RAPAMUNE TABLET 0.5 mg

PFIZER PRIVATE LIMITED

PFIZER PRIVATE LIMITED

Therapeutic

Prescription Only

TABLET, SUGAR COATED

**4.2. Posology and method of administration** **4.2.1. Dosage** Bioavailability has not been determined for tablets after they have been crushed, chewed, or split and therefore, this cannot be recommended. 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** It is recommended that Rapamune oral solution and 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 Cyclosporine should be withdrawn 2 to 4 months after renal transplantation in patients at low to moderate immunological risk, and the Rapamune dose should be increased to reach recommended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 **Section 4.1. Therapeutic indications** and **Section 5.1. Pharmacodynamic properties – Clinical Trials Data on Efficacy** – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). **Adults** _**Rapamune with Cyclosporine Therapy**_ The usual dosage regimen for Rapamune is a 6 mg oral loading dose, administered as soon as possible after transplantation, followed by 2 mg once daily. The Rapamune dose should then be individualized, to obtain whole blood trough levels of 4 to 12 ng/mL. 2 mg of Rapamune oral solution has been demonstrated to be clinically equivalent to 2 mg of Rapamune oral tablets, and hence are interchangeable on a mg to mg basis. 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 **Section 5.2. Pharmacokinetics – Absorption** – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_.) Rapamune is to be administered orally once daily. _**Rapamune Maintenance Regimen with Cyclosporine Withdrawal**_ 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 below) were close to these ranges (see **Section 4.2.2. Sirolimus whole blood trough level monitoring**). 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** It is recommended that Rapamune be taken 4 hours after cyclosporine microemulsion \[cyclosporine, USP\] administration. **Use in Children** Safety and efficacy of Rapamune in pediatric patients below the age of 13 years have not been established. It is recommended that sirolimus whole blood trough levels be monitored if used in pediatric patients <13 years of age. **Use in Elderly Patient** No dose adjustment is required in elderly patients. Clinical studies of Rapamune did not include sufficient number of patients aged 65 and over to determine whether they will respond differently than 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 Renal Impairment** No dosage adjustment is required. **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. The pharmacokinetics of Rapamune has not been studied in patients with severe hepatic impairment. In patients with hepatic impairment, it is recommended that sirolimus whole blood trough levels be monitored. **4.2.2. Sirolimus whole blood trough level monitoring** Blood sirolimus trough levels should be monitored: 1. in patients with hepatic impairment 2. in patients receiving concentration-controlled Rapamune 3. in pediatric patients 4. during concurrent administration of inhibitors and inducers of CYP3A4 and P-glycoprotein (P-gp) 5. if cyclosporine dosing is markedly reduced, or if cyclosporine is discontinued. Therapeutic drug monitoring should not be the sole basis for adjusting sirolimus therapy. Careful attention should be made 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. _**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, adjustments to the target therapeutic range must be made with a detailed knowledge of the site-specific assay used. A discussion of the different assay methods is contained in Clinical Therapeutics, Volume 22, Supplement B, April 2000. **4.2.3. Mode of administration** Rapamune is intended for oral administration only. Rapamune must be taken consistently with or without food to minimize variation in drug absorption. Only water or orange juice should be used for Rapamune oral solution dilution, using only glass or plastic cups. Do not dilute Rapamune with grapefruit juice (see **Section 4.5. Interaction with other medicinal products and other forms of interaction** – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_) or any other liquids. 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 the recommendations in **Section 4.2. Posology and method of administration** be followed closely.