Makena (AMAG Pharmaceuticals / Covis Pharma) — FDA approval WITHDRAWN April 2023; no longer commercially available in branded form · Makena subcutaneous auto-injector (Antares Pharma) — also withdrawn · Compounded 17-OHPC 250 mg/mL in castor oil (503A/503B compounding pharmacies) — currently only available formulation in the US; not FDA-approved · Prolutex (IBSA) — aqueous subcutaneous formulation, approved in Europe for luteal phase support in ART; not approved for PTB prevention · Progestin Depot (various international brand names in select markets)
Clinical safety rating: caution
17-Alpha Hydroxyprogesterone Caproate (17-OHPC) is a synthetic long-acting intramuscular progestogen administered as a weekly depot injection for the historical prevention of recurrent spontaneous preterm birth. It is the caproic acid ester of 17α-hydroxyprogesterone, engineered to provide sustained progestational activity via slow hydrolysis from an oily intramuscular depot. Its FDA-approved brand formulation (Makena) was withdrawn from the US market in April 2023 following failure of the confirmatory PROLONG trial to demonstrate efficacy. Compounded formulations remain available in the United States from 503B and 503A pharmacies but are not FDA-approved. Current ACOG and SMFM guidelines do not recommend 17-OHPC IM as standard prophylaxis for spontaneous preterm birth; vaginal progesterone is the preferred progestogen for the short cervix indication.
17-OHPC is a synthetic C21 pregnane progestogen and the caproic acid ester of 17α-hydroxyprogesterone. Its mechanism of action in preterm birth prevention is not fully elucidated. Proposed mechanisms include: (1) Progesterone receptor (PR)-mediated suppression of myometrial contractility via downregulation of contraction-associated proteins including connexin-43, oxytocin receptor, and prostaglandin F2α receptors; (2) Anti-inflammatory activity via inhibition of NF-κB signaling pathways, reducing expression of pro-inflammatory cytokines (IL-6, IL-8, TNF-α) in decidua and fetal membranes; (3) Cervical stromal stabilization via inhibition of matrix metalloproteinases (MMPs), potentially attenuating premature cervical remodeling; (4) Partial glucocorticoid receptor (GR) agonist activity at lower potency than cortisol, contributing to localized immunomodulation at the maternal-fetal interface. Notably, 17-OHPC has minimal affinity for the androgen receptor (unlike 19-nortestosterone-derived progestogens), minimal estrogenic activity, and no significant mineralocorticoid receptor activity. Its relatively weak binding to the membrane progesterone receptor (mPR) compared to natural progesterone may partly explain the discordance in clinical efficacy versus vaginally administered micronized progesterone, which achieves higher local uterine concentrations.
| Metabolism | Primarily hepatic metabolism via CYP3A4 (dominant pathway), CYP3A5, and CYP2C8 to multiple hydroxylated and conjugated metabolites. Key metabolic steps include: (1) Hydrolysis of the caproate ester bond to release 17α-hydroxyprogesterone, which retains modest but transient progestational activity before rapid further metabolism; (2) Ring A reduction via 5α-reductase and 5β-reductase to dihydro and tetrahydro metabolites; (3) Phase II glucuronidation (UGT enzymes) and sulfation (SULT enzymes) producing water-soluble conjugates for biliary and renal excretion. The caproate ester moiety confers the depot pharmacokinetic profile — slow hydrolysis from the intramuscular injection depot provides sustained drug release over 7–14 days, mechanistically supporting the once-weekly dosing schedule. IM administration bypasses hepatic first-pass metabolism, which is an important pharmacokinetic advantage over oral progestogens. All identified metabolites have low or negligible progestational receptor activity. Marked inter-individual pharmacokinetic variability has been documented, with higher maternal BMI correlating with substantially lower Cmax and AUC — a recognized potential confounder in the interpretation of efficacy trial outcomes. |
| Excretion | Primarily biliary/fecal excretion of glucuronide and sulfate conjugates (~50%). Renal excretion of conjugated water-soluble metabolites accounts for the remainder (~30–40%). Unchanged parent drug is not detected in urine. No clinically significant enterohepatic recirculation has been documented. |
| Half-life | Terminal elimination half-life: approximately 7–8 days (range 6–10 days) following single IM injection. Depot pharmacokinetics from the oily vehicle support once-weekly dosing. Steady state achieved after approximately 4–5 weeks of weekly administration. |
| Protein binding |
250 mg (1 mL of 250 mg/mL solution) via deep intramuscular injection into the upper outer quadrant of the gluteus maximus, administered once weekly. Initiate between 16 0/7 and 20 6/7 weeks of gestation. Continue through 36 6/7 weeks of gestation or delivery, whichever occurs first. Use a 21-gauge, 1.5-inch needle. Warm vial to room temperature before administration; inject slowly over >30 seconds. Rotate injection sites at each weekly visit.
