This page shows what was measured, who it was measured in, and what that does not settle.
What Hydroxyprogesterone caproate does in the body
The confirmatory trial, run in a different and lower-risk population, found no difference at all.
Progesterone keeps the uterus quiet during pregnancy, and the drop in its activity is part of what starts labour. Hydroxyprogesterone caproate is a long-acting synthetic version, injected weekly, intended to hold that quieting effect in place and delay labour. The first trial suggested it did.
Why people take it. A weekly injection in pregnancy intended to prevent a repeat premature birth
What happened in people
Fetal or early infant death 1.7 versus 1.9 per cent, relative risk 0.87 (0.4 to 1.81)
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The recorded finding that sits closest to something a person would notice. Written into the record, not signed off, and it carries no population or interval.
36.3 versus 54.9 per cent, relative risk 0.66 (95% CI 0.54 to 0.81); before 35 weeks 20.6 versus 30.7 per cent (0.67, 0.48 to 0.93); before 32 weeks 11.4 versus 19.6 per cent (0.58, 0.37 to 0.91)
Repeated elsewhere
Failed to Replicate
What this does not prove. Meeting one endpoint in one population does not carry to other goals or other people.
The limits of this study, and where it came from
Main limit. The trial was stopped early for benefit, which systematically biases the effect estimate upward. The placebo-arm preterm birth rate of 54.9 per cent is far above that of the later confirmatory population.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Weekly intramuscular injection, 250 mg in oil, from 16 to 36 weeks
Interval reported. 95% CI 0
Written into the record, not signed off as a reviewed claim.
ClinicalTrials.gov NCT01004029 — PROLONG (NCT01004029) · a recorded source, not a stored snapshot
Federal Register, 15 May 2023 — final decision on withdrawal of MAKENA (hydroxyprogesterone caproate) and eight abbreviated new drug applications (https://ww… · a recorded source, not a stored snapshot
Co-primary: preterm birth before 35 weeks, and a neonatal morbidity composite index including neonatal death, grade 3 or 4 intraventricular haemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotising enterocolitis or proven sepsis
✗ The study did not show it
Who was studied
NCT01004029
How many people
1708
Study design
Phase 3 international double-blind placebo-controlled confirmatory trial (PROLONG)
Compared against
A dummy treatment
Kind of result
Living longer, or avoiding a major event
What was found
Preterm birth before 35 weeks 11.0 versus 11.5 per cent, relative risk 0.95 (95% CI 0.71 to 1.26); neonatal morbidity index 5.6 versus 5.0 per cent (1.12, 0.68 to 1.61)
Repeated elsewhere
Failed to Replicate
What this does not prove. A study that did not show an effect does not show that no effect exists anywhere.
The limits of this study, and where it came from
Main limit. Only 23 per cent of patients were enrolled in the United States, and the population differed markedly from the original trial in baseline risk, ethnicity and social circumstance.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Weekly intramuscular injection, 250 mg in oil, from 16 to 36 weeks
Interval reported. 95% CI 0
Written into the record, not signed off as a reviewed claim.
ClinicalTrials.gov NCT01004029 — PROLONG (NCT01004029) · a recorded source, not a stored snapshot
Federal Register, 15 May 2023 — final decision on withdrawal of MAKENA (hydroxyprogesterone caproate) and eight abbreviated new drug applications (https://ww… · a recorded source, not a stored snapshot
What we know
RNAWiki holds 2 written-up human studies for this substance, each with the question it asked.
How we know it
Each card names the study, the number of people and what the study set out to measure.
What this does not prove
These summaries were written by a person and have not been signed off as reviewed claims.
Why it matters
A study that failed is as informative as one that worked, and both are here.
What we still do not know
No reviewed claim exists, so no exact population, effect size or interval is published yet.
What happened in people◇Read from sources, not yet reviewed
How close this is to real life
The top step is something a person would feel or care about. The bottom is a guess from software. Filled steps are where evidence exists for this substance.
□Living longer, or avoiding a major eventNo evidence recorded. Death, a heart attack, a stroke, a hospital stay.0 registered measures of this kind. 1 written-up study measured this and did not show a benefit.
