This entry has been updated with the latest FDA proposed decision and a summary of the review by Sibai et al. (Obstet Gynecol, 2020)
The authors of the PROLONG trial (Progestin’s Role in Optimizing Neonatal Gestation) reported on the use of 17α-hydroxyprogesterone caproate (17-OHPC) for the treatment of preterm birth (PTB)
In this study population, 250 mg 17-OHPC did not decrease recurrent PTB and was not associated with increased fetal/early infant death
On October 29, 2019, the FDA advisory committee recommended that the drug be withdrawn from the market (9 to 7 vote). On October 5, 2020, the Center for Drug Evaluation and Research (CDER) proposed that Makena be withdrawn from the market. The CDER proposal announcement further states
Makena and its approved generic equivalents will remain on the market until the manufacturers decide to remove the drugs or the FDA Commissioner mandates their removal
If AMAG Pharmaceuticals requests a hearing, the FDA Commissioner will determine whether to hold a public hearing and, following such hearing, decide whether to withdraw approval of Makena and its approved generic equivalents
In the interim, we recommend that health care professionals discuss Makena’s benefits, risks and uncertainties with their patients to decide whether to use Makena while a final decision is being made about the drug’s marketing status
We intend to hold a meeting with experts in obstetrics, neonatal care, and clinical trial design to discuss how to facilitate development of effective and safe therapies to treat preterm birth
SMFM has responded to the PROLONG trial results and makes the following substantive points comparing current data to Meis et. al. study
…it is reasonable for providers to use 17-OHPC in women with a profile more representative of the very high-risk population reported in the Meis trial. For all women at risk of recurrent sPTB, the risk/benefit discussion should incorporate a shared decision-making approach, taking into account the lack of short-term safety concerns but uncertainty regarding benefit
ACOG has likewise responded to the PROLONG trial with a Practice Advisory | Guidance remains unchanged following the FDA decision
A woman with a singleton gestation and a prior spontaneous preterm singleton birth should be offered progesterone supplementation starting at 16–24 weeks of gestation, regardless of transvaginal ultrasound cervical length, to reduce the risk of recurrent spontaneous preterm birth
is not changing our clinical recommendations at this time and continues to recommend offering hydroxyprogesterone caproate as outlined in Practice Bulletin # 130
Meis Trial
Prolong Trial
Authors’ Conclusion
We assert PROLONG was underpowered, based on substantially lower observed preterm birth rates than anticipated, and therefore was a false-negative study, rather than the Meis trial being a false-positive study
Careful assessment of these two trials is critical as removal of 17α-hydroxyprogesterone caproate from the U.S. marketplace may have substantial effects on public health
Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. (NEJM, 2003)
ACOG Statement on FDA Proposal to Withdraw 17p Hydroxyprogesterone Caproate
ACOG Practice Bulletin 130: Prediction and Prevention of Preterm Birth
FDA (October 2020): CDER proposes withdrawal of approval for Makena
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