17-Hydroxyprogesterone caproate

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17-Hydroxyprogesterone caproate
Hydroxyprogesterone caproate.svg
Systematic (IUPAC) name
[(8R,9S,10R,13S,14S,17R)-17-acetyl-10,13-dimethyl-
3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-
1H-cyclopenta[a]phenanthren-17-yl] hexanoate
Clinical data
Legal status
?
Identifiers
CAS number 630-56-8 N
ATC code ?
PubChem CID 169870
ChemSpider 148552 YesY
Chemical data
Formula C27H40O4 
Mol. mass 428.6041 g/mol
 N (what is this?)  (verify)

17α-Hydroxyprogesterone caproate is a synthetic steroid hormone that is similar to medroxyprogesterone acetate and megestrol acetate. It is an ester derivative of 17α-hydroxyprogesterone formed from caproic acid (hexanoic acid).

17α-Hydroxyprogesterone caproate was previously marketed under the trade name Delalutin by Squibb, which was approved by the U.S. Food and Drug Administration (FDA) in 1956 and withdrawn from marketing in 1999.

The US 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.

Safety[edit]

The use of 17-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.[1] 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. 17 alpha hydroxyprogesterone caproate 250 mg IM weekly preferably starting at 16–20 weeks until 36 weeks is recommended. In these women, if the transvaginal ultrasound cervcical length shortens to <25 mm at < 24 weeks, cervical cerclage may be offered. In the 2013 study the guideline recommendation is based on by [2] there was also a significant decrease of neonatal morbidity including lower rates of necrotizing enterocolitis (0 in treatment group vs 4 in control), intraventricular hemorrhage (4 in the treatment group compared with 8 in the control for relative risk of 0.25), and need for supplemental oxygen (14% in treatment group vs 24% in placebo for 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.

17 hydroxyprogesterone caproate 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".[3] There was a similar conclusion from a review by Marc Keirse of Flinders University.[4] Three clinical studies in singleton pregnancies of 250 mg/week of intramuscular 17-hydroxyprogesterone caproate have all shown a trend for an increase in pregnancy loss due to miscarriage compared to placebo.[5][6][7][8] 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 17OHP-C with increased risk of second trimester miscarriage and stillbirth.[9] 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 17-hydroxyprogesterone caproate.[10] as of 2008, 17-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 17-hydroxyprogesterone caproate formulation may not be beneficial for pregnancy.[11][12] Of note, the above-mentioned NEJM study by Meirs et al. compares the effect of 17-alpha hydroxyprogesterone caproate (with the castor oil component) to castor oil injection as the placebo.

Synthesis[edit]

Hydroxyprogesterone caproate can be prepared by the following sequence:[13]

It is made from 16-dehydropregnenolone acetate (16-DPA),[14] product of the Marker degradation.

Hydroxyprogesterone caproate.png

Makena[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".[15] However, the USFDA said it would not go after compounding pharmacies that filled prescriptions, and KV Pharmaceutical announced a lower price.[15]

Notes[edit]

  1. ^ SMFM Clinical Guideline: Progesterone and preterm birth prevention: translating clinical trials data into clinical practice, AJOG May 2012
  2. ^ Meirs et al. NEJM 2003
  3. ^ Dodd JM, Flenady V, Cincotta R, Crowther CA; The Cochrane Database of Systematic Reviews 2006 Issue 1
  4. ^ Keirse MJNC. Progesterone and preterm: seventy years of "déjà vu" or "still to be seen"?. Birth, 2004 September; 31:3.
  5. ^ Johnson JWC, Austin KL, Jones GS, Davis GH, King TM. Efficacy of 17 alpha-hydroxyprogesterone caproate in the prevention of premature labor. NEJM 1975 October. 293(14):675.
  6. ^ Yemini M, Borenstein R, Dreazen, et al. Prevention of premature labor by 17 alpha-hydroxyprogesterone caproate. Am J Obstet Gynecol. 1985;151(5):574-7.
  7. ^ Meis PJ et al. Prevention of Recurrent Preterm Delivery by 17 Alpha-hydroxyprogesterone Caproate. NEJM, 2003: vol 348, no 24, pg 2379-2385.
  8. ^ Keirse MJNC, Progestogen administration in pregnancy may prevent preterm delivery. Br J Obstet Gynecol 1990 February; 97:149.
  9. ^ Advisory Committees: CDER 2006 Meeting Documents
  10. ^ Hendrix AG, et al. Embriotoxicity of sex steroidal hormones in nonhuman primates: II. Hydroxyprogesterone caproate, estradiol valerate. Teratology 1987 February. 35 (1): 129.
  11. ^ Duke University Medical Center, New England Journal of Medicine, correspondence, vol 349.
  12. ^ Hauth JC, Gilstrap LC, Brekken AL, Hauth JM. The effect of 17 alpha-hydroxyprogesterone caproate on pregnancy outcome in an active-duty military population. Am J Obstet Gynecol. 1983 May; 146(2): 187.
  13. ^ Ringold, H. J.; Loken, B.; Rosenkraz, G.; Sondheimer, F. (1956). J. Amer. Chem. Soc. 78 (4): 816. doi:10.1021/ja01585a030. 
  14. ^ Goswami, A.; Kotoky, R.; Rastogi, R. C.; Ghosh, A. C. (2003). "A One-Pot Efficient Process for 16-Dehydropregnenolone Acetate". Organic Process Research & Development 7 (3): 306. doi:10.1021/op0200625.  edit
  15. ^ 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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