Mifepristone

(BAN, USAN, rINN)
Mifepristone Chemical formula
Synonyms: C-1073; Mifepriston; Mifepristona; Mifépristone; Mifepristoni; Mifepristonum; RU-486; RU-38486. 11 nyl)-17
Cyrillic synonym: Мифепристон.

💊 Chemical information

Chemical formula: C29H35NO2 = 429.6.
CAS — 84371-65-3.
ATC — G03XB01.
ATC Vet — QG03XB01.

Pharmacopoeias.

In Chin.

💊 Adverse Effects

Uterine bleeding and cramps often occur after the use of mifepristone in procedures for the termination of pregnancy, and will occur in almost all patients after the addition of a prostaglandin. Bleeding typically continues for about 9 to 16 days, and may be severe enough to warrant curettage and transfusion in a small proportion of patients. However, prolonged heavy bleeding may also be a sign of incomplete abortion or other complications that require medical or surgical intervention. Other adverse effects of mifepristone include malaise, dizziness, chills, fever, headache, diarrhoea, nausea, vomiting, skin rashes, and urticaria; although some of these effects may be caused by the prostaglandin given after mifepristone. Serious, sometimes fatal, infections have occurred in women undergoing abortion, although no causal relationship has been established between these events and the use of mifepristone.

Effects on the cardiovascular system.

For a report of a woman who died from cardiovascular shock during an abortion induced by mifepristone followed by sulprostone.

Effects on the fetus.

Studies in rabbits, but not rats or mice, suggest mifepristone causes fetal malformation. There have been reports of normal fetal development after the use of mifepristone alone in mothers who subsequently decided to continue their pregnancy.1,2 However, in two reports, use of mifepristone was possibly related to malformations of the fetus including sirenomelia.2,3 Cerebellar agenesis has been reported after a failed medical termination using mifepristone and gemeprost.
1. Lim BH, et al. Normal development after exposure to mifepristone in early pregnancy. Lancet 1990; 336: 257–8
2. Pons J-C, et al. Development after exposure to mifepristone in early pregnancy. Lancet 1991; 338: 763
3. Sitruk-Ware R, et al. Fetal malformation and failed medical termination of pregnancy. Lancet 1998; 352: 323.

Toxic shock syndrome.

Fatal toxic shock syndrome occurred in 5 women who underwent medical termination of pregnancy using mifepristone and misoprostol.1,2 In 4 cases it was specified that mifepristone 200 mg had been given orally, followed by misoprostol 800 micrograms vaginally.2 Within a week of termination, these patients presented with signs and symptoms that included abdominal pain, nausea and vomiting, tachycardia, hypotension, oedema, haemoconcentration, profound leucocytosis, and absence of fever. Postmortem examination found evidence of endometritis and toxic shock syndrome that was attributed to Clostridium sordellii infection. This is an infrequent human pathogen, but the authors of one report2 noted that C. sordellii infection of the genital tract had also been reported in 8 women after delivery, suggesting that pregnancy, childbirth, or termination of pregnancy may predispose a small number of women to acquire this organism, and that associated dilatation of the cervix may allow for ascending infection. Although there has also been some speculation about the possible mechanisms, both pharmacological3 and physical,4 by which oral mifepristone or vaginal misoprostol might potentiate C. sordellii infection, a causal relationship between these drugs and the 5 reported deaths has not been established.5
1. Sinave C, et al. Toxic shock syndrome due to Clostridium sordellii: a dramatic postpartum and postabortion disease. Clin Infect Dis 2002; 35: 1441–3
2. Fischer M, et al. Fatal toxic shock syndrome associated with Clostridium sordellii after medical abortion. N Engl J Med 2005; 353: 2352–60
3. Miech RP. Pathophysiology of mifepristone-induced septic shock due to Clostridium sordellii. Ann Pharmacother 2005; 39: 1483–8
4. Sicard D, Chauvelot-Moachon L. Comment: pathophysiology of mifepristone-induced septic shock due to Clostridium sordellii. Ann Pharmacother 2005; 39: 2142–3
5. FDA. Questions and answers on Mifeprex (mifepristone) November 4, 2005. Available at: http://www.fda.gov/cder/drug/ infopage/mifepristone/mifepristone-qa20050719.htm (accessed 30/06/08)

💊 Precautions

The use of mifepristone is contra-indicated in women with a confirmed or suspected ectopic pregnancy, because medical termination using mifepristone and a prostaglandin will not be effective (for use with methotrexate, see below). The expected symptoms of a medical termination may also be similar to those of a ruptured ectopic pregnancy. Mifepristone is also contra-indicated in patients with chronic adrenal failure or severe uncontrolled asthma. Use in those with renal or hepatic impairment is also not recommended. Mifepristone should be given with care to patients with less severe asthma or with chronic obstructive airways diseases, haemorrhagic or cardiovascular disease or associated risk factors, or anaemia. Therapy may need to be adjusted in patients receiving long-term corticosteroid treatment; a corticosteroid may need to be given if acute adrenal suppression is suspected. Care is also required in patients receiving anticoagulants because of the increased risk of severe bleeding. Patients with prosthetic heart valves or those with a history of infective endocarditis should be given chemoprophylaxis when undergoing pregnancy termination. As with other means of terminating pregnancy, rhesus-negative women who have not been rhesus immunised will require protection with anti-D immunoglobulin.

Porphyria.

Mifepristone is considered to be unsafe in patients with porphyria although there is conflicting experimental evidence of porphyrinogenicity.

💊 Interactions

The metabolism of mifepristone is mediated by the cytochrome P450 isoenzyme CYP3A4. Theoretically, use with other drugs that inhibit or induce this isoen zyme may result in changes in plasma concentration of mifepristone. In-vitro studies indicate that mifepristone itself inhibits CYP3A4; it should be used cautiously with CYP3A4 substrates that have a narrow therapeutic index.

NSAIDs.

The effects of mifepristone on the uterus and cervix may be mediated by increased prostanoid synthesis resulting from its inhibitory effect on progesterone. It has been suggested that aspirin and NSAIDs, which are prostaglandin synthetase inhibitors, might alter the efficacy of mifepristone. However, a placebo-controlled study1 in 28 women found that in the 13 given naproxen 500 mg orally 60, 48, 36, 24, and 12 hours before surgical termination of pregnancy the efficacy of mifepristone 100 mg given orally to soften the cervix was not reduced. Also, NSAIDs did not affect medical termination using mifepristone followed by misoprostol.
1. Rådestad A, Bygdeman M. Cervical softening with mifepristone (RU 486) after pretreatment with naproxen: a double-blind randomized study. Contraception 1992; 45: 221–7.

💊 Pharmacokinetics

After oral doses peak plasma concentrations of mifepristone occur after about 1 to 2 hours; bioavailability is about 70%. Mifepristone is about 98% bound to plasma proteins, mainly
Published November 04, 2018.