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of tacrolimus, further increasing the risk for adverse effects. If concomitant use is unavoidable, decrease tacrolimus dose and closely monitor tacrolimus serum concentrations. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased exposure to tacrolimus and its primary active metabolite by 51%.
Levonorgestrel; Ethinyl Estradiol: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
Linagliptin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. This drug may have direct beta-cell toxicity. Patients should be monitored for changes in glycemic control if therapy with immunosuppressant drugs is initiated in patients receiving linagliptin.
Linagliptin; Metformin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. This drug may have direct beta-cell toxicity. Patients should be monitored for changes in glycemic control if therapy with immunosuppressant drugs is initiated in patients receiving linagliptin.
Liraglutide: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents, including liraglutide. Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity.
Lisinopril: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including ACE inhibitors.
Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including ACE inhibitors.
Lithium: (Moderate) Concomitant use of lithium and tacrolimus 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.
Live Vaccines: (Contraindicated) Do not administer live vaccines to tacrolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving tacrolimus. At least 2 weeks before initiation of tacrolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Tacrolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Lixisenatide: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents, including lixisenatide. Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity.
Lofexidine: (Major) Monitor ECG if lofexidine is coadministered with tacrolimus due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Tacrolimus causes QT prolongation.
Lonafarnib: (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration with lonafarnib is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; lonafarnib is a strong CYP3A4 inhibitor.
Loperamide: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with loperamide. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest.
Loperamide; Simethicone: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with loperamide. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with tacrolimus due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration with ritonavir is necessary; a dose reduction to 0.5 mg to 1 mg once per week may be necessary. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; ritonavir is a strong CYP3A4 inhibitor. In 1 study, the tacrolimus half-life increased to 10.6 days in 1 patient and 20.6 days in another following coadministration with lopinavir; ritonavir. Up to 80% reductions in tacrolimus dosages and 7-fold increase in dosage intervals were needed when tacrolimus was coadministered with protease inhibitors in studies.
Lorlatinib: (Moderate) Measure tacrolimus whole blood trough concentrations and adjust the dose as clinically appropriate if coadministration with lorlatinib is necessary. Tacrolimus is a sensitive CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer may significantly increase tacrolimus clearance.
Lovastatin: (Major) Guidelines recommend avoiding coadministration of lovastatin with tacrolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving tacrolimus.
Lumacaftor; Ivacaftor: (Major) Concomitant use of tacrolimus and lumacaftor; ivacaftor is not recommended. Lumacaftor; ivacaftor may decrease the systemic exposure of tacrolimus. If concurrent use cannot be avoided, monitor tacrolimus whole blood trough concentrations closely and adjust the dose accordingly. Tacrolimus is a substrate of CYP3A, and lumacaftor; ivacaftor is a potent CYP3A inducer. (Major) Use caution when administering ivacaftor and tacrolimus concurrently; careful tacrolimus blood concentrations is warranted. Ivacaftor is an inhibitor of CYP3A, and tacrolimus is a CYP3A substrate. Co-administration can increase tacrolimus exposure leading to increased or prolonged therapeutic effects and adverse events.
Lumacaftor; Ivacaftor: (Major) Concomitant use of tacrolimus and lumacaftor; ivacaftor is not recommended. Lumacaftor; ivacaftor may decrease the systemic exposure of tacrolimus. If concurrent use cannot be avoided, monitor tacrolimus whole blood trough concentrations closely and adjust the dose accordingly. Tacrolimus is a substrate of CYP3A, and lumacaftor; ivacaftor is a potent CYP3A inducer.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as tacrolimus. 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. Tacrolimus causes QT prolongation.
Magnesium Hydroxide: (Major) Monitor tacrolimus whole blood trough concentration and reduce tacrolimus dose if needed during concurrent use of antacids. Magnesium and aluminum hydroxide antacids may increase the blood concentration of tacrolimus. In a single-dose crossover study in healthy volunteers, coadministration of tacrolimus and magnesium-aluminum-hydroxide resulted in a mean AUC increase of 21% and a 10% decrease in the mean tacrolimus Cmax, compared to tacrolimus administration alone.
Magnesium Salicylate: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Maprotiline: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with maprotiline. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and 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: (Minor) Use caution and careful monitoring with the coadministration of maraviroc and tacrolimus as increased maraviroc concentrations may occur. Maraviroc is a substrate of P-glycoprotein (P-gp); tacrolimus may be an inhibitor of P-gp. Conflicting data exist regarding any interaction between tacrolimus and P-gp. The effects of P-gp on the concentrations of maraviroc are unknown, although an increase in concentrations and thus, toxicity, are possible.
Maribavir: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with maribavir is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range and maribavir is a weak CYP3A4 inhibitor. Coadministration with maribavir increased the exposure of tacrolimus by approximately 50%.
Mavacamten: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with mavacamten is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; mavacamten is a moderate CYP3A inducer.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Do not administer live vaccines to tacrolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving tacrolimus. At least 2 weeks before initiation of tacrolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Tacrolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Do not administer live vaccines to tacrolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving tacrolimus. At least 2 weeks before initiation of tacrolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Tacrolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Meclofenamate Sodium: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Mefenamic Acid: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Mefloquine: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with mefloquine as concurrent use may increase the risk of QT prolongation. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). There is evidence that the use of halofantrine after mefloquine causes significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation.
Meglitinides: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Meloxicam: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Melphalan Flufenamide: (Minor) Bone marrow suppression is the most significant toxicity associated with melphalan in most patients. The bone marrow depressant effects of melphalan can be potentiated by concurrent or sequential administration of other bone marrow depressants and immunosuppressives.
Melphalan: (Minor) Bone marrow suppression is the most significant toxicity associated with melphalan in most patients. The bone marrow depressant effects of melphalan can be potentiated by concurrent or sequential administration of other bone marrow depressants and immunosuppressives.
Meropenem: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with meropenem is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; meropenem is a weak CYP3A inducer.
Meropenem; Vaborbactam: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with meropenem is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; meropenem is a weak CYP3A inducer.
Metformin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents.
Metformin; Repaglinide: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents.
Metformin; Saxagliptin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Monitor for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Metformin; Sitagliptin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Monitor for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Methadone: (Major) The need to coadminister methadone with drugs known to prolong the QT interval, such as tacrolimus, should be done with extreme caution and a careful assessment of treatment risks versus benefits. When coadministering tacrolimus with other substrates of CYP3A, especially those that also have the potential to prolong the QT interval, such as methadone, monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended. Consider obtaining electrocardiograms (ECGs) and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment in at-risk patients. Methadone is considered to be associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (more than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Tacrolimus may also prolong the QT interval and has been reported to cause TdP.
Methenamine; Sodium Salicylate: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Methohexital: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
Methotrexate: (Major) Avoid concomitant use of methotrexate with tacrolimus due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Tacrolimus and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with tacrolimus may result in decreased renal function as well as increased methotrexate plasma concentrations.
Methylprednisolone: (Major) Patients receiving tacrolimus and systemic corticosteroids concomitantly should be carefully monitored for alterations in tacrolimus whole blood concentrations. According to the manufacturer of tacrolimus, methylprednisolone may increase tacrolimus blood concentrations. The mechanism of the interaction is unclear. Tacrolimus is a CYP3A4 substrate, but methylprednisolone does not appear to have an inhibitory effect on CYP3A4 activity. For example, the pharmacokinetics and pharmacodynamics of the CYP3A4 substrate triazolam were determined in a three-phase cross-over study; the three treatment periods were placebo, methylprednisolone 32 mg PO 1 hour before triazolam 0.25 mg PO, and methylprednisolone 8 mg PO daily for 9 days before triazolam 0.25 mg PO. The single methylprednisolone dose did not significantly affect CYP3A4 activity. Methylprednisolone receipt for 9 days led to slightly reduced maximum triazolam concentrations, which may have been due to an inducing effect on the CYP3A4-mediated first-pass metabolism of triazolam.
Metoclopramide: (Major) Increased tacrolimus whole blood concentrations may be observed if a GI prokinetic agent like metoclopramide is added to therapy. Monitor tacrolimus serum concentrations carefully if a GI prokinetic agent is used concomitantly.
Metreleptin: (Moderate) Upon initiation or discontinuation of metreleptin in a patient receiving tacrolimus, drug concentration monitoring should be performed and the tacrolimus dosage adjusted as needed. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index, such as tacrolimus.
Metronidazole: (Moderate) Concomitant use of metronidazole and tacrolimus 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) Leukopenia, neutropenia, anemia, and thrombocytopenia have been associated with micafungin. In theory, patients who are taking immunosuppressive agents such as tacrolimus concomitantly with micafungin may have additive risks for infection or other side effects. However, the manufacturer has listed no particular precautions for co-use of micafungin with these medications. Concurrent administration of micafungin and tacrolimus did not alter the pharmacokinetic parameters of micafungin. Furthermore, there was no effect of a single or multiple doses of micafungin on tacrolimus pharmacokinetic parameters.
Midostaurin: (Major) The concomitant use of midostaurin and tacrolimus may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. There are post-marketing reports of QT prolongation and torsade de pointes with systemic tacrolimus administration.
