ROCKVILLE, Md. -- For the second time in two weeks, the FDA has informed physicians of an excess fracture risk in women taking an oral diabetes drug in the thiazolidinedione class. This time the drug is pioglitazone (Actos).
ROCKVILLE, Md., March 9 -- The FDA informed physicians today of an increased occurrence rate of arm, hand, and foot fractured among women taking pioglitazone (Actos) for type 2 diabetes.
The report follows on the heels of a similar one about rosiglitazone (Avandia), another thiazolidinedione, on excess limb fractures in women, issued on Feb. 21.
As with rosiglitizone, there was no evidence of increased fracture risk in men taking pioglitazone. Pioglitazone is marketed by Takeda and rosiglitazone by GlaxoSmithKline.
In a letter to physicians, Robert Spanheimer, M.D., of Takeda said that the fracture incidence in women was 1.9 fractures per 100 patient-years in the pioglitazone-treated group and 1.1 fractures per 100 patient-years in a comparator group.
On the basis of Takeda's analysis of data from more than 8,100 patients treated with pioglitazone and 7,400 patients in placebo or active treatment comparator groups followed for up to 3.5 years, the observed excess risk of fractures was 0.8 fractures per 100 patient-years of use.
Dr. Spanheimer said the explanation for the finding was unknown, but he pointed out that "none of the pioglitazone studies in the database addressed, or were designed to study, the effect on bone, but fractures were collected as adverse events."
For that reason, he said it was currently impossible to rule out multiple known risk fractures for fracture as confounding variables, but "further evaluation of these findings is ongoing."
He said the risk of fracture should be considered before initiating pioglitazone therapy in women with type 2 diabetes.
Drugs in the thiazolidinedione class have been shown to decrease fasting plasma glucose by 35 to 40 mg/dL and lower hemoglobin A1c by 0.5 to 1.5%.
The drugs work by stimulating peroxisome proliferative-insulin-activated receptors (PPAR) gamma receptor which cause insulin sensitizing effects on skeletal muscle and adipose tissue and by inhibiting hepatic gluconeogenesis.
A third drug in the class, troglitazone (Rezulin), was removed from the market due to hepatoxicity.
As a class the thiazolidinediones can cause edema, which can exacerbate heart failure. In post marketing studies of pioglitazone, there have been reports of new onset congestive heart failure. The drug is not indicated for patients with NYHA class III or IV heart failure and should be initiated at the lowest possible dose in patients with class II heart failure.
There have been postmarketing reports of hepatitis and of liver enzyme elevations of two to three times the upper limit of normal among patients taking pioglitazone. Rarely those reports involved liver failure, however causality has not been established. Liver enzymes should be evaluated before starting pioglitazone therapy and should be monitored periodically. Pioglitazone should pioglitazone should not be used if ALT values are greater than 2.5 times the upper limit of normal.
Pioglitazone may also be associated with hypoglycemia, edema, weight gain, and/or ovulation in premenopausal, anovulatory women. Pioglitazone may decrease the concentration of conjugated oral contraceptives.
In placebo-controlled studies the most common side effects reported for pioglitazone were upper respiratory tract infection, headache, sinusitis, myalgia, tooth disorder, aggravated diabetes mellitus, and pharyngitis.