2 DOSAGE AND ADMINISTRATION
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 Rapamune should be administered as soon as possible after transplantation. It is recommended that Rapamune be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and or/cyclosporine capsules (MODIFIED) [see Drug Interactions (7.2)].
Frequent Rapamune dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has a long half-life. Once Rapamune 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 Rapamune dose = current dose × (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: Rapamune loading dose = 3 × (new maintenance dose - current maintenance dose). The maximum Rapamune 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 Rapamune Oral Solution have been demonstrated to be clinically equivalent to 2 mg Rapamune Tablets; hence, at this dose these two formulations are interchangeable. However, it is not known if higher doses of Rapamune Oral Solution are clinically equivalent to higher doses of Rapamune Tablets on a mg-to-mg basis [see Clinical Pharmacology (12.3)].
2.2 Renal Transplant Patients at Low- to Moderate-Immunologic Risk
Rapamune and Cyclosporine Combination Therapy
For de novo renal transplant patients, it is recommended that Rapamune Oral Solution and Tablets be used initially in a regimen with cyclosporine and corticosteroids. A loading dose of Rapamune 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)].
Rapamune Following Cyclosporine Withdrawal
At 2 to 4 months following transplantation, cyclosporine should be progressively discontinued over 4 to 8 weeks, and the Rapamune 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 Rapamune dose is increased [see Clinical Pharmacology (12.3)].
2.3 Renal Transplant Patients at High-Immunologic Risk
In patients with high-immunologic risk, it is recommended that Rapamune be used in combination with cyclosporine and corticosteroids for the first 12 months following transplantation [see Clinical Studies (14.3)]. 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 Rapamune with cyclosporine, Rapamune 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 Rapamune should thereafter be adjusted [see Dosage and Administration (2.5)].
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 [see Dosage and Administration (2.5)]. 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 Rapamune 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 [see Dosage and Administration (2.5)].
In most patients, dose adjustments can be based on simple proportion: new Rapamune dose = current dose × (target concentration/current concentration). Frequent Rapamune dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or under dosing because sirolimus has a long half-life. Once Rapamune 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 Rapamune dosage form is made, and during concurrent administration of strong CYP3A4 inducers and inhibitors [see Drug Interactions (7)].
Therapeutic drug monitoring should not be the sole basis for adjusting Rapamune 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 [see Clinical Studies (14), Clinical Pharmacology (12.3)]. 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 [see Warnings and Precautions (5.17), Clinical Pharmacology (12.3)]. 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 [see References (15)].
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/m2/day. The loading dose should be 3 mg/m2.
2.7 Patients with Hepatic Impairment
It is recommended that the maintenance dose of Rapamune 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 Rapamune loading dose [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
2.8 Patients with Renal Impairment
Dosage adjustment is not needed in patients with impaired renal function [see Use in Specific Populations (8.7)].
2.9 Instructions for Dilution and Administration of Rapamune Oral Solution
The amber oral dose syringe should be used to withdraw the prescribed amount of Rapamune Oral Solution from the bottle. Empty the correct amount of Rapamune from the syringe into only a glass or plastic container holding at least two (2) ounces (1/4 cup, 60 mL) of water or orange juice. No other liquids, including grapefruit juice, should be used for dilution [see Drug Interactions (7.3), Clinical Pharmacology (12.3)]. Stir vigorously and drink at once. Refill the container with an additional volume [minimum of four (4) ounces (1/2 cup, 120 mL)] of water or orange juice, stir vigorously, and drink at once.
Rapamune 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 Rapamune Oral Solution. It is important that these recommendations be followed closely.