Mifepristone: (Contraindicated) Coadministration of systemic tacrolimus is contraindicated when mifepristone is used chronically, such as in the treatment of Cushing's syndrome. Mifepristone, a CYP3A4 inhibitor, is likely to increase tacrolimus concentrations and adverse effects, since tacrolimus is a CYP3A4 substrate with a narrow therapeutic index. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration.
Miglitol: (Moderate) Tacrolimus has been reported to cause hyperglycemia. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Mirtazapine: (Moderate) Concomitant use of mirtazapine and tacrolimus 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.
Mitapivat: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with mitapivat is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; mitapivat is a weak CYP3A inducer.
Mitotane: (Major) Use caution if mitotane and tacrolimus are used concomitantly, and monitor for decreased efficacy of tacrolimus and a possible change in dosage requirements. Monitor tacrolimus whole blood trough concentrations and adjust the dose of tacrolimus as necessary. Mitotane is a strong CYP3A4 inducer and tacrolimus is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of tacrolimus. Concomitant administration of immediate-release tacrolimus and another strong CYP3A inducer, rifampin, resulted in a significant decrease in the mean tacrolimus bioavailability (from 14% to 7%) and a significant increase in the mean tacrolimus clearance (from 0.035 L/hr/kg to 0.053 L/hr/kg) compared with tacrolimus alone in 6 healthy subjects. In another pharmacokinetic study in 22 healthy male subjects, the administration of a single 10 mg dose of extended-release tacrolimus (Astagraf XL) following 12 days of rifampin 600 mg/day decreased mean tacrolimus AUC and Cmax values by 56% and 46%, respectively.
Mobocertinib: (Major) Concomitant use of mobocertinib and tacrolimus 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. Concurrent use may also decrease tacrolimus concentrations. Monitor tacrolimus serum concentrations as appropriate and adjust tacrolimus dose as needed. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; mobocertinib is a weak CYP3A inducer.
Moexipril: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including ACE inhibitors.
Moxifloxacin: (Major) Concurrent use of tacrolimus and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Tacrolimus causes QT prolongation. Moxifloxacin has also been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded.
Mycophenolate: (Minor) Tacrolimus is a potent inhibitor of UDP-glucuronosyl transferase. As mycophenolic acid is metabolized by UDPGT, increased concentrations of mycophenolic acid would be anticipated.
Nabumetone: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Nanoparticle Albumin-Bound Sirolimus: (Moderate) The concomitant use of sirolimus with a calcineurin inhibitor, such as tacrolimus, may increase the risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy. In addition to a potential increased risk of thrombotic microangiopathy, sirolimus may decrease the blood concentration of tacrolimus.
Naproxen: (Moderate) Monitor patients for signs of worsening renal function during coadmi nistration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Naproxen; Esomeprazole: (Moderate) Esomeprazole may increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, nephrotoxicity, QT prolongation). Monitor tacrolimus whole blood trough concentrations and reduce the tacrolimus dose if needed. Tacrolimus is metabolized primarily by CYP3A4; esomeprazole inhibits CYP3A4 and thus may decrease CYP3A4-mediated metabolism of tacrolimus. (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Naproxen; Pseudoephedrine: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Natalizumab: (Major) The concomitant use of natalizumab and immunosuppressives may further increase the risk of infections, including progressive multifocal leukoencephalopathy (PML), over the risk observed with use of natalizumab alone. Prior treatment with an immunosuppressant is also a risk factor for PML. The safety and efficacy of natalizumab in combination with immunosuppressants has not been evaluated. Multiple sclerosis (MS) patients receiving chronic immunosuppressant therapy should not ordinarily be treated with natalizumab. Also, natalizumab for Crohn's disease should not be used in combination with tacrolimus.
Nateglinide: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Nefazodone: (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration with nefazodone if necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Delirium, renal failure, and high tacrolimus serum concentrations (46.4 ng/ml) were reported in a patient receiving tacrolimus and nefazodone. The patient discontinued nefazodone and was started on paroxetine instead. Three days after stopping the nefazodone the tacrolimus level was 10.2 ng/ml. In a separate report, a patient on stable doses of tacrolimus for 2 years developed headache, confusion and 'gray areas' in her vision without ophthalmologic findings 1 week after switching from sertraline to nefazodone for persistent depression. Her serum creatinine increased 1.5 mg/dl from baseline and her 12-hour trough tacrolimus level was greater than 30 ng/ml. The tacrolimus was held for 4 days and the patient restarted on sertraline with resolution of symptoms. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; nefazodone is a strong CYP3A4 inhibitor.
Nelfinavir: (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration with nelfinavir is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Consider a tacrolimus dose reduction to 0.5 mg to 1 mg once per week when coadministered with a protease inhibitor. In a clinical study in 5 liver transplant patients, concomitant use of immediate-release tacrolimus and nelfinavir resulted in significantly increased tacrolimus blood concentrations which required an average of a 16-fold tacrolimus dosage reduction to maintain mean trough concentrations of 9.7 nanograms/mL. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; nelfinavir is a strong CYP3A4 inhibitor.
Nevirapine: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with nevirapine is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range and nevirapine is a weak CYP3A4 inducer.
Nicardipine: (Moderate) Coadministration of nicardipine and tacrolimus may result in elevated plasma tacrolimus concentrations. Monitor plasma concentrations of tacrolimus closely, and adjust the dose as necessary. Tacrolimus is metabolized by CYP3A4; nicardipine is an inhibitor of CYP3A4.
NIFEdipine: (Moderate) Tacrolimus is metabolized by CYP3A4 isoenzyme. CYP3A4 is the major isoenzyme that metabolizes nifedipine. When coadministered with nifedipine, tacrolimus whole blood trough concentrations are increased. In a retrospective study of liver transplant patients with hypertension, nifedipine decreased the daily and cumulative dosage requirements of tacrolimus by 26%, 29%, and 38% at 3, 6, and 12 months, respectively, compared with the dosage for patients who did not receive nifedipine. It is recommended that tacrolimus blood concentrations be closely monitored when nifedipine and tacrolimus are administered concomitantly.
Nilotinib: (Major) Nilotinib and tacrolimus both prolong the QT interval. Additionally, tacrolimus is metabolized by CYP3A4 and nilotinib inhibits this isoenzyme. Coadministration of nilotinib and a drug that prolongs the QT interval is not advised, as nilotinib prolongs the QT interval. If concurrent administration with tacrolimus is unavoidable, the manufacturer of nilotinib recommends interruption of nilotinib treatment. If nilotinib must be continued, closely monitor the patient for QT interval prolongation. The manufacturer of tacrolimus advises reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation when coadministrating tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval such as nilotinib. Tacrolimus concentrations and thus other adverse reactions may also be increased during concomitant administration.
Nirmatrelvir; Ritonavir: (Major) Before prescribing ritonavir-boosted nirmatrelvir for a patient receiving tacrolimus, the patient's specialist provider(s) should be consulted, given the significant drug-drug interaction potential and because close monitoring may not be feasible. If this is not feasible, consider an alternative COVID-19 therapy. Coadministration may increase tacrolimus exposure resulting in increased toxicity. Tacrolimus is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration with ritonavir is necessary; a dose reduction to 0.5 mg to 1 mg once per week may be necessary. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; ritonavir is a strong CYP3A4 inhibitor. In 1 study, the tacrolimus half-life increased to 10.6 days in 1 patient and 20.6 days in another following coadministration with lopinavir; ritonavir. Up to 80% reductions in tacrolimus dosages and 7-fold increase in dosage intervals were needed when tacrolimus was coadministered with protease inhibitors in studies.
Nirogacestat: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with nirogacestat is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; nirogacestat is a moderate CYP3A inhibitor.
Nonsteroidal antiinflammatory drugs: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
Norethindrone; Ethinyl Estradiol: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
Norgestimate; Ethinyl Estradiol: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
Nortriptyline: (Minor) Tacrolimus has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and tricyclic antidepressants (TCAs) should be used together cautiously.
Odevixibat: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with odevixibat is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; odevixibat is a weak CYP3A inducer.
Ofloxacin: (Moderate) Concomitant use of ofloxacin and tacrolimus 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) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with olanzapine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). 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 tacrolimus 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) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with olanzapine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Olanzapine; Samidorphan: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with olanzapine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
Olutasidenib: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with olutasidenib is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; olutasidenib is a weak CYP3A inducer.
Omaveloxolone: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with omaveloxolone is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; omaveloxolone is a weak CYP3A inducer.
Omeprazole: (Moderate) Concomitant administration of omeprazole and tacrolimus may increase tacrolimus serum concentrations possibly leading to increased risk of serious adverse reactions (e.g., neurotoxicity, infection, QT prolongation), especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. Monitor tacrolimus whole blood concentrations; reduce tacrolimus dose if needed to maintain therapeutic concentrations.
Omeprazole; Amoxicillin; Rifabutin: (Major) Increase tacrolimus dose and monitor tacrolimus serum concentrations if coadministration with rifabutin is necessary. Concurrent use may decrease tacrolimus serum concentrations and increase the risk of rejection. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; rifabutin is a CYP3A inducer. (Moderate) Concomitant administration of omeprazole and tacrolimus may increase tacrolimus serum concentrations possibly leading to increased risk of serious adverse reactions (e.g., neurotoxicity, infection, QT prolongation), especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. Monitor tacrolimus whole blood concentrations; reduce tacrolimus dose if needed to maintain therapeutic concentrations.
