Ulipristal acetate

Structural formula
General
Non-proprietary name	Ulipristal acetate
other names	(8 S , 11 S , 13 S , 14 R , 17 R ) -17-Acetoxy-11- [4- (dimethylamino) phenyl] -19-norpregna-4,9-diene-3,20-dione ( IUPAC )
Molecular formula	C 30 H 37 NO 4
Brief description	white to yellow solid
External identifiers / databases
EC number	682-170-1
ECHA InfoCard	100.207.349
PubChem	130904
ChemSpider	115762
DrugBank	DB05366
Wikidata	Q975059
Drug information
ATC code	G03 AD02 ; G03 XB02 ;
Drug class	Emergency contraceptive; Progesterone receptor antagonist used to treat uterine fibroids ;
Mechanism of action	Progesterone receptor modulator
properties
Molar mass	475.62 g mol −1
Physical state	firmly
solubility	miscible with methylene chloride ; soluble in methanol , acetone and ethanol ; almost insoluble in water;
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
H and P phrases	H: 302-360-413
	P: ?
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Ulipristal acetate is used in gynecology as a morning-after pill for emergency contraception . At a lower dose, it is used to treat benign tumors of the uterus (trade name Esmya ).

In the countries of the EU, ulipristal acetate has been approved for emergency contraception as ellaOne since 2009 . Esmya was approved in 2012; its approval has been suspended since March 2020 as part of a risk assessment process.

Working principle

The desired effect of ulipristal acetate is based on the inhibition of the binding of the endogenous progestogen progesterone to the corresponding receptors . This can prevent or delay ovulation in women and suppress the tumor-promoting effect of progesterone on uterine fibroids .

The suspicion of an additional contraceptive effect by inhibiting the implantation of the fertilized egg cell in the uterine lining was discussed at the beginning of 2014.

application areas

Emergency contraception

Ulipristal acetate can be used for emergency contraception up to 120 hours after unprotected sexual intercourse or failure of used contraceptives . To avoid an unwanted pregnancy , one tablet EllaOne or Ella with 30 mg ulipristal acetate is administered as a single dose as early as possible. The preparation is effective regardless of whether it is taken with or outside of a meal. If vomiting occurs within three hours of ingestion , the preparation must be taken again. Ulipristal acetate should not be used for routine contraception. It is suitable for all women of childbearing age including adolescents. No differences were found in terms of efficacy and safety compared to adult use.

Treatment of benign uterine tumors

For fibroid treatment , pre- menopausal adult women are given one Esmya tablet containing five milligrams of ulipristal acetate per day for up to three months; treatment begins in the first week of the menstrual cycle . If the effect is insufficient, the treatment can be repeated once. By shielding progesterone activity, the tumor cells are killed, causing the fibroid to shrink and its effects to decrease. In corresponding studies, ulipristal acetate was certified to be as effective as leuprorelin .

Side effects and restrictions on use

The most commonly reported side effects are headache , nausea with and without vomiting, abdominal pain , muscle and back pain , fatigue, and menstrual cramps . More rarely occurred during treatment with ulipristal acetate mood swings , appetite disorders , migraines , blurred vision , acne , itching , fever , or hot flashes on.

Experience with ulipristal acetate overdoses is limited. In the past, single doses of up to 200 mg were withstood without serious consequences.

Simultaneous use with rifampicin , phenytoin , carbamazepine , phenobarbital , efavirenz , phosphenytoin , nevirapine , oxcarbazepine , primidone , rifabutin , ritanovir , St. John's wort preparations and levonorgestrel , which is also suitable as a morning-after pill , is not recommended. Ulipristal acetate can weaken the effect of other hormonal contraceptives based on gestagen and / or gestagen- estrogen alone .

The substance must not be used in the case of a known allergy to ulipristal acetate. A transfer into breast milk with the risk of effects occurring in the infant occurs, which is why emergency contraception with ulipristal acetate is not recommended during breastfeeding . In the treatment of benign uterine tumors, ulipristal acetate is contraindicated during pregnancy and breastfeeding . As a precaution, should not performed during treatment motor vehicles and machines not being served, even if the impact on the responsiveness is considered mildly to moderately and rarely about visual disturbances have been reported.

The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) launched a risk assessment process for the drug Esmya on December 1, 2017 to resolve four reports of severe liver damage in patients treated with ulipristal acetate and possible To consider the consequences of using the drug. The committee did not initially advise against using the drug. From February 2018, regular close laboratory monitoring of the patients was recommended. After a new case of severe liver damage after treatment with Esmya was reported in December 2019 despite compliance with these introduced risk minimization measures, the BfArM ordered the approval to be suspended. Medicines containing 5 mg ulipristal acetate must not be used until the risk assessment process has been completed. According to the PRAC, there have been no reports of liver damage from the use of ulipristal acetate as an emergency contraceptive, which is why this drug is currently not being tested.

Finished medicinal products

Ulipristal acetate for emergency contraception (30 mg): Ella (USA, CND), EllaOne (EU) and generics ( Lencya , Femke and others)
Ulipristal acetate to treat uterine fibroids (5 mg): Esmya (EU), Fibristal (CND)

The patent protection for EllaOne has expired since the end of May 2020.

Sales accrual

No prescription requirement in 2015

In the countries of the European Union, ulipristal acetate has been subject to prescription since its introduction . In February 2014, the European Medicines Agency received an application for the EU-wide release of the ulipristal acetate-containing drug EllaOne from prescription requirements. A prescription exemption for newer preparations by the EU is also possible against the will of the individual member states, since the approval (unlike in the case of levonorgestrel ) has been granted on a pan-European level. In Great Britain and Northern Ireland , ulipristal acetate had been dispensed without a prescription as a pharmacy-only drug as part of a trial (as of July 25, 2014).

