Rapamune Dosage/Direction for Use

Dosage: Bioavailability has not been determined for tablets after they have been crushed, chewed, or split and therefore this cannot be recommended.
Therapeutic drug monitoring is recommended for all patients receiving Rapamune (see details on drug monitoring in different patient populations as follows and Sirolimus whole blood trough level monitoring as follows).
Prophylaxis of organ rejection in renal transplantation: Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Rapamune. 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.
Patients at low to moderate immunologic risk: Rapamune and Cyclosporine Combination Therapy: For de novo transplant recipients, a loading dose of Rapamune corresponding to 3 times the maintenance dose should be given. A daily maintenance dose of 2 mg is recommended for use in renal transplant patients, with a loading dose of 6 mg.
It is recommended that Rapamune tablets be used initially in a regimen with cyclosporine and corticosteroids. Cyclosporine should be withdrawn 2 to 4 months after renal transplantation in patients at low to moderate immunologic risk, and the Rapamune dose should be increased to reach recommended blood concentrations. Cyclosporine withdrawal has not been studied in patients with Banff 93 grade III acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis-dependent, or with serum creatinine >4.5 mg/dL, Black patients, re-transplants, multi-organ transplants, or patients with high-panel reactive antibodies (see Indications/Uses and Pharmacology: Pharmacodynamics under Actions).
Rapamune following Cyclosporine withdrawal (Referred to as Rapamune Maintenance Regimen, RMR): Initially, patients should be receiving Rapamune and cyclosporine combination therapy. 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 whole blood trough concentrations within the range of 16 to 24 ng/mL (chromatographic method) for the first year following transplantation. Thereafter, the target sirolimus concentrations should be 12 to 20 ng/mL (chromatographic method). The actual observations at year 1 and 5 (see as follows) were close to these ranges (see Sirolimus whole blood trough level monitoring as follows). Therapeutic drug monitoring should not be the sole basis for adjusting Rapamune therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsy and laboratory parameters. Cyclosporine inhibits the metabolism and transport of sirolimus, and consequently, sirolimus concentrations will decrease when cyclosporine is discontinued unless the Rapamune dose is increased. The Rapamune dose will need to be approximately 4-fold higher to account for both the absence of the pharmacokinetic interaction (approximately 2-fold increase) and the augmented immunosuppressive requirement in the absence of cyclosporine (approximately 2-fold increase).
Patients at high immunologic risk: Rapamune Combination Therapy: It is recommended that Rapamune be used in a combination of cyclosporine and corticosteroids for the first year following transplantation in patients at high immunologic risk (defined as Black transplant 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%]) (see Pharmacology: Pharmacodynamics under Actions). The safety and efficacy of these combinations in high-risk patients have not been studied beyond one year. Therefore, after the first year 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 to achieve whole blood trough sirolimus concentrations of 10-15 ng/mL.
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 whole blood trough concentrations of 200-300 ng/mL for 14 days, 150-200 ng/mL from day 15 to the end of week 26, and 100-150 ng/mL from week 27 to the end of week 52. Prednisone should be administered at a minimum of 5 mg/day.
Antibody induction therapy may be used (see Pharmacology: Pharmacodynamics under Actions).
Rapamune use in all Renal Allograft Recipients: The initial dose of Rapamune should be administered as soon as possible after transplantation. 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 the Rapamune maintenance dose is adjusted, patients should be retained on the new maintenance dose at least for 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 x (target concentration/current concentration). A loading dose should be considered in addition to a new maintenance dose when it is necessary to considerably increase sirolimus trough concentrations: Rapamune loading dose = 3 x (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).
To minimize the variability of exposure to Rapamune, this drug should be taken consistently with or without food. Grapefruit juice reduces CYP3A4-mediated drug metabolism and potentially enhances P-glycoprotein (P-gp) - mediated drug counter-transport from enterocytes of the small intestine. Therefore, grapefruit juice must not be administered with Rapamune or used for dilution.
It is recommended that Rapamune be taken 4 hours after cyclosporine microemulsion [(cyclosporine, USP) MODIFIED]* administration (see Interactions).
Use in Children: The safety and efficacy of Rapamune in pediatric patients below the age of 13 years have not been established.
Safety and efficacy information from a controlled clinical trial in pediatric and adolescent (<18 years of age) renal transplant recipients judged to be at high immunologic risk, defined as a history of one or more acute rejection episodes and/or the presence of chronic allograft nephropathy, do not support the chronic use of Rapamune in combination with calcineurin inhibitors and corticosteroids, due to the increased risk of lipid abnormalities and deterioration of renal function associated with these immunosuppressive regimens, without increased benefit with respect to acute rejection, graft survival, or patient survival (see Pharmacology: Pharmacodynamics under Actions).
