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.

 Use in pregnancy and lactation:

Cytotec is contraindicated in pregnant women and in women planning a pregnancy as it increases uterine tone and contractions in pregnancy which may cause partial or complete expulsion of the products of conception. Use in pregnancy has been associated with birth defects.

It is also contraindicated in patients with a known allergy to prostaglandins.

Warnings

Use in pre-menopausal women (see also Contraindications): Cytotec should not be used in pre-menopausal women unless the patient requires nonsteroidal anti-inflammatory (NSAID) therapy and is at high risk of complications from NSAID-induced ulceration.

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)

If pregnancy is suspected the product should be discontinued.

Precautions

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.

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, diazepam and propranolol. In extensive clinical studies no drug interactions have been attributed to Cytotec. Additional evidence shows no clinically important pharmacokinetic or pharmacodynamic interaction with nonsteroidal anti-inflammatory drugs including aspirin, diclofenac and ibuprofen.

Pregnancy

See Contraindications.

Lactation

It is not known if the active metabolite of Cytotec is excreted in breast milk; therefore Cytotec should not be administered during breast feeding.

Not applicable.

Gastrointestinal system: Diarrhoea has been reported and is occasionally severe and prolonged and may require withdrawal of the drug. It 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.

Abdominal pain with or without associated dyspepsia or diarrhoea can follow misoprostol therapy.

Other gastrointestinal adverse effects reported include dyspepsia, flatulence, nausea and vomiting.

Female reproductive system: Menorrhagia, vaginal bleeding and intermenstrual bleeding have been reported in pre-and post-menopausal women.

Other adverse events: Skin rashes have been reported. Dizziness has been infrequently reported.

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

A number of side effects have been reported in clinical studies or in the literature following use of misoprostol for non-approved indications. These include abnormal uterine contractions, uterine haemorrhage, retained placenta, amniotic fluid embolism, incomplete abortion and premature birth.

Intensification of pharmacological effects may occur with overdose. In the event of overdosage symptomatic and supportive therapy should be given as appropriate. 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

June 2007.