Omeprazole; Sodium Bicarbonate: (Moderate) Administration of oral tacrolimus at the same time as sodium bicarbonate may result in pH-dependent degradation of tacrolimus. Administer oral Tacrolimus 1 hour before or 2 hours after the Sodium Bicarbonate dose to help limit an interaction. Separation of the oral tacrolimus and sodium bicarbonate doses by at least 2 hours may not be necessary, but more data are needed. Tacrolimus concentrations can be maintained with appropriate monitoring and dosage adjustment. Intravenous and topical forms of tacrolimus do not interact. (Moderate) Concomitant administration of omeprazole and tacrolimus may increase tacrolimus serum concentrations possibly leading to increased risk of serious adverse reactions (e.g., neurotoxicity, infection, QT prolongation), especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. Monitor tacrolimus whole blood concentrations; reduce tacrolimus dose if needed to maintain therapeutic concentrations.
Ondansetron: (Major) Concomitant use of tacrolimus and ondansetron 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. Do not exceed 16 mg of IV ondansetron in a single dose; the degree of QT prolongation associated with ondansetron significantly increases above this dose.
Oritavancin: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with oritavancin is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; oritavancin is a weak CYP3A inducer.
Osilodrostat: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with osilodrostat due to the risk of QT prolongation. Additionally, monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with osilodrostat is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A4 substrate that may prolong the QT interval and cause torsade de pointes (TdP). Osilodrostat is is a weak CYP3A4 inhibitor that is associated with dose-dependent QT prolongation.
Osimertinib: (Major) Avoid coadministration of tacrolimus with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Tacrolimus also causes QT prolongation.
Oxaliplatin: (Major) Avoid coadministration of oxaliplatin with tacrolimus due to the risk of increased oxaliplatin-related adverse reactions; there is also an increased risk of QT prolongation. Tacrolimus is known to be potentially nephrotoxic; because platinum-containing drugs like oxaliplatin are eliminated primarily through the kidney, oxaliplatin clearance may be decreased by coadministration with nephrotoxic agents. Tacrolimus causes QT prolongation. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
Oxaprozin: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Oxcarbazepine: (Moderate) The effectiveness of immunosuppressive medications such as tacrolimus could be decreased by the co-administration of oxcarbazepine. Monitoring of tacrolimus whole blood concentrations is recommended if oxcarbazepine is used concurrently with tacrolimus.
Ozanimod: (Major) Concomitant use of ozanimod and tacrolimus 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.
Pacritinib: (Major) Concomitant use of tacrolimus and pacritinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Concomitant use may also increase tacrolimus exposure and the risk for other tacrolimus-related adverse effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. If concomitant use is necessary, monitor tacrolimus serum concentrations as appropriate; the dose of tacrolimus may need to be reduced. Also, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Tacrolimus is a sensitive substrate of CYP3A4 with a narrow therapeutic range. Pacritinib is a weak CYP3A4 inhibitor.
Palbociclib: (Moderate) Monitor tacrolimus concentrations and watch for an increase in tacrolimus-related adverse reactions if coadministration with palbociclib is necessary. The tacrolimus dose may need to be reduced. Palbociclib is a weak time-dependent inhibitor of CYP3A and tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic index.
Paliperidone: (Major) Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as tacrolimus. However, if coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Pamidronate: (Moderate) Coadministration of pamidronate with other nephrotoxic drugs may increase the risk of developing nephrotoxicity following pamidronate administration, even in patients who have normal renal function.
Panobinostat: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include tacrolimus.
Paromomycin: (Moderate) Additive nephrotoxicity is possible if aminoglycosides are used with tacrolimus. Care should be taken in using tacrolimus with other nephrotoxic drugs. Assessment of renal function in patients who have received tacrolimus is recommended as the tacrolimus dosage may need to be reduced.
Pasireotide: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with pasireotide. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib and tacrolimus have been reported to prolong the QT interval. If pazopanib and tacrolimus must be continued, closely monitor the patient for QT interval prolongation. Also, reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended. In addition, pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and tacrolimus, a CYP3A4 substrate, may cause an increase in systemic concentrations of tacrolimus. Use caution when concurrent administration is necessary.
Pentamidine: (Major) Pentamidine has been associated with QT prolongation. Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) that should be used cautiously with pentamidine include tacrolimus. Tacrolimus has been associated with a possible risk for QT prolongation.
Pentobarbital: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
Perindopril: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including ACE inhibitors.
Perindopril; Amlodipine: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index. (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including ACE inhibitors.
Perphenazine: (Minor) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with perphenazine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Perphenazine is also associated with a possible risk for QT prolongation.
Perphenazine; Amitriptyline: (Minor) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with perphenazine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Perphenazine is also associated with a possible risk for QT prolongation.
Pexidartinib: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with pexidartinib is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; pexidartinib is a moderate CYP3A4 inducer.
Phenobarbital: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
Phenytoin: (Moderate) Phenytoin can induce the hepatic cytochrome P-450 enzyme system, thus decreasing plasma concentrations of tacrolimus. If phenytoin is added to tacrolimus, the levels of tacrolimus should be closely monitored and adjusted as needed until a new steady-state is achieved. Conversely, if phenytoin is discontinued, levels of tacrolimus could increase and result in toxicity.
Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as tacrolimus. Coadministration may increase the risk for QT prolongation.
Pimozide: (Contraindicated) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Because of the potential for TdP, use of tacrolimus with pimozide is contraindicated.
Pioglitazone: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Pioglitazone; Glimepiride: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents. (Moderate) Tacrolimus has been reported to cause hyperglycemia and has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Pioglitazone; Metformin: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents. (Moderate) Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if Tacrolimus is initiated in patients receiving antidiabetic agents.
Piroxicam: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Pirtobrutinib: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with pirtobrutinib is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; pirtobrutinib is a weak CYP3A inhibitor.
Pitavastatin: (Major) Guidelines recommend avoiding coadministration of pitavastatin with tacrolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving tacrolimus.
Pitolisant: (Major) Avoid coadministration of pitolisant with tacrolimus as concurrent use may increase the risk of QT prolongation. If concomitant use is necessary, consider ECG and electrolyte monitoring periodically during treatment. Pitolisant prolongs the QT interval. Tacrolimus may also prolong the QT interval and cause torsade de pointes (TdP).
Plazomicin: (Moderate) Additive nephrotoxicity is possible if aminoglycosides are used with tacrolimus. Care should be taken in using tacrolimus with other nephrotoxic drugs. Assessment of renal function in patients who have received tacrolimus is recommended as the tacrolimus dosage may need to be reduced.
Polymyxin B: (Minor) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including Polymixin B. Assessment of renal function in patients who have received tacrolimus is recommended, as the tacrolimus dosage may need to be reduced.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking tacrolimus due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If concomitant use is unavoidable, monitor ECGs, electrolytes, and for signs and symptoms of infection. 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. Tacrolimus may prolong the QT interval and cause TdP.
Posaconazole: (Major) A reduction in tacrolimus dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring of QT prolongation is recommended if coadministered with posaconazole as concurrent use may result in an increase tacrolimus exposure and additive QT prolongation. When initiating therapy with posaconazole in patients already receiving tacrolimus, reduce the tacrolimus dose by two-thirds (i.e., administer one-third of the pre-posaconazole dose) and make subsequent tacrolimus dose adjustments based on the tacrolimus whole blood concentrations. In a pharmacokinetic study in healthy subjects, the administration of a single 0.05 mg/kg dose of immediate-release tacrolimus after 7 days of posaconazole 400 mg PO every 12 hours increased tacrolimus AUC and Cmax values by 4.5-fold and 2-fold, respectively, compared with tacrolimus alone. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range that may prolong the QT interval and cause torsade de pointes (TdP). Posaconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation and TdP.
Potassium Acetate: (Moderate) Monitor serum potassium concentrations closely if potassium supplements and tacrolimus are used together. Concomitant use may increase the risk of hyperkalemia.
Potassium Bicarbonate: (Moderate) Monitor serum potassium concentrations closely if potassium supplements and tacrolimus are used together. Concomitant use may increase the risk of hyperkalemia.
Potassium Chloride: (Moderate) Monitor serum potassium concentrations closely if potassium supplements and tacrolimus are used together. Concomitant use may increase the risk of hyperkalemia.
Potassium Citrate: (Moderate) Monitor serum potassium concentrations closely if potassium supplements and tacrolimus are used together. Concomitant use may increase the risk of hyperkalemia.
Potassium Citrate; Citric Acid: (Moderate) Monitor serum potassium concentrations closely if potassium supplements and tacrolimus are used together. Concomitant use may increase the risk of hyperkalemia.
Potassium Gluconate: (Moderate) Monitor serum potassium concentrations closely if potassium supplements and tacrolimus are used together. Concomitant use may increase the risk of hyperkalemia.
Potassium Iodide, KI: (Moderate) Monitor serum potassium concentrations closely if potassium supplements and tacrolimus are used together. Concomitant use may increase the risk of hyperkalemia.
Potassium Phosphate: (Major) Avoid coadministration of potassium phosphate and tacrolimus as concurrent use may increase the risk of severe and potentially fatal hyperkalemia, particularly in high-risk patients (renal impairment, cardiac disease, adrenal insufficiency). If concomitant use is necessary, closely monitor serum potassium concentrations.
