Hydroxyprogesterone caproate

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Hydroxyprogesterone caproate
Hydroxyprogesterone caproate.svg
Clinical data
Pregnancy
category
  • B
Routes of
administration
Intramuscular injection
ATC code
Pharmacokinetic data
Bioavailability Oral: Very low (~3% in rats)[1]
Intramuscular: 100% (in rats)[1]
Biological half-life Non-pregnant: 7.8 days[2]
Singlet: 16 days[3]
Twins: 10 days[3]
Identifiers
Synonyms 17α-Hydroxyprogesterone caproate, 17α-OHPC, 17-Hydroxyprogesterone caproate, 17-OHPC, 17-HPC, 17α-HPC, HPC
CAS Number
PubChem CID
ChemSpider
UNII
ECHA InfoCard 100.010.127
Chemical and physical data
Formula C27H40O4
Molar mass 428.6041 g/mol
3D model (Jmol)
 NYesY (what is this?)  (verify)

Hydroxyprogesterone caproate (OHPC) (INN, USAN, JAN) (brand names Delalutin, Proluton, Makena, Prodrox, Hylutin, many others), also known as hydroxyprogesterone hexanoate (BANM), is a steroidal progestin and derivative of 17α-hydroxyprogesterone (17α-OHP) that is related to other 17α-OHP derivatives such as chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, and megestrol acetate.[4] It is an ester of 17α-OHP formed from caproic acid (hexanoic acid).[4]

OHPC was previously marketed under the trade name Delalutin by Squibb, which was approved by the United States (U.S.) Food and Drug Administration (FDA) in 1956 and withdrawn from marketing in 1999.[5] It is also sold as Proluton throughout Europe.[4] The U.S. FDA approved Makena from KV Pharmaceutical (previously named as Gestiva) on February 4, 2011 for prevention of preterm delivery in women with a history of preterm delivery, sparking a pricing controversy.

Medical uses[edit]

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.[3] 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.[3]

Preterm birth[edit]

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.[6] 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, [7] 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".[8] There was a similar conclusion from a review by Marc Keirse of Flinders University.[9] 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.[10][11][12] 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.[12] A follow-up study of the offspring showed no evidence that OHPC affected the children in the first years of life.[13] 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.[14] 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.[15] 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.[16][17] 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:[18]

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."[19]

Endometrial cancer[edit]

OHPC is significantly effective in extending life in both premenopausal and postmenopausal women with advanced endometrial cancer.[20]

Other uses[edit]

Transgender hormone therapy[edit]

OHPC is used as a component of hormone replacement therapy for transgender women.[21][22][23][24][25]

Benign prostatic hyperplasia[edit]

OHPC has been used to treat benign prostatic hyperplasia in men, although evidence of effectiveness is marginal and uncertain.[26] 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.[26] However, symptoms of hypogonadism may develop when OHPC is used for this indication, with two-thirds of men reportedly experiencing impotence.[27]

Acne in women[edit]

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.[28][29]

Pharmacology[edit]

Progestogen[edit]

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.[30] Through activation of the PR, OHPC has the potential for marked antigonadotropic effects,[31][32] and can significantly suppress gonadal sex hormone production.[33]

As a pure progestogen,[34] OHPC has no androgenic or glucocorticoid properties,[35] nor any estrogenic effects.[34] 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.[35] In relation to glucocorticoid activity, OHPC has been found not to alter cortisol levels in humans even with extremely high dosages via intramuscular injection,[36] 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).[37]

Pharmacokinetics[edit]

Absorption[edit]

In animals, the bioavailability of OHPC with intramuscular injection is nearly 100%, but its oral bioavailability is very low at less than 3%.[1] For this reason, oral administration is unfeasible for medical use.[1]

Metabolism[edit]

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.[38] OHPC is a much more potent progestogen relative to 17α-OHP, but does not have as high of affinity for the PR as progesterone.[38] However, in spite of this, it is more potent than progesterone in vivo, likely due to differences in the pharmacokinetics of the two compounds.[38] OHPC is not as potent as the related ester hydroxyprogesterone acetate.[38]

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.[2] 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).[28] In pregnant women, the half-life of OHPC appears to be longer, being 16 days.[3] However, in women pregnant with twins rather than a singlet, it appears to be shorter than this, at 10 days.[3]

History[edit]

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.[39][40][41][42][43] It was reportedly first marketed in Japan in 1954 or 1955,[44] 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.[12] 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.[45] 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.,[46] and KV reduced its price to $690 per dose.[47]

Society and culture[edit]

Pricing controversy[edit]

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".[48] However, the USFDA said it would not go after compounding pharmacies that filled prescriptions, and KV Pharmaceutical announced a lower price.[48]

