Ulipristal acetate
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| 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 |
| Licence data | EMA:Link, US FDA:link |
| Pregnancy cat. | X (US) |
| Legal status | POM (UK) ℞-only (US) |
| Routes | Oral |
| Pharmacokinetic data | |
| Bioavailability | Nearly 100% |
| Protein binding | 96.7–99.5% |
| Metabolism | Likely CYP3A4 |
| Half-life | 32 hours |
| Excretion | ca. 90% with faeces |
| Identifiers | |
| CAS number | 126784-99-4  |
| ATC code | G03AD02 |
| PubChem | CID 130904 |
| ChEMBL | CHEMBL260538  |
| Synonyms | CDB-2914 |
| Chemical data | |
| Formula | C30H37NO4 |
| Mol. mass | 475.62 g/mol |
| SMILES | eMolecules & PubChem |
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Ulipristal acetate (trade name ellaOne in the European Union, ella in the U.S.,[1] HRA Pharma) is a selective progesterone receptor modulator (SPRM) for emergency contraception[2] within 120 hours (5 days) after an unprotected intercourse or contraceptive failure. It has shown to prevent about 60% of expected pregnancies,[3] which is comparable to the emergency contraception scheme with levonorgestrel. Ulipristal acetate is available by prescription only.
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[edit] History
Ulipristal acetate was granted marketing authorization by the European Medicines Agency (EMA) in March 2009.[4]
The U.S. Food and Drug Administration approved the drug for use in the United States on August 13, 2010,[1] following the FDA advisory committee's recommendation.[5][6] Watson Pharmaceuticals announced the availability of ulipristal acetate in the United States on December 1, 2010, in retail pharmacies, clinics, and one on-line pharmacy, KwikMed.[7]
[edit] Other indications
There is mounting evidence that ulipristal acetate may be useful in the management of uterine fibroids.[8][9][10]
[edit] 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.[11]
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.[12]
[edit] 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 has no relevant affinity to the estrogen, androgen and mineralocorticoid receptors.[13] Phase II clinical trials suggest that the mechanism might consist of blocking or delaying ovulation and of delaying the maturation of the endometrium.[14]
[edit] Contraindications
Ulipristal acetate should not be taken by women with severe liver diseases[15] because of its CYP mediated metabolism. It has not been studied in women under the age of 18.[16]
[edit] Pregnancy
Unlike levonorgestrel, and like mifepristone, ulipristal acetate is embryotoxic in animal studies.[17] Before taking the drug, a pregnancy must be excluded.[15] The EMA proposed to avoid any allusion to a possible use as an abortifacient in the package insert to avert off-label use.[18] It is unlikely that Ellaone 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.[19] 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".[20]
[edit] 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.[15][21]
[edit] Side effects
Common side effects include abdominal pain and temporary menstrual disorder. Headache and nausea were observed under long-term administration (12 weeks), but not after a single dose.[15]
[edit] Interactions
No interaction studies have been conducted. Ulipristal acetate is likely to interact with substrates of CYP3A4, like St John's wort or carbamazepine, but this might not be clinically relevant because only a single dose of the drug is taken.[22] It might also interact with levonorgestrel and other substrates of the progesterone receptor, as well as with glucocorticoids.
[edit] References
- ^ a b "FDA grants approval of ella for emergency contraception" (Press release). HRA Pharma. August 13, 2010. http://www.hra-pharma.com/downloads/HRA%20FDA%20Approval%20FINAL.pdf. Retrieved 2010-08-15.
- ^ Creinin, MD; Schlaff, W; Archer, DF; Wan, L; Frezieres, R; Thomas, M; Rosenberg, M; Higgins, J (2006). "Progesterone receptor modulator for emergency contraception: a randomized controlled trial". Obstetrics and gynecology 108 (5): 1089–97. doi:10.1097/01.AOG.0000239440.02284.45. PMC 2853373. PMID 17077229. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2853373.
- ^ "European Public Assessment Report for Ellaone. Summary for the public". EMA. 2009. p. 2. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/001027/WC500023671.pdf. Retrieved 22 November 2009.
- ^ CHMP (2009). "Assessment Report for Ellaone". EMA. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001027/WC500023673.pdf. Retrieved 22 November 2009.
- ^ Emma Hitt (18 June 2010). "FDA Panel Gives Ulipristal Acetate Unanimous Positive Vote for Emergency Contraception Indication". http://www.medscape.com/viewarticle/723822. Retrieved 06-22-2010.
- ^ Harris, Gardiner (August 14, 2010). "F.D.A. Approves 5-Day Emergency Contraceptive". The New York Times. http://www.nytimes.com/2010/08/14/health/policy/14pill.html. Retrieved August 14, 2010.
- ^ Watson PR (1 December 2010). "Watson Launches ella(R)(ulipristal acetate)". http://ir.watson.com/phoenix.zhtml?c=65778&p=irol-newsArticle&ID=1501974. Retrieved 12-1-2010.
- ^ Nieman, L. K.; Blocker, W.; Nansel, T.; Mahoney, S.; Reynolds, J.; Blithe, D.; Wesley, R.; Armstrong, A. (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): 767–772.e1–772. doi:10.1016/j.fertnstert.2010.09.059. PMID 21055739.
- ^ Levens, E. D.; Potlog-Nahari, C.; Armstrong, A. Y.; Wesley, R.; Premkumar, A.; Blithe, D. L.; Blocker, W.; Nieman, L. K. (2008). "CDB-2914 for Uterine Leiomyomata Treatment". Obstetrics & Gynecology 111 (5): 1129–1136. doi:10.1097/AOG.0b013e3181705d0e. PMC 2742990. PMID 18448745. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2742990.
- ^ Jacques Donnez; Tetyana F. Tatarchuk, Philippe Bouchard, Lucian Puscasiu, Nataliya F. Zakharenko, Tatiana Ivanova, Gyula Ugocsai, Michal Mara, Manju P. Jilla, Elke Bestel, Paul Terrill, Ian Osterloh, and Ernest Loumaye, for the PEARL I Study Group. "Ulipristal Acetate versus Placebo for Fibroid Treatment before Surgery". New England Journal of Medicine. doi:10.1056/NEJMoa1103182. PMID 22296075.
- ^ CHMP (2009:12, 20)
- ^ CHMP (2009:13–14, 21)
- ^ Attardi, B.; Burgenson, J.; Hild, S.; Reel, J. (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): 277–288. doi:10.1016/j.jsbmb.2003.12.004. PMID 15120421.
- ^ CHMP (2009:22–23)
- ^ a b c d "Summary of Product Characteristics: ellaOne 30 mg tablet". http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001027/WC500023670.pdf. Retrieved 20 November 2010.
- ^ CHMP (2009:33, 43)
- ^ CHMP (2009:16)
- ^ CHMP (2009:41)
- ^ RCOG (2004) (PDF). The Care of Women Requesting Induced Abortion : Evidence-based clinical guideline number 7. London: RCOG Press. ISBN 1-904752-06-3. Archived from the original on February 27, 2008. http://web.archive.org/web/20080227213507/http://www.rcog.org.uk/resources/Public/pdf/induced_abortionfull.pdf.
- ^ CHMP (2009:37)
- ^ CHMP (2009:43)
- ^ CHMP (2009:12, 14)
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