□What a body can do day to dayNo evidence recorded. Walking, dressing, breathing, recovering.No registered study measures this.
□Measured performanceNo evidence recorded. How much was lifted, how far was run, how fast.No registered study measures this.
□Symptoms and quality of lifeNo evidence recorded. Pain, tiredness, mood, sleep, as the person rated it.No registered study measures this.
□A number that stands in for healthNo evidence recorded. Cholesterol, blood sugar, bone density. A stand-in, not the thing itself.No registered study measures this.
■A step measured inside a personEvidence recorded. Something measured in human tissue or human cells.A human record sits on the stored organism ladder.
□AnimalsNo evidence recorded. Mice, rats, dogs. Useful for ideas, not proof about people.No animal record is stored.
■Cells in a dishEvidence recorded. Cells or chemistry on a bench, far from a whole body.Stored mechanism abstracts describe steps measured in cells or tissue.
□A guess from softwareNo evidence recorded. Nobody measured it. RNAWiki never publishes one as a finding.RNAWiki stores no prediction for this record. Software can suggest a link. RNAWiki does not publish one as a finding.
Higher on these steps means closer to something a person would feel. It does not mean better done.
What it changes in the body◇Read from sources, not yet reviewed
The path through the body
From what a person takes to what changes. A solid line is a step measured in people. A dashed line is a step nobody has measured that way.
Start
Hydroxyprogesterone caproate
What a person takes: Weekly intramuscular injection, 250 mg in oil, from 16 to 36 weeks.
The measurement behind this step
Hydroxyprogesterone caproate 250 mg in castor oil with benzyl benzoate, injected intramuscularly once weekly, beginning at 16 0/7 to 20 6/7 weeks of gestation and continuing until delivery or 36 weeks. The caproate ester and oil vehicle create the depot that makes weekly dosing possible.
Getting in
A weekly intramuscular injection in oil
Given as an injection into the muscle once a week, starting between 16 and 20 weeks of pregnancy and continuing to 36 weeks.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Weekly intramuscular 250 mg hydroxyprogesterone caproate in castor oil with benzyl benzoate, initiated at 16 0/7 to 20 6/7 weeks and continued until delivery or 36 weeks.
ClinicalTrials.gov NCT01004029 — PROLONG (NCT01004029) · a recorded source, not a stored snapshot
Reaching the cell
The oil depot releases the ester slowly
The oil holds the drug at the injection site and lets it out gradually, which is what makes weekly dosing possible.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
The caproate ester and oil vehicle form an intramuscular depot with slow release over days. The ester is progressively hydrolysed, and trough concentrations across the weekly interval are a recognised source of pharmacokinetic variability between populations.
ClinicalTrials.gov NCT01004029 — PROLONG (NCT01004029) · a recorded source, not a stored snapshot
What it acts on
Binds the progesterone receptor in the uterus
It docks onto the same receptor natural progesterone uses in the muscle of the womb.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Binds nuclear progesterone receptor isoforms in myometrium and cervix, acting as a ligand-activated transcription factor rather than through a membrane signalling cascade.
ClinicalTrials.gov NCT01004029 — PROLONG (NCT01004029) · a recorded source, not a stored snapshot
The change it makes
Uterine quiescence is intended to be maintained
The idea is to keep the womb muscle quiet and delay the changes that start labour.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Progesterone receptor activation is proposed to suppress myometrial gap junction formation, oxytocin receptor expression and inflammatory gene programmes, maintaining quiescence and delaying cervical ripening.
ClinicalTrials.gov NCT01004029 — PROLONG (NCT01004029) · a recorded source, not a stored snapshot
What that does for a person
A large benefit in one trial and none in the other
The first trial found preterm birth fell from 54.9 to 36.3 per cent. The confirmatory trial found 11.0 per cent against 11.5 per cent — no difference.
──Measured in people. Written by a person from the study named beside the step. Not signed off as a reviewed claim.
The measurement behind this step
Measured: preterm birth before 37 weeks 36.3 versus 54.9 per cent, relative risk 0.66 (0.54 to 0.81) in 463 women. Measured: preterm birth before 35 weeks 11.0 versus 11.5 per cent, relative risk 0.95 (0.71 to 1.26) in 1,708 women. No difference in fetal or early infant death in either direction.
