Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2014 Publisher: EXELGYN, 216, Boulevard Saint-Germain, 75007 Paris, France
As misoprostol is used in combination with mifepristone, please refer to the contraindications for this mifepristone as well.
In the absence of specific studies, the combination of the sequential use of mifepristone and misoprostol is not recommended for use in patients with:
Because of its abortifacient properties, misoprostol should never be used in a woman with an ongoing pregnancy who wants to complete it.
The age of the pregnancy must be determined from the questioning and the clinical examination of the patient. Uterine ultrasound is always recommended.
Misoprostol MUST BE USED by oral route only:
Use of off label regimen enhances ALL risks related to the method
This method requires an active involvement of the woman who should be informed of the method’s requirements:
Because of possible acute effects of misoprostol, women should be fully counselled regarding the likely signs and symptoms they may experience and have direct access to the treatment centre by telephone or local access.
In the case of a pregnancy occurring with an intra-uterine device in situ, this device must be removed before administration of mifepristone/misoprostol.
The efficacy of the medical termination of pregnancy method decreases:
The non-negligible risk of an on-going pregnancy occurs in 1% of the cases where the medical termination of pregnancy was within 49 days of amenorrhea and after oral administration. This risk makes the follow-up visit mandatory in order to check that the expulsion is completed.
In rare case of non-complete expulsion, a surgical revision may be necessary.
The patient must be informed of the occurrence of prolonged vaginal bleeding (an average of about 12 days or more after mifepristone intake) which may be heavy. Bleeding occurs in almost all cases and is not in anyway a proof of complete expulsion.
The bleeding can occur very quickly after misoprostol intake, and sometimes later:
Rarely the expulsion may occur before misoprostol administration (around 3% of cases). This doesn’t preclude the control visit in order to check for the complete expulsion and the uterine vacuity.
The patient should be informed not to travel far away from the prescribing centre as long as complete expulsion has not been recorded. She will receive precise instructions as to whom she should contact and where to go in the event of any problems emerging, particularly in the case of excessive vaginal bleeding. This is bleeding that lasts longer than 12 days and/or that is heavier than the normal menstrual bleeding.
A follow-up visit must take place within a period of 14 to 21 days after the intake of mifepristone to verify by the appropriate means (clinical examination, together with beta-hCG measurement or ultrasound scan ) that expulsion has been completed and that vaginal bleeding has stopped. In case of persistent bleeding (even light) beyond the control visit, its disappearance should be checked within a few days.
Persistence of vaginal bleeding at this point could signify incomplete abortion, or an undiagnosed ectopic pregnancy, and appropriate treatment should be considered.
Since heavy bleeding requiring haemostatic curettage occurs in 0 to 1.4% of the cases during the medical method of pregnancy termination, special care should be given to patients with haemostatic disorders with hypocoagulability, or with anaemia. The decision to use the medical or the surgical method should be decided with specialised consultants according to the type of haemostatic disorder or the level of anaemia.
In the event of an ongoing pregnancy diagnosed after the follow-up visit, termination by a second termination of pregnancy procedure will be proposed to the woman.
Serious cases (including fatal cases) of toxic shock and septic shock following infections with atypical pathogens (Clostridium sordellii and perfringens, Klebsiella pneumoniae, Escherichia coli, group A Streptococcus), have been reported with the medical abortion, performed with unauthorised vaginal or buccal administration of misoprostol tablets.
Clinicians should be aware of this potentially fatal complication.
Patients who decide to continue the pregnancy after treatment must be informed of the risk of teratogenicity. This risk is inherent to the mifepristone and misoprostol regimen objective and is enhanced when regimens other than the one mentioned in section 4.2 Posology and method of administration is used. Exposure of the foetus to misoprostol or mifeprostone increases the risk of developing Moebius syndrome and/or an amniotic band syndrome. A second termination of pregnancy procedure shall be considered. In case of continuation of the pregnancy close monitoring by ultrasound scan must be performed in specialised centres.
Rare but serious cardiovascular accidents (myocardial infarction and/or spasm of the coronary arteries and severe hypotension) have been reported following the intra vaginal and intra muscular administration of a high dose of prostaglandin analogue, including misoprostol. For this reason, women with risk factors for cardiovascular disease (e.g. age over 35 years with chronic smoking, hyperlipidemia, diabetes) or established cardiovascular disease should be treated with caution.