See also[edit]

Notes[edit]

  1. ^ a b c d Shaik, Imam H.; Bastian, Jaime R.; Zhao, Yang; Caritis, Steve N.; Venkataramanan, Raman (2015). "Route of administration and formulation dependent pharmacokinetics of 17-hydroxyprogesterone caproate in rats". Xenobiotica. 46 (2): 169–174. doi:10.3109/00498254.2015.1057547. ISSN 0049-8254. 
  2. ^ a b April Hazard Vallerand; Cynthia A Sanoski (4 June 2014). Davis's Canadian Drug Guide for Nurses®. F.A. Davis. pp. 658–. ISBN 978-0-8036-4086-3. 
  3. ^ a b c d e f Feghali, Maisa; Venkataramanan, Raman; Caritis, Steve (2014). "Prevention of preterm delivery with 17-hydroxyprogesterone caproate: Pharmacologic considerations". Seminars in Perinatology. 38 (8): 516–522. doi:10.1053/j.semperi.2014.08.013. ISSN 0146-0005. 
  4. ^ a b c Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 532–. ISBN 978-3-88763-075-1. 
  5. ^ Kim S. "The Orphan Drug Act: How the FDA Unlawfully Usurped Market Exclusivity". Heinonline. 
  6. ^ SMFM Clinical Guideline: Progesterone and preterm birth prevention: translating clinical trials data into clinical practice, AJOG May 2012
  7. ^ Meirs et al. NEJM 2003
  8. ^ Dodd JM, Flenady V, Cincotta R, Crowther CA; The Cochrane Database of Systematic Reviews 2006 Issue 1
  9. ^ Keirse, MJNC; Progesterone (2004). "déjà vu" or "still to be seen"?.". Birth. 31: 3. 
  10. ^ Johnson, JWC; Austin, KL; Jones, GS; Davis, GH; King, TM (1975). "Efficacy of 17 alpha-hydroxyprogesterone caproate in the prevention of premature labor". NEJM. 293 (14): 675–680. doi:10.1056/nejm197510022931401. 
  11. ^ Yemini, M; Borenstein, R; Dreazen; et al. (1985). "Prevention of premature labor by 17 alpha-hydroxyprogesterone caproate". Am J Obstet Gynecol. 151 (5): 574–7. doi:10.1016/0002-9378(85)90141-3. 
  12. ^ a b c Meis PJ; Klebanoff M; Thom E; Dombrowski MP; Sibai B; Moawad AH; Spong CY; Hauth JC; Miodovnik M; Varner MW; Leveno KJ; Caritis SN; Iams JD; Wapner RJ; Conway D; O'Sullivan MJ; Carpenter M; Mercer B; Ramin SM; Thorp JM; Peaceman AM; Gabbe S; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. (2003). "Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.". N Engl J Med. 348 (24): 2379–85. doi:10.1056/NEJMoa035140. PMID 12802023. 
  13. ^ Northen AT; Norman GS; Anderson K; Moseley L; Divito M; Cotroneo M; Swain M; Bousleiman S; Johnson F; Dorman K; Milluzzi C; Tillinghast JA; Kerr M; Mallett G; Thom E; Pagliaro S; Anderson GD; National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network. (2007). "Follow-up of children exposed in utero to 17 alpha-hydroxyprogesterone caproate compared with placebo". Obstet Gynecol. 110 (4): 865–72. doi:10.1097/01.AOG.0000281348.51499.bc. PMID 17906021. 
  14. ^ Advisory Committees: CDER 2006 Meeting Documents
  15. ^ Hendrix AG, et al. Embriotoxicity of sex steroidal hormones in nonhuman primates: II. Hydroxyprogesterone caproate, estradiol valerate. Teratology 1987 February. 35 (1): 129.
  16. ^ Duke University Medical Center, New England Journal of Medicine, correspondence, vol 349.
  17. ^ Hauth, JC; Gilstrap, LC; Brekken, AL; Hauth, JM (1983). "The effect of 17 alpha-hydroxyprogesterone caproate on pregnancy outcome in an active-duty military population". Am J Obstet Gynecol. 146 (2): 187. 
  18. ^ Norman, Jane Elizabeth; Marlow, Neil; Messow, Claudia-Martina; Shennan, Andrew; Bennett, Phillip R; Thornton, Steven; Robson, Stephen C; McConnachie, Alex; Petrou, Stavros (2016-05-21). "Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial". The Lancet. 387 (10033): 2106–2116. doi:10.1016/S0140-6736(16)00350-0. ISSN 0140-6736. 
  19. ^ "BMJ Blogs: The BMJ  » Blog Archive  » Richard Lehman's journal review—23 May 2016". blogs.bmj.com. Retrieved 2016-05-25. 
  20. ^ Reifenstein, Edward C. (1971). "Hydroxyprogesterone caproate therapy in advanced endometrial cancer". Cancer. 27 (3): 485–502. doi:10.1002/1097-0142(197103)27:3<485::AID-CNCR2820270302>3.0.CO;2-1. ISSN 0008-543X. 