ClinicalTrials.gov NCT01004029 — PROLONG (NCT01004029) · a recorded source, not a stored snapshot
No suggested links are held for this record, so nothing is hidden from this path.
What we know
The record describes 5 steps from taking it to an effect in a person.
How we know it
Each step names the study behind it in the technical detail beside it.
What this does not prove
A change inside the body is a reason to look. It is not a result in a person.
Why it matters
A reader can see exactly where the chain stops being measured in people.
What we still do not know
No reviewed claim binds any of these steps to a named population.
What is missing or unclear◇Read from sources, not yet reviewed
Were people like you studied?
RNAWiki cannot tell whether a study fits you. It can show who was in it, and where the result stops carrying.
Who was studied
People similar to this profile were included.
Nobody, as Makena or its generics. Vaginal progesterone remains in use for a different population — women with a short cervix — on separate evidence.
Who is missing from the studies
Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
Where the result stopped carrying
Accelerated approval February 2011; confirmatory trial reported 2019; approval withdrawn by final decision in April 2023 after a requested public hearing
The Federal Register final decision of 15 May 2023 withdrew Makena and eight abbreviated new drug applications
The product remained on the market for the four years between the failed confirmatory trial and the withdrawal
This is a scope explorer, not a diagnosis engine.
It shows who was studied so you can see whether people similar to you were included.
RNAWiki cannot tell whether a study fits you. It can show who was in it.
What it would be like to take◇Read from sources, not yet reviewed
Why it might seem to do nothing
A real effect and a noticed effect are different things. These are the recorded reasons the two come apart.
It was studied for a different goal
The studies measured something else entirely.
On this record: Some registered studies measured things that match no goal on this page.
It was studied in different people
The people in the studies were not much like the reader.
On this record: Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
A different form was studied
The studied form is not the form on the shelf.
On this record: This record is linked to 1 related forms. Evidence does not carry across all of them.
The evidence may simply be wrong
Small early studies often do not hold up.
On this record: RNAWiki has not yet published a reviewed conclusion for this use.
Other reasons RNAWiki checked and found nothing for (9)
There was nothing to correct
Where a level is already normal, topping it up may change nothing. Nothing in this record points to this reason.
Something else had to happen too
In the studies it was paired with training, a diet or another treatment. Nothing in this record points to this reason.
The change is too small to feel
A real change can still sit below what a person notices. Nothing in this record points to this reason.
Day-to-day swing hides it
Sleep, food, stress and time of day move most numbers more than this would. Nothing in this record points to this reason.
Not enough time yet
The studies ran longer than the person has waited. Nothing in this record points to this reason.
It was not taken as studied
Missed days change the result, and studies count them. Nothing in this record points to this reason.
Something else changed at the same time
Two changes at once cannot be told apart afterwards. Nothing in this record points to this reason.
The product may not be what it says
Contents of a sold product are not always what the label states. Nothing in this record points to this reason.
No recorded reason
RNAWiki has nothing stored that would explain it. Nothing in this record points to this reason.
None of these is a reason to take more. Taking more is not a step this page ever suggests.
What it would be like to take◇Read from sources, not yet reviewed
What taking it involves
The recorded facts about getting hold of it and using it. Nothing here is a suggestion about what you should do.
How it is supplied
Withdrawn
❝ Quoted from a source
Where this came from
Copied from a source RNAWiki stored, with the source named.
Read from the recorded approval status.
No source is stored against this line.
Form and route
Weekly intramuscular injection, 250 mg in oil, from 16 to 36 weeks
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The form and route recorded on this substance.
No source is stored against this line.
Who oversees it
Professional supervision is normally required. A regulator classifies this substance in a way that restricts how it is supplied.
❝ Quoted from a source
Where this came from
Copied from a source RNAWiki stored, with the source named.
Suppression classes recorded: S8.
No source is stored against this line.
What is in the pack
Hydroxyprogesterone caproate 250 mg in castor oil with benzyl benzoate, injected intramuscularly once weekly, beginning at 16 0/7 to 20 6/7 weeks of gestation and continuing until delivery or 36 weeks.
