Hydroxyprogesterone caproate

Medical uses

OHPC is used in the treatment of threatened miscarriage, gynecological disorders such as dysmenorrhea, premenstrual syndrome, fibrocystic breast disease, adenosis, and breast pain, and endometrial cancer. It was used widely in the 1950s through the 1970s for these indications, but OHPC more recently has received the most attention in the prevention of preterm birth.

Preterm birth

The use of OHPC in pregnancy to prevent preterm birth in women with a history of preterm delivery between 20 weeks and 36 weeks and 6 days is supported by the Society of Maternal Fetal Medicine Clinic Guidelines put out in May 2012 as Level I and III evidence, Level A recommendation. Level I evidence refers to a properly powered randomized controlled trial, and level III evidence is support from expert opinion, while a Level A recommendation confers that the recommendation is made based on good and consistent scientific evidence. OHPC 250 mg IM weekly preferably starting at 16–20 weeks until 36 weeks is recommended. In these women, if the transvaginal ultrasound cervical length shortens to <25 mm at < 24 weeks, cervical cerclage may be offered. In the 2013 study the guideline recommendation is based on, there was also a significant decrease of neonatal morbidity including lower rates of necrotizing enterocolitis (0 in the treatment group vs 4 in the control), intraventricular hemorrhage (4 in the treatment group compared with 8 in the control for a relative risk of 0.25), and need for supplemental oxygen (14% in the treatment group vs 24% in the placebo for a relative risk of 0.42). Furthermore, this study contained 463 patients, 310 of whom received injection. Of these patients, 9 had infants with congenital malformations (2%), but there was no consistent pattern and none involved internal organs.

OHPC is currently (as of June 2014) pregnancy category B, meaning there is no evidence of fetal risk with use of this drug during pregnancy. Although this is now the recommendation, this has not always been the case. A 2006 Cochrane Review concluded "...important maternal and infant outcomes have been poorly reported to date... information regarding the potential harms of progesterone therapy to prevent preterm birth is limited". There was a similar conclusion from a review by Marc Keirse of Flinders University. Three clinical studies in singleton pregnancies of 250 mg/week of intramuscular OHPC have all shown a trend for an increase in pregnancy loss due to miscarriage compared to placebo. One of them, a large NIH study in 2003, looked at the effect of OHPC injections in women at risk for repeat premature birth and found that the treated group experienced premature birth in 37% versus 55% in the controls. A follow-up study of the offspring showed no evidence that OHPC affected the children in the first years of life. Based on these NIH data, 17 OHPC was approved by the FDA in 2011 as a drug to reduce the risk of premature birth in selected patients at risk. (v.i.)

The FDA expressed concern about miscarriage at the 2006 advisory committee meeting; the committee voted unanimously that further study was needed to evaluate the potential association of OHPC with increased risk of second trimester miscarriage and stillbirth. A toxicology study in rhesus monkeys resulted in the death of all rhesus fetuses exposed to 1 and 10 times the human dose equivalent of OHPC. as of 2008, OHPC was a category D progestin according to the FDA (that is, there is evidence of fetal harm). There is speculation that the castor oil in the OHPC formulation may not be beneficial for pregnancy. Of note, the above-mentioned NEJM study by Meirs et al. compares the effect of OHPC (with the castor oil component) to castor oil injection as the placebo.

A study published in February 2016 in The Lancet stated the below, amongst other findings:

OPPTIMUM strongly suggests that the efficacy of progesterone in improving outcomes is either non-existent or weak. Given the heterogeneity of the preterm labour syndrome we cannot exclude benefit in specific phenotypic or genotypic subgroups of women at risk. However, the subgroups of women who might benefit do not appear to be easily identifiable by current selection strategies, including cervical length measurement and fibronectin testing.

Reassuringly, our study suggests that progesterone is safe for those who wish to take it for preterm birth prophylaxis. The overall rate of maternal or child adverse events was similar in the progesterone and placebo groups. There were few differences in the incidence of adverse secondary outcomes in the two groups, with the exception of a higher rate of renal, gastrointestinal, and respiratory complications in childhood in the progesterone groups. Importantly, the absolute rates of these complications was low. Follow-up of other babies exposed in utero to vaginal progesterone would be helpful in determining whether the increased rate of some renal, gastrointestinal, and respiratory complications is a real effect or a type I error.

The journal reviewer Richard Lehman, senior Research Fellow at the Department of Primary Health Care at the University of Oxford made the following notable commentary on the OPPTIMUM study, "That's it. This story is ended, and nobody need ever use vaginal progesterone again to prevent preterm birth."

Endometrial cancer

OHPC is significantly effective in extending life in both premenopausal and postmenopausal women with advanced endometrial cancer.

