Tacrolimus

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.

Prograf (Janssen-Cilag)
1 mg and 5 mg capsules
solution for injection containing 5 mg/mL

Indication: immunosuppression for liver transplantation

Immunosuppressive drugs are used to reduce the risks of rejection after organ transplants. Cyclosporin is often used, but can have serious adverse effects such as renal dysfunction. Tacrolimus has been developed to try to provide immunosuppression with fewer adverse effects.

Tacrolimus is an antibiotic derived from a fungus found in soil. Its structure is not related to cyclosporin, but it has similar properties. The method of action is uncertain, but may involve inhibition of cytokine secretion. Both humoral and cell-mediated immune responses are suppressed.

As the drug is hepatotropic, it has been studied in patients having liver transplants. One study compared tacrolimus plus low-dose corticosteroids with a cyclosporin-based regimen in over 500 patients. After 12 months, acute rejection had occurred in 107 of the 264 patients given tacrolimus and 132of the 265 given cyclosporin. There were also significant differences in the rates of refractory acute rejection and chronic rejection.1 Although there was not a significant improvement in survival, tacrolimus has been approved for primary immunosuppression in liver allograft recipients.

Treatment with tacrolimus begins 6 hours after transplant surgery. Usually a continuous infusion will be given. Tacrolimus is incompatible with PVC, so tubing and syringes containing such plastics should not be used. Once the patient can swallow, the capsules are given twice a day. Absorption is erratic and is reduced by food. Tacrolimus is highly bound to red blood cells and plasma proteins. The half-life varies between 3.5 and 40.5 hours with most of the drug being metabolised in the liver.

Although tacrolimus and cyclosporin appear to have similar adverse effects, they are more likely to develop in patients given tacrolimus. In the comparative study1, all patients had adverse reactions and 76 taking tacrolimus had to withdraw compared with 64taking cyclosporin. The most common complaints are diarrhoea, headache, tremor and nausea. Glucose metabolism and renal function may be impaired. At least 30% of patients will develop hypertension, but this is less than the incidence in patients given cyclosporin.

In addition to routine monitoring of patients after transplantation, concentrations of tacrolimus should be monitored. Trough concentrations in whole blood can be used when adjusting the dose. Monitoring the blood concentration is important if certain drugs are given with tacrolimus. As tacrolimus is metabolized by cytochrome P450 3A4, the drugs it interacts with include ketoconazole and erythromycin.

Physicians and their patients must now decide if the effectiveness of tacrolimus outweighs the higher incidence of toxicity relative to cyclosporin.

References

  1. European FK506 Multi centre Liver Study Group. Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. Lancet 1994;344:423-8.