Potassium Phosphate; Sodium Phosphate: (Major) Avoid coadministration of potassium phosphate and tacrolimus as concurrent use may increase the risk of severe and potentially fatal hyperkalemia, particularly in high-risk patients (renal impairment, cardiac disease, adrenal insufficiency). If concomitant use is necessary, closely monitor serum potassium concentrations.
Potassium: (Moderate) Monitor serum potassium concentrations closely if potassium supplements and tacrolimus are used together. Concomitant use may increase the risk of hyperkalemia.
Pramlintide: (Moderate) Tacrolimus has been reported to cause hyperglycemia. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Monitor for worsening of glycemic control.
Pravastatin: (Moderate) Carefully weigh the benefits of combined use of tacrolimus and pravastatin against the potential risk of statin-induced myopathy/rhabdomyolysis. Guidelines recommend lower doses of statins in combination with tacrolimus. A maximum dose of pravastatin40 mg/day is recommended.
Primaquine: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with primaquine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Primaquine is associated with QT prolongation.
Primidone: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
Probenecid; Colchicine: (Minor) Monitor for colchicine-related adverse effects during concomitant use of tacrolimus. Concomitant use may increase colchicine exposure.
Procainamide: (Major) Tacrolimus should be used cautiously and with close clinical monitoring with procainamide. Procainamide is associated with a well-established risk of QT prolongation and torsades de pointes (TdP) and tacrolimus causes QT prolongation.
Prochlorperazine: (Minor) Consider monitoring of ECG and electrolytes when coadministering tacrolimus and prochlorperazine due to increased risk of QT prolongation and torsade de pointes. Prochlorperazine is also associated with a possible risk for QT prolongation.
Promethazine: (Moderate) Concomitant use of promethazine and tacrolimus 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 tacrolimus 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 tacrolimus 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) Concurrent use of tacrolimus and propafenone should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Tacrolimus prolongs the QT interval. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval. In addition, both drugs are metabolized by CYP3A4. Although the manufacturer recommends dose adjustment and close monitoring when tacrolimus is coadminsitered with other drugs that prolong the QT interval and are substrates or inhibitors of CYP3A4, it may be prudent to avoid coadministration as the risk of TdP may be increased.
Protriptyline: (Major) Tacrolimus has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and tricyclic antidepressants (TCAs) should be used together cautiously.
Quetiapine: (Major) Concurrent use of quetiapine and tacrolimus should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. Tacrolimus also causes QT prolongation. Additionally, both tacrolimus and quetiapine are substrates for CYP3A4. When coadministrating tacrolimus with other substrates of CYP3A4, it is recommended to reduce the tacrolimus dose and closely monitor tacrolimus whole blood concentrations.
Quinapril: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including ACE inhibitors.
Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including ACE inhibitors.
Quinidine: (Major) Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). As the risk of TdP is increased with greater QT prolongation, avoid use of quinidine with another drug that prolongs the QT interval such as tacrolimus. It should be noted that the manufacturer of tacrolimus recommends reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation when coadministrating tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval such as quinidine. Tacrolimus and quinidine are both metabolized by cytochrome P450 3A4.
Quinine: (Major) Concurrent use of quinine and tacrolimus should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Quinine has been associated with prolongation of the QT interval and rare cases of TdP. Tacrolimus also causes QT prolongation. In addition, concentrations of tacrolimus may be increased with concomitant use of quinine. Tacrolimus is a CYP3A4 substrate and quinine is a CYP3A4 inhibitor. Reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended when coadministrating tacrolimus with inhibitors of CYP3A4 that also have the potential to prolong the QT interval.
Quizartinib: (Major) Concomitant use of quizartinib and tacrolimus 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.
Rabeprazole: (Moderate) According to the FDA-approved labeling, concomitant use of tacrolimus and rabeprazole may result in increased exposure to tacrolimus, particularly in transplant patients who are intermediate or poor metabolizers of CYP2C19. The rabeprazole manufacturer recommends monitoring tacrolimus plasma concentrations during coadministration; dose adjustments may be needed to maintain therapeutic drug concentrations. However, in drug interaction studies, rabeprazole had little effect on tacrolimus drug concentrations. Rabeprazole uses a non-enzymatic pathway in addition to the CYP system and does not compete with tacrolimus for CYP3A4 compared with other PPIS; additionally, the effects of CYP2C19 polymorphism on rabeprazole are minimal compared to other PPIs.
Ramipril: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including ACE inhibitors.
Ranolazine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, in vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. The impact of coadministering ranolazine with other CYP3A4 substrates has not been studied. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates, potentially leading to adverse reactions, such as QT prolongation. Drugs that are CYP3A4 substrates that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include tacrolimus.
Regular Insulin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Regular Insulin; Isophane Insulin (NPH): (Moderate) Tacrolimus has been reported to cause hyperglycemia. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Relugolix: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with relugolix. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with relugolix. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Repaglinide: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Repotrectinib: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with repotrectinib is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; repotrectinib is a moderate CYP3A inducer.
Ribociclib: (Major) A reduction in tacrolimus dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended if coadministered with ribociclib as concurrent use may result in increased tacrolimus exposure and additive QT prolongation. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range that may prolong QT and cause torsade de pointes (TdP). Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner.
Ribociclib; Letrozole: (Major) A reduction in tacrolimus dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended if coadministered with ribociclib as concurrent use may result in increased tacrolimus exposure and additive QT prolongation. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range that may prolong QT and cause torsade de pointes (TdP). Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner.
Rifabutin: (Major) Increase tacrolimus dose and monitor tacrolimus serum concentrations if coadministration with rifabutin is necessary. Concurrent use may decrease tacrolimus serum concentrations and increase the risk of rejection. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; rifabutin is a CYP3A inducer.
Rifampin: (Major) Coadministration with strong CYP3A4-inducers such as rifampin is not recommended without adjustments in the dosing regimen of tacrolimus and subsequent close monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions. Strong CYP3A4-inducers can decrease whole blood concentrations of tacrolimus. In a study of 6 normal volunteers, a significant decrease in tacrolimus oral bioavailability (14 +/- 6% vs. 7 +/- 3%) was observed with concomitant rifampin administration (600 mg). In addition, there was a significant increase in tacrolimus clearance with concomitant rifampin administration.
Rifapentine: (Major) Increase tacrolimus dose and monitor tacrolimus serum concentrations if coadministration with rifapentine is necessary. Concurrent use may decrease tacrolimus serum concentrations and increase the risk of rejection. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; rifapentine is a strong CYP3A4 inducer.
Rilpivirine: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with rilpivirine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Risperidone: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with risperidone. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Risperidone has been associated with a possible risk for QT prolongation and/or torsade de pointes. Reports of QT prolongation and torsade de pointes during risperidone therapy are noted by the manufacturer, primarily in the overdosage setting.
Ritlecitinib: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with ritlecitinib is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; ritlecitinib is a moderate CYP3A inhibitor.
Ritonavir: (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration with ritonavir is necessary; a dose reduction to 0.5 mg to 1 mg once per week may be necessary. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; ritonavir is a strong CYP3A4 inhibitor. In 1 study, the tacrolimus half-life increased to 10.6 days in 1 patient and 20.6 days in another following coadministration with lopinavir; ritonavir. Up to 80% reductions in tacrolimus dosages and 7-fold increase in dosage intervals were needed when tacrolimus was coadministered with protease inhibitors in studies.
Romidepsin: (Major) Romidepsin has been reported to prolong the QT interval. Tacrolimus causes QT prolongation. Reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended when tacrolimus is coadministered with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval such as romidepsin. In addition, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
Rosiglitazone: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Rosuvastatin: (Moderate) Carefully weigh the benefits of combined use of tacrolimus and rosuvastatin against the potential risk of statin-induced myopathy/rhabdomyolysis. Guidelines recommend lower doses of statins in combination with tacrolimus. A maximum dose of rosuvastatin of 5 mg/day is recommended.
Rosuvastatin; Ezetimibe: (Moderate) Carefully weigh the benefits of combined use of tacrolimus and rosuvastatin against the potential risk of statin-induced myopathy/rhabdomyolysis. Guidelines recommend lower doses of statins in combination with tacrolimus. A maximum dose of rosuvastatin of 5 mg/day is recommended.
Rotavirus Vaccine: (Contraindicated) Do not administer live vaccines to tacrolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving tacrolimus. At least 2 weeks before initiation of tacrolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Tacrolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Rucaparib: (Moderate) Frequently monitor tacrolimus levels and watch for an increase in tacrolimus-related adverse reactions if coadministration with rucaparib is necessary. Tacrolimus is a sensitive substrate of CYP3A4 and rucaparib is a weak CYP3A4 inhibitor.
Rufinamide: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as tacrolimus, may occur during concurrent use with rufinamide.
Salicylates: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Salsalate: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Saquinavir: (Contraindicated) Concurrent administration of tacrolimus and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening cardiac arrhythmias. Saquinavir prolongs the QT and PR intervals in a dose-dependent fashion, which may increase the risk for serious cardiac arrhythmias such as torsades de pointes (TdP). The potential for saquinavir induced cardiac arrhythmias could increase if administered with other drugs that prolong the QT interval, such as tacrolimus. In addition to the potential for arrhythmias, inhibition of CYP3A4 by saquinavir boosted with ritonavir may increase the whole blood concentrations of tacrolimus and lead to other tacrolimus-related side effects such as nephrotoxicity.