On January 8, 2015, the EU Commission decided to abolish the EU-wide prescription requirement for the morning-after pill.

With the release from the prescription requirement on March 14, 2015, the assumption of costs by the health insurance company was also prescribed for patients under 20 years of age. The sale by mail order is not allowed. Direct application of the preparation is prohibited. The sale to young people from the age of 14 is also permitted without the consent of the legal guardian .

In the form of the Esmya preparation, ulipristal acetate remains subject to prescription.

Legal situation in Poland

After the prescription was no longer required across the EU in 2015, ellaOne was sold out in Poland after a short time. In 2017, at the end of the right-wing governing party Law and Justice , after a corresponding change in the law, it was made subject to prescription again in June 2017.

Legal situation in the USA

In the United States , pharmacies are legally required to supply medically prescribed ulipristal acetate as an emergency contraceptive. Individual pharmacists whose religious beliefs contradict the dispensing may only refuse the latter if another employee from the same pharmacy hands the preparation over to the patient in a timely manner. The Supreme Court ruled this binding in July 2016. In most other cases, pharmacists in the USA can decide for themselves which products they carry.

Distribution channel

According to German law, the use of ulipristal acetate is not considered to be an abortion ( Section 218, Paragraph 1, Sentence 2 of the Criminal Code), as there is no demonstrable discharge of the fertilized egg from the uterine lining and the pregnancy does not legally begin until the egg has implanted in the uterus . Accordingly, a special distribution channel according to § 47a AMG is not provided and the preparation is given directly to the patient in the pharmacy .

controversy

At the time of approval, normal live births were known after administration of various doses of ulipristal acetate, but overall the data on the effects of exposure on pregnancy were very limited. Citing the claim that "according to current research" ulipristal acetate prevents the implantation of fertilized egg cells in the uterus or leads to the rejection of already nested egg cells, in 2014 parts of the life rights movement and the Roman Catholic Church wrote that the remedy had an "early abortion effect" and an active principle similar to the "abortion pill" mifepristone (see also claimed effect ) and warned against the release. According to the information in the registration documents, ulipristal acetate does not lead to termination of an existing pregnancy.

Individual evidence

↑ ^a ^b ^c ^d ^e ^f ^g CHMP Assessment Report for EllaOne (PDF) June 2009.
↑ Template: CL Inventory / not harmonized There is not yet a harmonized classification for this substance . A label of (1R, 3aS, 3bS, 10R, 11aS) -1-acetyl-10- [4- (dimethylamino) phenyl] -11a-methyl-7-oxo-1H, 2H, is shown, which is derived from a self-classification by the distributor 3H, 3aH, 3bH, 4H, 5H, 7H, 8H, 9H, 10H, 11H, 11aH-cyclopenta [a] phenanthren-1-yl acetate in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on March 13, 2019 .

↑ ^a ^b ^c European Medicines Agency : Esmya, INN-Ulipristal. (PDF) Retrieved June 23, 2014.

↑ Mechanism of action of the morning-after pill. (PDF) Pro Familia .

↑ B. Mozzanega, p Gizzo, S. Di Gangi, E. Cosmi, GB Nardelli: ulipristal acetate: critical reviews about endometrial and ovulatory effects in emergency contraception. Department of Woman and Child Health, University of Padua, Padova, Italy In: Reproductive sciences (Thousand Oaks, Calif.). Volume 21, Number 6, June 2014, pp. 678-685, doi: 10.1177 / 1933719113519178 , PMID 24440997 (abstract).

↑ ^a ^b ^c ^d ^e ^f ^g Summary of Product Characteristics, EllaOne 30 mg . European Medicines Agency as of May 2020; ema.europa.eu (PDF).

↑ Guillaume E. Courtoy, Jacques Donnez, Etienne Marbaix, Marie-Madeleine Dolmans: In vivo mechanisms of uterine myoma volume reduction with ulipristal acetate treatment . In: Fertility and Sterility . tape 104 , no. 2 , August 2015, p. 426-434.e1 , doi : 10.1016 / j.fertnstert.2015.04.025 , PMID 26003270 .

↑ Esmya® for the treatment of uterine fibroids: risk assessment process for liver damage started. from December 1, 2017.

↑ Rote-Hand-Brief on ulipristal acetate 5 mg: No use for the treatment of uterine fibroids during the ongoing assessment process for the risk of liver damage . Federal Institute for Drugs and Medical Devices , March 23, 2020.

↑ EMA starts review of Esmya for uterine fibroids.

↑ Esmya® (ulipristal acetate) for the treatment of uterine fibroids: PRAC adopts preliminary measures to protect patients. ( Memento from February 12, 2018 in the Internet Archive ) from February 9, 2018.

↑ N. Tröbitscher: ellaOne: generic Hexal, Mylan and aliud. In: apotheke-adhoc.de. Retrieved June 30, 2020 .

↑ EU is considering abolishing the prescription requirement for the morning-after pill. In: Ärzteblatt , February 24, 2014.

↑ Morning after pill: European Medicines Agency examines release of "Ellaone". In: Spiegel online , February 24, 2014.

↑ Emergency Contraception Availability in Europe. European Consortium for Emergency Contraception ; Retrieved July 25, 2014.

↑ BGBl. I p. 278

↑ Federal Council approves the non-prescription morning-after pill . In: Süddeutsche Zeitung , March 6, 2015.

↑ § 10 Therapeutic Products Advertising Act .

↑ Dispensing of emergency contraceptives without prescription (“morning-after pill”) . ( Memento from April 2, 2015 in the Internet Archive ; PDF) Federal Chamber of Pharmacists , as of January 28, 2015, p. 10; accessed on February 27, 2015.