FDA Announces Withdrawal Approval of Premature Birth Drug, Makena, Prompting Compounded Vaginal Progesterone as a Potential Alternative

The FDA officially withdrew the accelerated approval of Makena, a hydroxyprogesterone caproate injection, on April 6, 2023. It is suggested compounders steer clear of compounding it to remain consistent with the FDA’s sentiment. 

Makena was intended to prevent preterm birth in women with a history of spontaneous preterm birth carrying a single fetus.

FDA Announces the Withdrawal Approval of Makena

The United States Food and Drug Administration (FDA) recently announced the withdrawal of its approval for privately held Covis Pharma's Makena (hydroxyprogesterone caproate injection) and all associated generic products.

The decision was based on a comprehensive review of the drug's safety and efficacy in preventing preterm birth and was made by the FDA's Commissioner and Chief Scientist.

Makena is a drug that was approved over a decade ago to mitigate the risk of preterm birth. Makena had been the only medication approved for this condition, making the decision significant for the medical community and pregnant women at risk of preterm delivery.

Covis said previously the drug has a strong safety record and adverse events are rare, but the FDA said some evidence suggests there may be long-term risks that aren't yet well understood.

The FDA says the drug is ineffective and that its benefits do not outweigh the risks.

The FDA's decision comes after an extensive review of data and clinical studies conducted over the past decade, which failed to establish the drug's efficacy in reducing preterm births. The FDA determined the drug's risks outweigh its potential benefits, prompting the agency to revoke its approval.

Covis said it would pull Makena voluntarily, but it wanted that process to wind down over several months, however, the FDA rejected that proposal.

Makena’s High cost and Limited Effectiveness Prompted the FDA to Review the Drug

Makena, also known as hydroxyprogesterone caproate, was approved in 2011 and has been used to prevent preterm births in pregnant women who have had a previous preterm birth. However, the drug has been controversial due to its high cost and limited effectiveness, prompting the FDA to review its safety and efficacy.

Covis, the drug manufacturer, reports that approximately 350,000 women have received treatment with Makena since its approval. A large study conducted in 2019 demonstrated the drug did not effectively prevent preterm birth.

The FDA's decision to withdraw Makena's approval is a big development in the field of maternal-fetal medicine and has implications for the care of pregnant women at risk of preterm birth.

The agency's decision is aimed at promoting the safety and well-being of pregnant women and their newborns and ensuring that robust clinical data and scientific evidence support treatments used in obstetrics.

The withdrawal of Makena's approval will require manufacturers to cease drug production and initiate a phase-out period to ensure that patients can access alternative treatments.

Remembering How Makena Blazed the FDA’s Approval Pathway in 2011

The FDA approved Makena in 2011 under the accelerated approval pathway following a determination that the drug had demonstrated a positive effect on an intermediate clinical endpoint deemed likely to predict clinical benefit.

The approval came with a requirement that the drug's sponsor conduct a post-marketing confirmatory study to verify clinical benefit.

However, the subsequent confirmatory study failed to confirm clinical benefit, prompting the FDA's Center for Drug Evaluation and Research (CDER) to propose withdrawing the drug's approval in 2020. In response, the sponsor requested a hearing held in October 2022.

The Times detailed in a February 2022 investigation how Covis Pharma and the companies that previously owned the rights to Makena profited by taking a cheap, decades-old medicine, a synthetic version of the hormone progesterone, with questionable effectiveness and safety, and securing FDA authorization for its use.

The APC’s Response to the Makena Withdrawal

The Alliance for Pharmacy Compounding, or APC, recently commented on the Makena withdrawal and mentioned the complications for pharmacy compounders regarding the use of hydroxyprogesterone.

“While hydroxyprogesterone has a USP monograph and is not on the list of drugs withdrawn for safety or efficacy at this time, it seems likely that it will be added to the list due to the reason for Makena’s removal from the market.

The FDA’s FAQs on the substance are correct from a strict reading of the law, but the issue lies in how compounding as a whole will be viewed if pharmacies continue to make a drug that the FDA panel has said doesn’t work and ultimately led to the removal of a similar drug from the market.

At present, it is unclear whether the FDA plans to officially put hydroxyprogesterone on the list of drugs withdrawn for safety of efficacy, and even if they did, it may not materially change the current situation.”

The APC suggests closely monitoring changes in the FDA’s list of drugs and adjusting practices accordingly.

Compounders May Potentially Suggest Vaginal Progesterone Preparations to Help With Premature Births

The FDA is urging healthcare providers to transition patients off Makena and on to other medications or interventions that are deemed effective and safe.

According to the FDAs announcement, "It is tragic that the scientific research and medical communities have not yet found a treatment shown to be effective in preventing preterm birth and improving neonatal outcomes—particularly in light of the fact that this serious condition has a disparate impact on communities of color, especially Black women," said FDA Commissioner Robert M. Califf, M.D. "Fundamentally, however, the touchstone of FDA drug approval is a favorable benefit-risk assessment; without that favorable assessment, the drug should not have the status of being FDA-approved."

Pharmacists can educate prescribers to stop prescribing Makena. Given the lack of FDA-approved alternatives, this could also prompt the clinical need for progesterone vaginal preparations as a potentially helpful alternative for this patient population.

In 2017, a study found on Pub Med compared "vaginal progesterone vs intramuscular 17α-hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth in singleton gestations.”

The results state, "Daily vaginal progesterone (either suppository or gel) started at about 16 weeks' gestation is a reasonable, if not better, alternative to weekly 17-OHPC injection for prevention of SPTB in women with singleton gestations and prior SPTB. However, the quality level of the summary estimates was low or very low as assessed by GRADE, indicating that the true effect may be, or is likely to be, substantially different from the estimate of the effect."

This is also something to consider when deciding how to help patients.

For additional information, see Makena Information on FDA.gov, which provides explanations and Frequently Asked Questions.

Does Your Facility Produce Quality Preparations?

If you’re ready to bring quality to the center of your compounding operations, consultants at Restore Health Consulting LLC can help you design a robust quality management system to promote patient safety and regulatory compliance.

Amy Summers