Misoprostol

Concomitant administration of NSAIDs and misoprostol in rare cases can cause a transaminase increase and peripheral oedema.

Drug interaction studies with misoprostol and several NSAIDs showed no clinically significant effect on the kinetics of ibuprofen, diclofenac, piroxicam, aspirin, naproxen or indomethacin.

Antacids may decrease the bioavailability of misoprostol.

Magnesium-containing antacids should be avoided during treatment with misoprostol as this may worsen the misoprostol-induced diarrhoea.

A modest increase in propranolol concentrations (mean approximately 20% in AUC, 30% in C_max) has been observed with multiple dosing of misoprostol.

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:

• in 60%, expulsion occurs within 4 hours following misoprostol intake
• in 40%, expulsion occurs within 24 to 72 hours following misoprostol intake.

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.

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.

Misoprostol should be used with caution in patients with conditions that predispose them to diarrhoea, such as inflammatory bowel disease. To minimise the risk of diarrhoea, misoprostol should be taken with food, and magnesium-containing antacids should be avoided.

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:

• Women should be informed, that due to the risk of failure of the medical method of pregnancy termination and to the risk for the foetus, the follow-up visit is mandatory.
• Should a failure of the method be diagnosed at the follow-up visit (viable ongoing pregnancy), and should the patient still agree, pregnancy termination should be completed by a second termination of pregnancy procedure.
• Should the patient wish to continue with her pregnancy, a careful ultrasound scan monitoring of the pregnancy, with a special attention to the limbs, must be established in a specialised centre.

Misoprostol is rapidly metabolised in the mother to misoprostol acid, which is biologically active and is excreted in breast milk. Misoprostol should not be administered to nursing mothers because the excretion of misoprostol acid could cause undesirable effects such as diarrhoea in nursing infants.

Women of childbearing potential

Women of childbearing potential must be informed about the risk of teratogenicity prior to treatment with misoprostol. Treatment must not be initiated until pregnancy is excluded, and women should be fully counselled on the importance of adequate contraception while undergoing treatment. If pregnancy is suspected, treatment must be immediately discontinued.

Fertility

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.

Misoprostol can cause dizziness. Patients should be cautioned about operating machinery and driving.