Rapamune Drug Interactions

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 isozyme in the 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, 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.
Verapamil: Verapamil is an inhibitor of CYP3A4. Sirolimus levels should be monitored and appropriate dose reductions of both medications should be considered.
Erythromycin: Erythromycin is an inhibitor of CYP3A4. Sirolimus levels should be monitored and appropriate dose reductions of both medications should be considered.
Ketoconazole: Ketoconazole is a strong inhibitor of CYP3A4 and P-gp. Co-administration of Rapamune and ketoconazole is not recommended.
Rifampicin: Rifampicin is a strong inducer of CYP3A4 and P-gp. Co-administration of Rapamune and rifampicin is not recommended.
Non-Interactions: No clinically significant pharmacokinetic drug-drug interactions were observed in studies of the following drugs: acyclovir, atorvastatin, digoxin, glibenclamide (glyburide), nifedipine, norgestrel 0.3 mg/ethinyl estradiol 0.03 mg, methylprednisolone, sulfamethoxazole/trimethoprim and tacrolimus.
Cyclosporine: Cyclosporine is a substrate and inhibitor of CYP3A4 and P-gp.
Patients administered Rapamune with cyclosporine should be monitored for the development of rhabdomyolysis (see Precautions).
Cyclosporine microemulsion [(cyclosporine, USP) MODIFIED]: It is recommended that Rapamune be taken 4 hours after cyclosporine microemulsion [(cyclosporine, USP) MODIFIED] administration.
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 wholeblood 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 Rapamune with a calcineurin inhibitor (see Precautions).
Vaccinations: 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 Rapamune 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 intestine. This juice must not be taken with Rapamune tablets (see Mode of Administration under Dosage & Administration).
Interference with laboratory and other diagnostic tests: Not applicable.