Sirolimus (Page 6 of 12)


Sirolimus is known to be a substrate for both cytochrome P-450 3A4 (CYP3A4) and p-glycoprotein (P-gp). Inducers of CYP3A4 and P-gp may decrease sirolimus concentrations whereas inhibitors of CYP3A4 and P-gp may increase sirolimus concentrations.

7.1 Use with Cyclosporine

Cyclosporine, a substrate and inhibitor of CYP3A4 and P-gp, was demonstrated to increase sirolimus concentrations when co-administered with sirolimus. In order to diminish the effect of this interaction with cyclosporine, it is recommended that sirolimus be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED). If cyclosporine is withdrawn from combination therapy with sirolimus, higher doses of sirolimus are needed to maintain the recommended sirolimus trough concentration ranges [ see Dosage and Administration (2.2), Clinical Pharmacology (12.3) ].

7.2 Strong Inducers and Strong Inhibitors of CYP3A4 and P-gp

Avoid concomitant use of sirolimus with strong inducers (e.g., rifampin, rifabutin) and strong inhibitors (e.g., ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin) of CYP3A4 and P-gp. Alternative agents with lesser interaction potential with sirolimus should be considered [ see Warnings and Precautions (5.20), Clinical Pharmacology (12.3) ].

7.3 Grapefruit Juice

Because grapefruit juice inhibits the CYP3A4-mediated metabolism of sirolimus, it must not be taken with or be used for dilution of sirolimus [ see Dosage and Administration (2.9), Drug Interactions (7.3), Clinical Pharmacology (12.3) ].

7.4 Weak and Moderate Inducers or Inhibitors of CYP3A4 and P-gp

Exercise caution when using sirolimus with drugs or agents that are modulators of CYP3A4 and P-gp. The dosage of sirolimus and/or the co-administered drug may need to be adjusted [ see Clinical Pharmacology (12.3) ].

  • Drugs that could increase sirolimus blood concentrations:

Bromocriptine, cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole, protease inhibitors (e.g., HIV and hepatitis C that include drugs such as ritonavir, indinavir, boceprevir, and telaprevir), metoclopramide, nicardipine, troleandomycin, verapamil

  • Drugs and other agents that could decrease sirolimus concentrations:

Carbamazepine, phenobarbital, phenytoin, rifapentine, St. John’s Wort ( Hypericum perforatum)

  • Drugs with concentrations that could increase when given with sirolimus: Verapamil


8.1 Pregnancy

Risk Summary

Based on animal studies and the mechanism of action, sirolimus can cause fetal harm when administered to a pregnant woman [ see Data, Clinical Pharmacology (12.1) ]. There are limited data on the use of sirolimus during pregnancy; however, these data are insufficient to inform a drug-associated risk of adverse developmental outcomes. In animal studies, sirolimus was embryo/fetotoxic in rats at sub-therapeutic doses [ see Data ]. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.


Animal Data

Sirolimus crossed the placenta and was toxic to the conceptus.

In rat embryo-fetal development studies, pregnant rats were administered sirolimus orally during the period of organogenesis (Gestational Day 6 to15). Sirolimus produced embryo-fetal lethality at 0.5 mg/kg (2.5-fold the clinical dose of 2 mg, on a body surface area basis) and reduced fetal weight at 1 mg/kg (5-fold the clinical dose of 2 mg). The no observed adverse effect level (NOAEL) for fetal toxicity in rats was 0.1 mg/kg (0.5-fold the clinical dose of 2 mg). Maternal toxicity (weight loss) was observed at 2 mg/kg (10-fold the clinical dose of 2 mg). The NOAEL for maternal toxicity was 1 mg/kg. In combination with cyclosporine, rats had increased embryo-fetal mortality compared with sirolimus alone.

In rabbit embryo-fetal development studies, pregnant rabbits were administered sirolimus orally during the period of organogenesis (Gestational Day 6 to18). There were no effects on embryo-fetal development at doses up to 0.05 mg/kg (0.5-fold the clinical dose of 2 mg, on a body surface area basis); however, at doses of 0.05 mg/kg and above, the ability to sustain a successful pregnancy was impaired (i.e. embryo-fetal abortion or early resorption). Maternal toxicity (decreased body weight) was observed at 0.05 mg/kg. The NOAEL for maternal toxicity was 0.025 mg/kg (0.25-fold the clinical dose of 2 mg).

In a pre- and post-natal development study in rats, pregnant females were dosed during gestation and lactation (Gestational Day 6 through Lactation Day 20). An increased incidence of dead pups, resulting in reduced live litter size, occurred at 0.5 mg/kg (2.5-fold the clinical dose of 2 mg/kg on a body surface area basis). At 0.1 mg/kg (0.5-fold the clinical dose of 2 mg), there were no adverse effects on offspring. Sirolimus did not cause maternal toxicity or affect developmental parameters in the surviving offspring (morphological development, motor activity, learning, or fertility assessment) at 0.5 mg/kg, the highest dose tested.

8.2 Lactation

Risk Summary

It is not known whether sirolimus is present in human milk. There are no data on its effects on the breastfed infant or milk production. The pharmacokinetic and safety profiles of sirolimus in infants are not known.

Sirolimus is present in the milk of lactating rats. There is potential for serious adverse effects from sirolimus in breastfed infants based on mechanism of action [ see Clinical Pharmacology (12.1)]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for sirolimus and any potential adverse effects on the breastfed child from sirolimus.

8.3 Females and Males of Reproductive Potential


Females should not be pregnant or become pregnant while receiving sirolimus. Advise females of reproductive potential that animal studies have been shown sirolimus to be harmful to the developing fetus. Females of reproductive potential are recommended to use highly effective contraceptive method. Effective contraception must be initiated before sirolimus therapy, during sirolimus therapy, and for 12 weeks after sirolimus therapy has been stopped [ see Warnings and Precautions (5.15), Use in Specific Populations (8.1) ].


Based on clinical findings and findings in animals, male and female fertility may be compromised by the treatment with sirolimus [ see Adverse Reactions (6.7), Nonclinical Toxicology (13.1) ]. Ovarian cysts and menstrual disorders (including amenorrhea and menorrhagia) have been reported in females with the use of sirolimus. Azoospermia has been reported in males with the use of sirolimus and has been reversible upon discontinuation of sirolimus in most cases.

8.4 Pediatric Use

Renal Transplant

The safety and efficacy of sirolimus in pediatric patients <13 years have not been established.

The safety and efficacy of sirolimus oral solution has been established for prophylaxis of organ rejection in renal transplantation in children ≥13 years judged to be at low- to moderate-immunologic risk. Use of sirolimus oral solution in this subpopulation of children ≥13 years is supported by evidence from adequate and well-controlled trials of sirolimus oral solution in adults with additional pharmacokinetic data in pediatric renal transplantation patients [ see Clinical Pharmacology (12.3) ].

Safety and efficacy information from a controlled clinical trial in pediatric and adolescent (<18 years of age) renal transplant patients judged to be at high-immunologic risk, defined as a history of one or more acute rejection episodes and/or the presence of chronic allograft nephropathy, do not support the chronic use of sirolimus oral solution in combination with calcineurin inhibitors and corticosteroids, due to the higher incidence of lipid abnormalities and deterioration of renal function associated with these immunosuppressive regimens compared to calcineurin inhibitors, without increased benefit with respect to acute rejection, graft survival, or patient survival [ see Clinical Studies (14.6) ].

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