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
Recorded notes on how this is sold. The rest of the recorded wording: The caproate ester and oil vehicle create the depot that makes weekly dosing possible.
No source is stored against this line.
Where it is registered
Regulatory records are listed in the technical disclosure at the foot of this page.
# Counted from records
Where this came from
A count of rows RNAWiki holds. It describes our records, not your body.
Register entries are stored per jurisdiction and shown with their dates.
No source is stored against this line.
Why people stop
Not recorded.
∅ Nothing recorded
Where this came from
RNAWiki holds nothing here and says so rather than guessing.
No record of why people stopped taking it is stored for this substance.
No source is stored against this line.
What it would be like to take◇Read from sources, not yet reviewed
What can go wrong
Sorted by where each line came from. A regulator's label and a report somebody sent in are not the same kind of fact.
·Worth asking a clinician aboutWritten into the record from the studies named on this page
The withdrawal was for lack of demonstrated efficacy, not for harm. In the confirmatory trial, fetal or early infant death was 1.7 per cent against 1.9 per cent on placebo (relative risk 0.87, 95% CI 0.4 to 1.81) and maternal outcomes were similar. Injection-site pain, swelling and pruritus were the common effects, with urticaria, nausea and diarrhoea reported. The oil vehicle and benzyl benzoate contribute to local reactions.
Nobody counted how many people took this and were fine, so this cannot be turned into a rate.
ClinicalTrials.gov NCT01004029 — PROLONG (NCT01004029) · a recorded source, not a stored snapshot
Reports sent to a regulator
These are reports people sent to a regulator. They do not show the medicine caused the reaction.
Nobody counted how many people took the medicine and reported nothing.
The same event can be reported more than once, and many reports are incomplete.
News coverage, lawsuits and new warnings change how often people report.
A count is not a rate and not a risk.
Hydroxyprogesterone caproate appears in spontaneous reports to regulators. Across the 10 most-reported reaction terms, 5317 reaction mentions were counted. One report can name several reactions.
The recorded terms (10)
premature baby — 1212 reaction mentions
premature delivery — 1191 reaction mentions
injection site pain — 722 reaction mentions
injection site pruritus — 622 reaction mentions
preterm premature rupture of membranes — 293 reaction mentions
injection site erythema — 281 reaction mentions
injection site swelling — 279 reaction mentions
premature labour — 259 reaction mentions
injection site mass — 250 reaction mentions
pruritus — 208 reaction mentions
open-targets-adr · recorded 2026-06-24 · a recorded source, not a stored snapshot
Over a long time. No completed tested study window is recorded, so long-term effects are not established by the registry record.
Groups the studies covered thinly. Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
What is missing or unclear◇Read from sources, not yet reviewed
Does the exact form matter?
Evidence belongs to the exact thing that was tested. A different salt, a different mixture or a different preparation is a different question.
The form that was studied
Weekly intramuscular injection, 250 mg in oil, from 16 to 36 weeks
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The form used in the studies cited on this page.
No source is stored against this line.
What is sold
The caproate ester and oil vehicle create the depot that makes weekly dosing possible.
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
Recorded notes on which forms are sold and how they compare.
No source is stored against this line.
What is recorded as being sold
10 products list this as an active ingredient in the United States drug directory. 10 of them contain it and nothing else.
FDA National Drug Code directory · 73377-174 · read 2026-08-29
They are sold as injection and powder, taken intramuscular.
FDA National Drug Code directory · 73377-174 · read 2026-08-29
The regulator's established pharmacologic class for it is progesterone congeners [cs] and progestin [epc].
FDA National Drug Code directory · 73377-174 · read 2026-08-29
1 published label names it as an active ingredient. 1 of them describe this substance alone, which is where its own label text on this page comes from.
US prescribing information · 687bcf42-f437-42c7-8909-a91f621f55df · read 2026-08-29
Those labels are classed as human prescription drug.
US prescribing information · 687bcf42-f437-42c7-8909-a91f621f55df · read 2026-08-29
Hydroxyprogesterone Caproate is intramuscular at HOW SUPPLIED Hydroxyprogesterone Caproate Injection, USP is available in vials providing hydroxyprogesterone caproate with a potency of 250 mg per mL., recorded as fda label in effect 2026-06-12 in the United States.