  21. ^ Gianna E. Israel; Donald E. Tarver; Joy Diane Shaffer (1 March 2001). Transgender Care: Recommended Guidelines, Practical Information, and Personal Accounts. Temple University Press. pp. 58–. ISBN 978-1-56639-852-7. 
  22. ^ Richard Ekins; Dave King (23 October 2006). The Transgender Phenomenon. SAGE Publications. pp. 48–. ISBN 978-1-84787-726-0. 
  23. ^ Richard K. Adler; Sandy Hirsch; Michelle Mordaunt (1 May 2012). Voice and Communication Therapy for The Transgender/Transsexual Client: A Comprehensive Clinical Guide. Plural Publishing. pp. 486–. ISBN 978-1-59756-631-5. 
  24. ^ Masumori, Naoya (2012). "Status of sex reassignment surgery for gender identity disorder in Japan". International Journal of Urology. 19 (5): 402–414. doi:10.1111/j.1442-2042.2012.02975.x. ISSN 0919-8172. 
  25. ^ Sharula, Chekir C, Emi Y, Arai F, Kikuchi Y, Sasaki A, Matsuda M, Shimizu K, Tabuchi K, Kamada Y, Hiramatsu Y, Nakatsuka M (2012). "Altered arterial stiffness in male-to-female transsexuals undergoing hormonal treatment". J. Obstet. Gynaecol. Res. 38 (6): 932–40. doi:10.1111/j.1447-0756.2011.01815.x. PMID 22487218. 
  26. ^ a b Benign Prostatic Hypertrophy. Springer Science & Business Media. 6 December 2012. pp. 266–. ISBN 978-1-4612-5476-8. 
  27. ^ Jeffrey K. Aronson (21 February 2009). Meyler's Side Effects of Endocrine and Metabolic Drugs. Elsevier. pp. 289–. ISBN 978-0-08-093292-7. 
  28. ^ a b Baker, Kenneth C. (1958). "Treatment of Persistent Acne in Women with 17 Alpha Hydroxyprogesterone Caproate (Delalutin)". Journal of Investigative Dermatology. 31 (5): 247–250. doi:10.1038/jid.1958.114. ISSN 0022-202X. 
  29. ^ Antibiotic Medicine and Clinical Therapy. 1959. p. 249. 
  30. ^ Kistner, Robert W. (1960). "The Use of Progestational Agents in Obstetrics and Gynecology". Clinical Obstetrics and Gynecology. 3 (4): 1047–1067. doi:10.1097/00003081-196003040-00019. ISSN 0009-9201. 50 mg of [medroxyprogesterone acetate], intramuscularly, is equivalent to 250 mg [hydroxyprogesterone caproate] 
  31. ^ Yang D, Zhu RL (1994). "[Changes in reproductive hormones levels in the treatment of endometrial precancerous lesion with hydroxyprogesterone caproate]". Zhonghua Fu Chan Ke Za Zhi (in Chinese). 29 (4): 205–6, 251. PMID 8082440. In this paper, 14 cases of precancerous lesion of endometrium were treated with hydroxyprogesterone caproate and a series of hormone determination was analysed before and after treatment. Results showed that LH and LH/FSH were dramatically decreased. (LH P < 0.05, LH/FSH P < 0.01). 
  32. ^ Benign Prostatic Hypertrophy. Springer Science & Business Media. 6 December 2012. pp. 266–. ISBN 978-1-4612-5476-8. Since the initial report by Geller and associates28 on the use of hydroxyprogesterone caproate in the treatment of BPH, a variety of progestins have been studied in the medical management of this disease: hydroxyprogesterone caproate, chlormadinone acetate,27 and medrogestone (6-methyl-6-dehydro-17-methylprogesterone).50 These drugs should have a beneficial effect in BPH as they inhibit testicular function by suppressing serum LH and have no intrinsic estrogenic or androgenic activity. 
  33. ^ J.E. Castro (9 March 2013). The Treatment of Prostatic Hypertrophy and Neoplasia. Springer Science & Business Media. pp. 39–. ISBN 978-94-015-7190-6. Geller has also demonstrated significant decreases in plasma or urine testosterone glucuronide levels following the administration of three other anti-androgens. These include Delalutin [hydroxyprogesterone caproate], chlormadinone acetate, and PH-218. It would appear that decreased androgen production is a property shared by all anti-androgens to date. 