Sarilumab: (Moderate) Monitor tacrolimus levels and adjust the dose of tacrolimus as appropriate if coadministration with sarilumab is necessary. Inhibition of IL-6 signaling by sarilumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as tacrolimus, may have fluctuations in drug levels and therapeutic effect when sarilumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping sarilumab. In vitro, sarilumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Tacrolimus is a CYP3A4 substrate and narrow therapeutic index drug.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Saxagliptin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Monitor for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Secobarbital: (Major) Drugs such as barbiturates, which can induce cytochrome P-450 3A4, may decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended.
Secukinumab: (Moderate) If secukinumab is initiated or discontinued in a patient taking tacrolimus, monitor tacrolimus concentrations; tacrolimus dose adjustments may be needed. The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during secukinumab administration. In theory, clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as tacrolimus. These interactions remain theoretical. Results from a drug-drug interaction study in subjects with moderate to severe psoriasis showed no clinically relevant interaction for drugs metabolized by CYP3A4.
Segesterone Acetate; Ethinyl Estradiol: (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 3A4. Drugs that inhibit this isoenzyme, such as ethinyl estradiol, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
Selpercatinib: (Major) A reduction in tacrolimus dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended if coadministered with selpercatinib as concurrent use may result in increased tacrolimus exposure and additive QT prolongation. Tacrolimus is a CYP3A4 substrate that may prolong the QT interval and cause torsade de pointes (TdP). Selpercatinib is a weak CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation.
Semaglutide: (Moderate) Consider increased clinical or laboratory monitoring for oral tacrolimus administered with oral semaglutide as the absorption of tacrolimus may be altered. Semaglutide delays gastric emptying and therefore has the potential to affect absorption of other orally administered medications. Be sure to administer oral semaglutide as directed, separately from other oral medications. This absorption interaction does not occur with subcutaneous semaglutide or IV tacrolimus. Patients should also be monitored for worsening of glycemic control when any form of systemic tacrolimus is initiated in patients receiving antidiabetic agents, including semaglutide. Tacrolimus has been reported to cause hyperglycemia. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity.
Sertraline: (Moderate) Concomitant use of sertraline and tacrolimus 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.
Sevelamer: (Moderate) Although drug interaction studies have not been conducted, it may be prudent to separate the timing of administration of tacrolimus from sevelamer. According to the manufacturer of sevelamer, clinicians should consider separating the timing of administration of sevelamer and drugs where a reduction in the bioavailability of would have a clinically significant effect on its safety or efficacy. The duration of separation should be based on the absorption characteristics of the coadministered drug. Because tacrolimus has a narrow therapeutic index, consider monitoring clinical response and serum concentrations during concurrent use of sevelamer.
Sevoflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with tacrolimus. Halogenated anesthetics and tacrolimus can prolong the QT interval.
Sildenafil: (Moderate) Consider initiating sildenafil at a low dose (25 mg) in kidney transplant recipients receiving tacrolimus. In a study of renal transplant patients, coadministration of tacrolimus with a single 50 mg dose of sildenafil resulted in an increase in the AUC, Cmax, and half-life of sildenafil. Decreases in blood pressure were also observed. No significant effect on the pharmacokinetic parameters of tacrolimus were observed.
Siltuximab: (Moderate) Monitor tacrolimus levels and adjust the dose of tacrolimus as appropriate if coadministration with siltuximab is necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as tacrolimus, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Tacrolimus is a CYP3A4 substrate and narrow therapeutic index drug.
Simvastatin: (Major) Guidelines recommend avoiding coadministration of simvastatin with tacrolimus due to the potential for increased risk of myopathy/rhabdomyolysis. Consider use of an alternative statin such as atorvastatin, fluvastatin, pravastatin, or rosuvastatin with dose limitations in patients receiving tacrolimus.
Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving tacrolimus 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. Tacrolimus also causes QT prolongation.
Sirolimus: (Moderate) The concomitant use of sirolimus with a calcineurin inhibitor, such as tacrolimus, may increase the risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy. In addition to a potential increased risk of thrombotic microangiopathy, sirolimus may decrease the blood concentration of tacrolimus.
Sitagliptin: (Moderate) Tacrolimus has been reported to cause hyperglycemia. Monitor for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Do not administer live vaccines to tacrolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving tacrolimus. At least 2 weeks before initiation of tacrolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Tacrolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Do not administer live vaccines to tacrolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving tacrolimus. At least 2 weeks before initiation of tacrolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Tacrolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Sodium Bicarbonate: (Moderate) Administration of oral tacrolimus at the same time as sodium bicarbonate may result in pH-dependent degradation of tacrolimus. Administer oral Tacrolimus 1 hour before or 2 hours after the Sodium Bicarbonate dose to help limit an interaction. Separation of the oral tacrolimus and sodium bicarbonate doses by at least 2 hours may not be necessary, but more data are needed. Tacrolimus concentrations can be maintained with appropriate monitoring and dosage adjustment. Intravenous and topical forms of tacrolimus do not interact.
Sodium Phenylbutyrate; Taurursodiol: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with taurursodiol is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; taurursodiol is a weak CYP3A inducer.
Sodium Stibogluconate: (Moderate) Concomitant use of sodium stibogluconate and tacrolimus 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.
Sodium Sulfate; Magnesium Sulfate; Potassium Chloride: (Moderate) Monitor serum potassium concentrations closely if potassium supplements and tacrolimus are used together. Concomitant use may increase the risk of hyperkalemia.
Sodium Zirconium Cyclosilicate: (Moderate) Administer tacrolimus 2 hours before or 2 hours after sodium zirconium cyclosilicate and monitor tacrolimus serum concentrations as appropriate. Simultaneous coadministration may decrease the absorption of tacrolimus due to the effects of sodium zirconium cyclosilicate on gastric pH. Coadministration of sodium zirconium cyclosilicate decreased the systemic exposure of tacrolimus by approximately 35%.
Sofosbuvir: (Moderate) Closely monitor tacrolimus serum concentrations if coadministration with a direct acting antiviral (DAA) agent, such as sofosbuvir, is necessary; dosage adjustments may be required. Changes in liver function due to clearance of the hepatitis C virus by DAA therapy may alter tacrolimus serum concentrations.
Sofosbuvir; Velpatasvir: (Moderate) Closely monitor tacrolimus serum concentrations if coadministration with a direct acting antiviral (DAA) agent, such as sofosbuvir, is necessary; dosage adjustments may be required. Changes in liver function due to clearance of the hepatitis C virus by DAA therapy may alter tacrolimus serum concentrations. (Moderate) Use caution when administering velpatasvir with tacrolimus. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); tacrolimus is an inhibitor of both P-gp and BCRP.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Closely monitor tacrolimus serum concentrations if coadministration with a direct acting antiviral (DAA) agent, such as sofosbuvir, is necessary; dosage adjustments may be required. Changes in liver function due to clearance of the hepatitis C virus by DAA therapy may alter tacrolimus serum concentrations. (Moderate) Closely monitor tacrolimus serum concentrations if coadministration with a direct acting antiviral (DAA) agent, such as voxilaprevir, is necessary; dosage adjustments may be required. Changes in liver function due to clearance of the hepatitis C virus by DAA therapy may alter tacrolimus serum concentrations. (Moderate) Use caution when administering velpatasvir with tacrolimus. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); tacrolimus is an inhibitor of both P-gp and BCRP.
Solifenacin: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with solifenacin. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Solifenacin has been associated with dose-dependent prolongation of the QT interval. TdP has been reported with postmarketing use, although causality was not determined.
Sorafenib: (Major) Avoid coadministration of sorafenib with tacrolimus 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. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Sorafenib is also associated with QTc prolongation.
Sotalol: (Major) Concomitant use of tacrolimus and sotalol 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.
Sotorasib: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with sotorasib is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; sotorasib is a moderate CYP3A4 inducer.
Spironolactone: (Major) Avoid concomitant use of tacrolimus and potassium-sparing diuretics, such as spironolactone, due to the risk of hyperkalemia. If concomitant use is necessary, closely monitor serum potassium concentrations. Additionally, monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with spironolactone is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; spironolactone is a weak CYP3A inhibitor.
Spironolactone; Hydrochlorothiazide, HCTZ: (Major) Avoid concomitant use of tacrolimus and potassium-sparing diuretics, such as spironolactone, due to the risk of hyperkalemia. If concomitant use is necessary, closely monitor serum potassium concentrations. Additionally, monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with spironolactone is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; spironolactone is a weak CYP3A inhibitor.
St. John's Wort, Hypericum perforatum: (Major) St. John's Wort, Hypericum perforatum may increase the metabolism of tacrolimus through induction of the hepatic CYP3A4 isoenzyme and decreased serum concentrations of tacrolimus would be expected if St. John's Wort was co-administered. St. John's Wort in all forms, including teas, should be avoided in patients treated with tacrolimus.
Stiripentol: (Moderate) Consider a dose adjustment of tacrolimus when coadministered with stiripentol. Coadministration may alter plasma concentrations of tacrolimus resulting in an increased risk of adverse reactions and/or decreased efficacy. Tacrolimus is a sensitive CYP3A4 substrate. In vitro data predicts inhibition or induction of CYP3A4 by stiripentol potentially resulting in clinically significant interactions.