US prescribing information · 687bcf42-f437-42c7-8909-a91f621f55df · read 2026-08-30
Evidence carries across two names for one substance. It does not carry across a salt, a mirror form or a mixture.
Evidence on this page does not automatically apply to this one.
What it would be like to take◇Read from sources, not yet reviewed
What you could measure
This one is decided with a clinician, so this section holds questions to ask rather than a plan to run.
Self-experiment planning is not offered for a prescription or clinician-supervised medicine, withdrawn medicine. The questions below are for a clinician or pharmacist.
Questions worth asking
Which of the trials of Hydroxyprogesterone caproate studied people like me?
What was measured, and for how long?
Was the result a laboratory value or a health outcome?
What would we watch for, and when would we stop?
Tracking can show whether something changed for you. It cannot show what caused it.
RNAWiki records evidence. It does not say whether this substance is right for you.
What is missing or unclear◇Read from sources, not yet reviewed
Claims that go past the evidence
Things said about this substance that sound reasonable, and the exact step that is missing between the evidence and the claim.
✗Goes past the evidence
That a relative risk of 0.66 from a trial stopped early for benefit is an unbiased effect estimate
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
✗Goes past the evidence
That the two trials are directly comparable — placebo-arm preterm birth before 35 weeks was 30.7 per cent in one and 11.5 per cent in the other
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
✗Goes past the evidence
That the withdrawal implies vaginal progesterone is ineffective for short cervix; different molecule, route and population
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
What is missing or unclear◇Read from sources, not yet reviewed
What nobody knows yet
Open questions, each with why it is open and what would close it.
Missing populations
Which groups were under-represented in the studies has not been recorded.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Missing long-term data
No completed tested study window is recorded.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
No reviewed conclusion
RNAWiki has not yet published a reviewed conclusion for this use.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Missing interaction studies
No interaction was found in the registers checked. Not finding one is not the same as showing there is none.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Formulation uncertainty
Several salts, forms or products of Hydroxyprogesterone caproate are recorded. Results from one form may not transfer to another.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Mechanism not reviewed
No reviewed mechanism story exists for this substance.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
What happened in people◇Read from sources, not yet reviewed
Check any of this yourself
Every line above traced back to the study it came from. This is the technical layer, and the vocabulary changes here.
Every line above can be traced to the study named beside it. Follow the link and read it.
Meis trial: preterm birth before 37 weeks in 36.3 per cent against 54.9 per cent
In plain words
The trial that led to approval enrolled 463 women with a previous premature birth. Just over a third on the drug delivered early, against more than half on placebo.
What was measured
Incidence of delivery before 37, 35 and 32 weeks, 17-OHPC versus placebo, in 463 women
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
A double-blind placebo-controlled trial in pregnant women with a documented history of spontaneous preterm delivery, enrolled at 19 clinical centres at 16 to 20 weeks and randomised 2:1 to weekly 250 mg 17-alpha-hydroxyprogesterone caproate or inert oil placebo until delivery or 36 weeks. Among 310 women on progestin and 153 on placebo, delivery before 37 weeks occurred in 36.3 per cent against 54.9 per cent (relative risk 0.66, 95% CI 0.54 to 0.81); before 35 weeks in 20.6 against 30.7 per cent (0.67, 0.48 to 0.93); before 32 weeks in 11.4 against 19.6 per cent (0.58, 0.37 to 0.91). Infants of treated women had lower rates of necrotising enterocolitis, intraventricular haemorrhage and need for supplemental oxygen.
Written into the record, not signed off as a reviewed claim
PROLONG: 11.0 per cent against 11.5 per cent, in 1,708 women
In plain words
The confirmatory trial was nearly four times larger and found no difference at all on either of its two main outcomes.
What was measured
Preterm birth before 35 weeks and neonatal morbidity composite, 17-OHPC versus placebo, in 1,708 women
Effect estimate
No reviewed effect estimate exists for this record.
Limits
This entry records a failure.
