Rapamune - Drug Monograph

Introduction

Rapamune (sirolimus) is an immunosuppressive macrolide antibiotic produced by Streptomyces hygroscopicus. It represents a distinct class of immunosuppressive agents that differ mechanistically from calcineurin inhibitors and corticosteroids. Approved by the FDA in 1999, Rapamune is primarily used to prevent organ rejection in renal transplant recipients, typically as part of a maintenance immunosuppressive regimen following initial therapy with other agents.

Mechanism of Action

Sirolimus exerts its immunosuppressive effects by binding to the cytosolic immunophilin FK Binding Protein-12 (FKBP-12), forming a complex that inhibits the mammalian Target of Rapamycin (mTOR). This inhibition blocks cytokine-driven T-cell proliferation by preventing progression from the G1 to the S phase of the cell cycle. Unlike calcineurin inhibitors, sirolimus does not inhibit calcineurin activity or cytokine production, but rather inhibits the cellular response to cytokines. Additionally, sirolimus inhibits antibody production and may have antiproliferative effects on vascular smooth muscle cells.

Indications

• Primary indication: Prophylaxis of organ rejection in patients receiving renal transplants (typically used in combination with corticosteroids and calcineurin inhibitors)
• Off-label uses:

- Liver and heart transplantation (as maintenance immunosuppression) - Lymphangioleiomyomatosis (LAM) - Tuberous sclerosis complex - Psoriasis - Certain autoimmune disorders - Vascular anomalies

Dosage and Administration

• Oral administration only
• Should be taken consistently with or without food
• Tablets should be swallowed whole; do not crush, chew, or split
• Oral solution should be mixed only with water or orange juice

• Hepatic impairment: Reduce maintenance dose by approximately 33%
• Pediatric patients: Dose based on body surface area (1 mg/m²/day)
• Elderly: No specific dosage adjustment recommended, but monitor carefully
• Cytochrome P450 3A4 inhibitors/inducers: Significant dosage adjustments required

Pharmacokinetics

Contraindications

• Hypersensitivity to sirolimus, its derivatives, or any component of the formulation
• Use with strong CYP3A4 inhibitors (e.g., ketoconazole, voriconazole, itraconazole, clarithromycin, telithromycin)
• Use with strong CYP3A4 inducers (e.g., rifampin, rifabutin)
• Patients with significantly impaired liver function not adequately managed

Warnings and Precautions

• Increased susceptibility to infection and potential development of lymphoma and other malignancies
• Increased risk of hepatic artery thrombosis in liver transplant recipients
• Increased mortality in heart transplant recipients

• Hyperlipidemia: Significant increases in serum cholesterol and triglycerides requiring management
• Renal impairment: May be associated with delayed recovery from acute tubular necrosis
• Wound healing complications: Increased risk of wound dehiscence and fluid collections
• Interstitial lung disease: Includes pneumonitis, bronchiolitis obliterans organizing pneumonia, and pulmonary fibrosis
• Proteinuria and nephrotic syndrome reported in some patients
• Thrombocytopenia, anemia, and neutropenia may occur

Drug Interactions

• CYP3A4 inhibitors: Increased sirolimus levels (e.g., ketoconazole, erythromycin, diltiazem, verapamil)
• CYP3A4 inducers: Decreased sirolimus levels (e.g., rifampin, carbamazepine, phenytoin)
• Grapefruit juice: May increase sirolimus concentrations
• Other immunosuppressants: Additive immunosuppressive effects and increased infection risk
• Live vaccines: Avoid concurrent administration

Adverse Effects

• Hypercholesterolemia (38-46%)
• Hypertension (33-49%)
• Anemia (24-33%)
• Thrombocytopenia (14-30%)
• Fever (20-24%)
• Abdominal pain (20-23%)
• Nausea (20-22%)
• Diarrhea (18-21%)
• Acne (15-20%)
• Arthralgia (18-20%)
• Peripheral edema (17-20%)
• Rash (10-20%)

• Pneumonitis (0.7-3.5%)
• Lymphoma and other malignancies (0.7-2.0%)
• Serious infections (10-13%)
• Hepatic artery thrombosis (liver transplant: 2.1-4.1%)
• Delayed wound healing (1.5-4.7%)
• Nephrotic syndrome (0.4%)
• Interstitial lung disease

Monitoring Parameters

• Trough sirolimus concentrations (target range typically 4-20 ng/mL)
• Frequency: Weekly until stable, then monthly or as clinically indicated

• Complete blood count (weekly initially, then monthly)
• Lipid profile (baseline, then at 3 months, then quarterly)
• Renal function (serum creatinine, BUN)
• Liver function tests
• Urinalysis and urine protein quantification
• Blood glucose
• Electrolytes, particularly potassium and magnesium

• Signs and symptoms of infection
• Wound healing assessment
• Respiratory symptoms (cough, dyspnea)
• Blood pressure
• Edema assessment
• Skin examination for malignancies

Patient Education

• Take medication at the same time each day, consistently with or without food
• Do not crush, chew, or split tablets
• Oral solution should be mixed only with water or orange juice
• Avoid grapefruit and grapefruit juice during therapy
• Report any signs of infection (fever, chills, sore throat)
• Report unusual bleeding, bruising, or fatigue
• Report new respiratory symptoms (cough, shortness of breath)
• Use sun protection due to increased skin cancer risk
• Avoid live vaccines unless specifically approved by transplant team
• Inform all healthcare providers about sirolimus use
• Adhere to regular laboratory monitoring appointments
• Notify transplant team before starting any new medications
• Women of childbearing potential should use effective contraception

References

1. Product Information: RAPAMUNE® oral solution, tablets, sirolimus oral solution, tablets. Pfizer Labs, New York, NY, 2021. 2. Kahan BD. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. Lancet. 2000;356(9225):194-202. 3. MacDonald AS; RAPAMUNE Global Study Group. A phase III study of sirolimus compared with azathioprine in combination with cyclosporine and corticosteroids in primary renal allograft recipients. Transplantation. 2001;72(5):875-880. 4. Kaplan B, Schold JD, Meier-Kriesche HU. Sirolimus and chronic allograft nephropathy: results of a multicenter, randomized, controlled trial. Transplantation. 2005;80(1):123-128. 5. Augustine JJ, Hricik DE. Sirolimus: a decade of experience in renal transplantation. Am J Transplant. 2009;9(4):741-748. 6. Weir MR, Fink JC. Risk for posttransplant diabetes mellitus with current immunosuppressive medications. Am J Kidney Dis. 1999;34(1):1-13. 7. Nashan B. Early clinical experience with a novel rapamycin derivative. Ther Drug Monit. 2002;24(1):53-58. 8. Clinical Pharmacology [Internet]. Tampa (FL): Gold Standard, Inc.; 2023. Sirolimus. 9. Lexicomp Online [Internet]. Hudson (OH): Wolters Kluwer Clinical Drug Information, Inc.; 2023. Sirolimus. 10. Transplant Pharmacy Specialist Practice Group of the American Society of Health-System Pharmacists. Guidelines for the use of sirolimus in kidney transplantation. Am J Health Syst Pharm. 2003;60(14):1421-1432.