  34. ^ a b Geller, Jack (1965). "Treatment of Benign Prostatic Hypertrophy With Hydroxyprogesterone Caproate". JAMA. 193 (2): 121. doi:10.1001/jama.1965.03090020035009. ISSN 0098-7484. 
  35. ^ a b Meis PJ (2005). "17 hydroxyprogesterone for the prevention of preterm delivery". Obstet Gynecol. 105 (5 Pt 1): 1128–35. doi:10.1097/01.AOG.0000160432.95395.8f. PMID 15863556. 
  36. ^ Onsrud, Mathias; Paus, Elisabeth; Haug, Egil; Ørstad, Kjell K (1985). "Intramuscular Administration of Hydroxyprogesterone Caproate in patients with Endometrial Carcinoma: Pharmacokinetics and effects on adrenal function". Acta Obstetricia et Gynecologica Scandinavica. 64 (6): 519–523. doi:10.3109/00016348509156732. ISSN 0001-6349. 
  37. ^ Varga A, Henriksen E. Clinical and Histopathologic Evaluation of the Effect of 17-alpha-Hydroxyprogesterone-17-n-caproate on Endometrial Carcinoma. Obstetrics & Gynecology. December 1961. Volume 18. Issue 6. pp. 658-672.
  38. ^ a b c d Attardi BJ, Zeleznik A, Simhan H, Chiao JP, Mattison DR, Caritis SN (2007). "Comparison of progesterone and glucocorticoid receptor binding and stimulation of gene expression by progesterone, 17-alpha hydroxyprogesterone caproate, and related progestins". Am. J. Obstet. Gynecol. 197 (6): 599.e1–7. doi:10.1016/j.ajog.2007.05.024. PMC 2278032Freely accessible. PMID 18060946. 
  39. ^ M. Edward Davis. M. Edward Davis Reprints. p. 406. Chemically pure progesterone was the only substance with progestational properties in general use which could be administered parenterally until Junkmann (1) developed in 1953, 17-alpha-hydroxyprogesterone acetate and 17-alpha-hydroxyprogesterone caproate. 
  40. ^ WIED GL, DAVIS ME (1958). "Comparative activity of progestational agents on the human endometrium and vaginal epithelium of surgical castrates". Ann. N. Y. Acad. Sci. 71 (5): 599–616. PMID 13583817. In the group of new parenteral progestational agents, three substances developed by Karl Junkmann1,2 are the most outstanding and interesting: 17a-hydroxyprogesterone caproate and 17a-hydroxyprogesterone acetate, introduced in 1953, and the most potent of all new parenteral progestational agents, 17-ethynyl-19-nortestosterone enanthate, introduced in 1956. 
  41. ^ ACRH. U.S. Dept. of Energy. 1960. p. 71. [The] minimal activity [of 17(a)-hydroxyprogesterone] is magnified to an unexpected degree by the esterification of this steroid with caproic acid to produce 17(a)-hydroxyprogesterone-17-n-caproate, first reported by Karl Junkmann in 1954.6,7 
  42. ^ Ralph Isadore Dorfman (1966). Methods in Hormone Research. Academic Press. p. 86. Junkmann (1954) reported that the acetate, butyrate, and caproate forms had both increased and prolonged activity, [...] 
  43. ^ Norman Applezweig (1962). Steroid Drugs. Blakiston Division, McGraw-Hill. pp. 101–102. Junkmann of Schering, AG., however, was able to show that long chain esters of 17a-hydroxyprogesterones such as the 17a-caproate produced powerful long-acting progestational effect. This compound is marketed in the United States as Delalutin by Squibb, and has been heavily used for the treatment of habitual abortion. 
  44. ^ International Agency for Research on Cancer (1979). Sex Hormones (II). International Agency for Research on Cancer. p. 401. ISBN 978-92-832-1221-8. 17α-Hydroxyprogesterone caproate was first marketed commercially in Japan in 1954-1955. 
  45. ^ FDA press release regarding Makena approval
  46. ^ http://www.macleans.ca/article.jsp?content=w6411446
  47. ^ "Price of preterm birth medicine cut". Boston.com. Associated Press. April 2, 2011. Retrieved April 2, 2011. 
  48. ^ a b Armstrong J (May 2011). "Unintended consequences — the cost of preventing preterm births after FDA approval of a branded version of 17OHP". N. Engl. J. Med. 364 (18): 1689–91. doi:10.1056/NEJMp1102796. PMID 21410391. 

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