From the source
PROLONG (NCT01004029) was a double-blind placebo-controlled international trial enrolling women with a previous singleton spontaneous preterm birth at 93 centres — 41 in the United States and 52 outside — at 16 0/7 to 20 6/7 weeks, randomised 2:1 to weekly intramuscular 250 mg 17-OHPC or inert oil placebo until delivery or 36 weeks. Co-primary outcomes were preterm birth before 35 weeks and a neonatal morbidity composite. Among 1,130 women on 17-OHPC and 578 on placebo, preterm birth before 35 weeks occurred in 11.0 against 11.5 per cent (relative risk 0.95, 95% CI 0.71 to 1.26), and the neonatal morbidity index in 5.6 against 5.0 per cent (1.12, 0.68 to 1.61). Fetal or early infant death was 1.7 against 1.9 per cent (0.87, 0.4 to 1.81). The planned sample of 1,707 provided 98 per cent power to detect a 30 per cent reduction in preterm birth before 35 weeks.
Written into the record, not signed off as a reviewed claim
The two trials enrolled populations at very different baseline risk
In plain words
In the first trial, more than half the placebo group delivered before 37 weeks. In the second, only about one in nine placebo patients delivered before 35 weeks. The two groups were not comparable.
What was measured
Not recorded
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
The placebo-arm event rates differ substantially. In the Meis trial, 54.9 per cent of placebo patients delivered before 37 weeks and 30.7 per cent before 35 weeks. In PROLONG, 11.5 per cent of placebo patients delivered before 35 weeks — under half the Meis placebo rate at the same threshold. PROLONG was 87 per cent Caucasian, 89 per cent married or living with a partner, 7 per cent smokers, and 12 per cent had more than one prior spontaneous preterm birth, with 52 of 93 centres outside the United States. In the United States subgroup of 391 women, preterm birth before 35 weeks was higher than in the overall study at 15.6 against 17.6 per cent, but with no significant difference between groups (relative risk 0.88, 95% CI 0.55 to 1.40). A treatment effect can be real in a high-risk population and undetectable in a low-risk one, and this is the strongest available explanation for the discordance. It is also, as of the withdrawal decision, an explanation rather than a demonstration.
Written into the record, not signed off as a reviewed claim
The original trial was stopped early, which inflates an apparent effect
In plain words
The trial that led to approval was stopped ahead of schedule because the benefit looked large. Trials stopped early for benefit systematically overstate how large the benefit is.
What was measured
That a relative risk of 0.66 from a trial stopped early for benefit is an unbiased estimate of the effect
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
The PROLONG investigators note directly that the only prior large United States trial comparing 17-OHPC with placebo was stopped early due to a large treatment benefit. Early stopping for benefit is a recognised source of effect overestimation: the decision to stop is triggered by a random high excursion in the accumulating estimate, so the estimate at the stopping point is upward-biased by construction. This does not make the Meis result wrong, and it does mean that a relative risk of 0.66 obtained at an early stop is not the same evidential object as a relative risk of 0.66 obtained at planned completion. It also means the accelerated approval of 2011 rested on a figure whose expected value was above the truth.
Written into the record, not signed off as a reviewed claim
Twelve years between accelerated approval and withdrawal, with a hearing in between
In plain words
The confirmatory trial reported in 2019. The approval was not withdrawn until a formal decision in 2023, after the sponsor requested and received a public hearing.
What was measured
Not recorded
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Accelerated approval was granted in February 2011. PROLONG reported in 2019. The FDA proposed withdrawal, the sponsor requested a hearing, and the Federal Register of 17 August 2022 records the proposal to withdraw approval of Makena and the granting of that hearing. The final decision, published on 15 May 2023, withdrew approval of Makena and eight abbreviated new drug applications for hydroxyprogesterone caproate injection. The four-year interval between the failed confirmatory trial and the withdrawal is the cost of due process, and it is a real cost: the product remained on sale throughout. Set against aducanumab, where the confirmatory trial was abandoned and the sponsor simply exited, this is what completing the accelerated-approval bargain actually looks like.
