Hydroxyprogesterone caproate, sold under the brand name Delalutin among others, is a medication used to reduce the risk of preterm birth in women pregnant with one baby who have a history of spontaneous preterm birth. In March 2023, the manufacturer, Covis Pharma, agreed to withdraw the drug from the US market. The approval of this drug substance was withdrawn by the US Food and Drug Administration (FDA) in April 2023. In May 2024, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency recommended suspending the marketing authorizations of medications containing 17-hydroxyprogesterone caproate in the European Union. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
Hydroxyprogesterone caproate is a progestin medication which was used to prevent preterm birth in pregnant women with a history of the condition and to treat gynecological disorders. It has also been formulated in combination with estrogens for various indications (brand names Gravibinon and Primosiston) and as a form of long-lasting injectable birth control (brand name Chinese Injectable No. 1). It is not used by mouth and is instead given by injection into muscle or fat.
Hydroxyprogesterone caproate is generally well tolerated and produces few side effects. Injection site reactions such as pain and swelling are the most common side effect of hydroxyprogesterone caproate. The medication may increase the risk of gestational diabetes when used in pregnant women. Hydroxyprogesterone caproate is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. It has some antimineralocorticoid activity and no other important hormonal activity. The medication shows a number of differences from natural progesterone.
Hydroxyprogesterone caproate was discovered in 1953 and was introduced for medical use in 1954 or 1955. It was marketed in the United States under the brand name Delalutin and throughout Europe under the brand name Proluton. The medication was discontinued in the United States in 1999. However, hydroxyprogesterone caproate was subsequently reintroduced in the United States under the brand name Makena for the treatment of preterm birth in 2011 until the FDA banned 17α-OHPC in 2023.
Medical uses
Preterm birth The use of hydroxyprogesterone caproate 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.SMFM Clinical Guideline: Progesterone and preterm birth prevention: translating clinical trials data into clinical practice, AJOG May 2012 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. Hydroxyprogesterone caproate 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 women, 310 of whom received injection. Of these women, 9 had infants with congenital malformations (2%), but there was no consistent pattern and none involved internal organs.
There is no evidence of fetal risk with use of hydroxyprogesterone caproate during pregnancy. A review concluded that information about the potential harms was lacking. Three clinical studies in singleton pregnancies of 250 mg/week of intramuscular hydroxyprogesterone caproate have all shown a trend for an increase in pregnancy loss due to miscarriage compared to placebo. One of them, a large National Institutes of Health (NIH) study in 2003, looked at the effect of hydroxyprogesterone caproate 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 hydroxyprogesterone caproate affected the children in the first years of life. Based on these NIH data, hydroxyprogesterone caproate was approved by the US Food and Drug Administration (FDA) in 2011, as a medication to reduce the risk of premature birth in selected women at risk.
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 hydroxyprogesterone caproate 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 hydroxyprogesterone caproate. , hydroxyprogesterone caproate 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 hydroxyprogesterone caproate formulation may not be beneficial for pregnancy.Duke University Medical Center, New England Journal of Medicine, correspondence, vol 349. Of note, the above-mentioned NEJM study by Meirs et al. compares the effect of hydroxyprogesterone caproate (with the castor oil component) to castor oil injection as the placebo.
A study published in February 2016, found amongst other findings:
The journal reviewer 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."
A Cochrane review on progestogen for preventing preterm birth concluded that there was little evidence that either vaginal or intramuscular progesterone helped to reduce the risk of preterm birth in women with a multiple pregnancy.
Gynecological disorders Hydroxyprogesterone caproate is used in the treatment of threatened miscarriage, gynecological disorders such as dysmenorrhea, premenstrual syndrome, fibrocystic breast disease, adenosis, and breast pain. In addition, hydroxyprogesterone caproate is used in the treatment of endometrial cancer and has been found to be significantly effective in extending life in both premenopausal and postmenopausal women with the disease. The medication was used widely in the 1950s through the 1970s for such indications, but hydroxyprogesterone caproate more recently has received the most attention in the prevention of preterm birth.
Birth control Hydroxyprogesterone caproate is available in combination with estradiol valerate as a once-monthly combined injectable contraceptive in some countries.
