SIROLIMUS- sirolimus tablet


  • Increased susceptibility to infection and the possible development of lymphoma and other malignancies may result from immunosuppression

Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. O nly physicians experienced in immunosuppressive therapy and management of renal transplant patients should use sirolimus for prophylaxis of organ rejection in patients receiving renal transplants. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient [see Warnings and Precautions ( 5.1) ].

  • The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in liver or lung transplant patients, and therefore, such use is not recommended [see Warnings and Precautions ( 5.2 , 5.3 ) ].
  • Liver Transplantation — Excess Mortality, Graft Loss, and Hepatic Artery Thrombosis (HAT)

The use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss in a study in de novo liver transplant patients. Many of these patients had evidence of infection at or near the time of death.

In this and another study in de novo liver transplant patients, the use of sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in HAT; most cases of HAT occurred within 30 days post-transplantation and most led to graft loss or death [see Warnings and Precautions (5.2)] .

  • Lung Transplantation — Bronchial Anastomotic Dehiscence

Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen [see Warnings and Precautions ( 5.3 ) ].


1.1 Prophylaxis of Organ Rejection in Renal Transplantation

Sirolimus tablets are indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants.

In patients at low- to moderate-immunologic risk, it is recommended that sirolimus tablets be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn 2 to 4 months after transplantation [see Dosage and Administration ( 2.2) ].

In patients at high-immunologic risk (defined as Black recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reason and/or patients with high panel-reactive antibodies [PRA; peak PRA level > 80%]), it is recommended that sirolimus tablets be used in combination with cyclosporine and corticosteroids for the first year following transplantation [see Dosage and Administration ( 2.3), Clinical Studies ( 14.3) ].

1.2 Limitations of Use in Renal Transplantation

Cyclosporine withdrawal has not been studied in patients with Banff Grade 3 acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis-dependent, those with serum creatinine >4.5 mg/dL, Black patients, patients of multi-organ transplants, secondary transplants, or those with high levels of panel-reactive antibodies [see Clinical Studies (14.2)].

In patients at high-immunologic risk,the safety and efficacy of sirolimus tablets used in combination with cyclosporine and corticosteroids has not been studied beyond one year; therefore after the first 12 months following transplantation, any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient [see Clinical Studies ( 14.3) ].

In pediatric patients, the safety and efficacy of sirolimus tablets have not been established in patients <13 years old, or in pediatric (<18 years) renal transplant patients considered at high- immunologic risk [see Adverse Reactions ( 6.5), Clinical Studies ( 14.6) ].

The safety and efficacy of de novo use of sirolimus tablets without cyclosporine have not been established in renal transplant patients [see Warnings and Precautions ( 5.12) ].

The safety and efficacy of conversion from calcineurin inhibitors to sirolimus tabletsin maintenance renal transplant patients have not been established [see Clinical Studies ( 14.4) ].

1.3 Treatment of Patients with Lymphangioleiomyomatosis

Sirolimus is indicated for the treatment of patients with lymphangioleiomyomatosis (LAM).


Sirolimus tablets are to be administered orally once daily, consistently with or without food [see Dosage and Administration ( 2.5), Clinical Pharmacology (12.3)].

Tablets should not be crushed, chewed or split. Patients unable to take the tablets should be prescribed the solution and instructed in its use.

2.1 General Dosing Guidance for Renal Transplant Patients

The initial dose of sirolimus tablets should be administered as soon as possible after transplantation. It is recommended that sirolimus tablets be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and or/cyclosporine capsules (MODIFIED) [see Drug Interactions (7.2)].

Frequent sirolimus tablets dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has a long half-life. Once sirolimus tablets maintenance dose is adjusted, patients should continue on the new maintenance dose for at least 7 to 14 days before further dosage adjustment with concentration monitoring. In most patients, dose adjustments can be based on simple proportion: new sirolimus tablets dose = current dose x (target concentration/current concentration). A loading dose should be considered in addition to a new maintenance dose when it is necessary to increase sirolimus trough concentrations: sirolimus tablets loading dose = 3 x (new maintenance dose — current maintenance dose). The maximum sirolimus tablets dose administered on any day should not exceed 40 mg. If an estimated daily dose exceeds 40 mg due to the addition of a loading dose, the loading dose should be administered over 2 days. Sirolimus trough concentrations should be monitored at least 3 to 4 days after a loading dose(s).

Two milligrams (2 mg) of sirolimus oral solution have been demonstrated to be clinically equivalent to 2 mg sirolimus tablets; hence, at this dose these two formulations are interchangeable. However, it is not known if higher doses of sirolimus oral solution are clinically equivalent to higher doses of sirolimus tablets on a mg-to-mg basis [see Clinical Pharmacology ( 12.3) ].

2.2 Renal Transplant Patients at Low- to Moderate-Immunologic Risk

Sirolimus Tablets and Cyclosporine Combination Therapy

For de novo renal transplant patients, it is recommended that sirolimus oral solution and tablets be used initially in a regimen with cyclosporine and corticosteroids. A loading dose of sirolimus tablets equivalent to 3 times the maintenance dose should be given, i.e. a daily maintenance dose of 2 mg should be preceded with a loading dose of 6 mg. Therapeutic drug monitoring should be used to maintain sirolimus drug concentrations within the target-range [see Dosage and Administration (2.5)].

Sirolimus Tablets Following Cyclosporine Withdrawal

At 2 to 4 months following transplantation, cyclosporine should be progressively discontinued over 4 to 8 weeks, and the sirolimus tablets dose should be adjusted to obtain sirolimus whole blood trough concentrations within the target-range [see Dosage and Administration (2.5)]. Because cyclosporine inhibits the metabolism and transport of sirolimus, sirolimus concentrations may decrease when cyclosporine is discontinued, unless the sirolimus tablets dose is increased [see Clinical Pharmacology (12.3)].

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