CYTOTEC Tablet Ref.[7772] Active ingredients: Misoprostol

In women of childbearing potential Cytotec must not bestarted on misoprostol until pregnancy is excluded, and should be fully counselled on the importance of adequate contraception while undergoing treatment. If pregnancy is suspected, use of the product should be discontinued (see sections 4.3, 4.6 and 4.8).

In such patients it is advised that Cytotec should only be used if the patient:

• takes effective contraceptive measures
• has been advised of the risks of taking Cytotec if pregnant (see section 4.3)

Gastrointestinal bleeding, ulceration, and perforation have occurred in NSAID-treated patients receiving misoprostol. Physicians and patients should remain alert for ulceration, even in the absence of gastrointestinal symptoms, and, where appropriate, endoscopy and biopsy should be carried out before use to ensure that malignant disease is absent in the upper gastrointestinal tract. These investigations and any others considered necessary by the clinician should be repeated at appropriate intervals for follow-up purposes.

Symptomatic responses to misoprostol do not preclude the presence of gastric malignancy.

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 (see section 4.5).

Misoprostol should be used with caution in patients in whom dehydration would be dangerous. These patients should be monitored carefully.

The results of clinical studies indicate that Cytotec does not produce hypotension at dosages effective in promoting the healing of gastric and duodenal ulcers. Nevertheless, Cytotec should be used with caution in the presence of disease states where hypotension might precipitate severe complications, e.g. cerebrovascular disease, coronary artery disease or severe peripheral vascular disease including hypertension.

There is no evidence that Cytotec has adverse effects on glucose metabolism in human volunteers or patients with diabetes mellitus.

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

Cytotec is predominantly metabolised via fatty acid oxidising systems and has shown no adverse effect on the hepatic microsomal mixed function oxidase (P450) enzyme system. In specific studies no clinically significant pharmacokinetic interaction has been demonstrated with antipyrine or diazepam. A modest increase in propranolol concentrations (mean approximately 20% in AUC, 30% in Cmax) has been observed with multiple dosing of misoprostol. In extensive clinical studies no drug interactions have been attributed to Cytotec. Drug interaction studies with misoprostol and several NSAIDs showed no clinically significant effect on the kinetics of ibuprofen, diclofenac, piroxicam, aspirin, naproxen or indomethacin.

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

Women of childbearing potential

Women of childbearing potential must be informed about the risk of teratogenicity prior to treatment with Cytotec. 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 (see sections 4.3 and 4.4).

Pregnancy

Misoprostol

Misoprostol induces uterine contractions and is associated with abortion, premature birth, foetal death and foetal malformations.

Approximately a 3-fold increased risk of malformations was reported in pregnancies exposed to misoprostol during the first trimester, compared to a control group incidence of 2%. In particular, prenatal exposure to misoprostol has been associated with Moebius syndrome (congenital facial paralysis leading to hypomimia, troubles of suckling and deglutition and eye movements, with or without limb defects); amniotic band syndrome (limb deformities/ amputations, especially clubfoot, acheiria, olygodactyly, cleft palate inter alia) and central nervous system anomalies (cerebral and cranial anomalies as anencephaly, hydrocephaly, cerebellar hypoplasia, neural tube defects). Other defects including arthrogryposis have been observed.

Consequently:

• Women should be informed of the risk of teratogenicity.
• Should the patient wish to continue with her pregnancy after exposure of misoprostol in utero, a careful ultrasound scan monitoring of the pregnancy, with special attention to the limbs and head must be carried out.

The risk of uterine rupture increases with advancing gestational age and with prior uterine surgery, including Caesarean delivery. Grand multiparity also appears to be a risk factor for uterine rupture.

Breast-feeding

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.

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

The Adverse reaction terms were then categorised utilising the incidence rate as follows:

Very Common: ≥1/10 (≥10%)
Common: ≥1/100 and <1/10, (≥1% and <10%)
Uncommon: ≥1/1000 and <1/100, (≥0.1% and <1%)
Rare: ≥1/10,000 and <1/1000, (≥0.01% and <0.1%)
Very Rare: <1/10,000, (<0.01%)
Not Known

Immune System Disorder

Not Known: Anaphylactic reaction

Nervous System Disorders

Common: Dizziness, headache

Gastrointestinal Disorders

Very common: Diarrhoea*

Common: Abdominal pain*, constipation, dyspepsia, flatulence, nausea, vomiting

Skin and Subcutaneous Tissue Disorders

Very Common: Rash

Pregnancy, puerperium, and perinatal conditions

Rare: Uterine rupture**

Not Known: Amniotic fluid embolism, abnormal uterine contractions, foetal death, incomplete abortion, premature birth, retained placenta, uterine perforation

Reproductive System and Breast Disorders

Uncommon: Vaginal haemorrhage (including postmenopausal bleeding), intermenstrual bleeding, menstrual disorder, uterine cramping

Rare: Menorrhagia, dysmenorrhoea

Not Known: Uterine haemorrhage

Congenital, Familial and Genetic Disorders

Common: Foetal malformations

General Disorders and Administration Site Conditions

Not Known: Chills

Uncommon: Pyrexia

* Diarrhoea and abdominal pain were dose-related, usually developed early in the course of therapy, and were typically self-limiting. Rare instances of profound diarrhoea leading to severe dehydration has been reported.
** Uterine rupture has been uncommonly reported after prostaglandin intake during the second or third trimester of pregnancy. Uterine ruptures occurred particularly in multiparous women or in women with a caesarean section scar.

Diarrhoea can be minimised by using single doses not exceeding 200 micrograms with food and by avoiding the use of predominantly magnesium containing antacids when an antacid is required.

The pattern of adverse events associated with Cytotec is similar when an NSAID is given concomitantly.

Clinical trials

In clinical trials, over 15,000 patients and subjects received at least one dose of misoprostol. Adverse reactions involved primarily the gastrointestinal system.

Diarrhoea and abdominal pain were dose-related, usually developed early in the course of therapy, and were typically self-limiting. Rare instances of profound diarrhoea leading to severe dehydration have been reported.

The profile for adverse reactions with >1% incidence was similar for subacute (four to twelve weeks duration) and long- term (up to one year) clinical trials.

The safety of long-term (greater than 12 weeks) administration of misoprostol has been demonstrated in several studies in which patients were treated continuously for up to one year. This includes no adverse or unusual change in the morphology of gastric mucosa, as determined by gastric biopsy.

Special populations

There were no significant differences in the safety profile of misoprostol in patients who were 65 years of age or older, compared with younger patients.

The use of misoprostol in children has not been evaluated.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Not applicable.