Ulipristal acetate

Ulipristal acetate
Systematic (IUPAC) name
(8S,11S,13S,14R,17R)-17-Acetoxy-11-[4-(dimethylamino)phenyl]-19-norpregna-4,9-diene-3,20-dione
Clinical data
Trade names Ellaone, Ella, Esmya
AHFS/Drugs.com Multum Consumer Information
License data
Pregnancy
category
  • US: X (Contraindicated)
Routes of
administration		 Oral
Legal status
Legal status
Pharmacokinetic data
Bioavailability Nearly 100%
Protein binding 96.7–99.5%
Metabolism Likely CYP3A4
Biological half-life 32 hours
Excretion ca. 90% with faeces
Identifiers
CAS Number 126784-99-4 YesY
ATC code G03AD02 (WHO) G03XB02
PubChem CID 130904
IUPHAR/BPS 7460
ChemSpider 115762 N
ChEBI CHEBI:71025 N
ChEMBL CHEMBL260538 N
Synonyms CDB-2914
Chemical data
Formula C30H37NO4
Molar mass 475.62 g/mol
 NYesY (what is this?)  (verify)

Ulipristal acetate (trade name EllaOne in the European Union, Ella in the U.S. for contraception,[1] and Esmya for uterine fibroid) is a selective progesterone receptor modulator (SPRM).

Medical uses

Emergency contraception

For emergency contraception[2] a 30 mg tablet is used within 120 hours (5 days) after an unprotected intercourse or contraceptive failure.[3] It has been shown to prevent about 62–85% of expected pregnancies,[4] and prevents more pregnancies than emergency contraception with levonorgestrel.[5] Ulipristal acetate is available by prescription for emergency contraception in over 50 countries, with access through pharmacists without a prescription being tested in the United Kingdom.[6][7][8][9]

Treatment of uterine fibroids

Ulipristal acetate is used for pre-operative treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age in a daily dose of a 5 mg tablet.[10]

Treatment of uterine fibroids with ulipristal acetate for 13 weeks effectively controlled excessive bleeding due to uterine fibroids and reduced the size of the fibroids.[11][12][13]

Two intermittent 3-months treatment courses of ulipristal acetate 10 mg resulted in amenorrhea at the end of the first treatment course in 79.5%, at the end of the second course in 88.5% of subjects. Mean myoma volume reduction observed during the first treatment course (−41.9%) was maintained during the second one (−43.7%).[10] After two to four 3-months courses of treatment, UPA-treated fibroids shown about -70% in volume reduction.[14] This phenomenon was temptatively explained by the combination of multifactorial events involving control of proliferation of the tumor cells, induction of apoptosis and remodeling of the extracellular matrix.[15]

Adverse effects

Common side effects include abdominal pain and temporary menstrual irregularity or disruption. Headache and nausea were observed under long-term administration (12 weeks), but not after a single dose.[3]

Interactions

Ulipristal acetate is metabolized by CYP3A4 in vitro. Ulipristal acetate is likely to interact with substrates of CYP3A4, like rifampicin, phenytoin, St John's wort, carbamazepine or ritonavir, therefore concomitant use with these agents is not recommended.[10][16] It might also interact with hormonal contraceptives and progestogens such as levonorgestrel and other substrates of the progesterone receptor, as well as with glucocorticoids.[10]

Contraindications

Ulipristal acetate should not be taken by women with severe liver diseases[3] because of its CYP mediated metabolism. It has not been studied in women under the age of 18.[17]

Pregnancy

Unlike levonorgestrel, and like mifepristone, ulipristal acetate is embryotoxic in animal studies.[18] Before taking the drug, a pregnancy must be excluded.[3] The EMA proposed to avoid any allusion to a possible use as an abortifacient in the package insert to avert off-label use.[19] It is unlikely that ulipristal acetate could effectively be used as an abortifacient, since it is used in much lower doses (30 mg) than the roughly equipotent mifepristone (600 mg), and since mifepristone has to be combined with a prostaglandin for the induction of abortion.[20] However, data on embryotoxicity in humans are very limited, and it is not clear what the risk for an abortion or for teratogenicity (birth defects) is. Of the 29 women studied who became pregnant despite taking ulipristal acetate, 16 had induced abortions, six had spontaneous abortions, six continued the pregnancies, and one was lost to follow-up.[21]

Lactation

It is not recommended to breast feed within 36 hours of taking the drug since it is not known whether ulipristal acetate or its metabolites are excreted into the breast milk.[3][22]