Source
Federal Register, 15 May 2023 — final decision on withdrawal of Makena (hydroxyprogesterone caproate) and eight abbreviated new drug applications
Role in the trial
Not matched to a registered study
Identity check
no open identity hold
Audit mark
verified
Review state
Written into the record, not signed off as a reviewed claim
No safety signal was the reason — the reason was that it did not work
In plain words
Nothing harmful was found. Fetal and infant death rates were the same in both arms. It was withdrawn because the confirmatory trial found no benefit.
What was measured
Fetal and early infant death and maternal outcomes, 17-OHPC versus placebo, in 1,708 women
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
PROLONG found no difference in fetal or early infant death — 1.7 per cent on 17-OHPC against 1.9 per cent on placebo, relative risk 0.87 (95% CI 0.4 to 1.81) — and maternal outcomes were similar between groups. The trial was powered at 82.8 per cent to rule out a doubling of fetal or early infant death risk. The authors conclude that 17-OHPC did not decrease recurrent preterm birth and was not associated with increased fetal or early infant death. This distinguishes the entry sharply from the rest of this file: rofecoxib, cerivastatin, pergolide and propoxyphene were removed for harm, and this one was removed for absence of benefit. Efficacy withdrawal is much rarer than safety withdrawal, and it is the mechanism accelerated approval was designed to provide.
Written into the record, not signed off as a reviewed claim
Vaginal progesterone is a different drug for a different population
In plain words
Progesterone given vaginally to women with a short cervix was not affected by this withdrawal, and conflating the two is easy and wrong.
What was measured
That the Makena withdrawal implies vaginal progesterone is ineffective for short cervix
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Three things differ between the withdrawn product and vaginal progesterone: the molecule — a caproate ester of 17-alpha-hydroxyprogesterone against natural progesterone; the route — a weekly intramuscular depot against daily local administration; and the indicated population — a history of spontaneous preterm birth against a sonographically short cervix. The Makena withdrawal addresses one specific product in one specific population and says nothing about the others. Statements of the form "progesterone does not prevent preterm birth" collapse three separate evidence bases into one, and are not supported by the trial that produced this withdrawal.
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The older medicine-wide conclusion held in this record
Written for a clinical reader, and about the medicine as a whole rather than about one indication, population and set of trials. RNAWiki does not treat it as a programme conclusion and no reviewer has signed it off in that form. It is here word for word because it is what the record holds.
A weekly progestin injection approved in 2011 on a 463-woman trial that found recurrent preterm birth before 37 weeks in 36.3 per cent against 54.9 per cent on placebo, and withdrawn in 2023 after a 1,708-woman confirmatory trial found preterm birth before 35 weeks in 11.0 per cent against 11.5 per cent — relative risk 0.95, confidence interval 0.71 to 1.26.
Recorded evidence blocks (11)
Q2
What did Hydroxyprogesterone caproate's largest trial (1740 people) and its longest (9 years) measure?
1740 people in Hydroxyprogesterone caproate's largest registered study, 9 years in its longest registered window, measuring Plasma concentrations of hydroxyprogesterone caproate and metabolites. ClinicalTrials.gov · 2026-09-01
3 phase3, 2 phase1, 2 phase2, 2 phase4; NCT01004029; 2018-10; no ageing endpoint recorded. Last human test completed 2021, NCT02913495.
Interpretation These counts include studies where Hydroxyprogesterone caproate was a comparison treatment, a background treatment or an exposure in an observational study, and the longest window may be a planned end date. Trial roles have not yet been classified for this record.
Show the evidence
phase3
3
phase1
2
phase2
2
phase4
2
Last recorded human testNCT02913495
2021-09
recorded 2026-09-01 · last checked 2026-09-04
Q3
Hydroxyprogesterone caproate was tested only in human — what did it show?
Which of clinical pregnancy rate, clinical pregnancy rate fetal heart beat and gestational age at delivery did Hydroxyprogesterone caproate's trials measure?
clinical pregnancy rate, clinical pregnancy rate fetal heart beat and gestational age at delivery lead 6 outcome terms across Hydroxyprogesterone caproate's trials. ClinicalTrials.gov · 2026-09-01
Which 2 trials of Hydroxyprogesterone caproate posted no result?
