Ulipristal acetate

Emergency contraception

For emergency contraception a 30 mg tablet is used within 120 hours (5 days) after an unprotected intercourse or contraceptive failure. It has been shown to prevent about 62–85% of expected pregnancies, and prevents more pregnancies than emergency contraception with levonorgestrel. 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. Since July 2016, it is available without prescription in Israel.

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.

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.

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%). After two to four 3-months courses of treatment, UPA-treated fibroids shown about -70% in volume reduction. This phenomenon 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.

Adverse effects

Common side effects include nausea, abdominal pain, emesis, dysmenorrhea, pelvic pain, breast tenderness, headache, dizziness, mood swings, myalgia, and fatigue.

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. It might also interact with hormonal contraceptives and progestogens such as levonorgestrel and other substrates of the progesterone receptor, as well as with glucocorticoids.

Contraindications

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

Pregnancy

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

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.

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.

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.

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, and has no relevant affinity to the estrogen, androgen and mineralocorticoid receptors. Phase II clinical trials suggest that the mechanism might consist of blocking or delaying ovulation and of delaying the maturation of the endometrium.

History

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

The U.S. Food and Drug Administration approved the drug for use in the United States on 13 August 2010, following the FDA advisory committee's recommendation. 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.