Cytotec 200mcg tablets.

Each tablet contains 200 micrograms misoprostol.

For excipients, see 6.1.

White to off-white hexagonal tablets scored both sides, engraved SEARLE 1461 on one side for oral administration.

Cytotec is indicated for the healing of duodenal ulcer and gastric ulcer including those induced by nonsteroidal anti-inflammatory drugs (NSAID) in arthritic patients at risk, whilst continuing their NSAID therapy. In addition, Cytotec can be used for the prophylaxis of NSAID-induced ulcers.

Adults

Healing of duodenal ulcer, gastric ulcer and NSAID-induced peptic ulcer: 800 micrograms daily in two or four divided doses taken with breakfast and / or each main meal and at bedtime.

Treatment should be given initially for at least 4 weeks even if symptomatic relief has been achieved sooner. In most patients ulcers will be healed in 4 weeks but treatment may be continued for up to 8 weeks if required. If the ulcer relapses further treatment courses may be given.

Prophylaxis of NSAID-induced peptic ulcer: 200 micrograms twice daily, three times daily or four times daily. Treatment can be continued as required. Dosage should be individualised according to the clinical condition of each patient.

Elderly

The usual dosage may be used.

Renal impairment: Available evidence indicates that no adjustment of dosage is necessary in patients with renal impairment.

Hepatic impairment: Cytotec is metabolised by fatty acid oxidising systems present in organs throughout the body. Its metabolism and plasma levels are therefore unlikely to be affected markedly in patients with hepatic impairment.

Children

Use of Cytotec in children has not yet been evaluated in the treatment of peptic ulceration or NSAID-induced peptic ulcer disease.

Misoprostol is contraindicated in patients:

• Who are pregnant, or in whom pregnancy has not been excluded, or women planning a pregnancy as Misoprostol increases uterine tone and contractions in pregnancy which may cause partial or complete expulsion of the products of conception. (see Sections 4.4, 4.6 and 4.8). Use in pregnancy has been associated with birth defects.

• With a known hypersensitivity to misoprostol or any other component of the product, or to other prostaglandins.

Women of childbearing potential should not be started 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 Contraindications)

Gastrointestinal bleeding, ulceration, and perforation may occurr 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.

Patients with conditions that predispose them to diarrhoea, such as inflammatory bowel disease. To minimize the risk of diarrhoea, misoprostol should be taken with food, and magnesium-containing antacids should be avoided (see Section 4.5).

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.

Pregnancy

Misoprostol is contraindicated in women who are pregnant because it induces uterine contractions and is associated with abortion, premature birth, and foetal death and birth defects, First trimester exposure to misoprostol is associated with a significantly increased risk of two birth defects ; Mobius sequence, i.e., palsies of cranial nerves VI and VII, and terminal transverse limb defects. Other defects including arthrogryposis have been observed.

Lactation

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 categorized utilizing the incidence rate as follows:

* 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.

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.

Signs and Symptoms of Overdose

The toxic dose of misoprostol in humans has not been determined. Clinical signs that may indicate an overdose are sedation, tremor, convulsions, dyspnea, abdominal pain, diarrhoea, fever, palpitations, hypotension, or bradycardia.

Treatment of Overdose

Because misoprostol is metabolized like a fatty acid, it is unlikely that dialysis would be appropriate treatment for overdosage. In cases of overdose, standard supportive measures should be adopted as required.

In clinical trials patients have tolerated 1200 micrograms daily for three months without significant adverse effects.

Cytotec is an analogue of naturally occurring prostaglandin E₁ which promotes peptic ulcer healing and symptomatic relief.

Cytotec protects the gastroduodenal mucosa by inhibiting basal, stimulated and nocturnal acid secretion and by reducing the volume of gastric secretions, the proteolytic activity of the gastric fluid, and increasing bicarbonate and mucus secretion.

Cytotec is rapidly absorbed following oral administration, with peak plasma levels of the active metabolite (misoprostol acid) occurring after about 30 minutes. The plasma elimination half-life of misoprostol acid is 20-40 minutes. No accumulation of misoprostol acid in plasma occurs after repeated dosing of 400 micrograms twice daily.

In single and repeat-dose studies in dogs, rats and mice at multiples of the human dose, toxicological findings were consistent with the known pharmacological effects of the E-type prostaglandins, the main symptoms being diarrhoea, vomiting, mydriasis, tremors and hyperpyrexia. Gastric mucosal hyperplasia was also observed in the mouse, rat and the dog. In the rat and the dog the hyperplasia was reversible on discontinuation of misoprostol following one year of dosing. Histological examination of gastric biopsies in humans has shown no adverse tissue response after up to one year's treatment. In studies of fertility, teratogenicity and peri/post-natal toxicity in rats and rabbits there were no major findings. A decrease in implantations and some pup growth retardation was observed at doses greater than 100 times the human dose. It was concluded that misoprostol does not significantly affect fertility, is not teratogenic or embryotoxic and does not affect rat pups in the peri/post-natal period.

Misoprostol was negative in a battery of 6 in vitro assays and one in vivo test to assess mutagenic potential. In carcinogenicity studies in the rat and mouse it was concluded that there was no risk of carcinogenic hazard.

Microcrystalline cellulose,

Sodium starch glycolate (Type A),

Hydrogenated castor oil,

Hypromellose.

Not applicable.

3 years.

Do not store above 30°C. Store in the original package.

Cold-formed aluminium blister packs of 56, 60, 112, 120 or 140 tablets.

Not all pack sizes may be marketed.

No Special Requirements.

Pharmacia Limited

Ramsgate Road

Sandwich, Kent

CT13 9NJ

United Kingdom

PL 00032/0404

First authorised: 10 May 2002

November 2010