Ulipristal acetate

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Ulipristal acetate
Ulipristal acetate skeletal.svg
Clinical data
Trade names Ella, EllaOne, Esmya, others
Other namesCDB-2914; 11β-[4-(Dimethylamino)phenyl]-17α-acetoxy-19-norpregna-4,9-diene-3,20-dione
AHFS/Drugs.com Monograph
License data
Routes of
administration 		By mouth
Drug class Selective progesterone receptor modulator [1]
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Nearly 100%
Protein binding 96.7–99.5%
Metabolism Likely CYP3A4
Elimination half-life 32 hours [1]
Excretion ca. 90% with feces
Identifiers
  • [(8S,11R,13S,14S,17R)-17-acetyl-11-[4-(dimethylamino)phenyl]-13-methyl-3-oxo-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-17-yl] acetate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.207.349 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C30H37NO4
Molar mass 475.629 g·mol−1
3D model (JSmol)
  • CC(=O)OC4(C(C)=O)CCC3C1CCC2=CC(=O)CCC2=C1C(CC34C)c5ccc(N(C)C)cc5
  • InChI=1S/C30H37NO4/c1-18(32)30(35-19(2)33)15-14-27-25-12-8-21-16-23(34)11-13-24(21)28(25)26(17-29(27,30)3)20-6-9-22(10-7-20)31(4)5/h6-7,9-10,16,25-27H,8,11-15,17H2,1-5H3/t25-,26+,27-,29-,30-/m0/s1 X mark.svgN
  • Key:OOLLAFOLCSJHRE-ZHAKMVSLSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Ulipristal acetate, sold under the brand name Ella among others, is a medication used for emergency contraception (birth control) and uterine fibroids. [1] [5] [6] As emergency contraception it should be used within 120 hours of vaginally penetrating intercourse. [1] For fibroids it may be taken for up to six months. [7] It is taken by mouth. [1]

Contents

Common side effects include headache, nausea, feeling tired, and abdominal pain. [1] It should not be used in women who are already pregnant. [1] It is in the selective progesterone receptor modulator (SPRM) class of medications. [1] It works by preventing the effects of progesterone, therefore preventing ovulation but not affecting fertilization or implantation. [8] [9]

Ulipristal acetate was approved for medical use in the United States in 2010. [1] It is on the World Health Organization's List of Essential Medicines. [10] [11]

Medical uses

Emergency contraception

For emergency contraception [12] a 30 mg tablet is used within 120 hours (5 days) after unprotected intercourse or contraceptive failure. [13] It has been shown to prevent about 62–85% of expected pregnancies, [14] and prevents more pregnancies than emergency contraception with levonorgestrel. [15] 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. [16] [17] [18] [19] In November 2014, the European Medicines Agency (EMA) recommended availability of ellaOne emergency contraceptive without prescription in the European Union. [20] In January 2015 the European Commission issued an implementing decision amending accordingly the marketing authorization of EllaOne in the EU. [21] Since July 2016, it is available without prescription in Israel.

Uterine fibroids

Ulipristal acetate is used for pre-operative treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age. [22] The use of ulipristal acetate to treat fibroids was suspended in the European Union in March 2020. [22]

In November 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended that ulipristal acetate be used only to treat uterine fibroids in premenopausal women for whom surgical procedures (including uterine fibroid embolization) are not appropriate or have not worked. [23] In addition, the committee stated that ulipristal acetate must not be used for controlling symptoms of uterine fibroids while awaiting surgical treatment. [23]

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. [24] [25] [26]

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%). [22] After two to four 3-months courses of treatment, UPA-treated fibroids shown about -70% in volume reduction. [27]

Volume reduction of uterine fibroid induced by ulipristal acetate was tentatively explained by the combination of multifactorial events involving control of proliferation of the tumor cells, induction of apoptosis and remodeling of the extracellular matrix [28] under the action of matrix metalloproteinases. [29]

