No major safety problems were identified in the Food and Drug Administration’s review of compounded formulations of hydroxyprogesterone caproate, but the agency continues to emphasize that the approved version of the product, known as Makena, used to reduce the risk of preterm birth in certain patients, is more reliable.
A statement issued by the FDA on June 15 says that the agency’s analyses of a "limited sample" of compounded formulations of hydroxyprogesterone caproate and samples of the active ingredient used to make these formulations – obtained from compounding pharmacies, physician’s offices, distributors of the active pharmaceutical ingredient (API) and imported APIs – found that most had met potency and purity standards. However, approved products such as Makena, the FDA-approved version of hydroxyprogesterone caproate, "provide a greater assurance of safety and effectiveness than do compounded products," the statement said.
Hydroxyprogesterone caproate, a progestin, is the active ingredient in Makena, which was approved by the FDA in February 2011, for reducing the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth; it is administered intramuscularly once a week. Before the approval of Makena, formulations of hydroxyprogesterone caproate compounded by pharmacists had been used for years, and the availability of a reliable approved version was welcomed, but enthusiasm was quickly tempered by the high price tag of the approved version.
In November 2011, the FDA announced that it had started to conduct analyses of compounded hydroxyprogesterone caproate products and bulk APIs, and that it would review data submitted by K-V Pharmaceuticals, the sponsor of Makena, which had found "variability" in their purity and potency.
In the June 15 statement, the FDA provided the final results of its testing and analyses: All 16 samples of the hydroxyprogesterone caproate API passed the tests for potency as specified by the United States Pharmacopeia (USP), and passed the potency tests used in the approval application for Makena. All 16 of these samples also passed the standard for total purity that was used in the Makena application, but "failed" to meet the limit for unidentified impurities used in the Makena application. The FDA also identified four impurities that exceeded the levels allowed in the Makena application, but they "do not raise safety concerns," the statement said,
Of the 13 compounded hydroxyprogesterone caproate products from eight pharmacies, one was subpotent, at about 80% of declared potency. All samples met the standard for total purity in the Makena application, and 2 of the 13 samples did not meet the standard for unidentified impurities used in the Makena application.
In the FDA’s analysis of the 26 samples of the compounded product from the laboratories that had conducted the testing for K-V, 3 failed to meet the potency standard with the method used in the Makena new drug application (NDA), and 7 of these samples failed the standard for unidentified purities that were used in the Makena NDA.
"Although the analysis of this limited sample of compounded hydroxyprogesterone caproate products and APIs did not identify any major safety problems, approved drug products, such as Makena, provide a greater assurance of safety and effectiveness than do compounded products," the FDA statement said. "Before approving the Makena NDA, FDA reviewed manufacturing information, such as the source of the API used by its manufacturer, proposed manufacturing processes, and the firm’s adherence to current good manufacturing practice."
Compounded products are not FDA approved, and compounding of any drug "should not exceed the scope of traditional pharmacy compounding," according to the FDA.
The full FDA statement is available.