Streptogramins: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with dalfopristin; quinupristin. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Dalfopristin; quinupristin is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
Streptomycin: (Moderate) Additive nephrotoxicity is possible if aminoglycosides are used with tacrolimus. Care should be taken in using tacrolimus with other nephrotoxic drugs. Assessment of renal function in patients who have received tacrolimus is recommended as the tacrolimus dosage may need to be reduced.
Sulfonylureas: (Moderate) Tacrolimus has been reported to cause hyperglycemia and has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Tacrolimus may have direct beta-cell toxicity. Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Sulindac: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Sumatriptan; Naproxen: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Sunitinib: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with sunitinib. Sunitinib can prolong the QT interval. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP).
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if concomitant use of tacrolimus is necessary. Concomitant use may increase talazoparib exposure. Talazoparib is a BCRP substrate and tacrolimus is a BCRP inhibitor.
Tamoxifen: (Moderate) Concomitant use of tamoxifen and tacrolimus 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.
Tazemetostat: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with tazemetostat is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; tazemetostat is a weak CYP3A4 inducer.
Teduglutide: (Moderate) Teduglutide may increase absorption of tacrolimus because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of tacrolimus is recommended.
Telavancin: (Major) Concurrent or sequential use of telavancin with other potentially nephrotoxic drugs such as tacrolimus may lead to additive nephrotoxicity. Closely monitor renal function and adjust telavancin doses based on calculated creatinine clearance. In addition, telavancin has been associated with QT prolongation. According to the manufacturer, telavancin should be used with caution when prescribing other agents known to prolong the QT interval such as tacrolimus.
Telmisartan; Amlodipine: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
Telotristat Ethyl: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with telotristat is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; telotristat is a weak CYP3A4 inducer.
Temozolomide: (Minor) Concurrent use of temozolomide with other agents that cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Tenofovir Alafenamide: (Moderate) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Use of these medications together may result in elevated tacrolimus serum concentrations. Additionally, monitoring for changes in renal function is advised if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as tacrolimus. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions.
Tenofovir Alafenamide: (Moderate) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Use of these medications together may result in elevated tacrolimus serum concentrations. Additionally, monitoring for changes in renal function is advised if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as tacrolimus. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions.
Tenofovir Disoproxil Fumarate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent, including tacrolimus.
Tetrabenazine: (Major) Tetrabenazine causes a small increase in the corrected QT interval. Caution is advisable during concurrent use of other agents associated with a possible risk for QT prolongation and TdP including tacrolimus.
Tezacaftor; Ivacaftor: (Major) Use caution when administering ivacaftor and tacrolimus concurrently; careful tacrolimus blood concentrations is warranted. Ivacaftor is an inhibitor of CYP3A, and tacrolimus is a CYP3A substrate. Co-administration can increase tacrolimus exposure leading to increased or prolonged therapeutic effects and adverse events. (Moderate) Administration of tezacaftor; ivacaftor may increase the systemic exposure of tacrolimus. Appropriate monitoring should be used; adjust tacrolimus dosage as necessary. Tacrolimus is a P-gp substrate; ivacaftor is a weak inhibitor of P-gp.
Theophylline, Aminophylline: (Moderate) Addition of aminophylline to tacrolimus therapy may result in increased concentrations of tacrolimus. Monitor serum tacrolimus and creatinine concentrations and renal function in patents who are stabilized on tacrolimus if aminophylline is added. (Moderate) Addition of theophylline to tacrolimus therapy may result in increased concentrations of tacrolimus. Closely monitor serum tacrolimus concentrations, serum creatinine concentrations, and renal function in patents who are stabilized on tacrolimus if theophylline is added, changed or discontinued.
Thiazolidinediones: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents.
Thioridazine: (Contraindicated) The use of thioridazine with tacrolimus is contraindicated due to the risk for QT prolongation and torsade de pointes (TdP). Thioridazine is also associated with a well-established risk of QT prolongation and TdP. Tacrolimus has been associated with QT prolongation.
Ticagrelor: (Minor) Coadministration of ticagrelor and tacrolimus may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate. Tacrolimus may be a P-gp inhibitor; however, data are conflicting. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
Tigecycline: (Moderate) Monitor tacrolimus serum trough concentrations during treatment with tigecycline to avoid tacrolimus toxicity. Concomitant use of tacrolimus and tigecycline may lead to an increase in serum trough concentrations of tacrolimus.
Tinidazole: (Moderate) Monitor for signs of calcineurin-inhibitor associated toxicities during coadministration of tinidazole and tacrolimus. Data suggest that another nitroimidazole has the potential to increase tacrolimus concentrations.
Tipranavir: (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration with tipranavir is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Consider a tacrolimus dose reduction to 0.5 mg to 1 mg once per week when coadministered with a protease inhibitor. In one study, the tacrolimus half-life increased to 10.6 days in one patient and 20.6 days in another following coadministration of tacrolimus and a protease inhibitor combination. Up to 80% reductions in tacrolimus dosages and 7-fold increase in dosage intervals were needed when tacrolimus was coadministered with protease inhibitors in studies. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; tipranavir is a strong CYP3A4 inhibitor.
Tirzepatide: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with tacrolimus is initiated in patients receiving antidiabetic agents, including tirzepatide. Tacrolimus has been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. The mechanism of hyperglycemia is thought to be through direct beta-cell toxicity.
Tobramycin: (Moderate) Additive nephrotoxicity is possible if aminoglycosides are used with tacrolimus. Care should be taken in using tacrolimus with other nephrotoxic drugs. Assessment of renal function in patients who have received tacrolimus is recommended as the tacrolimus dosage may need to be reduced.
Tocilizumab: (Moderate) Monitor tacrolimus levels and adjust the dose of tacrolimus as appropriate if coadministration with tocilizumab is necessary. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as tacrolimus, may have fluctuations in drug levels and therapeutic effect when tocilizumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Tacrolimus is a CYP3A4 substrate and narrow therapeutic index drug.
Tofacitinib: (Major) Concomitant use of tofacitinib with potent immunosuppressants, such as tacrolimus, is not recommended; coadministration may result in additive immunosuppression and increased risk of infection. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
Tolmetin: (Moderate) Monitor patients for signs of worsening renal function during coadministration of tacrolimus and nonsteroidal antiinflammatory drugs. Coadministration may increase the risk for drug-induced nephrotoxicity.
Tolterodine: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with tolterodine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Tolterodine has been asociated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Topotecan: (Major) Avoid coadministration of tacrolimus with oral topotecan due to increased topotecan exposure; tacrolimus may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and tacrolimus is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
Toremifene: (Major) Avoid coadministration of tacrolimus 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 has been shown to prolong the QTc interval in a dose- and concentration-related manner. Tacrolimus also causes QT prolongation.
Trandolapril: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including ACE inhibitors.
Trandolapril; Verapamil: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including ACE inhibitors. (Moderate) Verapamil, a CYP3A4 substrate, may inhibit tacrolimus metabolism by inhibiting CYP3A4 intestinal metabolism. If verapamil is added to tacrolimus therapy, blood trough concentrations of tacrolimus should be monitored and dose adjustments may be necessary.
Trazodone: (Major) Concomitant use of trazodone and tacrolimus 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.
Triamterene: (Major) Avoid concomitant use of tacrolimus and potassium-sparing diuretics, such as triamterene, due to the risk of hyperkalemia. If concomitant use is necessary, closely monitor serum potassium concentrations.
Triamterene; Hydrochlorothiazide, HCTZ: (Major) Avoid concomitant use of tacrolimus and potassium-sparing diuretics, such as triamterene, due to the risk of hyperkalemia. If concomitant use is necessary, closely monitor serum potassium concentrations.
Triclabendazole: (Moderate) Concomitant use of triclabendazole and tacrolimus may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Trifluoperazine: (Minor) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with trifluoperazine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Trifluoperazine is also associated with a possible risk for QT prolongation.
Trimipramine: (Minor) Tacrolimus has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and tricyclic antidepressants (TCAs) should be used together cautiously.
Triptorelin: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with triptorelin. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Androgen deprivation therapy (i.e., triptorelin) may also prolong the QT/QTc interval.
Trofinetide: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with trofinetide is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; trofinetide is a weak CYP3A inhibitor.
Tucatinib: (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentration if coadministration with tucatinib is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; tucatinib is a strong CYP3A4 inhibitor.
Typhoid Vaccine: (Contraindicated) Do not administer live vaccines to tacrolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving tacrolimus. At least 2 weeks before initiation of tacrolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Tacrolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with tacrolimus. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the BCRP drug transporter; tacrolimus is a BCRP inhibitor.
Upadacitinib: (Major) Avoid use of upadacitinib in combination with potent immunosuppressants such as tacrolimus. A risk of added immunosuppression exists when upadacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose upadacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
Valacyclovir: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, including valacyclovir. Assessment of renal function in patients who have received tacrolimus is recommended, as the tacrolimus dosage may need to be reduced.
Valganciclovir: (Moderate) Use valganciclovir and tacrolimus together only if the potential benefits outweigh the risks. Monitor renal function when valganciclovir is coadministered with tacrolimus because of the potential increase in serum creatinine. Acute renal failure may occur in patients concomitantly receiving potential nephrotoxic drugs.
