Sirolimusdosage

Sirolimus Oral Solution is to be administered orally once daily, consistently with or without food.

Renal Transplant Patients: Administer once daily by mouth, consistently with or without food. Administer the initial dose as soon as possible after transplantation and 4 hours after CsA. Adjust the sirolimus maintenance dose to achieve sirolimus trough concentrations within the target-range.

Hepatic impairment: Reduce maintenance dose in patients with hepatic impairment. In renal transplant patients at low-to moderate-immunologic risk: Sirolimus and CsA Combination Therapy: One loading dose of 6 mg on day 1, followed by daily maintenance doses of 2 mg.

Sirolimus Following CsA Withdrawal: 2-4 months post transplantation, withdraw CsA over 4-8 weeks. In renal transplant patients at high-immunologic risk: Sirolimus and CsA Combination Therapy (for the first 12 months post- transplantation): One loading dose of up to 15 mg on day 1, followed by daily maintenance doses of 5 mg.

Lymphangioleiomyomatosis Patients: Administer once daily by mouth, consistently with or without food. Recommended initial sirolimus dose is 2 mg/day. Adjust the sirolimus dose to achieve sirolimus trough concentrations between 5-15 ng/mL.

Hepatic impairment: Reduce maintenance dose in patients with hepatic impairment. Therapeutic drug monitoring is recommended for all patients.

2.1 General

Dosing Guidance for Renal Transplant Patients The initial dose of Sirolimus Oral Solution should be administered as soon as possible after transplantation. It is recommended that Sirolimus Oral Solution be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED). Frequent Sirolimus Oral Solution dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has a long half-life. Once Sirolimus Oral Solution 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 Oral Solution 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 Oral Solution loading dose = 3 x (new maintenance dose - current maintenance dose). The maximum Sirolimus Oral Solution 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.

2.2 Renal Transplant

Patients at Low- to Moderate-Immunologic Risk Sirolimus Oral Solution 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 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. Sirolimus Oral Solution Following Cyclosporine Withdrawal At 2 to 4 months following transplantation, cyclosporine should be progressively discontinued over 4 to 8 weeks, and the Sirolimus Oral Solution dose should be adjusted to obtain sirolimus whole blood trough concentrations within the target-range. Because cyclosporine inhibits the metabolism and transport of sirolimus, sirolimus concentrations may decrease when cyclosporine is discontinued, unless the Sirolimus Oral Solution dose is increased.

2.3 Renal Transplant

Patients at High-Immunologic Risk In patients with high-immunologic risk, it is recommended that Sirolimus Oral Solution be used in combination with cyclosporine and corticosteroids for the first 12 months following transplantation. The safety and efficacy of this combination in high-immunologic risk patients has not been studied beyond the first 12 months. 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. For patients receiving Sirolimus Oral Solution with cyclosporine, Sirolimus Oral Solution therapy should be initiated with a loading dose of up to 15 mg on day 1 post-transplantation. Beginning on day 2, an initial maintenance dose of 5 mg/day should be given. A trough level should be obtained between days 5 and 7, and the daily dose of Sirolimus Oral Solution should thereafter be adjusted. The starting dose of cyclosporine should be up to 7 mg/kg/day in divided doses and the dose should subsequently be adjusted to achieve target whole blood trough concentrations. Prednisone should be administered at a minimum of 5 mg/day. Antibody induction therapy may be used.

2.4 Dosing in

Patients with Lymphangioleiomyomatosis For patients with lymphangioleiomyomatosis, the initial sirolimus dose should be 2 mg/day. Sirolimus whole blood trough concentrations should be measured in 10-20 days, with dosage adjustment to maintain concentrations between 5-15 ng/mL. In most patients, dose adjustments can be based on simple proportion: new sirolimus dose = current dose x (target concentration/current concentration). Frequent sirolimus dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or under dosing because sirolimus has a long half-life. Once sirolimus 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. Once a stable dose is achieved, therapeutic drug monitoring should be performed at least every three months.

2.5 Therapeutic

Drug Monitoring Monitoring of sirolimus trough concentrations is recommended for all patients, especially in those patients likely to have altered drug metabolism, in patients ≥ 13 years who weigh less than 40 kg, in patients with hepatic impairment, when a change in the sirolimus dosage form is made, and during concurrent administration of strong CYP3A4 inducers and inhibitors. Therapeutic drug monitoring should not be the sole basis for adjusting sirolimus therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsy findings, and laboratory parameters. When used in combination with cyclosporine, sirolimus trough concentrations should be maintained within the target-range. Following cyclosporine withdrawal in transplant patients at low- to moderate-immunologic risk, the target sirolimus trough concentrations should be 16 to 24 ng/mL for the first year following transplantation. Thereafter, the target sirolimus concentrations should be 12 to 20 ng/mL. The above recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic methods. Currently in clinical practice, sirolimus whole blood concentrations are being measured by both chromatographic and immunoassay methodologies. Because the measured sirolimus whole blood concentrations depend on the type of assay used, the concentrations obtained by these different methodologies are not interchangeable. Adjustments to the targeted range should be made according to the assay utilized to determine sirolimus trough concentrations. Since results are assay and laboratory dependent, and the results may change over time, adjustments to the targeted therapeutic range must be made with a detailed knowledge of the site-specific assay used. Therefore, communication should be maintained with the laboratory performing the assay. A discussion of different assay methods is contained in Clinical Therapeutics, Volume 22, Supplement B, April 2000.

2.6 Patients with

Low Body Weight The initial dosage in patients ≥ 13 years who weigh less than 40 kg should be adjusted, based on body surface area, to 1 mg/m 2 /day. The loading dose should be 3 mg/m 2.

2.7 Patients with

Hepatic Impairment It is recommended that the maintenance dose of Sirolimus Oral Solution be reduced by approximately one third in patients with mild or moderate hepatic impairment and by approximately one half in patients with severe hepatic impairment. It is not necessary to modify the Sirolimus Oral Solution loading dose.

2.8 Patients with

Renal Impairment Dosage adjustment is not needed in patients with impaired renal function.

2.9 Instructions for

Dilution and Administration of Sirolimus Oral Solution The amber oral dose syringe should be used to withdraw the prescribed amount of Sirolimus Oral Solution from the bottle. Empty the correct amount of Sirolimus Oral Solution from the syringe into only a glass or plastic container holding at least two ounces (1/4 cup, 60 mL) of water or orange juice. No other liquids, including grapefruit juice, should be used for dilution. Stir vigorously and drink at once. Refill the container with an additional volume [minimum of four ounces (1/2 cup, 120 mL)] of water or orange juice, stir vigorously, and drink at once. Sirolimus Oral Solution contains polysorbate 80, which is known to increase the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC). This should be considered during the preparation and administration of Sirolimus Oral Solution. It is important that these recommendations be followed closely.