Interactions : אינטראקציות

4.5 Interaction with other medicinal products and other forms of interaction

Sirolimus is extensively metabolised by the CYP3A4 isozyme in the intestinal wall and liver.
Sirolimus is also a substrate for the multidrug efflux pump, P-glycoprotein (P-gp) located in the small intestine. Therefore, absorption and the subsequent elimination of sirolimus may be influenced by substances that affect these proteins. Inhibitors of CYP3A4 (such as ketoconazole, voriconazole, itraconazole, telithromycin, or clarithromycin) decrease the metabolism of sirolimus and increase sirolimus levels. Inducers of CYP3A4 (such as rifampin or rifabutin) increase the metabolism of sirolimus and decrease sirolimus levels. Co- administration of sirolimus with strong inhibitors of CYP3A4 or inducers of CYP3A4 is not recommended (see section 4.4).

Rifampicin (CYP3A4 inducer)

Administration of multiple doses of rifampicin decreased sirolimus whole blood concentrations following a single 10 mg dose of Rapamune oral solution. Rifampicin increased the clearance of sirolimus by approximately 5.5-fold and decreased AUC and Cmax by approximately 82% and 71%, respectively. Co-administration of sirolimus and rifampicin is not recommended (see section 4.4).

Ketoconazole (CYP3A4 inhibitor)

Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure from Rapamune oral solution as reflected by increases in 
sirolimus Cmax, tmax, and AUC of 4.4-fold, 1.4-fold, and 10.9-fold, respectively. Co- administration of sirolimus and ketoconazole is not recommended (see section 4.4).

Voriconazole (CYP3A4 inhibitor)

Co-administration of sirolimus (2 mg single dose) with multiple-dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 100 mg every 12 hours for 8 days) in healthy subjects has been reported to increase sirolimus Cmax and AUC by an average of 7- fold and 11-fold, respectively. Co-administration of sirolimus and voriconazole is not recommended (see section 4.4).

Diltiazem (CYP3A4 inhibitor)

The simultaneous oral administration of 10 mg of Rapamune oral solution and 120 mg of diltiazem significantly affected the bioavailability of sirolimus. Sirolimus Cmax, tmax, and AUC were increased 1.4-fold, 1.3-fold, and 1.6-fold, respectively. Sirolimus did not affect the pharmacokinetics of either diltiazem or its metabolites desacetyldiltiazem and desmethyldiltiazem. If diltiazem is administered, sirolimus blood levels should be monitored and a dose adjustment may be necessary.

Verapamil (CYP3A4 inhibitor)

Multiple-dose administration of verapamil and sirolimus oral solution significantly affected the rate and extent of absorption of both medicinal products. Whole blood sirolimus Cmax, tmax, and AUC were increased 2.3-fold, 1.1-fold, and 2.2-fold, respectively. Plasma S-(-) verapamil Cmax and AUC were both increased 1.5-fold, and tmax was decreased 24%. Sirolimus levels should be monitored, and appropriate dose reductions of both medicinal products should be considered.

Erythromycin (CYP3A4 inhibitor)

Multiple-dose administration of erythromycin and sirolimus oral solution significantly increased the rate and extent of absorption of both medicinal products. Whole blood sirolimus Cmax, tmax, and AUC were increased 4.4-fold, 1.4-fold, and 4.2-fold, respectively. The Cmax, tmax, and AUC of plasma erythromycin base were increased 1.6-fold, 1.3-fold, and 1.7-fold, respectively. Sirolimus levels should be monitored and appropriate dose reductions of both medicinal products should be considered.

Ciclosporin (CYP3A4 substrate)

The rate and extent of sirolimus absorption was significantly increased by ciclosporin A (CsA). Sirolimus administered concomitantly (5 mg), and at 2 hours (5 mg) and 4 hours (10 mg) after CsA (300 mg), resulted in increased sirolimus AUC by approximately 183%, 141% and 80%, respectively. The effect of CsA was also reflected by increases in sirolimus Cmax and tmax. When given 2 hours before CsA administration, sirolimus Cmax and AUC were not affected. Single-dose sirolimus did not affect the pharmacokinetics of ciclosporin (microemulsion) in healthy volunteers when administered simultaneously or 4 hours apart. It is recommended that Rapamune be administered 4 hours after ciclosporin (microemulsion).

Oral contraceptives

No clinically significant pharmacokinetic interaction was observed between Rapamune oral solution and 0.3 mg norgestrel/0.03 mg ethinyl estradiol. Although the results of a single-dose interaction study with an oral contraceptive suggest the lack of a pharmacokinetic interaction, the results cannot exclude the possibility of changes in the pharmacokinetics that might affect the efficacy of the oral contraceptive during long-term treatment with Rapamune.

Other possible interactions

Inhibitors of CYP3A4 may decrease the metabolism of sirolimus and increase sirolimus blood levels. Such inhibitors include certain antifungals (e.g. clotrimazole, fluconazole, itraconazole, voriconazole), certain antibiotics (e.g. troleandomycin, telithromycin, clarithromycin), certain protease inhibitors (e.g. ritonavir, indinavir, boceprevir, and telaprevir), nicardipine, bromocriptine, cimetidine, and danazol.

Inducers of CYP3A4 may increase the metabolism of sirolimus and decrease sirolimus blood levels (e.g., St. John's Wort (Hypericum perforatum), anticonvulsants: carbamazepine, phenobarbital, phenytoin).

Although sirolimus inhibits human liver microsomal cytochrome P450 CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 in vitro, the active substance is not expected to inhibit the activity of these isozymes in vivo since the sirolimus concentrations necessary to produce inhibition are much higher than those observed in patients receiving therapeutic doses of Rapamune.
Inhibitors of P gp may decrease the efflux of sirolimus from intestinal cells and increase sirolimus levels.



Grapefruit juice affects CYP3A4-mediated metabolism, and should therefore be avoided.

Pharmacokinetic interactions may be observed with gastrointestinal prokinetic agents, such as cisapride and metoclopramide.

No clinically significant pharmacokinetic interaction was observed between sirolimus and any of the following substances: acyclovir, atorvastatin, digoxin, glibenclamide, methylprednisolone, nifedipine, prednisolone, and trimethoprim/sulfamethoxazole.

Paediatric population

Interaction studies have only been performed in adults.