FDA approved Makena (hydroxyprogesterone caproate) in February 2011 for the reduction of the risk of certain preterm births in women who have had at least one prior preterm birth. Beginning many years before Makena was approved, a version of the active ingredient of Makena has been available to patients whose physicians requested the drug from a pharmacist who compounded the drug.
The FDA received information in October 2011 from Makena’s sponsor, K-V Pharmaceuticals, regarding the potency and purity of samples of bulk hydroxyprogesterone caproate active pharmaceutical ingredients (APIs) and compounded hydroxyprogesterone caproate products. In November 2011, the Agency explained that the FDA had carefully reviewed the data K-V submitted and would conduct an on-site review of the laboratory analyses. The Agency also stated that FDA had begun its own sampling and analysis of compounded hydroxyprogesterone caproate products and the bulk APIs used to make them.
FDA has completed its review, and the Agency is now providing a brief summary of the results.
FDA collected samples of compounded hydroxyprogesterone caproate products and hydroxyprogesterone caproate APIs. These samples generally were collected from compounding pharmacies, doctor’s offices, API distributors and APIs offered for importation.
FDA tested 16 samples of hydroxyprogesterone caproate API using the methods specified in the United States Pharmacopeia (USP) as well as the methods used in the Makena new drug application (NDA).
- All 16 API samples passed USP tests for potency (97-103 percent) and purity and all 16 API samples passed the potency tests in the Makena NDA.
- All 16 of the API samples passed the total purity standard in the Makena NDA but failed the Makena NDA’s limit for unidentified impurities.
- FDA also isolated and identified four impurities that appeared at levels above those permitted in the Makena NDA. Based on information available to FDA, the impurities observed in these samples do not raise safety concerns.
FDA also tested 13 samples of compounded hydroxyprogesterone caproate prepared by eight pharmacies.
- One of 13 samples was subpotent and was in the range of 80 percent of declared potency. (The standard for potency is 90-110 percent). All 13 of the samples met the standard in the Makena NDA for total purity.
- Two of the 13 samples failed to meet the standard for unidentified impurities in the Makena NDA.
- FDA also obtained the available retained samples of compounded products from the laboratories that K-V hired to perform the tests on the compounded products that were submitted to the agency in October 2011. FDA’s testing of the retained samples found that three of 26 samples failed the standard for potency (90-110 percent) using the method in the Makena NDA (The samples were not large enough for FDA also to test them using the USP method). The three products that failed potency testing were in the 115 percent range. Seven of 26 samples failed the standard for unidentified impurities 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.
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.
The drugs that pharmacists compound (including compounded hydroxyprogesterone caproate) are not FDA approved, which means they do not undergo premarket review nor do they have an FDA finding of safety and efficacy.
Compounding large volumes of drugs that are copies of FDA-approved drugs circumvents important public health requirements, including the Federal Food, Drug, and Cosmetic Act’s drug approval provisions. Consumers and health professionals rely on the Act’s evidence-based drug approval process to ensure that drugs are safe and effective. For that reason, one factor that the agency considers when determining whether a drug may be compounded is whether the prescribing practitioner has determined that a compounded product is necessary for the particular patient and would provide a significant difference for the patient as compared to the FDA-approved commercially available drug product.
FDA emphasizes that it is applying its normal enforcement policies for compounded drugs to compounded hydroxyprogesterone caproate. The compounding of any drug, including hydroxyprogesterone caproate, should not exceed the scope of traditional pharmacy compounding. As the Agency has previously explained, FDA generally prioritizes enforcement actions related to compounded drugs using a risk-based approach, giving the highest enforcement priority to pharmacies that compound products that are causing harm or that amount to health fraud.