INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
CYTOTEC® Tablets

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

CYTOTEC^® Tablets

COMPOSITION:
Each CYTOTEC tablet contains 200 mcg misoprostol.

PHARMACOLOGICAL CLASSIFICATION:
A 11.10 - Medicines acting on the gastrointestinal tract - Special combinations and/or substances.

PHARMACOLOGICAL ACTION:
CYTOTEC is a synthetic prostaglandin E1 analogue which has gastric antisecretory and mucosal protective properties. The antisecretory activity is mediated by direct action on specific prostaglandin receptors on the surface of gastric parietal cells. The mucosal protective effect against various damaging agents has been demonstrated in humans with doses that inhibit, and doses which minimally affect acid secretion.
Antisecretory activity:
Effect on acid secretion: In healthy human subjects, CYTOTEC inhibits daytime and nocturnal basal gastric acid secretion and acid secretion stimulated by histamine, pentagastrin, food, tetragastrin, betazole and coffee.
Effect on pepsin secretion and gastric fluid volume: CYTOTEC decreases pepsin and gastric volume under basal conditions.
Effect on serum gastrin: CYTOTEC has no persistent effects on fasting levels of, or on postprandial increase in, serum gastrin.
Mucosal protective activity:
CYTOTEC has properties in animals and humans that strengthen the integrity of the gastroduodenal mucosal barrier against damaging agents. These include stimulation of duodenal bicarbonate secretion and gastric mucus production. In addition, CYTOTEC maintains mucosal haemodynamics.
Other pharmacological effects:
CYTOTEC has been shown to produce uterine contractions which may endanger pregnancy (see Contra-indications).
CYTOTEC does not produce clinically significant effects on serum prolactin, gonadotrophins, TSH, GH, thyroxine, cortisol, gastro-intestinal hormones (somatostatin, gastrin, vaso-active intestinal polypeptide and motilin), creatinine, or uric acid, gastric emptying, immunological competence, platelet aggregation, pulmonary function, or the cardiovascular system.

PHARMACOKINETICS:
CYTOTEC is rapidly absorbed following oral administration.
After an oral dose of radiolabelled CYTOTEC, about 73% of the administered radio-activity is excreted in the urine.
Pharmacokinetic studies in patients with mild to moderate renal impairment showed an increase in T½, Cmax and AUC in renal impaired, compared to normal patients. In patients with total renal failure, there was an approximate two-fold increase in AUC in four of six patients.
CYTOTEC does not accumulate in red blood cells. The serum protein binding of misoprostol acid is less than 90% and is concentration-independent in the therapeutic range.
CYTOTEC is metabolized by fatty-acid oxidizing systems (beta and omega oxidation) which are present in organs throughout the body. It’s metabolism and plasma levels are therefore unlikely to be markedly affected in hepatically-impaired patients. CYTOTEC does not interfere with hepatic drug-metabolizing enzymes nor hepatic blood flow in animals. In multiple-dose human studies, CYTOTEC did not alter the pharmacokinetics or the bio-availability of propranolol, antipyrine or diazepam.
CYTOTEC bio-availability was reduced (by 16%) when it was co-administered with high doses of antacid. Administration of CYTOTEC with a high fat content meal did not alter the extent of misoprostol absorption but did reduce the rate of absorption resulting in lower Cmax and higher Tmax values for misoprostol acid.
In healthy elderly subjects over 64 years of age, the AUC for misoprostol acid was slightly increased from that in younger subjects. This was attributed to the reduced clearance probably due partly to decreased volume of distribution and a slight prolongation of elimination T½ of this metabolite in the elderly.

INDICATIONS:
CYTOTEC is indicated for co-administration with non-steroidal anti-inflammatory drugs (NSAIDs) for the prevention of gastric and duodenal ulcers, haemorrhagic lesions and erosions induced by NSAIDs.

CONTRA-INDICATIONS:
CYTOTEC should not be administered to anyone with a known hypersensitivity to misoprostol or other prostaglandins.

CYTOTEC SHOULD NOT BE USED IN PREGNANT WOMEN AS TERATOGENICITY IN ANIMALS HAS BEEN DEMONSTRATED AND IT INDUCES UTERINE CONTRACTIONS AND THEREFORE HAS ABORTIFACIENT POTENTIAL. WOMEN OF CHILDBEARING POTENTIAL SHOULD NOT BE STARTED ON CYTOTEC UNTIL PREGNANCY IS EXCLUDED AND SHOULD BE FULLY COUNSELLED ON THE IMPORTANCE OF ADEQUATE CONTRACEPTION WHILE UNDERGOING TREATMENT.

