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 (2.3) ]. 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) ].
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 (14.2) ]. 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 (2.3) ].
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 (2.3) ]. Prednisone should be administered at a minimum of 5 mg/day.
Antibody induction therapy may be used.
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. On average, chromatographic methods (HPLC UV or LC/MS/MS) yield results that are approximately 20% lower than the immunoassay for whole blood concentration determinations. 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 (5.14), Clinical Pharmacology (12.3) ]. Adjustments to the targeted range should be made according to the assay utilized to determine sirolimus trough concentrations. A discussion of different assay methods is contained in Clinical Therapeutics, Volume 22, Supplement B, April 2000 [see References (15) ].
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.
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 Clinical Pharmacology (12.3) ].
Patients with Renal Impairment
Dosage adjustment is not needed in patients with impaired renal function [see Use in Specific Populations (8.7) ].
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.
DOSAGE FORMS AND STRENGTHS
Rapamune Oral Solution
- 60 mg per 60 mL in amber glass bottle.
- 1 mg, white, triangular-shaped tablets marked “RAPAMUNE 1 mg” on one side.
- 2 mg, yellow-to-beige triangular-shaped tablets marked “RAPAMUNE 2 mg” on one side.