Everolimus

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.

Certican (Novartis)
0.25 mg, 0.5 mg and 0.75 mg tablets
Approved indication: transplantation
Australian Medicines Handbook section 14.1

Everolimus is a derivative of the immunosuppressant drug sirolimus. It has been approved for use by patients receiving a heart or kidney transplant.

Although patients' survival after transplant has improved, problems may develop in the long term. For example, treatment with cyclosporin can damage the transplanted kidney and vasculopathy may complicate heart transplants. Everolimus may therefore have a role in preventing organ rejection because it inhibits cell proliferation. This inhibition includes vascular smooth muscle cells as well as T-cells.

Treatment begins as soon as possible after transplantation. Peak concentrations occur within two hours of an oral dose, but absorption is reduced by food. Steady state concentrations are reached within four days. Everolimus is metabolised by liver enzymes including cytochrome P450 3A4. Most of the metabolites are excreted in the faeces. The half-life of everolimus is approximately 28 hours.

Everolimus was compared with azathioprine in patients following heart transplantation. These 634 patients were also treated with cyclosporin, corticosteroids and a 'statin'. The end point of the study was a mixture of death or rejection. After 12 months, 52.8% of the azathioprine group had reached this end point. This was significantly more than the 41.6% of the 209 patients given everolimus 1.5 mg, and the 32.2% of the 211 patients given everolimus 3.0 mg.¹

Studies in renal transplantation used mycofenolate mofetil as a comparator. Rejection had occurred by six months in 23.5% of the mycofenolate group, 21.6% of those taking everolimus 1.5 mg and 18.2% of those taking everolimus 3.0 mg.

Two studies used everolimus to lower the dose of cyclosporin used after renal transplantation. Although there was no comparator arm in the studies, both doses of everolimus were associated with satisfactory renal function after six months.²

As rejection occurs more frequently with lower concentrations, the blood concentration of everolimus must be monitored regularly. More frequent monitoring will be needed if the patient is started on a drug which inhibits (ketoconazole) or induces (rifampicin) CYP3A4.

Adverse events occur in almost everyone treated with everolimus. Approximately 10-22% of patients will discontinue treatment because of adverse events. These include anaemia, leucopenia, thrombocytopenia and infections.^1,2 In the heart transplant study significantly more bacterial infections occurred in the everolimus group. Even if the patients are taking 'statins' their triglyceride and cholesterol concentrations are likely to increase.¹

Managing patients after transplantation requires balancing the risk of organ rejection against the adverse effects of immunosuppression. Further study will be needed to define the place of everolimus. The results of a Cochrane review of the effects of everolimus and sirolimus in renal transplantation are not yet available.³