The medical termination of pregnancy requires rhesus determination and hence the prevention of rhesus allo-immunisation as well as other general measures taken usually during any termination of pregnancy.
During clinical trials, new pregnancies occurred between embryo expulsion and the resumption of menses. Therefore, when a termination of pregnancy conducted by medical procedure is medically confirmed, it is recommended to start contraception immediately.
The precautions related to mifepristone should also be followed.
Misoprostol is predominantly metabolised via fatty acid oxidising systems and has shown no adverse effect on the hepatic microsomal mixed function oxidase (P450) enzyme system.
A decrease of the efficacy of misoprostol can theoretically occur due to the antiprostaglandin properties of non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin (acetyl salicylic acid). Limited evidence suggests that co-administration of NSAIDs on the day of misoprostol administration does not adversely influence the effects of mifepristone or misoprostol on cervical ripening or uterine contractility and does not reduce the clinical efficacy of medical termination of pregnancy.
Antacids may decrease the bioavailability of misoprostol.
Antacids containing magnesium may aggravate diarrhoea caused by misoprostol.
Use in pregnancy has been associated with birth defects/malformations for ongoing pregnancies exposed to mifepristone and misoprostol or misoprostol alone. Prenatal exposure to misoprostol has been associated with Moebius syndrome (congenital facial paralysis, with or without limb defects) and with amniotic band syndrome (limb deformities/amputations, especially clubfoot, acheiria, olygodactyly, cleft palate inter alia). Women considering medical termination of pregnancy should be precisely counselled on the risks to their foetus if an abortion failure occurs and a second termination of pregnancy procedure is not desirable.
Consequently:
Mifepristone is a lipophilic compound and may theoretically be excreted in the mother’s breast milk. However, no data is available. Misoprostol may also be excreted in breast milk and consequently, women should avoid breastfeeding while taking mifepristone and misoprostol.
Misoprostol does not affect fertility. It is possible that the woman becomes pregnant again as soon as the termination of pregnancy is completed. Therefore it is important to inform the patient to start contraception immediately after the termination of the pregnancy is confirmed.
No data showing an effect on the ability to drive are known. Dizziness could occur as a side effect. When driving or using machines one should take this possible side effect into account.
The side effects of misoprostol are usually an extension of the pharmacological action and of the drug bioavailability. The most common adverse reactions are gastrointestinal disorders e.g. nausea, vomiting, diarrhoea and abdominal pain.
The frequencies of occurrence of side effects are classified as follows: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1.000 to <1/100), Rare (≥1/10.000 to <1/1.000), Very rare (<1/10.000), Not known (cannot be estimated from the available data).
Common: Infection following abortion. Suspected or confirmed infections (endometritis, pelvic inflammatory disease) have been reported in less than 5% of women.
Very rare: Very rare cases of serious or fatal toxic and septic shocks (caused by Clostridium sordellii or perfringens, Klebsiella pneumoniae, Escherichia coli, group A Streptococcus), which can be with or without fever or other obvious symptoms of infection, have been reported with the use of unauthorised vaginal or buccal administration of misoprostol tablets. Clinicians should be aware of this potentially fatal complication (see section 4.4. – Special warnings and special precautions for use).
Not known: Anaphylaxis, hypersensitivity.
Rare: Headache.
Rare but serious cardiovascular accidents (myocardial infarction and/or spasm of the coronary arteries and severe hypotension) have been reported mainly with the use of non-authorised vaginal administration of misoprostol tablets.
Very common: Nausea, vomiting, diarrhoea (these gastro-intestinal effects related to prostaglandin use are frequently reported).
Common: Cramping, light or moderate.
Uncommon: Hypersensitivity: Skin rashes uncommon (0.2%).
Rare: Single cases of urticaria, erythroderma, erythema nodosum, toxic epidermal necrolysis have also been reported.
Very rare: Angioedema
Not known: Back pain.
Very common: Very common uterine contractions or cramping (10 to 45%) in the hours following misoprostol intake.
Common: Heavy bleeding occurs in about 5% of the cases and may require hemostatic curettage in up to 1.4% of the cases.
Rare: foetal death, birth defects.
Rare: Malaise, vagal symptoms (hot flushes, dizziness, chills), fever.
Not applicable.
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