Pharmacokinetics

In animal studies, the drug was quickly and nearly completely absorbed from the gut. Intake of food delays absorption, but it is not known whether this is clinically relevant.[23]

Ulipristal acetate is metabolized in the liver, most likely by CYP3A4, and to a small extent by CYP1A2 and CYP2D6. The two main metabolites have been shown to be pharmacologically active, but less than the original drug. The main excretion route is via the faeces.[24]

Pharmacodynamics

As a SPRM, ulipristal acetate has partial agonistic as well as antagonistic effects on the progesterone receptor. It also binds to the glucocorticoid receptor, but is only a weak antiglucocorticoid relative to mifepristone,[25] and has no relevant affinity to the estrogen, androgen and mineralocorticoid receptors.[26] Phase II clinical trials suggest that the mechanism might consist of blocking or delaying ovulation and of delaying the maturation of the endometrium.[27]

History

Ulipristal acetate was granted marketing authorization by the European Medicines Agency (EMA) in March 2009.[28]

The U.S. Food and Drug Administration approved the drug for use in the United States on 13 August 2010,[29] following the FDA advisory committee's recommendation.[30][31] Watson Pharmaceuticals announced the availability of ulipristal acetate in the United States on 1 December 2010, in retail pharmacies, clinics, and one on-line pharmacy, KwikMed.[32]