| Renal impairment | No validated dose adjustment for renal impairment. The primary elimination route is biliary/fecal (conjugated metabolites), with secondary renal excretion of water-soluble conjugates. Unchanged parent drug is not renally excreted. Standard dosing is generally continued in mild-to-moderate renal impairment with clinical monitoring; severe renal impairment data are absent. |
| Liver impairment | Contraindicated in active or severe hepatic disease. 17-OHPC is extensively metabolized by hepatic CYP3A4, CYP3A5, and CYP2C8 — hepatic dysfunction will significantly impair drug clearance and increase plasma concentrations. Do not initiate in patients with clinical or biochemical hepatic dysfunction. Discontinue if hepatotoxicity develops during treatment. |
| 1st trimester | Not indicated. No data support use in the first trimester for PTB prevention (the studied initiation window is 16 0/7–20 6/7 weeks). First-trimester progestogen supplementation for threatened miscarriage or recurrent pregnancy loss (RPL) is a separate indication using different agents (micronized vaginal progesterone; PROMISE/PRISM trials) and does not apply to 17-OHPC IM. |
| 2nd trimester | Previously the primary window of use (initiation 16–21 weeks, continuation through 36 6/7 weeks). No longer recommended as standard of care per ACOG (2023) and SMFM given failure of PROLONG trial and EPPPIC meta-analysis to confirm efficacy. May still be considered on an individualized, informed-consent basis for patients at very high risk (e.g., prior PTB <28 weeks, ≥2 prior sPTBs) after explicit discussion of the withdrawn FDA approval status, limited evidence base, and availability of compounded-only formulations. Cervical length should be monitored transvaginally every 2–4 weeks; if short cervix develops (≤25 mm), vaginal progesterone is supported by stronger evidence. |
| 3rd trimester | Continuation through 36 6/7 weeks per original study protocol if initiated in T2. Do not initiate de novo in the third trimester — no evidence supports late initiation. Discontinue at 36 6/7 weeks; continuing beyond this point was not studied and may be associated with theoretical neonatal adrenal effects. Monitor for signs of preterm labor at each injection visit. |
Clinical note
Intramuscular synthetic progestogen (C21 steroid) historically used for prevention of recurrent spontaneous preterm birth (sPTB) in singleton gestations with a prior sPTB. The landmark MFMU Network PREIS trial (Meis et al., NEJM 2003) demonstrated a 34% relative risk reduction in PTB <37 weeks, forming the basis of FDA accelerated approval of Makena (AMAG Pharmaceuticals) in 2011. However, the adequately powered PROLONG trial (Blackwell et al., 2019), conducted in a broader international population, failed to replicate efficacy on either primary or secondary outcomes. The 2021 EPPPIC individual patient data meta-analysis (Lancet) further confirmed no significant benefit on neonatal composite outcomes for 17-OHPC IM. Following an FDA advisory committee vote in 2019 and a formal benefit-risk reassessment, the FDA withdrew approval of Makena in April 2023 — the first withdrawal of an obstetric drug under the accelerated approval pathway. Current ACOG guidance (Practice Bulletin 234, reaffirmed 2023) and SMFM no longer recommend 17-OHPC IM as a standard strategy for sPTB prevention. Vaginal progesterone (90 mg gel or 200 mg micronized capsule) remains the preferred option for asymptomatic patients with a singleton pregnancy and sonographic short cervix (≤25 mm) at 16–24 weeks, supported by individual patient data meta-analyses (IPDMA, Romero et al., 2018).
■ FDA Black Box Warning
None formally issued at the time of FDA approval. The FDA withdrawal of Makena in April 2023 was based on failure to verify clinical benefit (negative PROLONG trial) under the accelerated approval pathway — not a new safety signal. No black box warning was added prior to withdrawal.
Absolute contraindications include: active or prior thromboembolic disorder (DVT, PE, thrombophlebitis); known or suspected progestogen-sensitive malignancy (breast carcinoma); active or severe hepatic disease or dysfunction (including cholestatic jaundice, hepatic adenoma, hepatocellular carcinoma, Dubin-Johnson syndrome, Rotor syndrome); undiagnosed abnormal vaginal bleeding unrelated to pregnancy; known hypersensitivity to 17-OHPC, castor oil, or benzyl benzoate (vehicle components). Contraindicated in multiple gestation (twins or higher-order multiples) based on MFMU RCT data showing no benefit and a trend toward harm. Not indicated for isolated short cervix without prior sPTB history.
Loading safety data…
| Approximately 95–99%; primarily to albumin with secondary binding to SHBG and CBG. |
| FDA category | Category FDA Pregnancy Category B (historical, pre-2015 letter-category system). Under the current Pregnancy and Lactation Labeling Rule (PLLR, 2015), 17-OHPC had no adequate well-controlled studies demonstrating fetal risk, and animal reproductive studies were reassuring at clinically relevant doses. FDA approval of Makena was formally withdrawn in April 2023 following failure of the PROLONG confirmatory trial; no current approved labeling applies to any branded 17-OHPC formulation. Compounded 17-OHPC (250 mg/mL in castor oil) remains available from 503A/503B pharmacies but is not FDA-approved and carries additional regulatory and quality-assurance uncertainty. |
| Placental transfer | Moderate to significant placental transfer has been demonstrated in ex vivo human placental perfusion models. 17-OHPC is highly lipophilic (logP ~4.5) and extensively protein-bound to albumin and SHBG, which may slow but does not prevent transplacental passage. Fetal-to-maternal plasma concentration ratio is approximately 0.2–0.4 at steady state in pharmacokinetic studies. Fetal exposure is considered pharmacologically relevant at steady-state maternal concentrations, though no adverse fetal hormonal effects have been demonstrated at therapeutic doses. Placental CYP enzymes and sulfotransferases contribute to partial inactivation of 17-OHPC prior to entry into the fetal circulation, providing a degree of fetal metabolic protection. |
| Breastfeeding | 17-OHPC is an antepartum-only medication administered between 16 and 36 weeks of gestation. Postpartum lactation exposure is not a practical clinical concern. Theoretical transfer into breast milk is possible given its lipophilic nature and prolonged half-life, but no human lactation studies have been conducted. Hale's Lactation Risk Category L3 (Moderately Safe) reflects theoretical concern and absence of human data rather than a documented safety signal. Progestogens as a class are not known to suppress established lactation when initiated postpartum. |
