Rapamune Drug Interactions

Sirolimus is known to be a substrate for both cytochrome CYP3A4 and P-glycoprotein (P-gp). The pharmacokinetic interaction between sirolimus and concomitantly administered drugs is discussed as follows. Drug interaction studies have not been conducted with drugs other than those described as follows.
Inhibitors and inducers of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp): Co-administration of Rapamune with strong inhibitors of CYP3A4 (such as ketoconazole, voriconazole, itraconazole, telithromycin, or clarithromycin) or inducers of CYP3A4 (such as rifampin or rifabutin) is not recommended. Sirolimus is extensively metabolized by the CYP3A4 isoenzyme intestinal wall and liver and undergoes counter-transport from enterocytes of the small intestine by the P-glycoprotein (P-gp) drug-efflux pump. Therefore, absorption and the subsequent elimination of systemically absorbed sirolimus may be influenced by drugs that affect these proteins. Inhibitors of CYP3A4 and P-gp may increase sirolimus levels. Inducers of CYP3A4 and P-gp may decrease sirolimus levels. In patients in whom strong inhibitors or inducers of CYP3A4 and P-gp are indicated, alternative therapeutic agents with less potential for inhibition or induction of CYP3A4 and P-gp should be considered.
Substances that inhibit CYP3A4 include but are not limited to: Calcium channel blockers: diltiazem, nicardipine, verapamil.
Antifungal agents: clotrimazole, fluconazole, itraconazole, ketoconazole, voriconazole.
Antibiotics: clarithromycin, erythromycin, telithromycin, troleandomycin.
Gastrointestinal prokinetic agents: cisapride, metoclopramide.
Other drugs: bromocriptine, cimetidine, cyclosporine, danazol, letermovir, protease inhibitors (e.g., for HIV and hepatitis C that include drugs such as ritonavir, indinavir, boceprevir, and telaprevir).
Grapefruit juice.
Substances that induce CYP3A4 include but are not limited to: Anticonvulsants: carbamazepine, phenobarbital, phenytoin.
Antibiotics: rifabutin, rifampicin, rifapentine.
Herbal preparations: St. John's Wort (Hypericum perforatum, hypericin).
The pharmacokinetic interaction between sirolimus and concomitantly administered drugs is discussed as follows. Drug interaction studies have been conducted with the following: Diltiazem: Diltiazem is a substrate and inhibitor of CYP3A4 and P-gp. Sirolimus levels should be monitored and a dose reduction may be necessary if diltiazem is co-administered.
The simultaneous oral administration of 10 mg of sirolimus oral solution and 120 mg of diltiazem to 18 healthy volunteers significantly increased the bioavailability of sirolimus. Sirolimus C_max, t_max, and AUC were increased 1.4-, 1.3-, and 1.6-fold, respectively. Sirolimus did not affect the pharmacokinetics of either diltiazem or its metabolites desacetyldiltiazem and desmethyldiltiazem.
Verapamil: Verapamil is an inhibitor of CYP3A4 and P-gp. Sirolimus levels should be monitored and appropriate dose reduction of both medications should be considered.
Multiple-dose administration of verapamil and Rapamune oral solution significantly affected the rate and extent of absorption of both drugs. In a study of 25 healthy volunteers, whole blood sirolimus C_max, t_max, and AUC were increased 2.3-fold, 1.1-fold, and 2.2-fold, respectively. Plasma S-(-) verapamil C_max and AUC were both increased 1.5-fold, and t_max was decreased 24%.
Erythromycin: Erythromycin is an inhibitor of CYP3A4 and P-gp. Sirolimus levels should be monitored and appropriate dose reductions of both medications should be considered.
Multiple-dose administration of erythromycin ethylsuccinate and Rapamune oral solution significantly increased the rate and extent of absorption of both drugs. In a study of 24 healthy volunteers, whole blood sirolimus C_max, t_max, and AUC were increased 4.4-fold, 1.4-fold, and 4.2-fold, respectively. The C_max, t_max, and AUC of plasma erythromycin base were increased 1.6-fold, 1.3-fold, and 1.7-fold, respectively.