Transgender hormone therapy

OHPC is used as a component of hormone replacement therapy for transgender women.

Benign prostatic hyperplasia

OHPC has been used to treat benign prostatic hyperplasia in men, although evidence of effectiveness is marginal and uncertain. The mechanism of action of OHPC in this use is suppression of testicular androgen production via suppression of luteinizing hormone secretion, which are the result of the progestogenic and antigonadotropic activity of OHPC. However, symptoms of hypogonadism may develop when OHPC is used for this indication, with two-thirds of men reportedly experiencing impotence.

Acne in women

Cyclical intramuscular doses of 150 mg OHPC has been found to be very effective in the treatment of women with persistent, treatment-refractory acne, with 84% (64 of 76) responding to the treatment and experiencing a "good-to-excellent" improvement in symptoms.

Progestogen

OHPC, unlike many other progestins, is very similar to natural progesterone both structurally and pharmacologically, and is a pure progestogen – that is, a highly selective agonist of the progesterone receptor (PR), without other hormonal activities. However, relative to progesterone, OHPC has improved pharmacokinetics, namely, a much longer duration with depot injection. Via intramuscular injection, 250 mg OHPC is said to be equivalent to 50 mg of medroxyprogesterone acetate. Through activation of the PR, OHPC has the potential for marked antigonadotropic effects, and can significantly suppress gonadal sex hormone production.

As a pure progestogen, OHPC has no androgenic or glucocorticoid properties, nor any estrogenic effects. Due to its lack of androgenic properties, similarly to progesterone, OHPC does not have any teratogenic effects on the fetus, making it safe for use during pregnancy. In relation to glucocorticoid activity, OHPC has been found not to alter cortisol levels in humans even with extremely high dosages via intramuscular injection, which is of relevance because drugs with significant glucocorticoid activity suppress cortisol levels (due to increased negative feedback on the hypothalamic-pituitary-adrenal axis). OHPC has been studied in humans at dosages as high as 5,000 mg per week via intramuscular injection (in the treatment of endometrial cancer specifically, with safety and effectiveness observed).

Absorption

In animals, the bioavailability of OHPC with intramuscular injection is nearly 100%, but its oral bioavailability is very low at less than 3%. For this reason, oral administration is unfeasible for medical use.

Metabolism

The caproate ester of OHPC is not cleaved from it during metabolism, so the drug is not converted in vivo to 17α-OHP, nor to progesterone; that is, it is not a prodrug of 17α-OHP or progesterone. OHPC is a much more potent progestogen relative to 17α-OHP, but does not have as high of affinity for the PR as progesterone. However, in spite of this, it is more potent than progesterone in vivo, likely due to differences in the pharmacokinetics of the two compounds. OHPC is not as potent as the related ester hydroxyprogesterone acetate.

OHPC in an oil-based formulation has been found to have a terminal half-life of 7.8 days via intramuscular injection in non-pregnant women. Its total duration is said to be 10–14 days, which is much longer than the duration of intramuscularly administered progesterone in an oil formulation (2–3 days). In pregnant women, the half-life of OHPC appears to be longer, being 16 days. However, in women pregnant with twins rather than a singlet, it appears to be shorter than this, at 10 days.

History

Along with hydroxyprogesterone acetate, OHPC was developed by Karl Junkmann of Schering AG in 1953 and was first reported by him in the medical literature in 1954. It was reportedly first marketed in Japan in 1954 or 1955, and was subsequently introduced as Delalutin in the United States in 1956. After decades of use, Squibb, the manufacturer, voluntarily withdrew the brand, however, physicians continued to use OHPC "off-label". Renewed interest was sparked with a large NIH-sponsored study in 2003 that found that OHPC reduced the risk of premature birth in selected at-risk pregnant women. With follow-up data showing no evidence of harmful effects on the offspring, the FDA approved the drug, as sponsored by KV Pharmaceutical as Makena, as an orphan drug in February 2011 to reduce the risk of premature birth in women prior to 37 weeks gestation with a single fetus who had at least one previous premature birth. The drug is not effective in preventing premature birth in women with multiples. With the arrival of Makena as an orphan drug, the price of the drug was to increase from $15 to $1,500 per dose meaning a typical treatment would cost $25–30,000, - a pricing strategy that was strongly criticized. The FDA then announced that pharmacies could continue to compound the drug at their usual cost of $10~20 per dose without fear of legal reprisals., and KV reduced its price to $690 per dose.

Pricing controversy

A 2011 decision by the USFDA was going to result in driving "up the [US] cost of an available medication from about $300 to $30,000 – about a 100-fold increase – with minimal added clinical benefit". However, the USFDA said it would not go after compounding pharmacies that filled prescriptions, and KV Pharmaceutical announced a lower price.