Rapamune Tablets

Rapamune is to be administered orally once daily, consistently with or without food [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

Tablets should not be crushed, chewed or split. Patients unable to take the tablets should be prescribed the solution and instructed in its use.

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)].

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)].

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.

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.

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 (5.15), 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)].

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 Use in Specific Populations (8.6), 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies were conducted in mice and rats. In an 86-week female mouse study at sirolimus doses 30 to 120 times higher than the 2 mg daily clinical dose (adjusted for body surface area), there was a statistically significant increase in malignant lymphoma at all dose levels compared with controls. In a second mouse study at dosages that were approximately 3 to 16 times the clinical dose (adjusted for body surface area), hepatocellular adenoma and carcinoma in males were considered sirolimus-related. In the 104-week rat study at dosages equal to or lower than the clinical dose of 2 mg daily (adjusted for body surface area), there were no significant findings.

Sirolimus was not genotoxic in the in vitro bacterial reverse mutation assay, the Chinese hamster ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or the in vivo mouse micronucleus assay.

Fertility was diminished slightly in both male and female rats following oral administration of sirolimus at doses approximately 10 times or 2 times, respectively, the clinical dose of 2 mg daily (adjusted for body surface area). In male rats, atrophy of testes, epididymides, prostate, seminiferous tubules and/or reduction in sperm counts were observed. In female rats, reduced size of ovaries and uteri was observed. Reduction of sperm count in male rats was reversible upon cessation of dosing in one study. Testicular tubular degeneration was also seen in a 4-week intravenous study of sirolimus in monkeys at doses that were approximately equal to the clinical dose (adjusted for body surface area).

Advise patients, their families, and their caregivers to read the Medication Guide and assist them in understanding its contents. The complete text of the Medication Guide is reprinted at the end of the document.

See FDA-Approved Medication Guide.

Dosage

Patients should be given complete dosage instructions [see FDA-Approved Medication Guide].

Skin Cancer Events

Patients should be told that exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor because of the increased risk for skin cancer [see Warnings and Precautions (5.16)].

Pregnancy Risks

Women of childbearing potential should be informed of the potential risks during pregnancy and told that they should use effective contraception prior to initiation of Rapamune therapy, during Rapamune therapy, and for 12 weeks after Rapamune therapy has been stopped [see Use in Specific Populations (8.1)].

This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com.

LAB-0473-9.0

ALWAYS DISPENSE WITH MEDICATION GUIDE

Pfizer
NDC 0008-1041-10

Rapamune®
(sirolimus) Tablets

1 mg

For oral use only.

Unit Dose - 100 Tablets
(10 Blister Cards of 10 Tablets Each)
Rx only

ALWAYS DISPENSE WITH MEDICATION GUIDE

Pfizer
NDC 0008-1042-05

Rapamune®
(sirolimus) Tablets

2 mg

For oral use only.

100 Tablets
Rx only

FOR PATIENTS AT LOW TO MODERATE IMMUNOLOGIC RISK:
Dosing by body weight:
-Less than 40 kg:
Loading dose: 3 mg/m2 on day 1
Maintenance: 1 mg/m2 once daily
-Greater than or equal to 40 kg:
Loading dose: 6 mg orally on day 1
Maintenance: 2 mg orally once daily

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 greater than 80%]):
-For patients receiving sirolimus with cyclosporine:
Loading Dose: Up to 15 mg on day one post-transplantation
Maintenance Dose: 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 should be adjusted thereafter.
-Antibody induction therapy may be used.

Comments:
-It is recommended that this sirolimus be used in a regimen with cyclosporine and corticosteroids.
-Sirolimus should be taken consistently with or without food.
-Once the 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.

MAINTENANCE THERAPY AFTER WITHDRAWAL OF CYCLOSPORINE:
-Cyclosporine withdrawal is not recommended in high-immunological risk patients. Following 2 to 4 months of combined therapy, withdrawal of cyclosporine may be considered in low-to-moderate risk patients. Cyclosporine should be discontinued over 4 to 8 weeks, and a necessary increase in the dosage of sirolimus (up to 4-fold) should be anticipated due to removal of metabolic inhibition by cyclosporine and to maintain adequate immunosuppressive effects. -Dose-adjusted trough target concentrations are typically 16 to 24 ng/mL for the first year post-transplant and 12 to 20 ng/mL thereafter (measured by chromatographic methodology).

Use:
-As an immunosuppressive agent indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplant.

-Initial dose: 2 mg/day
-Sirolimus whole blood trough concentrations should be measured in 10 to 20 days, with dosage adjustment to maintain concentrations between 5 and 15 ng/mL.

Comment:
-This drug should be taken consistently with or without food.

General Use:
-For the treatment of patients with lymphangioleiomyomatosis

No dosage adjustment is necessary in loading or maintenance dose. However, adjustment of the regimen (including discontinuation of therapy) should be considered when used concurrently with cyclosporine and elevated or increasing serum creatinine is noted.

Data not available