Use in Elderly Patients: No dose adjustment is required in elderly patients.
Clinical studies of Rapamune did not include sufficient numbers of patients aged 65 and over to determine whether safety and efficacy differ in this population from younger patients. Sirolimus trough concentration data in 35 renal transplant patients >65 years of age were similar to those in the adult population (n=822) from 18 to 65 years of age.
Patients with Hepatic Impairment: In patients with hepatic impairment, it is recommended that the maintenance dose of Rapamune be reduced by approximately one-third to one-half. It is not necessary to modify the Rapamune loading dose.
In patients with hepatic impairment, it is recommended that sirolimus whole blood trough levels be monitored.
Patients with Renal Impairment: Based on clinical pharmacokinetics data, the Rapamune dosage need not be adjusted because of impaired renal function.
Sirolimus whole blood trough level monitoring: Blood sirolimus trough levels should be monitored (See Assay Methodology as follows): in patients receiving concentration-controlled Rapamune; in pediatric patients; in patients with hepatic impairment; during concurrent administration of inhibitors and inducers of CYP3A4 and P-glycoprotein (P-gp); if the cyclosporine dose is markedly reduced, or if cyclosporine is discontinued.
Therapeutic drug monitoring should not be the sole basis for adjusting sirolimus therapy. Careful attention should also be paid to clinical signs/symptoms, tissue biopsies, and laboratory parameters.
It is recommended that patients switched from the solution to the tablet formulation on a mg per mg basis have a trough concentration taken 1 or 2 weeks after switching formulations to confirm that the trough concentration is within the recommended target range.
In controlled clinical trials with concomitant cyclosporine, mean sirolimus whole blood trough levels through Month 6 following transplantation, expressed as chromatographic assay value, were approximately 7.2 ng/mL (range 3.6 - 11 ng/mL) for the 2 mg/day treatment group (n=226), and 14 ng/mL (range 8.0 - 22 ng/mL [10^th to 90^th percentile]) for the 5 mg/day dose (n=219; values were obtained using a research immunoassay, but are expressed as chromatographic equivalent values, accounting for immunoassay bias).
In the controlled clinical trial with cyclosporine withdrawal, the mean sirolimus whole blood trough concentrations during months 4 through 12 following transplantation, as measured by chromatography, were 8.6 ng/mL (range 5.0 - 12.7 ng/mL [10^th to 90^th percentile]) in the concomitant Rapamune and cyclosporine treatment group (n=205) and were 18.6 ng/mL (range 13.6 - 22.4 ng/mL [10^th to 90^th percentile]) in the cyclosporine withdrawal treatment group (n=201). By month 60, the mean sirolimus whole blood trough concentrations remained stable in the concomitant Rapamune and cyclosporine group (n=71) at 9.1 ng/mL (range 5.4 to 13.9 ng/mL [10^th to 90^th percentile]). For the cyclosporine withdrawal group (n=104) by month 60, the mean sirolimus whole blood concentration had fallen to 16.3 ng/mL (range 11.2 to 21.9 ng/mL [10^th to 90^th percentile]).
In a concentration-controlled clinical trial in high-risk adult patients, the mean whole blood sirolimus trough concentrations, during months 9 through 12 months following transplantation, as measured by chromatography, in the sirolimus/tacrolimus group, were 10.7 ng/mL (range 5.6 - 15.1 ng/mL [10^th to 90^th percentile]) (n=117), and the mean whole blood trough concentrations of tacrolimus were 5.3 ng/mL (range 3.0 - 8.6 ng/mL [10^th to 90^th percentile]). Additionally, the mean whole blood trough concentrations of sirolimus in the sirolimus/cyclosporine group were 11.2 ng/mL (range 6.8 - 15.9 ng/mL [10^th to 90^th percentile]) (n=127), and the mean whole blood trough concentrations of cyclosporine were 133 ng/mL (range 54 - 215 ng/mL [10^th to 90^th percentile]).
Assay Methodology: The recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic methods. Several assay methodologies have been used to measure the whole blood concentrations of sirolimus. Currently in clinical practice, sirolimus whole blood concentrations are being measured by both chromatographic and immunoassay methodologies. The concentration values obtained by these different methodologies are not interchangeable. Adjustments to the targeted range should be made according to the assay being utilized to determine the sirolimus trough concentration. Since results are assay and laboratory dependent, and the results may change over time, adjustment to the targeted therapeutic range must be made with a detailed knowledge of the site-specific assay used. A discussion of different assay methods is contained in Clinical Therapeutics 2000; 22 Suppl. B:B1-B132.
Mode of Administration: Rapamune is intended for oral administration only.
Rapamune must be taken consistently either with or without food to minimize variation in drug absorption.
It is important that the recommendations in Dosage & Administration be followed closely.