RAPAMUNE

What it is

Rapamune is a medicine containing sirolimus. It is available as tablets containing 0.5 mg, 1 mg and 2 mg sirolimus, or as an oral solution containing 1 mg/mL sirolimus. Sirolimus is a selective immunosuppressant agent that inhibits T cell activation induced by most stimuli by blocking calcium dependent and calcium-independent intracellular signal transduction.

Approved indications

— Prophylaxis of organ rejection in patients at mild to moderate immunological risk receiving renal transplants.

Dosing overview

Adults usually receive an initial 6 mg oral loading dose of Rapamune as soon as possible after transplantation, followed by 2 mg once daily in combination with ciclosporin and corticosteroids. The dose is then individualised to obtain sirolimus whole blood trough concentrations of 4–12 ng/mL (chromatographic assay). After 2 to 4 months, ciclosporin is progressively discontinued over 4 to 8 weeks and the Rapamune dose adjusted to obtain sirolimus whole blood trough concentrations of 12–20 ng/mL (chromatographic assay). The maximum Rapamune dose administered on any day should not exceed 40 mg. In patients with hepatic impairment, the maintenance dose should be reduced by approximately one third in mild to moderate hepatic impairment and by approximately one half in severe hepatic impairment.

Key safety warnings mTOR inhibitors such as sirolimus have been shown to inhibit production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability, and there have been reports of impaired or delayed wound healing in patients receiving Rapamune, including lymphocele and wound dehiscence. There have also been reports of fluid accumulation, including peripheral oedema, lymphoedema, pleural effusion and pericardial effusions (including haemodynamically significant effusions in children and adults), in patients receiving Rapamune. Immunosuppression increases the susceptibility to the development of lymphoma and other malignancies, particularly of the skin, and patients taking Rapamune should limit exposure to sunlight and UV light by wearing protective clothing and using a sunscreen with a high protective factor. Over-suppression of the immune system can increase susceptibility to opportunistic infections, sepsis and fatal infections. The use of Rapamune in renal transplant patients was associated with increased serum cholesterol and triglyceride concentrations that may require treatment, and patients should be monitored for hyperlipidaemia using laboratory tests. Cases of interstitial lung disease (including pneumonitis, and infrequently bronchiolitis obliterans with organising pneumonia and pulmonary fibrosis), some fatal, with no identified infectious aetiology have occurred in patients receiving immunosuppressive regimens including Rapamune, and in some cases the interstitial lung disease has resolved upon discontinuation or dose reduction of Rapamune. Patients treated with immunosuppressants, including Rapamune, are at increased risk for opportunistic infections, including activation of latent viral infections such as BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy, which may lead to serious or fatal outcomes, including graft loss.

Contraindications

Rapamune is contraindicated in patients with a known hypersensitivity to sirolimus or its derivatives or any of the excipients.

PBS listing

Rapamune is listed on the PBS in four strengths: oral solution 1 mg per mL (60 mL bottle) with an ex-manufacturer price of A$462.01; tablet 1 mg with an ex-manufacturer price of A$587.52; tablet 2 mg with an ex-manufacturer price of A$1175.06; and tablet 0.5 mg with an ex-manufacturer price of A$293.77. The listing includes items with unrestricted, restricted, and streamlined restriction types.

Regulatory history

Rapamune oral solution (1 mg/mL, 60 mL) was first listed on the ARTG on 21 May 2002. The tablet formulations followed: 1 mg and 2 mg tablets were first listed on 4 July 2006, and 0.5 mg tablets on 3 February 2011.