Rapamune (sirolimus) - 2 indications

Scroll down for more information on each indication:

• for the prevention of organ rejection in patients receiving kidney transplants; approved September 1999
• for the treatment of lymphangioleiomyomatosis; approved May of 2015

General Information

Rapamune (sirolimus) is an immunosuppressant.

Rapamune is specifically indicated for the following:

• for the prophylaxis of organ rejection in patients aged ≥13 years receiving renal transplants:
  • Patients at low- to moderate-immunologic risk: Use initially with cyclosporine (CsA) and corticosteroids. CsA withdrawal is recommended 2–4 months after transplantation.
  • Patients at high-immunologic risk: Use in combination with CsA and corticosteroids for the first 12 months following transplantation. Safety and efficacy of CsA withdrawal has not been established in high risk patients.
• for the treatment of patients with lymphangioleiomyomatosis 

Rapamune is supplied as an oral solution and as tablets for oral administration. Scroll down for the recommended dosing/administration for each indication.

Mechanism of Action

Rapamune (sirolimus) inhibits T-lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin [IL]-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. The sirolimus:FKBP-12 complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian target of rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G1 to the S phase of the cell cycle.

Lymphangioleiomyomatosis involves lung tissue infiltration with smooth muscle-like cells that harbor inactivating mutations of the tuberous sclerosis complex (TSC) gene (LAM cells). Loss of TSC gene function activates the mTOR signaling pathway, resulting in cellular proliferation and release of lymphangiogenic growth factors. Sirolimus inhibits the activated mTOR pathway and thus the proliferation of LAM cells.

Side Effects

Adverse effects associated with the use of Rapamune for the prophylaxis of organ rejection in patients receiving renal transplants may include, but are not limited to, the following:

• peripheral edema
• hypertriglyceridemia
• hypertension
• hypercholesterolemia
• creatinine increased
• abdominal pain
• diarrhea
• headache
• fever
• urinary tract infection
• anemia
• nausea
• arthralgia
• pain
• thrombocytopenia

Adverse effects associated with the use of Rapamune for the treatment of lymphangioleiomyomatosis may include, but are not limited to, the following:

• stomatitis
• diarrhea
• abdominal pain
• nausea
• nasopharyngitis
• acne
• chest pain
• peripheral edema
• upper respiratory tract infection
• headache
• dizziness
• myalgia
• hypercholesterolemia

The Rapamune drug label comes with the following Black Box Warning: IMMUNOSUPPRESSION, USE IS NOT RECOMMENDED IN LIVER OR LUNG TRANSPLANT PATIENTS. Increased susceptibility to infection and the possible development of lymphoma and other malignancies may result from immunosuppression. 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. 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.

Indication 1 - the prevention of organ rejection in patients receiving kidney transplants

approved September 1999

Dosing/Administration

• Administer once daily by mouth, consistently with or without food.
• Administer the initial dose as soon as possible after transplantation and 4 hours after CsA
• Adjust the Rapamune maintenance dose to achieve sirolimus trough concentrations within the target-range
• Hepatic impairment: Reduce maintenance dose in patients with hepatic impairment

In renal transplant patients at low-to moderate-immunologic risk:

• Rapamune and CsA Combination Therapy: One loading dose of 6 mg on day 1, followed by daily maintenance doses of 2 mg.
• Rapamune Following CsA Withdrawal: 2–4 months post-transplantation, withdraw CsA over 4–8 weeks.

In renal transplant patients at high-immunologic risk:

• Rapamune and CsA 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 

Clinical Trial Results

The safety and efficacy of Rapamune Oral Solution for the prevention of organ rejection following renal transplantation were assessed in two randomized, double-blind, multicenter, controlled trials. These studies compared two dose levels of Rapamune Oral Solution (2 mg and 5 mg, once daily) with azathioprine (Study 1) or placebo (Study 2) when administered in combination with cyclosporine and corticosteroids. Study 1 was conducted in the United States at 38 sites. Seven hundred nineteen (719) patients were enrolled in this trial and randomized following transplantation; 284 were randomized to receive Rapamune Oral Solution 2 mg/day; 274 were randomized to receive Rapamune Oral Solution 5 mg/day, and 161 to receive azathioprine 2–3 mg/kg/day. Study 2 was conducted in Australia, Canada, Europe, and the United States, at a total of 34 sites. Five hundred seventy-six (576) patients were enrolled in this trial and randomized before transplantation; 227 were randomized to receive Rapamune Oral Solution 2 mg/day; 219 were randomized to receive Rapamune Oral Solution 5 mg/day, and 130 to receive placebo. In both studies, the use of antilymphocyte antibody induction therapy was prohibited. In both studies, the primary efficacy endpoint was the rate of efficacy failure in the first 6 months after transplantation. Efficacy failure was defined as the first occurrence of an acute rejection episode (confirmed by biopsy), graft loss, or death.

Rapamune Oral Solution, at doses of 2 mg/day and 5 mg/day, significantly reduced the incidence of efficacy failure at 6 months following transplantation compared with both azathioprine and placebo.

Indication 2 - the treatment of lymphangioleiomyomatosis

approved May of 2015

Dosing/Administration

• Administer once daily by mouth, consistently with or without food.
• Recommended initial Rapamune dose is 2 mg/day.
• Adjust the Rapamune dose to achieve sirolimus trough concentrations between 5–15 ng/mL.
• Reduce maintenance dose in patients with hepatic impairment

Clinical Trial Results

The safety and efficacy of Rapamune for treatment of lymphangioleiomyomatosis (LAM) were assessed in a randomized, double-blind, multicenter, controlled trial. This study compared Rapamune (dose-adjusted to maintain blood trough concentrations between 5–15 ng/mL) with placebo for a 12-month treatment period, followed by a 12-month observation period. Eighty-nine (89) patients were enrolled; 43 patients were randomized to receive placebo and 46 patients to receive Rapamune. The primary endpoint was the difference between the groups in the rate of change (slope) per month in forced expiratory volume in 1 second (FEV1). During the treatment period, the FEV1 slope was -12±2 mL per month in the placebo group and 1±2 mL per month in the Rapamune group (treatment difference = 13 mL). The absolute between-group difference in the mean change in FEV1 during the 12-month treatment period was 153 mL, or approximately 11% of the mean FEV1 at enrollment. Similar improvements were seen for forced vital capacity (FVC). After discontinuation of Rapamune, the decline in lung function resumed in the Rapamune group and paralleled that in the placebo group