In May 2018, the European Medicines Agency (EMA) recommended measures to minimize the risk of rare but serious liver injury with ulipristal, including contraindication in women with known liver problems; liver tests before, during and after stopping treatment; a card for women to inform them about the need for liver monitoring and to contact their doctor should they develop symptoms of liver injury. In addition, use of the medicine for more than one treatment course has been restricted to women who are not eligible for surgery. [30]

Contraindications

Ulipristal acetate should not be taken by women with severe liver diseases [31] because of its CYP mediated metabolism. It has not been studied in women under the age of 18. [32] : 33, 43 

It is also not recommended for women with severe asthma receiving glucocorticoid treatment because it has shown antiglucocorticoid effects in animal studies. [32] : 10, 44 

Pregnancy

Unlike levonorgestrel, and like mifepristone, ulipristal acetate is embryotoxic in animal studies. [32] : 16  Before taking the drug, a pregnancy must be excluded. [13] The EMA proposed to avoid any allusion to a possible use as an abortifacient in the package insert to avert off-label use. [32] : 41  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. [33] 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. [32] : 37 

Lactation

It is not recommended to breast feed within seven days of taking the drug since ulipristal acetate is excreted into the breast milk, and possible effects on the infant have not been studied. [31] [32] : 43 

Side effects

The most common side effects include headache, nausea (feeling sick), abdominal pain (stomach ache), and dysmenorrhea (period pains). [13]

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. [22] [32] : 12, 14  It might also interact with hormonal contraceptives and progestogens such as levonorgestrel and other substrates of the progesterone receptor, as well as with glucocorticoids. [22]

Pharmacology

Pharmacodynamics

As an SPRM, ulipristal acetate has partial agonistic as well as antagonistic effects on the progesterone receptor. Ulipristal acetate exhibits similar potency to antagonize progesterone receptor as mifepristone in vitro. [34] It also binds to the androgen receptor and the glucocorticoid receptor, but is only a weak antiandrogen and antiglucocorticoid relative to flutamide and mifepristone, respectively. [35] [36] Ulipristal acetate has no relevant affinity to the estrogen and mineralocorticoid receptors. [37] Phase II clinical trials suggest that the mechanism might consist of blocking or delaying ovulation and of delaying the maturation of the endometrium. [32] : 22–23 

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. [32] : 12, 20 

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 feces. [32] : 13–14, 21 

History

Ulipristal acetate was granted marketing authorization by the European Medicines Agency (EMA) in May 2009. [13] In 2014, the EMA recommended ulipristal be made available without a prescription in the European Union. [38] [13]

The U.S. Food and Drug Administration (FDA) approved the drug for use in the United States on 13 August 2010, [39] following the FDA advisory committee's recommendation. [40] [41] 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. [42]

Society and culture

Brand names

Ulipristal acetate is marketed in the United States under the brand name Ella and in Canada under the brand name Fibristal. [6] It is also marketed under the brand names EllaOne and Esmya in many countries including the United Kingdom and Ireland. [6] A few less-widely used brand names also exist. [6]

Related Research Articles

<span class="mw-page-title-main">Emergency contraception</span> Birth control measures taken after sexual intercourse

Emergency contraception (EC) is a birth control measure, used after sexual intercourse to prevent pregnancy.

<span class="mw-page-title-main">Mifepristone</span> Often used as an emergency contraceptive

Mifepristone, also known as RU-486, is a medication typically used in combination with misoprostol to bring about a medical abortion during pregnancy and manage early miscarriage. This combination is 97% effective during the first 63 days of pregnancy. It is also effective in the second trimester of pregnancy. It is taken by mouth.

<span class="mw-page-title-main">Levonorgestrel</span> Hormonal medication used for birth control

Levonorgestrel is a hormonal medication which is used in a number of birth control methods. It is combined with an estrogen to make combination birth control pills. As an emergency birth control, sold under the brand name Plan B One-Step among others, it is useful within 72 hours of unprotected sex. The more time that has passed since sex, the less effective the medication becomes, and it does not work after pregnancy (implantation) has occurred. Levonorgestrel works by preventing ovulation or fertilization from occurring. It decreases the chances of pregnancy by 57 to 93%. In an intrauterine device (IUD), such as Mirena among others, it is effective for the long-term prevention of pregnancy. A levonorgestrel-releasing implant is also available in some countries.