Posted no result
2 of 2 completed trials
Registrations
NCT00141908 and NCT01899846
Completion dates
oldest 2012-12; newest 2014-08
Show the evidence
Trial
NCT00141908
2012-12
NCT01899846
2014-08
Q8
At the median, Hydroxyprogesterone caproate's trials enrolled 137 people — anything larger?
Median enrolment
137
Largest enrolment
1740
Registered trials counted
8
Q9
What do 5317 spontaneous reports say about Hydroxyprogesterone caproate — and not say?
These are reports people sent to a regulator. They do not show the medicine caused the reaction. Nobody counted how many people took the medicine and reported nothing. The same event can be reported more than once, and many reports are incomplete. News coverage, lawsuits and new warnings change how often people report. A count is not a rate and not a risk.
Hydroxyprogesterone caproate appears in spontaneous reports to regulators. Across the 10 most-reported reaction terms, 5317 reaction mentions were counted: premature baby 1212; premature delivery 1191; injection site pain 722; injection site pruritus 622. open-targets-adr · CHEMBL1200848 · 2026-06-24
Show the evidence
premature baby
1212
premature delivery
1191
injection site pain
722
injection site pruritus
622
preterm premature rupture of membranes
293
injection site erythema
281
4 more recorded rows
injection site swelling
279
premature labour
259
injection site mass
250
pruritus
208
recorded 2026-06-24 · last checked 2026-09-04
Q10
Hydroxyprogesterone caproate and CYP3A4 and CYP3A5: shared by which compounds?
CYP3A4 and CYP3A5 appear in Hydroxyprogesterone caproate's recorded interaction sentences, 2 in all. openfda-label+europepmc · 2026-08-30
Interpretation clinical_pharmacology
Show the evidence
CYP3A4clinical_pharmacology
In vitro data indicate that the metabolism of hydroxyprogesterone caproate is predominantly mediated by CYP3A4 and CYP3A5.
CYP3A5clinical_pharmacology
In vitro data indicate that the metabolism of hydroxyprogesterone caproate is predominantly mediated by CYP3A4 and CYP3A5.
recorded 2026-08-30 · last checked 2026-09-04
Q11
Was Hydroxyprogesterone caproate studied with fasting?
fasting is named in Hydroxyprogesterone caproate's label sentences: "In 24 eligible randomised controlled trials (RCTs) involving 564 participants who received metformin therapy, metformin was associated with significant reduction in body weight by 3.13 kg (95% CI: -5.33, -0.93), body mass index (BMI) by 0.82 kg/m² (95% CI: -1.22, -0.41), fasting blood glucose…" openfda-label+europepmc · 2026-08-30
1 recorded statement; fasting
Show the evidence
fasting
In 24 eligible randomised controlled trials (RCTs) involving 564 participants who received metformin therapy, metformin was associated with significant reduction in body weight by 3.13 kg (95% CI: -5.33, -0.93), body mass index (BMI) by 0.82 kg/m² (95% CI: -1.22, -0.41), fasting blood glucose [standardised mean difference (SMD): -0.23; 95% CI: -0.40, -0.06], low-density lipoprotein cholesterol…
recorded 2026-08-30 · last checked 2026-09-04
Q12
What is recorded about Hydroxyprogesterone caproate and mTOR?
"Three novel 'mTOR general' binders were identified, carvedilol, testosterone propionate, and hydroxyprogesterone, which inhibited both mTORC1 and mTORC2." — where Hydroxyprogesterone caproate and mTOR appear together. Europe PMC · pathway abstract search · 2018-07-17
mTOR, NAD+; PMID 30028993, 16137639
Show the evidence
mTORPMID 30028993
"Three novel 'mTOR general' binders were identified, carvedilol, testosterone propionate, and hydroxyprogesterone, which inhibited both mTORC1 and mTORC2."
NAD+PMID 16137639
"Corticosterone (CS), dehydrocoticosterone (DHC), 11alpha- and 11beta-hydroxyprogesterone, and carbenoxolone completely inhibited these reactions, while 7-oxo-DHEA only inhibited the NAD+-dependent reaction."
recorded 2018-07-17 · last checked 2026-09-04
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