Makena (hydroxyprogesterone caproate injection) Information
FDA Press Release
4/6/2023 – FDA Commissioner and Chief Scientist Announce Decision to Withdraw Approval of Makena
CDER Statements
On October 17–19, 2022, the Office of the Commissioner of the Food and Drug Administration conducted a hearing under 21 CFR 314.530 on the Center for Drug Evaluation and Research's proposal to withdraw approval of Makena (hydroxyprogesterone caproate injection, 250 milligrams (mg) per milliliter (mL), once weekly), new drug application (NDA) 021945, held by Covis Pharma Group/Covis Pharma GmbH (Covis).
As part of the hearing, the Obstetrics, Reproductive and Urologic Drugs Advisory Committee (the Committee) voted on whether the confirmatory trial verified the clinical benefit of Makena on neonatal morbidity and mortality from complications of preterm birth and whether the available evidence demonstrates that Makena is effective for its approved indication, which is to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. The Committee also voted on whether FDA should allow Makena to remain on the market while an appropriate confirmatory study is designed and conducted. The FDA Commissioner and Chief Scientist will decide whether to withdraw approval.
For more information about the hearing and the Committee’s votes, please see the transcript posted to the Makena docket at Docket (FDA-2020-N-2029); FDA-2020-N-2029-0376; and FDA-2020-N-2029-0377.
For further event materials (which are also located in the Makena docket), please see FDA’s Advisory Committee website.
The Food and Drug Administration has granted a hearing on the Center for Drug Evaluation and Research's proposal to withdraw approval of Makena (hydroxyprogesterone caproate injection, 250 milligrams (mg) per milliliter (mL), once weekly), new drug application (NDA) 021945, held by Covis Pharma Group/Covis Pharma GmbH (Covis). As part of the hearing process, the Obstetrics, Reproductive and Urologic Drugs Advisory Committee (the Committee) will discuss whether a confirmatory trial verified the clinical benefit of Makena and whether available evidence demonstrates that Makena is effective for its approved indication, which is to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. The Committee will also discuss whether FDA should allow Makena to remain on the market while an appropriate confirmatory study is designed and conducted.
The hearing will be held in a virtual format. Additional details are provided in the Federal Register notice announcing the hearing: Proposal to Withdraw Approval of MAKENA. Members of the public, including ANDA holders, wishing to make a formal presentation at the hearing must register at the following link by 5:00 p.m. EDT on September 14, 2022: Request to Present at Hearing on Proposal to Withdraw Approval of Makena. To complete your request for an opportunity to make a presentation at the hearing, you must also submit a comment to the docket for this hearing matter (DOCKET NO. FDA-2020-N-2029) by 11:59 p.m. EDT on September 14, 2022, and clearly indicate in the heading and/or cover page that your comment is a “Request for Oral Presentation.”
The U.S. Food and Drug Administration’s Center for Drug Evaluation and Research (CDER) is aware of the recently published EPPPIC meta-analysis reporting the efficacy of various progestogens, with various routes of administration (vaginal progesterone, oral progesterone, intramuscular hydroxyprogesterone caproate [HPC]) to reduce the risk of pre-term birth (PTB) in at-risk women with singleton or multifetal pregnancies. CDER’s recent proposal to withdraw the accelerated approval of Makena (HPC) was based upon a large randomized trial that failed to confirm the benefit of this drug to newborns or reduce the risk of PTB. In making the decision to propose Makena’s withdrawal, CDER also reviewed results from prior studies of progestins (HPC and other similar drugs) for PTB, including studies relevant to Makena that are included in the EPPPIC meta-analysis. Therefore, the publication of the EPPPIC meta-analysis does not change CDER’s proposal to withdraw the approval of Makena. See full CDER Statement.
The U.S. Food and Drug Administration’s Center for Drug Evaluation and Research (CDER) proposed that Makena (hydroxyprogesterone caproate injection) be withdrawn from the market because the required postmarket study failed to verify clinical benefit and we have concluded that the available evidence does not show Makena is effective for its approved use. See CDER Statement: Makena withdrawal request.
Frequently Asked Questions
Q. Why did FDA withdraw approval of Makena and its generics?
A. Makena and its generics (i.e., generic versions of Makena) are not shown to be effective for reducing the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. Nor have Makena and its generics been shown to be effective for any subgroup of this population, including in women at high risk of preterm birth. In addition, there are known risks associated with Makena. FDA determined that given effectiveness has not been shown, no level of risk is justified.