<span class="mw-page-title-main">Uterine fibroid</span> Medical condition with benign tumors of uterus

Uterine fibroids, also known as uterine leiomyomas or fibroids, are benign smooth muscle tumors of the uterus. Most women with fibroids have no symptoms while others may have painful or heavy periods. If large enough, they may push on the bladder, causing a frequent need to urinate. They may also cause pain during penetrative sex or lower back pain. A woman can have one uterine fibroid or many. Occasionally, fibroids may make it difficult to become pregnant, although this is uncommon.

<span class="mw-page-title-main">Desogestrel</span> Medication

Desogestrel is a progestin medication which is used in birth control pills for women. It is also used in the treatment of menopausal symptoms in women. The medication is available and used alone or in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Norgestimate</span> Chemical compound

Norgestimate, sold under the brand names Ortho Tri-Cyclen and Previfem among others, is a progestin medication which is used in birth control pills for women and in menopausal hormone therapy. The medication is available in combination with an estrogen and is not available alone. It is taken by mouth.

<span class="mw-page-title-main">Selective progesterone receptor modulator</span>

A selective progesterone receptor modulator (SPRM) is an agent that acts on the progesterone receptor (PR), the biological target of progestogens like progesterone. A characteristic that distinguishes such substances from full receptor agonists and full antagonists is that their action differs in different tissues, i.e. agonist in some tissues while antagonist in others. This mixed profile of action leads to stimulation or inhibition in tissue-specific manner, which further raises the possibility of dissociating undesirable adverse effects from the development of synthetic PR-modulator drug candidates.

<span class="mw-page-title-main">Hormonal contraception</span> Birth control methods that act on the endocrine system

Hormonal contraception refers to birth control methods that act on the endocrine system. Almost all methods are composed of steroid hormones, although in India one selective estrogen receptor modulator is marketed as a contraceptive. The original hormonal method—the combined oral contraceptive pill—was first marketed as a contraceptive in 1960. In the ensuing decades many other delivery methods have been developed, although the oral and injectable methods are by far the most popular. Hormonal contraception is highly effective: when taken on the prescribed schedule, users of steroid hormone methods experience pregnancy rates of less than 1% per year. Perfect-use pregnancy rates for most hormonal contraceptives are usually around the 0.3% rate or less. Currently available methods can only be used by women; the development of a male hormonal contraceptive is an active research area.

<span class="mw-page-title-main">Asoprisnil</span> Chemical compound

Asoprisnil is a synthetic, steroidal selective progesterone receptor modulator that was under development by Schering and TAP Pharmaceutical Products for the treatment of uterine fibroids. In 2005, phase III clinical trials were discontinued due to endometrial changes in patients.

<span class="mw-page-title-main">Antiprogestogen</span> Class of compounds

Antiprogestogens, or antiprogestins, also known as progesterone antagonists or progesterone blockers, are a class of drugs which prevent progestogens like progesterone from mediating their biological effects in the body. They act by blocking the progesterone receptor (PR) and/or inhibiting or suppressing progestogen production. Antiprogestogens are one of three types of sex hormone antagonists, the others being antiestrogens and antiandrogens.

<span class="mw-page-title-main">Dienogest</span> Chemical compound

Dienogest, sold under the brand name Visanne among others, is a progestin medication which is used in birth control pills and in the treatment of endometriosis. It is also used in menopausal hormone therapy and to treat heavy periods. Dienogest is available both alone and in combination with estrogens. It is taken by mouth.