Vancomycin: (Moderate) Concomitant use of parenteral vancomycin with other nephrotoxic drugs, such as tacrolimus, can lead to additive nephrotoxicity. Monitor renal function closely and adjust vancomycin or tacrolimus doses according to serum concentrations.
Vandetanib: (Major) Avoid coadministration of vandetanib with tacrolimus 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. Tacrolimus also causes QT prolongation.
Vardenafil: (Moderate) Concomitant use of vardenafil and tacrolimus 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.
Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Do not administer live vaccines to tacrolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving tacrolimus. At least 2 weeks before initiation of tacrolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Tacrolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Vemurafenib: (Major) Tacrolimus causes QT prolongation. Vemurafenib has also been associated with QT prolongation. Reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation (including ECG monitoring) is recommended when coadministrating tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval such as vemurafenib.
Venlafaxine: (Moderate) Concomitant use of venlafaxine and tacrolimus 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.
Verapamil: (Moderate) Verapamil, a CYP3A4 substrate, may inhibit tacrolimus metabolism by inhibiting CYP3A4 intestinal metabolism. If verapamil is added to tacrolimus therapy, blood trough concentrations of tacrolimus should be monitored and dose adjustments may be necessary.
Viloxazine: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with viloxazine is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; viloxazine is a weak CYP3A4 inhibitor.
Vonoprazan: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with vonoprazan is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; vonoprazan is a weak CYP3A inhibitor.
Vonoprazan; Amoxicillin: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with vonoprazan is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; vonoprazan is a weak CYP3A inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) A reduction in tacrolimus dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended if coadministered with clarithromycin as concurrent use may result in increased tacrolimus exposure and additive QT prolongation. Additional tacrolimus dosage reductions may be required. Despite an initial reduction in tacrolimus dose, a rapid, sharp increase in tacrolimus levels has been reported during coadministration with clarithromycin. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; clarithromycin is a strong CYP3A4 inhibitor. Both tacrolimus and clarithromycin are associated with an established risk of QT prolongation and torsade de pointes (TdP). Use this combination with caution. (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with vonoprazan is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; vonoprazan is a weak CYP3A inhibitor.
Voriconazole: (Major) A reduction in tacrolimus dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring of QT prolongation is recommended if coadministered with voriconazole as concurrent use may result in an increase tacrolimus exposure and additive QT prolongation. When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose by two-thirds (i.e., administer one-third of the pre-voriconazole dose) and make subsequent tacrolimus dose adjustments based on the tacrolimus whole blood concentrations. Use of these drugs together has resulted in a 2-fold and 3-fold increase in the maximum plasma concentrations and systemic exposure of tacrolimus, respectively. Tacrolimus concentrations should be frequently assessed. When voriconazole is discontinued, tacrolimus concentrations should be carefully monitored, and the dose increased as needed. In all cases, renal function in these patients should be carefully monitored. In addition, both drugs are associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range that may prolong the QT interval and cause torsade de pointes (TdP). Posaconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation and TdP.
Vorinostat: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with vorinostat. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Vorinostat therapy is associated with a risk of QT prolongation.
Voxelotor: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with voxelotor is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; voxelotor is a moderate CYP3A inhibitor.
Yellow Fever Vaccine, Live: (Contraindicated) Do not administer live vaccines to tacrolimus recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving tacrolimus. At least 2 weeks before initiation of tacrolimus therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Tacrolimus recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Zanubrutinib: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with zanubrutinib is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; zanubrutinib is a weak CYP3A4 inducer.
Ziprasidone: (Contraindicated) Concomitant use of ziprasidone and tacrolimus is contraindicated by the manufacturer of ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. Tacrolimus causes QT prolongation.
Zoledronic Acid: (Moderate) Since zoledronic acid is eliminated by the kidney, coadministration of zoledronic acid with other potentially nephrotoxic drugs, such as tacrolimus, may increase serum concentrations of either zoledronic acid and/or tacrolimus.
How Supplied
ASTAGRAF XL Oral Cap ER: 0.5mg, 1mg, 5mg
ENVARSUS Oral Tab ER: 0.75mg, 1mg, 4mg
HECORIA/Prograf/Tacrolimus Oral Cap: 0.5mg, 1mg, 5mg
Prograf Intravenous Inj Sol: 1mL, 5mg
Prograf Oral Gran F/Recon: 0.2mg, 1mg
Protopic/Tacrolimus Topical Ointment: 0.03%, 0.1%
Maximum Dosage
Maximum dosage for systemic formulations is dependent on indication, route of therapy, and tacrolimus serum concentrations; 2 applications/day topically.
ElderlyMaximum dosage for systemic formulations is dependent on indication, route of therapy, and tacrolimus serum concentrations; 2 applications/day topically.
AdolescentsMaximum dosage for systemic formulations is dependent on indication, route of therapy, and tacrolimus serum concentrations; 2 applications/day topically.
ChildrenMaximum dosage for systemic formulations is dependent on indication, route of therapy, and tacrolimus serum concentrations; 2 applications/day topically.
Mechanism Of Action
Mechanism of Action: Tacrolimus induces immunosuppression by inhibiting the first phase of T-cell activation. The first phase of T-cell activation causes transcriptional activation of immediate and early proteins (e.g., interleukin (IL)-2, IL-3, IL-4, granulocyte-macrophage colony stimulating factor (GM-CSF), and interferon gamma) that allow T-cells to progress from the G0- to G1-phase. Tacrolimus binds to an immunophilin termed FK binding protein (FKBP), specifically FKBP12. Immunophilins (cyclophilin and FK binding proteins) are immunosuppressant-binding proteins that are distributed in all cellular compartments and play an important role in protein activation. The tacrolimus-FK binding protein complex binds to and inhibits the phosphatase activity of calcineurin. The calcineurin enzyme catalyzes critical dephosphorylation reactions necessary for early lymphokine gene transcription. Calcineurin inhibition results in blockade of signal transduction by the cytosol component of the nuclear factor of activated T-cells (NF-AT), which results in a failure to activate NF-AT regulated genes. NF-AT activated genes include those required for B-cell activation (e.g., IL-4 and CD40 ligand) and those required for T-cell activation (e.g., IL-2, TNF-alpha, and interferon gamma). Reduced circulating levels of T-cell activators result in inhibition of T-cell proliferative responses to antigens and mitogens including mixed lymphocyte reactivity and cytotoxic T-cell generation. Compared to cyclosporine, tacrolimus is about 100-times more potent in inhibiting T-cell proliferative responses.In atopic dermatitis, topical tacrolimus acts to inhibit inflammation primarily by inhibiting T-cells. Tacrolimus may also bind to cell surface steroid receptors, inhibit the release of mast cell mediators, down-regulate IL-8 receptors, and decrease intracellular adhesion molecule-1 and E-selectin lesional blood vessel expression. These activities lead to decreased antigen recognition and down-regulation of the entire inflammatory cascade leading to a clinical response. Topical tacrolimus does not inhibit collagen synthesis and, therefore, does not cause skin atrophy as seen with corticosteroid therapy.