As a condition of Makena’s accelerated approval, the sponsor was required to conduct a confirmatory clinical trial to verify and describe the predicted clinical benefit to newborns. This trial, which was nearly four times larger than the trial that supported Makena’s approval, did not show improvement in the health of the babies born to mothers who were treated with Makena. It also failed to show that Makena reduced the risk of preterm birth.
For more information on accelerated approval, please see FDA’s Accelerated Approval Program webpage.
Q. What does the withdrawal of approval of Makena and its generics mean?
A. Makena and its generics are not shown to be effective for reducing the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. In addition, the drugs are not shown to improve the health of the babies born to this population. We also note that Makena and its generics are not shown to be effective for any subgroup of this population. Accordingly, these drugs do not have benefits that outweigh their risks to patients.
As a result of this withdrawal of approval, Makena and its generics are now unapproved products and cannot lawfully be distributed in interstate commerce.
Q. Can patients who have started taking Makena complete the treatment course? What should I do if I’m currently receiving Makena?
A. Patients currently receiving treatment should talk to their health care provider. FDA withdrew approval of Makena and its generics because these drugs are no longer shown to be effective.
Q. Can health care providers still prescribe Makena or its generics?
FDA has withdrawn the approvals of Makena and its generics but recognizes that a limited supply of these drugs has already been distributed, including to physicians’ offices and pharmacies. FDA acknowledges that some health care providers might continue to prescribe or administer that limited remaining supply to their patients. However, we recommend health care practitioners consider FDA’s conclusion that these drug products are not shown to be effective for the indication for which they were approved and do not have benefits that outweigh their risks to patients.
Q. Why did FDA grant accelerated approval to Makena?
A. In 2011, FDA approved Makena to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. This approval was based on a trial that showed the drug reduced deliveries before 37 weeks of pregnancy, an intermediate clinical endpoint that FDA determined was reasonably likely to predict clinical benefit to the newborn. As a condition of Makena’s approval, the sponsor was required to conduct a confirmatory clinical trial to verify and describe the predicted clinical benefit to newborns.
FDA’s 2011 decision to approve Makena also took into account, among other things, the significant public health impact of newborns born prematurely, the lack of approved treatments for prevention of preterm birth, and the potential benefits of earlier patient access to this treatment.
In light of all of the evidence available today, including the results of the confirmatory trial, as well as other information concerning Makena, this drug is no longer shown to be effective at reducing the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth.
Q. Are there other drugs approved for the same indication as Makena?
A. No. Makena and the generics of Makena were the only products approved to reduce the risk of preterm birth.
Q. Can compounders use hydroxyprogesterone caproate (HPC), the active ingredient in Makena, to compound drugs for patients?
A. Drug products containing hydroxyprogesterone caproate, the active ingredient in Makena, may be compounded under certain sections of the Federal Food, Drug, and Cosmetic Act if the conditions described in those sections are met.
A health care practitioner considering whether to prescribe compounded drug products containing hydroxyprogesterone caproate should be aware of FDA’s determination that Makena and its generics are not shown to be effective in reducing the risk of preterm birth in women with a prior spontaneous preterm birth. In addition, as a general matter, we note that compounded drugs, including compounded drugs containing hydroxyprogesterone caproate, do not undergo FDA premarket review for safety, effectiveness, or quality.
Q. Do the data from the clinical trials show that Makena is effective in Black women?
A. No. The trial conducted prior to Makena’s approval enrolled approximately 60% Black women. In this trial, there was a reduction in preterm birth in both Black and non-Black women treated with Makena. In the post-approval confirmatory trial, there was no evidence of an effect of Makena in either Black or non-Black women. Considering all of the evidence, Makena is not shown to be effective in Black women – or any group of women.
Q. Do the differences in the women enrolled in the pre-approval trial and the confirmatory trial explain why one was positive and the other was negative for Makena’s effectiveness?
A. No. FDA conducted additional analyses of the confirmatory trial using several statistical methods. FDA’s analyses showed that factors that differed between the two trials, such as the population of women enrolled (e.g., with respect to race of the mother or whether the mother was being treated outside the U.S.), did not explain the different findings between these two trials. Makena is not shown to be effective in low, medium, or high-risk groups.
Related Information
- Makena final decision memorandum
- Presiding Officer’s report
- Makena Hearing Docket, FDA 2020-N-2029
- October 17 – 19, 2022: Hearing Announcement involving the Obstetrics, Reproductive, and Urologic Drugs Advisory Committee
- Proposal to Withdraw Marketing Approval; Notice of Opportunity for Hearing
- Letter from FDA granting hearing request
- Makena Prescribing and Labeling Information
- October 29, 2019 Meeting of Bone, Reproductive and Urologic Drugs Advisory Committee for Makena