FDA Approves Combo PrandiMet for Treating Diabetes

The US Food and Drug Administration (FDA) has approved repaglinide plus metformin HCl tablets for the treatment of type 2 diabetes mellitus reducing A1c by 1.4%. This combines the effect of reducing fasting and postprandial blood sugars. On June 23, the FDA approved a fixed-dose combination of the meglitinide, repaglinide, with the biguanide, metformin HCl (PrandiMet; Novo Nordisk, Inc, and marketed by Sciele Pharma) for use as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus who are already being treated with a meglitinide and metformin or who have not achieved adequate glycemic control with either component alone.

The repaglinide/metformin tablets at 1 mg/500 mg and 2 mg/500 mg are bioequivalent to corresponding doses of co-administered individual components and will be available by prescription during the second half of 2008.

According to a company news release, only 57% of people with diabetes in the United States are meeting recommended blood glucose levels (hemoglobin A1c ≤ 7%). "We’ve seen that many patients need more than one therapy to control their type 2 diabetes," noted Patrick Fourteau, chief executive officer of Sciele Pharma, Inc.

By combining the insulin secretagogue repaglinide (Prandin; Novo Nordisk) with the sensitizer metformin, the combination tablets conveniently address 3 abnormalities of type 2 diabetes: impaired insulin secretion, insulin resistance, and excessive hepatic glucose production.

Their approval was based in part on data from a double-blind clinical trial of 83 patients with inadequate glycemic control while receiving metformin monotherapy, who were randomized to receive add-on repaglinide, repaglinide monotherapy, or continued treatment with metformin. Repaglinide dosing was titrated for 4 to 8 weeks, followed by a 3-month dose maintenance period.

Results showed that the addition of repaglinide to metformin significantly improved hemoglobin A1c and fasting plasma glucose levels from baseline vs repaglinide or metformin alone (Δ hemoglobin A1c: –1.4% vs –0.4% and –0.3%; P < .05 for both; Δ fasting plasma glucose levels: –39 mg/dL vs +9 mg/dL and –5 mg/dL; P < .05 for both).

The most commonly reported adverse events associated with use of repaglinide/metformin combination therapy were hypoglycemia and headache. Patients receiving combination therapy experienced a higher incidence of hypoglycemia vs repaglinide alone (33% vs 11%).

Also, those receiving repaglinide with or without metformin experienced weight gain, whereas patients given metformin alone had weight loss. Gastrointestinal tract effects are the most common adverse effect of metformin and are more frequent at higher doses.

Repaglinide/metformin can be administered 2 to 3 times a day, up to a maximal daily dose of 10 mg/2500 mg/day or 4 mg/1000 mg per meal. The recommended starting dose of repaglinide/metformin is 1 mg/500 mg taken twice daily 15 to 30 minutes before meals, unless the patient is already taking higher doses of the individual components. Dose escalation should be gradual (according to glycemic response) to reduce the risk for hypoglycemia with repaglinide and gastrointestinal tract adverse effects associated with metformin.

Use of the combination product is contraindicated in patients with renal impairment or metabolic acidosis and in those receiving both gemfibrozil and itraconazole. The FDA advises that renal function should be assessed and verified as normal before initiation of therapy and at least annually thereafter.