<span class="mw-page-title-main">Perampanel</span> Anti-epileptic medication

Perampanel, sold under the brand name Fycompa, is an anti-epileptic medication developed by Eisai Co. that is used in addition to other drugs to treat partial seizures and generalized tonic-clonic seizures for people older than twelve years. It was first approved in 2012, and as of 2016, its optimal role in the treatment of epilepsy relative to other drugs was not clear. It was the first antiepileptic drug in the class of selective non-competitive antagonist of AMPA receptors.

<span class="mw-page-title-main">Chlormadinone acetate</span> Chemical compound

Chlormadinone acetate (CMA), sold under the brand names Belara, Gynorelle, Lutéran, and Prostal among others, is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy, as a component of menopausal hormone therapy, in the treatment of gynecological disorders, and in the treatment of androgen-dependent conditions like enlarged prostate and prostate cancer in men and acne and hirsutism in women. It is available both at a low dose in combination with an estrogen in birth control pills and, in a few countries like France and Japan, at low, moderate, and high doses alone for various indications. It is taken by mouth.

<span class="mw-page-title-main">Medroxyprogesterone acetate</span> Injectible form of birth control

Medroxyprogesterone acetate (MPA), also known as depot medroxyprogesterone acetate (DMPA) in injectable form and sold under the brand name Depo-Provera among others, is a hormonal medication of the progestin type. It is used as a method of birth control and as a part of menopausal hormone therapy. It is also used to treat endometriosis, abnormal uterine bleeding, abnormal sexuality in males, and certain types of cancer. The medication is available both alone and in combination with an estrogen. It is taken by mouth, used under the tongue, or by injection into a muscle or fat.

<span class="mw-page-title-main">Nomegestrol acetate</span> Chemical compound

Nomegestrol acetate (NOMAC), sold under the brand names Lutenyl and Zoely among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. It is available both alone and in combination with an estrogen. NOMAC is taken by mouth. A birth control implant for placement under the skin was also developed but ultimately was not marketed.

<span class="mw-page-title-main">Relugolix</span> Chemical compound

Relugolix, sold under the brand names Orgovyx and Relumina among others, is a gonadotropin-releasing hormone antagonist medication which is used in the treatment of prostate cancer in men and uterine fibroids in women. It is also under development for use in the treatment of endometriosis. It is taken by mouth once per day.

<span class="mw-page-title-main">Vilaprisan</span> Chemical compound

Vilaprisan is a synthetic and steroidal selective progesterone receptor modulator (SPRM) which is under development by Bayer HealthCare Pharmaceuticals for the treatment of endometriosis and uterine fibroids. It is a potent and highly selective partial agonist of the progesterone receptor (PR). As of 2017, the drug is in phase II clinical trials for the aforementioned indications.

<span class="mw-page-title-main">Asoprisnil ecamate</span> Chemical compound

Asoprisnil ecamate (INN) is a synthetic, steroidal selective progesterone receptor modulator (SPRM) which was under development for the treatment of endometriosis, uterine fibroids, and menopausal symptoms but was discontinued. It is a potent and highly selective ligand of the progesterone receptor with mixed agonistic and antagonistic activity and much reduced antiglucocorticoid activity relative to mifepristone. The drug reached phase III clinical trials for the aforementioned indications prior to its discontinuation.

<span class="mw-page-title-main">Linzagolix</span> Chemical compound

Linzagolix, sold under the brand name Yselty, is a medication used in the treatment of uterine fibroids. Linzagolix is a small-molecule, non-peptide, orally active gonadotropin-releasing hormone antagonist developed by Kissei Pharmaceutical and ObsEva.

<span class="mw-page-title-main">Relugolix/estradiol/norethisterone acetate</span> Combination medication

Relugolix/estradiol/norethisterone acetate, sold under the brand names Myfembree and Ryeqo, is a fixed-dose combination hormonal medication which is used for the treatment of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) and for moderate to severe pain associated with endometriosis. It contains relugolix, an orally active gonadotropin-releasing hormone antagonist, estradiol, an estrogen, and norethisterone acetate, a progestin. The medication is taken by mouth.

