Sirolimus (sirolimus)

Commercially available sirolimus tablets and oral solution are not bioequivalent. However, the manufacturer states that because 2 mg doses of sirolimus given as conventional tablets and as the oral solution have been shown to be therapeutically equivalent, such formulations may be interchangeable on a mg-per-mg basis at doses that do not exceed 2 mg. It is not known whether the commercially available sirolimus tablets and the oral solution are therapeutically equivalent at doses exceeding 2 mg.

Sirolimus is administered orally as tablets or oral solution. To minimize variability in systemic exposure to sirolimus, the drug should be given once daily, consistently with or without food. Grapefruit juice reduces cytochrome P-450 (CYP) 3A4 (CYP3A4)-mediated metabolism of sirolimus and should not be administered with or used for dilution of the drug.

Sirolimus tablets should not be crushed, chewed, or split; the oral solution should be used in patients who are unable to take the tablets.

For dilution and administration of sirolimus oral solution, the prescribed amount of oral solution should be withdrawn from the bottle using the amber oral dose syringe supplied by the manufacturer and then the correct amount of the drug emptied into a glass or plastic container that holds at least 2 ounces (1/4 cup or 60 mL) of water or orange juice. Other liquids, including grapefruit juice, should not be used for dilution. The diluted oral solution should be stirred vigorously and drunk at once. The container should be refilled with an additional volume (minimum of 4 ounces (1/2 cup or 120 mL)) of water or orange juice, stirred vigorously, and then drunk at once.

Sirolimus therapy should be initiated as soon as possible following renal transplantation as part of an initial immunosuppressive regimen that includes both cyclosporine and corticosteroids. At 2-4 months following transplantation, gradual discontinuance of cyclosporine and adjustment of the sirolimus dosage to achieve recommended blood concentrations of the drug are recommended in patients at low to moderate immunologic risk. In patients at high immunologic risk (defined as Black ethnicity, repeat transplant following loss of a previous allograft for immunologic reasons, and/or recipients with a high level of PRAs (peak PRA level over 80%)), the manufacturer recommends that sirolimus be used in combination with cyclosporine and corticosteroids for the first 12 months following renal transplantation.

No dosing information is available for this tab.

No dosing information is available for this tab.

There is no enhanced messaging for this drug.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

*Known hypersensitivity to sirolimus or its derivatives or any ingredient in the sirolimus formulation.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

Adverse reactions occurring in >=30% of patients receiving sirolimus in clinical trials for prevention of rejection of renal allografts include peripheral edema, hypercholesterolemia, hypertriglyceridemia, hypertension, increased serum creatinine concentrations, constipation, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia.

Adverse reactions occurring in >=20% of patients receiving sirolimus in clinical trials for treatment of lymphangioleiomyomatosis include stomatitis, diarrhea, abdominal pain, nausea, nasopharyngitis, acne, chest pain, peripheral edema, upper respiratory tract infection, headache, dizziness, myalgia, and hypercholesterolemia.

There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

No enhanced messaging available.

Safety and efficacy of sirolimus have not been established in pediatric patients <13 years of age for prophylaxis of organ rejection in renal transplantation.

Safety and efficacy of sirolimus have been established in pediatric and adolescent renal transplant patients >=13 years of age judged to be at low to moderate immunologic risk. Use of sirolimus in this subpopulation of pediatric patients is supported by evidence from adequate and well-controlled trials of sirolimus in adults with additional pharmacokinetic data in pediatric renal transplant patients.

Safety and efficacy data from a controlled, multicenter clinical trial of 36 months' duration in pediatric and adolescent renal transplant patients <18 years of age judged to be at high immunologic risk (i.e., history of one or more acute rejection episodes and/or presence of chronic allograft nephropathy) did not support the chronic use of sirolimus in combination with calcineurin inhibitors and corticosteroids because of the higher incidence of lipid abnormalities and deterioration of renal function and the lack of a demonstrated therapeutic benefit compared with a calcineurin inhibitor-based regimen.

Safety and efficacy of sirolimus in pediatric patients <18 years of age have not been established for the treatment of lymphangioleiomyomatosis.

Sirolimus can cause fetal harm when administered to a pregnant woman based on animal studies and the drug's mechanism of action. There are limited data on the use of sirolimus during pregnancy to inform a drug-associated risk of adverse developmental outcomes. Animal studies showed that the drug was embryotoxic and fetotoxic at subtherapeutic doses. Advise pregnant females of the potential risk to a fetus.

The National Transplantation Pregnancy Registry (NTPR) is a pregnancy registry for pregnant women receiving immunosuppressants following any solid organ transplantation; the NTPR encourages reporting of all immunosuppressant exposures during pregnancy in transplant patients by telephone at 877-955-6877 or via their website: https://www.transplantpregnancyregistry.org/.

Sirolimus is distributed into milk in trace amounts in rats; it is not known whether the drug is distributed into milk in humans. It is not known whether sirolimus has any effects on the breastfed infant or on milk production. Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for sirolimus and any potential adverse effects on the breastfed infant from the drug.

The manufacturer states that routine dosage adjustment in geriatric patients receiving sirolimus is not necessary; however, dosage selection in geriatric patients should be cautious, usually starting at the lower end of the dosage range, reflecting the greater frequency of decreased hepatic or cardiac function and of concomitant diseases or other drug therapy in this population.

Clinical studies of sirolimus did not include a sufficient number of patients >=65 years of age to determine whether they respond differently than younger patients. Differences in responses between geriatric patients and younger patients have not been identified. Following administration of sirolimus oral solution or tablets, sirolimus trough concentrations in renal transplant patients >65 years of age were similar to those observed in adults 18-65 years of age. These data suggest that dosage adjustments based solely on age are not necessary in geriatric renal transplant patients. The manufacturer states that dosage selection in geriatric patients should generally be cautious, usually starting at the low end of the dosage range, reflecting the greater frequency of decreased hepatic or cardiac function and of concomitant disease or other drug therapy.