Ketoconazole: Ketoconazole is a strong inhibitor of CYP3A4 and P-gp. Co-administration of Rapamune and ketoconazole is not recommended.
In a study of 24 healthy volunteers, it was found that multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure after administration of Rapamune Oral Solution, as reflected by increases in sirolimus C_max, t_max, and AUC of 4.4-fold, 1.4-fold, and 10.9-fold, respectively. However, the terminal t_½ of sirolimus was not changed. Single-dose Rapamune did not affect steady-state 12-hour plasma ketoconazole concentrations.
Rifampicin: Rifampin is a strong inducer of CYP3A4 and P-gp. Co-administration of Rapamune and rifampin is not recommended.
Pretreatment of 14 healthy volunteers with multiple doses of rifampicin (600 mg daily for 14 days) followed by a single 20 mg-dose of Rapamune oral solution, greatly increased sirolimus oral-dose clearance by 5.5-fold (range = 2.8 to 10), which represents mean decreases in AUC and C_max of about 82% and 71%, respectively.
Non-interactions: Clinically significant pharmacokinetic drug-drug interactions were not observed in studies of drugs listed as follows. A synopsis of the type of study performed for each drug is provided. Sirolimus and these drugs may be co-administered without dose adjustments.
Acyclovir: Acyclovir, 200 mg, was administered once daily for 3 days followed by a single 10-mg dose of sirolimus oral solution on day 3 in 20 adult healthy volunteers.
Atorvastatin: Atorvastatin, 20 mg, was given daily for 10 days to 23 healthy volunteers, followed by a combined regimen of sirolimus oral solution, 2 mg, and atorvastatin, 20 mg, for 5 days.
Digoxin: Digoxin, 0.25 mg, was administered daily for 8 days and a single 10-mg dose of sirolimus oral solution was given on day 8 to 24 healthy volunteers.
Glyburide: A single 5-mg dose of glyburide and a single 10-mg dose of sirolimus oral solution were administered to 24 healthy volunteers. Sirolimus did not affect the hypoglycemic action of glyburide.
Nifedipine: A single 60-mg dose of nifedipine and a single 10-mg dose of sirolimus oral solution were administered to 24 healthy volunteers.
Norgestrel/ethinyl estradiol (Lo/Ovral): Sirolimus oral solution, 2 mg, was given daily for 7 days to 21 healthy female volunteers on norgestrel/ethinyl estradiol.
Prednisone: Pharmacokinetic information was obtained from 42 stable renal transplant patients receiving daily doses of prednisone (5-20 mg/day) and either single or multiple doses of sirolimus oral solution (0.5-5 mg/m² q 12h).
Sulfamethoxazole/trimethoprim (Bactrim): A single oral dose of sulfamethoxazole (400 mg)/trimethoprim, (80 mg) was given to 15 renal transplant patients receiving daily oral doses of sirolimus (8 to 25 mg/m²).
Cyclosporine: Cyclosporine is a substrate and inhibitor of CYP3A4 and P-gp.
Patients administered sirolimus with cyclosporine together with HMG-CoA reductase inhibitor and/or fibrate should be monitored for the development of rhabdomyolysis (see Precautions).
Cyclosporine microemulsion (cyclosporine, USP): It is recommended that Rapamune be taken 4 hours after cyclosporine microemulsion (cyclosporine, USP) administration.
In a single-dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg Rapamune oral solution either simultaneously or 4 hours after a 300 mg dose of cyclosporine microemulsion (cyclosporine, USP). For simultaneous administration, the mean C_max and AUC of sirolimus were increased by 116% and 230%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after cyclosporine microemulsion (cyclosporine, USP) administration, sirolimus C_max and AUC were increased by 37% and 80%, respectively, compared to administration of Rapamune alone.
