ROCKVILLE, MD. — Need proof that postmarketing risk management programs can work?
From March 1, 2005, through March 17, 2006, the year after the diabetes drug pramlintide became available in the United States, there were 10 reports of medically assisted severe hypoglycemia (MASH) in patients treated with the drug, Dr. Gary L. Bloomgren said at a meeting sponsored by the International Society for Pharmacoepidemiology.
This is a rate of 0.06 events per 1,000 units or vials of pramlintide dispensed, all occurring in type 1 patients within the first month of treatment, which “fits very clearly” with what was observed in the preapproval clinical program, noted Dr. Bloomgren, executive director of global safety, Amylin Pharmaceuticals Inc., San Diego.
The phase II and III controlled trials were blinded and allowed patients to make only minimal changes to their diets, a circumstance that may have contributed to higher rates of insulin-induced hypoglycemia, Dr. Bloomgren said. During the first 3 months of the trials, the incidence of MASH was 3% among those on placebo and insulin vs. about 7% among those on pramlintide and insulin in placebo-controlled studies in which insulin was not reduced.
The cumulative MASH reports during the year after approval were estimated as 3 cases per 1,000 patient-years of use among type 1 diabetics. He compared this with 100 MASH cases per 1,000 patient-years among those on pramlintide and insulin during the first 3 months of use in the open-label clinical practice study (in which the insulin dose was reduced during initiation), and 40 MASH events per 1,000 patient-years over the subsequent 3–6 months of treatment.
Dr. Bloomgren attributed what he described as a “safe start” to the drug's use in the United States to the risk management program in place when it was approved. The plan, which included warnings in the label about the risk of severe hypoglycemia and limited drug promotion to diabetes specialists, is the reason the drug is on the market today, he said.
Pramlintide, which is marketed by Amylin under the trade name Symlin, is a synthetic analogue of human amylin, a naturally occurring neuroendocrine hormone that is secreted with insulin by pancreatic B cells and is also deficient in diabetes. It was approved in March 2005 for use at mealtimes as an adjunct to insulin in patients with type 1 or 2 diabetes who have not achieved their desired glucose control despite optimal insulin therapy.
The risk management program was instituted to manage the risk of severe insulin-induced hypoglycemia, which had been identified as a serious safety issue associated with the drug. Overall, the risk-benefit assessment favored approval, given the glycemic control evidenced by HbA1c and postprandial glucose values.
MASH is defined as hypoglycemia requiring treatment with a glucagon injection or IV glucose, hospitalization or an emergency department visit, or paramedic assistance. This was distinguished from mild to moderate hypoglycemia and patient-ascertained severe hypoglycemia.
Factors that were identified before approval as increasing the risk of insulin-induced hypoglycemia included being a type 1 diabetic, having had recent episodes of hypoglycemia and/or a history of hypoglycemia unawareness, and not reducing mealtime insulin before starting pramlintide. Carefully selecting candidates for pramlintide was emphasized as “critical” to the safe and effective use of the drug, Dr. Bloomgren said.