Other uses Hydroxyprogesterone caproate has been used as a component of menopausal hormone therapy in women.
Hydroxyprogesterone caproate has been used to treat benign prostatic hyperplasia in men, although evidence of effectiveness is marginal and uncertain. It has also been used to treat prostate cancer, at a dosage of 1,500 mg twice per week. The mechanism of action of hydroxyprogesterone caproate in these uses is suppression of testicular androgen production via suppression of luteinizing hormone secretion, which are the result of the progestogenic and antigonadotropic activity of hydroxyprogesterone caproate. However, symptoms of hypogonadism may develop when hydroxyprogesterone caproate is used for this indication, with two-thirds of men reportedly experiencing impotence.
Hydroxyprogesterone caproate has been used as a component of feminizing hormone therapy for transgender women. Due to micronization, bioidentical progestogens are more commonly used.
Available forms
Hydroxyprogesterone caproate is available alone in the form of ampoules and vials of 125 and 250 mg/mL oil solutions for intramuscular injection (brand names Proluton, Makena). It is also available alone in the form of a 250 mg/mL autoinjector for use by subcutaneous injection (brand name Makena).
Hydroxyprogesterone caproate is or was available in combination with estradiol valerate in the form of ampoules and vials of 250 mg/mL OHPC and 5 mg/mL estradiol valerate oil solutions for intramuscular injection (brand names Gravibinon, Chinese Injectable No. 1). The medication is or was available in combination with estradiol benzoate in the form of ampoules of 125–250 mg OHPC and 10 mg estradiol benzoate in oil solution for intramuscular injection (brand name Primosiston) as well. In addition, hydroxyprogesterone caproate has been marketed in combination with estradiol dipropionate in the form of 50 mg/mL hydroxyprogesterone caproate and 1 mg/mL estradiol dipropionate (brand name EP Hormone Depot) in Japan.
Contraindications Contraindications of hydroxyprogesterone caproate include previous or current thrombosis or thromboembolic disease, known or suspected breast cancer, past or present history of other hormone-sensitive cancer, undiagnosed abnormal vaginal bleeding unrelated to pregnancy, cholestatic jaundice of pregnancy, liver tumors or active liver disease, and uncontrolled hypertension. A few relative contraindications also exist for hydroxyprogesterone caproate.
Side effects
Hydroxyprogesterone caproate is generally well tolerated and produces relatively few side effects. Injection site reactions such as pain, soreness, swelling, itching, bruising, and lumps are the most common side effect of hydroxyprogesterone caproate. In contrast to large doses of progesterone however, which produce moderate-to-severe such reactions, hydroxyprogesterone caproate is relatively free from injection site reactions. Side effects of hydroxyprogesterone caproate that occur in greater than or equal to 2% of users include injection site pain (34.8%), injection site swelling (17.1%), urticaria (12.3%), pruritus (7.7%), injection site pruritus (5.8%), nausea (5.8%), injection site nodules (4.5%), and diarrhea (2.3%). Numerically increased rates relative to controls of miscarriage (2.4% vs. 0%), stillbirth (2.0% vs. 1.3%), admission for preterm labor (16.0% vs. 13.8%), preeclampsia or gestational hypertension (8.8% vs. 4.6%), gestational diabetes (5.6% vs. 4.6%), and oligohydramnios (3.6% vs. 1.3%) have been observed with hydroxyprogesterone caproate in clinical trials in which it was given to pregnant women to prevent preterm birth.
Overdose There have been no reports of overdose of hydroxyprogesterone caproate. In the event of overdose, treatment should be based on symptoms. Hydroxyprogesterone caproate has been studied in humans at high doses of 2,000 to 5,000 mg per week by intramuscular injection, without safety concerns.
Interactions
Hydroxyprogesterone caproate is not likely to affect most cytochrome P450 enzymes at therapeutic concentrations. Drug interaction studies have not been performed with hydroxyprogesterone caproate.
Pharmacology
Pharmacodynamics Hydroxyprogesterone caproate has progestogenic activity, some antimineralocorticoid activity, and no other important hormonal activity.
Progestogenic activity