Although it is not known whether CYTOTEC or misoprostol acid is excreted in human milk, CYTOTEC should not be administered to nursing mothers because the potential excretion of misoprostol acid could cause diarrhoea in nursing infants.
Moderate to severely impaired renal function.

DOSAGE AND DIRECTIONS FOR USE:
For the prevention of gastric ulcers, haemorrhagic lesions and erosions induced by NSAIDs:
A minimum of 200 mcg (one tablet) with food, twice daily, together with the prescribed NSAID. Dosage may be increased to 200 mcg three times daily or to a maximum of 200 mcg four times daily, to correspond to the NSAID administration schedule or if indicated by the clinical condition of the patient.
For the prevention of duodenal ulcers induced by NSAIDs:
800 mcg (four tablets) daily, in divided doses, with food.
Antacids containing aluminium may be given as needed for relief of pain.
To minimize the risk of diarrhoea, CYTOTEC should be taken with food, and magnesium-containing antacids should be avoided.
No dosage adjustment is recommended in older patients.
Safety and effectiveness in children under the age of 18 years have not been established.

SIDE EFFECTS AND SPECIAL PRECAUTIONS:
Special precautions:
Symptomatic responses to CYTOTEC do not preclude the presence of gastric malignancy. Patients with conditions that predispose to diarrhoea, such as inflammatory bowel disease, or those in whom dehydration would be dangerous, should be monitored carefully.
In animals, prostaglandins of the E type have the capacity to produce hypotension through peripheral vasodilation. The results of clinical trials indicate that CYTOTEC does not produce hypotension at dosages of up to 800 mcg per day. However, CYTOTEC should be used with caution in the presence of disease states where hypotension might precipitate severe complications, e.g. cerebral vascular disease or coronary artery disease.
Gastro-intestinal bleeding, ulceration, and perforation have occurred in NSAID-treated patients receiving CYTOTEC. Physicians and patients should remain alert for ulceration, even in the absence of gastro-intestinal symptoms.
Interactions:
Interaction studies with CYTOTEC showed no clinically significant effect on the kinetics of ibuprofen, diclofenac, piroxicam or indomethacin. CYTOTEC also did not exert any clinically significant effect on the steady-state blood level or anti-platelet effects of therapeutic doses of aspirin.
Side effects:
In clinical trials, the most frequent adverse events were diarrhoea, abdominal pain, nausea, flatulence, dyspepsia, headache, vomiting, constipation and dizziness. The diarrhoea and abdominal pain are transient and mild in severity, self-limiting and require discontinuation of CYTOTEC in the minority of patients. Instances of profound diarrhoea leading to severe dehydration have been reported. Dose adjustment may also be helpful.
Women who received CYTOTEC during clinical trials reported the following gynaecological disorders: cramps, menorrhagia, menstrual disorder, dysmenorrhoea, intermenstrual bleeding and vaginal haemorrhage (including postmenopausal bleeding).

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
The toxic dose of CYTOTEC in humans has not been determined. Cumulative total daily doses of 1600 mcg have been tolerated with only symptoms of gastro-intestinal discomfort being reported. In animals, the acute toxic effects are similar to those reported for other prostaglandins: relaxation of stomach muscle, respiratory difficulties and depression of the central nervous system. Clinical signs that may indicate an overdose are sedation, tremor, convulsions, dyspnoea, abdominal pain, diarrhoea, fever, palpitations, hypotension and bradycardia. Symptoms should be treated with supportive therapy. Because CYTOTEC is metabolised like a fatty acid, it is unlikely that dialysis would be appropriate treatment for overdosage.

IDENTIFICATION:
CYTOTEC tablets are white, scored, uncoated, flat, hexagonal-shaped tablets, debossed on one side “SEARLE”over “1461”.

PRESENTATION:
CYTOTEC tablets are supplied in blister packs of 60 or 120 tablets packed in cartons.

STORAGE INSTRUCTIONS:
Store in the original packaging in a dry place below 30°C.
Do not use after expiration date.
Keep out of reach of children.

REGISTRATION NUMBER:
S/11.10/392

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
Pharmacia South Africa (Pty) Ltd
Alphen West G
George Street
Midrand
1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
6 April 1998

New addition to this site: January 2005
Source: Pharmaceutical Industry
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