Pharmacokinetics
Tacrolimus is administered topically, parenterally, and orally. Due to high lipophilicity, tissue distribution of tacrolimus after oral or parenteral therapy is extensive. Tacrolimus crosses the placenta creating fetal cord plasma concentrations that are 35% of the maternal plasma concentration. The drug is also excreted in breast milk with concentrations similar to those in plasma. Protein binding is approximately 99%. Tacrolimus is mainly bound to albumin and alpha1-acid glycoprotein. Erythrocytes bind 75% to 80% of the drug resulting in whole blood concentrations that are 10- to 30-times higher than plasma concentrations. The distribution of tacrolimus between erythrocytes and plasma is dependent upon tacrolimus concentration, hematocrit, and temperature. Metabolism of tacrolimus is mainly by demethylation and hydroxylation via the hepatic cytochrome P450 system (CYP3A4 and CYP3A5). Genetic polymorphisms in CYP3A5 are known to influence tacrolimus dose requirements. In a study, patients with at least 1 CYP3A5(1) allele had lower tacrolimus area under the time versus blood concentration curves or lower trough concentrations as compared with data from CYP3A5 nonexpressors. Specifically, after administration of 0.1 mg/kg/dose twice a day, the median systemic exposure was 2.1- to 2.6-fold higher in nonexpressors. Patients with at least 1 CYP3A5(1) allele may need a higher tacrolimus loading dose.[34513] The formation of 8 possible metabolites has been proposed. The major metabolite identified in vitro is 13-demethyl tacrolimus, which in vitro has been reported to have the same activity as tacrolimus. After IV tacrolimus administration, the mean volume of distribution was 1.91 L/kg in healthy subjects, 1.41 L/kg in kidney transplant patients, and 0.85 L/kg in adult liver transplant patients and the mean clearance was 0.04 L/kg/hour in healthy subjects, 0.083 L/kg/hour in kidney transplant patients, 0.053 L/kg/hour in adult liver transplant patients, and 0.51 L/kg/hour in heart transplant patients. Less than 1% of the dose was excreted unchanged in the urine. After the administration of radiolabeled IV tacrolimus to 6 healthy volunteers, fecal elimination accounted for 92.4% of the radioactivity. After radiolabeled oral tacrolimus, fecal and urinary elimination accounted for 92.6% and 2.3% of the radioactivity, respectively. After IV tacrolimus administration, the mean elimination half-life was 34.2 hours in healthy subjects, 18.8 hours in kidney transplant patients, 11.7 hours in adult liver transplant patients, and 23.6 hours in heart transplant patients.[28611] The mean elimination half-life was 37.9 +/- 3.4 hours in 24 healthy subjects after the administration of tacrolimus extended-release capsules (Astagraf XL) 4 mg PO for 10 days.[55401] The mean elimination half-life was 31 +/- 8.1 hours in 25 healthy subjects after administration of tacrolimus extended-release tablets (Envarsus XR) 2 mg PO for 10 days.[60497]
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-gp
Tacrolimus is a substrate of CYP3A4. It may be an inhibitor of P-glycoprotein (P-gp); however, conflicting data exist regarding any interaction between tacrolimus and P-gp.[52498] In vitro data suggest that tacrolimus is neither a substrate nor an inhibitor of P-gp.[34512] Monitor tacrolimus whole blood trough concentrations and adjust the dose as needed if tacrolimus is used together with a strong CYP3A4 inhibitor or inducer as concomitant use may result in increased or decreased tacrolimus concentrations. Also monitor for increased adverse reactions, including QT prolongation, if tacrolimus is administered with a strong CYP3A4 inhibitor.[28611] [55401] Based on the extent of topical absorption, concomitant administration of tacrolimus ointment with systemically administered drugs is unlikely to result in an interaction; however, use tacrolimus ointment and known CYP3A4 inhibitors with caution in patients with widespread and/or erythrodermic disease.[30973]
Immediate-release capsules:
Oral tacrolimus absorption is poor and variable with the absolute bioavailability ranging from 17% to 23%. The pharmacokinetics of immediate-release tacrolimus have been studied in healthy subjects (n = 16; 5 mg PO), kidney transplant patients (n = 26; 0.2 mg/kg/day and 0.3 mg/kg/day), liver transplant patients (n = 17; 0.3 mg/kg/day), and heart transplant patients (n = 11, 0.075 mg/kg/day; n = 14, 0.15 mg/kg/day). In these patient populations, the mean Cmax ranged from 14.7 to 68.5 ng/mL; the mean Tmax ranged from 1.5 to 3 hours; and the AUC values (measuring times varied between populations) ranged from 82.7 to 3,300 ng x hour/mL.
Food effects: The presence of food can alter both the rate and the extent of tacrolimus absorption; administer immediate-release tacrolimus consistently with or without food. When immediate-release tacrolimus was administered with a high-fat meal in 15 healthy volunteers, the mean AUC and Cmax values were decreased by 37% and 77%, respectively; the Tmax increased 5-fold. Tacrolimus administered with a high carbohydrate meal decreased the mean AUC and Cmax by 28% and 65%, respectively. When immediate-release tacrolimus was administered 15 minutes after a high-fat meal to 11 liver transplant patients, the mean AUC and Cmax values were decreased by 27% and 50%, respectively.[28611]
Immediate-release granules for oral suspension:
In healthy adult volunteers, the systemic exposure to tacrolimus (AUC = 320 ng x hour/mL) for the granules was approximately 16% higher than that for tacrolimus capsules when administered as single doses. Maximum concentrations (Cmax = 35.6 ng/mL) were attained 1.3 hours after administration. Half-life was approximately 32 hours.[28611]
Extended-release capsules (Astagraf XL):
In 24 healthy subjects who received extended-release tacrolimus 4 mg/day for 10 days, the mean Cmax, mean trough concentration prior to the next dose (Ctrough), and AUC values were 11.6 ng/mL, 4.7 ng/mL, and 155 ng x hour/mL, respectively. The median Tmax was 2 hours (range, 1 to 3 hours). In 17 de novo kidney transplant patients who received tacrolimus extended-release capsules 5.4 mg/day for 14 days, the mean Cmax, Ctrough, and AUC values were 32.7 ng/mL, 11.2 ng/mL, and 412 ng x hour/mL, respectively. The median Tmax was 2 hours (range, 1 to 4 hours). In 60 kidney transplant patients at least 6 months post-transplant who received tacrolimus extended-release capsules (dose range, 0.18 to 0.2 mg/kg/day), the mean Cmax, Ctrough, and AUC values were 16.1 ng/mL, 6.7 ng/mL, and 222 ng x hour/mL, respectively, on day 14; the Tmax was 2 hours (range, 1 to 6 hours).
On day 1 post-kidney transplant, the dose-adjusted 24-hour AUC was 16% lower with once-daily tacrolimus extended-release capsules (Astagraf XL) compared with twice-daily tacrolimus immediate-release capsules (Prograf). The dose-adjusted 24-hour AUC (AUC24) was similar between the 2 formulations by day 3 post-transplant and was 21% higher with Astagraf XL on day 14 post-transplant (with comparable trough concentrations).
Food effects: The presence of food can alter both the rate and the extent of tacrolimus absorption; administer extended-release tacrolimus capsules on an empty stomach at least 1 hour prior to or 2 hours after a meal. When extended-release capsules were administered immediately after a high-fat meal in 24 healthy subjects, the mean AUC and Cmax values were both decreased by about 25%; the Tmax increased from 2 hours to 4 hours.
Chronopharmacokinetic effect: A diurnal effect on absorption has been observed with tacrolimus; take extended-release capsules at the same time daily in the morning. In 23 healthy subjects, the AUC value was decreased by 35% when extended-release capsules were taken in the evening relative to a morning dose.[55401]
Extended-release tablets (Envarsus XR):
On day 1 post-kidney transplant, the AUC24 for 21 de novo adult kidney transplant patients given extended-release tacrolimus 0.14 mg/kg/day, was up to 10% lower than that of twice-daily, immediate-release tacrolimus at a dose of 0.1 mg/kg/day; trough concentrations were similar. Typically, steady-state was achieved within 7 days of stable extended-release tacrolimus dosing. At steady-state, trough concentrations were comparable between the 2 formulations, but AUC24 was approximately 15% higher with extended-release tacrolimus compared to immediate-release. In 47 adults more than 6 months post-kidney transplant given 67% to 80% of the daily dose of tacrolimus immediate-release capsules, AUC24 (216 +/- 63 ng x hour/mL) and tacrolimus trough concentrations (7 +/- 2.3 ng/mL) achieved with extended-release tablets were similar to AUC and trough concentrations prior to the switch. The mean Cmax was 30% lower after the switch and the median Tmax was prolonged with the extended-release formulation (6 hours vs. 2 hours).[60497]
Chronopharmacokinetic effect: In 26 healthy subjects, administration of extended-release tablets in the evening produced an AUC that was 15% lower and tacrolimus trough concentrations that were 20% lower compared to morning dosing.[60497]
The absolute bioavailability of tacrolimus applied topically is unknown. After topical administration of single or multiple doses of the 0.1% ointment to adults, peak tacrolimus blood concentrations ranged from undetectable to 20 ng/mL. Most patients had peak blood concentrations less than 5 ng/mL. In pediatric patients, application of the 0.1% ointment resulted in peak blood concentrations below 1.6 ng/mL. There is no evidence that tacrolimus accumulates systemically after topical administration. The lowest tacrolimus blood concentration that may elicit systemic effects is unknown.
Pregnancy And Lactation
Tacrolimus can cause fetal harm when administered during pregnancy. Human data suggest that infants exposed to tacrolimus in utero are at risk of prematurity, birth defects/congenital anomalies, low birth weight, and fetal distress. Advise pregnant women of the potential risk to the fetus. The Transplantation Pregnancy Registry International (TPRI) is a voluntary pregnancy exposure registry that monitors outcomes of pregnancy in female transplant recipients and those fathered by male transplant recipients exposed to immunosuppressants; patients can register by contacting 1-877-955-6877 or www.transplantregistry.org. Tacrolimus may increase hyperglycemia in pregnant women with diabetes, including those with gestational diabetes. In addition, exacerbation of hypertension may increase the risk of pre-eclampsia. Monitor blood glucose concentrations and blood pressure regularly and treat as appropriate. Renal dysfunction, transient neonatal hyperkalemia, and low birth weight have been reported at the time of delivery in newborns of mothers taking tacrolimus. The experience with topical tacrolimus in pregnant women is too limited to permit assessment of the safety of its use during pregnancy. Tacrolimus should be used during pregnancy only when clearly needed.[28611] [30973][55401][60497]
Use tacrolimus with caution during breast-feeding. Controlled lactation studies have not been conducted in humans; however, tacrolimus has been reported to be present in human milk after systemic use. The effects of tacrolimus on the breastfed infant or milk production have not been assessed.[28611] [60497] Limited data indicate that the amount of tacrolimus excreted into breast-milk after systemic administration is low.[49424] [49425] In addition, no adverse reactions have been reported in nursing infants.[49426] The systemic absorption of tacrolimus after topical administration is minimal; 90% (1,253/1,391) of subjects in a pharmacokinetic trial with periodic blood sampling had blood concentrations of less than 2 ng/mL.[30973] Therefore, it is unlikely that a clinically significant exposure would occur via breast milk. Do not allow direct contact of the infant's skin to treated areas and do not apply to the nipple area if nursing. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.