Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Rapamune (Wyeth)
1 mg/mL oral solution in 60 mL glass bottles
Approved indication: renal transplantation
Australian Medicines Handbook Section 14.1.1

Patients require immunosuppression after renal transplantation to prevent rejection of the allograft. Although cyclosporin is often used as an immunosuppressant it is associated with nephrotoxicity and hypertension. Including sirolimus in the regimen may enable cyclosporin to be withdrawn 2-4 months after transplantation.

Sirolimus is a substance produced by Streptomyces hygroscopicus. It inhibits antibody production and the activation and proliferation of T lymphocytes. Treatment should begin as soon as possible after the transplant.

The oral solution is rapidly absorbed. As its bioavailability of 14% is affected by food, patients should consistently take the drug with or without food. Sirolimus is metabolised by CYP3A4, so it should not be taken with grapefruit juice. Other drugs which affect this enzyme may increase or decrease concentrations of sirolimus. Blood concentrations of sirolimus should be routinely monitored. As cyclosporin is one of the drugs which inhibit the metabolism of sirolimus, the dose of sirolimus required to maintain the required blood concentration will increase if cyclosporin is withdrawn from the treatment regimen. The long half-life of sirolimus (62 hours) needs to be considered when assessing the effect of a change in dose. Only 2% of the drug and its metabolites are excreted in the urine.

A study of 719 patients compared two doses of sirolimus with azathioprine, in addition to a regimen of cyclosporin and corticosteroids. After a year, the acute rejection rate in the azathioprine group was 31% compared with 22% in patients taking 2 mg sirolimus daily and 15% in those taking 5 mg sirolimus daily. The rejection episodes were less severe in the sirolimus group, but after a year graft survival was similar in all groups.1

Treatment with sirolimus seemed to exacerbate cyclosporin-induced renal dysfunction and hypertension. The patients treated with sirolimus also had significantly higher creatinine concentrations. As this may be due to a drug interaction, regimens which discontinue cyclosporin could have an advantage.

In a clinical trial 430 patients were randomised to stop cyclosporin after three months or continue taking it with sirolimus and corticosteroids. Although graft survival after one year was similar (95-97%), the patients who had cyclosporin withdrawn had a significantly higher glomerular filtration rate. They also had significantly lower blood pressure. However, withdrawal of cyclosporin was associated with a higher incidence of acute rejection (20% versus 13.5%).2

Most patients will experience adverse events while taking a combination of drugs after renal transplantation. Very common adverse reactions include peripheral oedema, anaemia, thrombocytopenia, epistaxis and arthralgia. Immunosuppression increases the risk of infection and the development of malignancies. Patients are advised to protect themselves from sunlight to limit the risk of skin cancers. Prophylaxis against Pneumocystis carinii is also recommended. Sirolimus is associated with increases in cholesterol and lipids which may be severe enough to require drug treatment.

The best regimen for patients after a renal transplant is still to be determined. While sirolimus has some benefit its long-term safety and effectiveness are unknown. It also needs to be compared with other regimens, such as those using mycophenolate mofetil.