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RAPAMUNE (sirolimus) ORAL SOLUTION AND TABLETS
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Rapamune safely and effectively.
See full prescribing information for Rapamune.
RAPAMUNE (sirolimus) ORAL SOLUTION AND TABLETS
Initial U.S. Approval: 1999
WARNING: IMMUNOSUPPRESSION, USE IS NOT RECOMMENDED IN LIVER OR LUNG TRANSPLANT PATIENTS
See Full Prescribing Information for complete Boxed Warning.
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Increased susceptibility to infection and the possible development of lymphoma and other malignancies may result from immunosuppression (5.1). Only physicians experienced in immunosuppressive therapy and management of renal transplant patients should use Rapamune for prophylaxis of organ rejection in patients receiving renal transplants.
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The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in liver or lung transplant patients, and therefore, such use is not recommended (5.2, 5.3).
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Liver Transplantation – Excess mortality, graft loss, and hepatic artery thrombosis (5.2).
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Lung Transplantation – Bronchial anastomotic dehiscence (5.3).
RECENT MAJOR CHANGES
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Indications and Usage, Treatment of Patients with Lymphangioleiomyomatosis (1.3) |
5/2015 |
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Dosing in Patients with Lymphangioleiomyomatosis (2.4) |
5/2015 |
INDICATIONS AND USAGE
Rapamune is indicated:
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As an immunosuppressive agent indicated for the prophylaxis of organ rejection in patients aged ≥13 years receiving renal transplants.
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Patients at low- to moderate-immunologic risk: Use initially with cyclosporine (CsA) and corticosteroids. CsA withdrawal is recommended 2-4 months after transplantation ( 1.1).
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Patients at high-immunologic risk: Use in combination with cyclosporine and corticosteroids for the first 12 months following transplantation ( 1.1). Safety and efficacy of CsA withdrawal has not been established in high risk patients ( 1.1, 1.2, 14.3).
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Therapeutic drug monitoring is recommended for all patients ( 2.5, 5.15).
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For the treatment of patients with lymphangioleiomyomatosis.
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Therapeutic drug monitoring is recommended for all patients ( 2.5, 5.15).
DOSAGE AND ADMINISTRATION
In renal transplant patients
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Take once daily by mouth, consistently with or without food. Take the initial dose as soon as possible after transplantation and 4 hours after CsA (2, 7.1). Adjust the Rapamune maintenance dose to achieve sirolimus trough concentrations within the target-range (2.5).
In renal transplant patients at low-to moderate-immunologic risk
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Rapamune and Cyclosporine Combination Therapy: One loading dose of 6 mg on day 1, followed by daily maintenance doses of 2 mg (2.2).
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Rapamune Following Cyclosporine Withdrawal: 2-4 months post-transplantation, withdraw CsA over 4–8 weeks (2.2).
In renal transplant patients at high-immunologic risk
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Rapamune and Cyclosporine Combination Therapy (for the first 12 months post-transplantation): One loading dose of up to 15 mg on day 1, followed by daily maintenance doses of 5 mg (2.3).
In lymphangioleiomyomatosis patients
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Take once daily by mouth, consistently with or without food. The initial Rapamune dose should be 2 mg/day. Adjust the Rapamune dose to achieve sirolimus trough concentrations between 5–15 ng/mL (2.4).
DOSAGE FORMS AND STRENGTHS
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Rapamune Oral Solution: 60 mg per 60 mL in amber glass bottle (3.1).
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Rapamune Tablets: 0.5 mg, tan; 1 mg, white; 2 mg, yellow-to-beige (3.2).
CONTRAINDICATIONS
Hypersensitivity to Rapamune (4).
WARNINGS AND PRECAUTIONS
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Hypersensitivity Reactions (5.4)
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Angioedema (5.5)
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Fluid Accumulation and Wound Healing (5.6)
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Hyperlipidemia (5.7)
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Renal Function (5.8)
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Proteinuria (5.9)
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Latent Viral Infections (5.10)
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Interstitial Lung Disease/Non-Infectious Pneumonitis (5.11)
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De Novo Use Without Cyclosporine (5.12)
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Increased Risk of Calcineurin Inhibitor-induced HUS/TTP/TMA (5.13)
ADVERSE REACTIONS
Prophylaxis of organ rejection in patients receiving renal transplants: Most common adverse reactions (incidence ≥ 30%) are peripheral edema, hypertriglyceridemia, hypertension, hypercholesterolemia, creatinine increased, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia (6).
Lymphangioleiomyomatosis: Most common adverse reactions (incidence ≥ 20%) are stomatitis, diarrhea, abdominal pain, nausea, nasopharyngitis, acne, chest pain, peripheral edema, upper respiratory tract infection, headache, dizziness, myalgia, and hypercholesterolemia.
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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Avoid concomitant use with strong CYP3A4/P-gp inducers or strong CYP3A4/P‑gp inhibitors that decrease or increase sirolimus concentrations (7.4, 12.3).
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Exercise caution when administering with drugs that are inhibitors/inducers of CYP3A4/P-gp (7.4, 12.3).
USE IN SPECIFIC POPULATIONS
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Pregnancy: Use only if the potential benefit outweighs the potential risk to the embryo/fetus (8.1).
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Hepatic impairment: Reduce maintenance dose in patients with hepatic impairment (2.7, 8.6, 12.3).
See 17 for PATIENT COUNSELING INFORMATION and the FDA-approved Medication Guide
See 17 for Medication Guide.
Revised: 10/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Prophylaxis of Organ Rejection in Renal Transplantation
Rapamune (sirolimus) is indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants. Therapeutic drug monitoring is recommended for all patients receiving Rapamune [see Dosage and Administration (2.5), Warnings and Precautions (5.15)].
In patients at low-to moderate-immunologic risk, it is recommended that Rapamune be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn 2 to 4 months after transplantation [see Dosage and Administration (2.2)].
In patients at high-immunologic risk (defined as Black 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%]), it is recommended that Rapamune be used in combination with cyclosporine and corticosteroids for the first year following transplantation [see Dosage and Administration (2.3), Clinical Studies (14.3)].
1.2 Limitations of Use in Renal Transplantation
Cyclosporine withdrawal has not been studied in patients with Banff Grade 3 acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis-dependent, those with serum creatinine > 4.5 mg/dL, Black patients, patients of multi-organ transplants, secondary transplants, or those with high levels of panel-reactive antibodies [see Clinical Studies (14.2)].
In patients at high-immunologic risk, the safety and efficacy of Rapamune used in combination with cyclosporine and corticosteroids has not been studied beyond one year; 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 [see Clinical Studies (14.3)].
In pediatric patients, the safety and efficacy of Rapamune have not been established in patients < 13 years old, or in pediatric (< 18 years) renal transplant patients considered at high-immunologic risk [see Adverse Reactions (6.5), Clinical Studies (14.6)]. The safety and efficacy of de novo use of Rapamune without cyclosporine have not been established in renal transplant patients [see Warnings and Precautions (5.12)].
The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients have not been established [see Clinical Studies (14.4)].
2 DOSAGE AND ADMINISTRATION
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.
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 x (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 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).
Two milligrams (2 mg) of Rapamune Oral Solution have been demonstrated to be clinically equivalent to 2 mg Rapamune Tablets; 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 Clinical Pharmacology (12.3)].
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