In an otherwise identical study, Rapamune was administered as a 10 mg dose by tablet. For simultaneous administration, mean C_max and AUC were increased by 6.1-fold and 2.5-fold, respectively, relative to administration of Rapamune alone. However, when given 4 hours after cyclosporine microemulsion (cyclosporine, USP) administration, sirolimus C_max and AUC were both increased by only 33% compared with administration of Rapamune alone.
After multiple-dose administration of Rapamune by oral solution given 4 hours after cyclosporine microemulsion (cyclosporine, USP) in renal post-transplant patients over 6 months, cyclosporine oral-dose clearance was reduced, and lower doses of cyclosporine microemulsion (cyclosporine, USP) were needed to maintain target cyclosporine concentrations.
Rapamune Oral Solution: In a single dose drug-drug interaction study, 24 healthy volunteers were administered 5 mg Rapamune either simultaneously or 2 hours before and after a 300 mg dose of cyclosporine microemulsion (cyclosporine, USP). For simultaneous administration, the mean C_max and AUC of sirolimus were increased by 117% and 183%, respectively, relative to administration of Rapamune alone. When given 2 hours after cyclosporine microemulsion (cyclosporine, USP) administration, sirolimus C_max and AUC were increased by 126% and 141%, respectively, compared to administration of Rapamune alone. When given 2 hours before cyclosporine microemulsion (cyclosporine, USP) administration, sirolimus C_max and AUC were not affected.
Sandimmune Soft Gelatin Capsules (cyclosporine capsules) are not bioequivalent to Neoral Soft Gelatin Capsules (cyclosporine capsules) and should not be used interchangeably.
Cyclosporine oral solution: In a multiple-dose study in 150 psoriasis patients, sirolimus 0.5, 1.5 and 3 mg/m²/day was administered simultaneously with Sandimmune Oral Solution (cyclosporine oral solution) 1.25 mg/kg/day. The increase in average sirolimus trough concentrations ranged between 67% to 86% relative to when sirolimus was administered without cyclosporine. The intersubject variability (%CV) for sirolimus trough concentrations ranged from 39.7% to 68.7%. There was no significant effect of multiple-dose sirolimus on cyclosporine trough concentrations following Sandimmune Oral Solution (cyclosporine oral solution) administration. However, the (%CV) was higher (range 85.9% - 165%) than those from previous studies.
Sandimmune Oral Solution (cyclosporine oral solution) is not bioequivalent to Neoral Oral Solution (cyclosporine oral solution), and should not be used interchangeably. Although there is no published data comparing Sandimmune Oral Solution (cyclosporine oral solution) to SandCya Oral Solution (cyclosporine oral solution), they should not be used interchangeably.
Cannabidiol: There have been reports of increased blood levels of sirolimus during concomitant use with cannabidiol. Caution should be used when cannabidiol and Rapamune are co-administered, closely monitor sirolimus blood levels and for adverse events suggestive of sirolimus toxicity (see Sirolimus whole blood trough level monitoring under Dosage & Administration and Precautions).
HMG-CoA reductase inhibitors, fibrates: Patients administered Rapamune with HMG-CoA reductase inhibitors and/or fibrates should be monitored for the development of rhabdomyolysis (see Precautions).
Calcineurin inhibitors: Calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) has been reported in patients receiving sirolimus with a calcineurin inhibitor (see Precautions).
Vaccination: Immunosuppressants may affect response to vaccination. During treatment with immunosuppressants, including Rapamune, vaccination may be less effective. The use of live vaccines should be avoided during treatment with Rapamune.
Food: The bioavailability of sirolimus is affected by concomitant food intake after administration by either Rapamune oral solution or tablet. Rapamune should be taken consistently with or without food to minimize blood level variability.
Grapefruit juice reduces CYP3A4-mediated drug metabolism and potentially enhances P-gp-mediated drug counter-transport from enterocytes of the small intestines. This juice must not be taken with Rapamune tablets or oral solution or be used for oral solution dilution (see Mode of Administration under Dosage & Administration).
Interference with laboratory and other diagnostic tests: There are no studies on the interactions of Rapamune in commonly employed clinical laboratory tests.