Notes

  1. ↑ "FDA approves ella tablets for prescription emergency contraception" (Press release). FDA. 13 August 2010. Retrieved 2013-06-12.
  2. ↑ Creinin, Mitchell D.; Schlaff, William; Archer, David F.; Wan, Livia; Frezieres, Ron; Thomas, Michael; Rosenberg, Michael; Higgins, James (2006). "Progesterone Receptor Modulator for Emergency Contraception". Obstetrics & Gynecology 108 (5): 1089–97. doi:10.1097/01.AOG.0000239440.02284.45. PMC 2853373. PMID 17077229.
  3. 1 2 3 4 5 "Summary of Product Characteristics: ellaOne 30 mg tablet" (PDF). Retrieved 20 November 2010.
  4. ↑ Trussell, James; Raymond, Elizabeth G.; Cleland, Kelly (2014). "Emergency Contraception: A Last Chance to Prevent Unintended Pregnancy" (PDF). Contemporary Readings in Law and Social Justice 6 (2): 7–38.
  5. ↑ Glasier, Anna F; Cameron, Sharon T; Fine, Paul M; Logan, Susan JS; Casale, William; Van Horn, Jennifer; Sogor, Laszlo; Blithe, Diana L; Scherrer, Bruno; Mathe, Henri; Jaspart, Amelie; Ulmann, Andre; Gainer, Erin (2010). "Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-inferiority trial and meta-analysis". The Lancet 375 (9714): 555–62. doi:10.1016/S0140-6736(10)60101-8. PMID 20116841.
  6. ↑ Trussell, James; Cleland, Kelly (February 13, 2013). "Dedicated emergency contraceptive pills worldwide" (PDF). Princeton: Office of Population Research at Princeton University, Association of Reproductive Health Professionals. Retrieved March 25, 2014.
  7. ↑ ICEC (2014). "EC pill types and countries of availability, by brand". New York: International Consortium for Emergency Contraception (ICEC). Retrieved March 25, 2014.
  8. ↑ HRA Pharma (March 2013). "Countries where ellaOne was launched". Paris: HRA Pharma. Retrieved March 25, 2014.
  9. ↑ ECEC (2014). "Emergency contraception availability in Europe". New York: European Consortium for Emergency Contraception (ECEC). Retrieved March 25, 2014. Ulipristal acetate Emergency Contraception Pills (UPA ECPs), while available in most European countries since 2010, are not yet available in Albania, Estonia, Macedonia, Malta, Switzerland and Turkey. For now UPA ECPs are sold with a prescription in all countries, although provision without a prescription is currently being tested in the United Kingdom.
  10. 1 2 3 4 "Summary of Product Characteristics: Esmya 5mg tablet" (PDF). Retrieved 20 February 2014.
  11. ↑ Nieman, Lynnette K.; Blocker, Wendy; Nansel, Tonja; Mahoney, Sheila; Reynolds, James; Blithe, Diana; Wesley, Robert; Armstrong, Alicia (2011). "Efficacy and tolerability of CDB-2914 treatment for symptomatic uterine fibroids: a randomized, double-blind, placebo-controlled, phase IIb study". Fertility and Sterility 95 (2): 767–72.e1–2. doi:10.1016/j.fertnstert.2010.09.059. PMC 4180231. PMID 21055739.
  12. ↑ Levens, Eric D.; Potlog-Nahari, Clariss; Armstrong, Alicia Y.; Wesley, Robert; Premkumar, Ahalya; Blithe, Diana L.; Blocker, Wendy; Nieman, Lynnette K. (2008). "CDB-2914 for Uterine Leiomyomata Treatment". Obstetrics & Gynecology 111 (5): 1129–36. doi:10.1097/AOG.0b013e3181705d0e. PMC 2742990. PMID 18448745.
  13. ↑ Donnez, Jacques; Tatarchuk, Tetyana F.; Bouchard, Philippe; Puscasiu, Lucian; Zakharenko, Nataliya F.; Ivanova, Tatiana; Ugocsai, Gyula; Mara, Michal; Jilla, Manju P.; Bestel, Elke; Terrill, Paul; Osterloh, Ian; Loumaye, Ernest (2012). "Ulipristal Acetate versus Placebo for Fibroid Treatment before Surgery". New England Journal of Medicine 366 (5): 409–20. doi:10.1056/NEJMoa1103182. PMID 22296075.
  14. ↑ Donnez, Jacques; Vázquez, Francisco; Tomaszewski, Janusz; Nouri, Kazem; Bouchard, Philippe; Fauser, Bart C.J.M.; Barlow, David H.; Palacios, Santiago; Donnez, Olivier; Bestel, Elke; Osterloh, Ian; Loumaye, Ernest (2014). "Long-term treatment of uterine fibroids with ulipristal acetate". Fertility and Sterility 101 (6): 1565–73.e1–18. doi:10.1016/j.fertnstert.2014.02.008. PMID 24630081.
  15. ↑ Courtoy, Guillaume E.; Donnez, Jacques; Marbaix, Etienne; Dolmans, Marie-Madeleine (2015). "In vivo mechanisms of uterine myoma volume reduction with ulipristal acetate treatment". Fertility and Sterility 104 (2): 426–34.e1. doi:10.1016/j.fertnstert.2015.04.025. PMID 26003270.
  16. ↑ CHMP (2009:12, 14)
  17. ↑ CHMP (2009:33, 43)
  18. ↑ CHMP (2009:16)
  19. ↑ CHMP (2009:41)
  20. ↑ RCOG (2004). The Care of Women Requesting Induced Abortion : Evidence-based clinical guideline number 7 (PDF). London: RCOG Press. ISBN 1-904752-06-3. Archived from the original (PDF) on 27 February 2008.
  21. ↑ CHMP (2009:37)
  22. ↑ CHMP (2009:43)
  23. ↑ CHMP (2009:12, 20)
  24. ↑ CHMP (2009:13–14, 21)
  25. ↑ Hilal-Dandan, Randa; Brunton, Laurence L. (2013). Goodman and Gilman's Manual of Pharmacology and Therapeutics. McGraw Hill Professional. ISBN 978-0-07-176917-4.
  26. ↑ Attardi, Barbara J.; Burgenson, Janet; Hild, Sheri A.; Reel, Jerry R. (2004). "In vitro antiprogestational/antiglucocorticoid activity and progestin and glucocorticoid receptor binding of the putative metabolites and synthetic derivatives of CDB-2914, CDB-4124, and mifepristone". The Journal of Steroid Biochemistry and Molecular Biology 88 (3): 277–88. doi:10.1016/j.jsbmb.2003.12.004. PMID 15120421.
  27. ↑ CHMP (2009:22–23)
  28. ↑ CHMP (2009:)
  29. ↑ "FDA grants approval of ella for emergency contraception" (PDF) (Press release). HRA Pharma. 13 August 2010. Retrieved 2010-08-15.
  30. ↑ Emma Hitt (18 June 2010). "FDA Panel Gives Ulipristal Acetate Unanimous Positive Vote for Emergency Contraception Indication". Retrieved 2010-06-22.
  31. ↑ Harris, Gardiner (14 August 2010). "F.D.A. Approves 5-Day Emergency Contraceptive". The New York Times. Retrieved 14 August 2010.
  32. ↑ Watson PR (1 December 2010). "Watson Launches ella(R)(ulipristal acetate)". Retrieved 12 January 2010.

References

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