Rosiglitazone maleate

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.

Avandia (SmithKline Beecham)
4 mg and 8 mg film-coated tablets
Approved indication: type 2 diabetes
Australian Medicines Handbook Section 10.1

Rosiglitazone is the second drug of its class to be approved for use in Australia. It has wider indications than troglitazone, the first drug to be approved (see 'New drugs' Aust Prescr 1999;22:150). Rosiglitazone can be prescribed when a patient's blood glucose is not controlled by diet. It can also be used in combination with metformin and sulfonylureas.

Like troglitazone, rosiglitazone reduces insulin resistance. Although reductions in fasting blood glucose occur soon after starting treatment, the full effect on insulin sensitivity is not seen for six to eight weeks. The starting dose of 4 mg daily may be increased to 8 mg daily after this interval.

The tablets can be taken once or twice daily. They are completely absorbed and have a bioavailability of 99%. Rosiglitazone is completely metabolised by the liver. Cytochrome P450 2C8 is the main enzyme involved. The drug is not recommended for people with liver disease. Most of the metabolites are excreted in the urine, but a dose reduction is not required if there is renal impairment.

There are not many published clinical trials of rosiglitazone. A 26-week study of 493 patients with type 2 diabetes found that a twice-daily dose of 2 mg or 4 mg reduced glycated haemoglobin (HbA1c) by 0.9-1.5% more than placebo. Twice-daily doses appeared to have greater efficacy than once daily.

Rosiglitazone was as effective as glibenclamide in reducing HbA1c in a comparative study. After a year, HbA1c was reduced 0.7% by glibenclamide and 0.5% by rosiglitazone 4 mg twice daily. The HbA1c of patients given 2 mg rosiglitazone twice daily fell by only 0.3%, but both doses of rosiglitazone had a greater effect on fasting plasma glucose than glibenclamide did.

Other trials have studied the use of rosiglitazone in combination with metformin or sulfonylureas. The combinations usually improve glycaemic control more than monotherapy. For example, adding rosiglitazone 4 mg twice daily to metformin will reduce HbA1c by 0.8% more than metformin alone.

In the clinical trials rosiglitazone was generally well tolerated. Some patients will develop fluid retention so there is a risk of precipitating heart failure. Rosiglitazone increases LDL and HDL cholesterol and can cause anaemia.

The first drug of this class, troglitazone, was withdrawn following reports of hepatic toxicity. Although only 0.2% of patients taking rosiglitazone have had hepatic adverse events, there is a concern that the toxicity may be a class effect. Patients should therefore have their liver function checked before treatment and every two months during the first year of therapy, then periodically thereafter. Rosiglitazone has not been approved for use in Europe and an American consumer drug bulletin has advised its readers not to use rosiglitazone for five years.1