References

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  2. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2015". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  3. ↑ "ellaOne 30 mg - Summary of Product Characteristics (SmPC)". (emc). 1 July 2021. Retrieved 28 February 2022.
  4. ↑ "Esmya 5 mg Tablets (ulipristal acetate) - Summary of Product Characteristics (SmPC)". (emc). 17 February 2021. Retrieved 28 February 2022.
  5. ↑ Garnock-Jones KP, Duggan ST (October 2017). "Ulipristal Acetate: A Review in Symptomatic Uterine Fibroids". Drugs. 77 (15): 1665–1675. doi:10.1007/s40265-017-0812-3. PMID   28900897. S2CID   207489367.
  6. 1 2 3 4 "Ulipristal - Drugs.com". Drugs.com. Archived from the original on 14 December 2017. Retrieved 14 December 2017.
  7. ↑ British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. pp. 510, 560. ISBN   9780857111562.
  8. ↑ Likis FE (2016). Women's Gynecologic Health. Jones & Bartlett Publishers. p. 243. ISBN   9781284076028. Archived from the original on 10 December 2017.
  9. ↑ Li HW, Resche-Rigon M, Bagchi IC, Gemzell-Danielsson K, Glasier A (November 2019). "Does ulipristal acetate emergency contraception (ella®) interfere with implantation?". Contraception. 100 (5): 386–390. doi:10.1016/j.contraception.2019.07.140. PMID   31351035. S2CID   198952998.
  10. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
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  30. ↑ "Esmya: new measures to minimise risk of rare but serious liver injury". European Medicines Agency (EMA). 8 August 2018. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  31. 1 2 "ellaOne: EPAR - Product Information" (PDF). European Medicines Agency (EMA). 26 May 2020.
  32. 1 2 3 4 5 6 7 8 9 10 CHMP (2009). "Assessment Report for Ellaone" (PDF). EMA. Retrieved 22 November 2009.
  33. ↑ 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.
  34. ↑ Šauer P, Stará A, Golovko O, Valentová O, Bořík A, Grabic R, Kroupová HK (June 2018). "Two synthetic progestins and natural progesterone are responsible for most of the progestagenic activities in municipal wastewater treatment plant effluents in the Czech and Slovak republics". Water Research. 137: 64–71. Bibcode:2018WatRe.137...64S. doi:10.1016/j.watres.2018.02.065. PMID   29544204. S2CID   4726126.
  35. ↑ Šauer P, Bořík A, Golovko O, Grabic R, Staňová AV, Valentová O, et al. (November 2018). "Do progestins contribute to (anti-)androgenic activities in aquatic environments?". Environmental Pollution. 242 (Pt A): 417–425. doi:10.1016/j.envpol.2018.06.104. PMID   29990947. S2CID   51622914.
  36. ↑ Hilal-Dandan R, Brunton L (2013). Goodman and Gilman's Manual of Pharmacology and Therapeutics. McGraw Hill Professional. ISBN   978-0-07-176917-4.[ page needed ]
  37. ↑ Attardi BJ, Burgenson J, Hild SA, Reel JR (March 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. S2CID   23958876.
  38. ↑ "EMA recommends availability of ellaOne emergency contraceptive without prescription". European Medicines Agency (EMA) (Press release). 17 September 2018. Retrieved 7 July 2020.
  39. ↑ "FDA grants approval of ella for emergency contraception" (PDF) (Press release). HRA Pharma. 13 August 2010. Retrieved 15 August 2010.[ permanent dead link ]
  40. ↑ Hitt E (18 June 2010). "FDA Panel Gives Ulipristal Acetate Unanimous Positive Vote for Emergency Contraception Indication". Archived from the original on 9 March 2011. Retrieved 22 June 2010.
  41. ↑ Harris G (14 August 2010). "F.D.A. Approves 5-Day Emergency Contraceptive". The New York Times. Archived from the original on 3 April 2012. Retrieved 14 August 2010.
  42. ↑ Watson PR (1 December 2010). "Watson Launches ella(R)(ulipristal acetate)" . Retrieved 12 January 2010.[ permanent dead link ]
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