FDA Supports Compounding of Off-Label Drug to Prevent Preterm Labor

Recently, the U.S. Food and Drug Administration (FDA) approved the new drug Makena (17-hydroxyprogesterone caproate) for the prevention of preterm labor. This is the first FDA-approved drug for this indication, but the active ingredient in the drug has been a standard of care for preventing preterm labor for nearly a decade. Until now, it has been compounded by pharmacies consequent to an individual medication order; this is not an approved practice in the eyes of the FDA, since the drug was never approved for use in preterm labor. Makena was originally met with triumph, but it soon felt like a tragedy to countless physicians and patients when KV Pharmaceuticals, the manufacturer of Makena, announced that it would sell Makena for $1500 per injection. When compounded individually, the drug is available for $10 to $20 per injection. Up to 20 injections are needed per pregnancy. The FDA announced on March 30, 2011, that it will allow pharmacies to continue compounding individual orders for hydroxyprogesterone caproate injections without repercussions.

Preterm birth, a birth that occurs prior to 37 weeks gestation, is a leading cause of morbidity and mortality among neonates in the United States. Preterm labor precedes most of these births. According to the American College of Obstetricians and Gynecologists (ACOG), preterm birth accounts for 35% of all healthcare spending for infants and 10% of all healthcare spending for children. Preterm birth can lead to significant medical and social disabilities, including cerebral palsy, mental retardation, behavioral and emotional disorders, vision and hearing impairments, epilepsy, and neonatal death. Preventing preterm birth and managing preterm labor are primary concerns of many obstetricians in an effort to save lives, reduce costs, and improve quality of life.

The first trials to report the success of 17-alpha-hydroxyprogesterone caproate, a synthetic progestin hormone, were published in the early 1970s. Since then, it has been shown to be effective in reducing preterm births among women at risk for such complications, namely women who are pregnant with one child and have had a preterm delivery in the past. In 1956, 17-alpha-hydroxyprogesterone was approved by the FDA under the name Delalutin and used for a variety of female hormone-related disorders: amenorrhea, dysfunctional bleeding, endometrial cancer, recurrent or threatened abortion, and postpartum pain. Though never officially approved for preventing preterm labor, Delalutin was routinely used off-label for this use. The manufacturer was seeking a preterm labor approval for Delalutin when it discontinued marketing the product in 2000. The FDA therefore withdrew its application for approval. The withdrawal and discontinuation were unrelated to safety concerns.

Since the discontinuation of Delalutin, pharmacies have been compounding 17-hydroxyprogesterone injections pursuant to individual medication orders. The FDA officially bans the compounding of products for off-label use, but has exercised enforcement discretion until now, choosing to allow pharmacies to continue this practice, as long as the product is prepared safely and appropriately in accordance with a valid physician order. When Makena was approved by the FDA, its manufacturer sent letters to pharmacies advising them to cease compounding 17-hydroxyprogesterone injections, and warning that the FDA would begin enforcing its ban on compounding 17-hydroxyprogesterone. The FDA announced on March 30 that KV Pharmaceutical’s claims were false and misleading; the FDA has no intention of preventing the safe and necessary compounding of this drug.

KV Pharmaceuticals has received much aid from the federal government prior to the approval of Makena, and it seems upset that the support has ended. Makena was developed from research funded by the National Institutes of Health, and it was awarded seven years of exclusive marketing rights under the Orphan Drug Act. It also gained FDA approval under expedited review. But now, even the federal government is at the forefront of the charge against KV Pharmaceuticals owing to the predatory pricing.

Many women and children in this country need access to this drug for the prevention of preterm labor and birth, and the ensuing complications. By pricing the drug up to 150 times higher than it has been available previously, the manufacturer is restricting access to women who might need this drug the most. KV Pharmaceuticals asserts that individual compounding does not guarantee consistency or safety among preparations, and that physicians and patients should be relieved to have access to a quality manufactured product. That’s a bitter pill to swallow when KV Pharmaceuticals admits that Makena has a 97.5% profit margin.

Senators, along with ACOG, the American Society for Health-System Pharmacists, the March of Dimes, and other medical societies, are putting pressure on Makena’s manufacturer to bring the price down. In response, KV Pharmaceuticals will make it available at a lower cost to patients who demonstrate financial need. But, this is not enough for many with a stake in the game. More research is needed to determine what actually causes preterm labor and how it should best be prevented, but, for now, a much-needed therapy with a proven track record of preventing countless complications and even more dollars should be available to every mom-to-be who needs it.


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Makena (hydroxyprogesterone caproate injection) package insert. Bloomington, IN: Baxter Pharmaceutical Solutions, LLC. Feb 2011.

ACOG Committee on Practice Bulletins–Obstetrics (2003). ACOG practice bulletin. Management of preterm labor. Number 43, May 2003. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics, 82 (1), 127-35 PMID: 12834934

Mason MV, Poole-Yaeger A, Krueger CR, House KM, & Lucas B (2010). Impact of 17P usage on NICU admissions in a managed medicaid population–a five-year review. Managed care (Langhorne, Pa.), 19 (2), 46-52 PMID: 20550052

Petrini JR, Callaghan WM, Klebanoff M, Green NS, Lackritz EM, Howse JL, Schwarz RH, & Damus K (2005). Estimated effect of 17 alpha-hydroxyprogesterone caproate on preterm birth in the United States. Obstetrics and gynecology, 105 (2), 267-72 PMID: 15684150

U.S. Food and Drug Administration, Press Release: FDA Statement on Makena. March 30, 2011.

Jennifer Gibson, PharmD

Jennifer Gibson, PharmD, is a practicing clinical pharmacist and medical writer/editor with experience in researching and preparing scientific publications, developing public relations materials, creating educational resources and presentations, and editing technical manuscripts. She is the owner of Excalibur Scientific, LLC.
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