PREPULSID® FORTE tablets

INDICATIONS CONTRA-INDICATIONS DOSAGE SIDE-EFFECTS PREGNANCY OVERDOSE IDENTIFICATION PATIENT INFORMATION

PREPULSID® FORTE tablets

SCHEDULING STATUS:
Schedule 4.

PROPRIETARY NAME
(and dosage form):

PREPULSID^® FORTE tablets

COMPOSITION
Each tablet contains 10,387 mg cisapride monohydrate equivalent to 10 mg cisapride.

PHARMACOLOGICAL CLASSIFICATION
A.11 Medicines acting on the gastro-intestinal tract.

PHARMACOLOGICAL ACTION
In Animals: In isolated organs PREPULSID prevents gastric atony and enhances gastric peristaltic activity, antroduodenal co-ordination and small and large bowel motility. In dogs PREPULSID enhances digestive antroduodenal motility and co-ordination, accelerates gastric emptying increases small bowel propulsive contractions and shortens intestinal transit time. Gastric secretion is not affected.

The mechanism of action of PREPULSID is mainly due to an enhancement of the physiological release of acetylcholine at the myenteric plexus level. PREPULSID does not induce muscarinic or nicotinic receptor stimulation, nor does it inhibit acetylcholinesterase activity. PREPULSID is free of dopamine receptor blocking properties.

In Man: Gastrointestinal motility:
Oesophagus: PREPULSID increases oesophageal peristaltic activity and lower oesophageal sphincter tone. PREPULSID decreases oesophageal reflux of gastric contents and improves oesophageal clearance.

Stomach: PREPULSID increases gastric and duodenal contractility and antroduodenal co-ordination. PREPULSID decreases duodenogastric reflux. PREPULSID accelerates gastric and duodenal emptying.

Intestinal region: PREPULSID enhances intestinal propulsive activity and accelerates small and large bowel transit.

Other Effects: Due to its lack of direct cholinomimetic effects, PREPULSID does not increase basal and pentagastrin induced gastric acid secretion. Due to its lack of dopamine antagonistic properties PREPULSID does not affect prolactin plasma levels. The onset of pharmacological action of PREPULSID is approximately 30 to 60 minutes after oral administration.

After oral administration PREPULSID is rapidly and completely absorbed. Peak plasma levels are attained within 1 to 2 hours. The elimination half-life is 10 hours.

PREPULSID is extensively metabolized by oxidative N-dealkylation and aromatic hydroxylation. The excretion is almost exclusively metabolites and is about 50% of the dose in both urine and faeces. The excretion in maternal milk is very limited.

The absolute bioavailability of orally administered PREPULSID is around 40%. Plasma levels proportionally increase with oral doses from 5 to 20 mg.

Pharmacokinetics and steady state levels are unrelated to the duration of treatment. Concomitant treatment with cimetidine slightly increases the oral bioavailability of PREPULSID. Cisapride is extensively bound to plasma proteins (97,5%).

INDICATIONS
Gastroparesis, idiopathic or associated with diabetic neuropathy.

Symptoms of X-ray or endoscopy negative upper digestive discomfort characterised by early satiety, postprandial fullness, bloating, excessive belching, anorexia, vomiting or by ulcer-like complaints, epigastric burning or pain).

Gastro-oesophageal reflux disorders including oesophagitis and the maintenance treatment thereof.

CONTRA-INDICATIONS
Known hypersensitivity to PREPULSID.
Safety in pregnancy and lactation has not been established.

WARNINGS
Caution should be observed in patients in whom an increase of gastro-intestinal motility could be harmful.

DOSAGE AND DIRECTIONS FOR USE
Adults: Gastroparesis and symptoms of X-ray or endoscopy negative upper digestive discomfort: One PREPULSID FORTE (10 mg) tablet, two to four times daily depending of the severity of the condition.

In Oesophagitis: 2 PREPULSID FORTE (20 mg) tablets, two times daily (before breakfast and before retiring). Alternatively, 1 PREPULSID FORTE (10 mg) tablet three to four times a day before meals and before retiring.

For Maintenance treatment of oesophagitis: 2 PREPULSID FORTE (20 mg) tablets, once daily (before retiring). Alternatively 1 PREPULSID FORTE (10 mg) tablet, twice a day (before breakfast and on retiring). In patients with very severe disease it may be necessary to double the dose to maximum of 20 mg twice daily.

In the treatment of upper digestive disorders, PREPULSID is given at least 15 minutes before a meal together with some beverage.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Abdominal cramps, borborygmi and diarrhoea may occur. Should severe abdominal cramps occur with 20 mg per intake, it is recommended to halve the dose per intake.

Cases of hypersensitivity, headache or lightheadedness have been reported less frequently.

Exceptional cases of reversible liver function abnormalities, with or without cholestatis, have been reported.

There are isolated reports of central nervous system effects ie. convulsive seizures and extrapyramidal effects, and of urinary frequency.

Driving and machine operating ability: PREPULSID does not affect psychomotor function and does not induce sedation or drowsiness. PREPULSID may however accelerate the absorption of central nervous system depressants and alcohol. Caution should, therefore be exercised when PREPULSID is administered with these drugs.

Interactions:

–	The acceleration by PREPULSID of gastric emptying may affect the rate of absorption of drugs: absorption of drugs from the stomach may be diminished, whereas absorption of drugs from the small bowel may be accelerated (eg. benzodiazepines, anticoagulants, paracetamol, H₂-blockers).
	In patients receiving anticoagulants, the coagulation time may increase. It is advisable to check the coagulation time within the first few days after start and discontinuation of PREPULSID treatment to adapt the anticoagulant dose if necessary.
	In the case of drugs that require individual titration, it may be useful to monitor plasma levels of such drugs when PREPULSID is associated.
–	The sedative effects of central nervous system depressants and of alcohol may be accelerated.
–	The effects of PREPULSID on gastrointestinal motility are for the most part antagonised by anticholinergic drugs.
–	In hepatic and renal insufficiency, it is recommended to halve the initial daily dose. Subsequently, this dose can be adapted, depending on the therapeutics or possible side-effects.
–	In the elderly, steady state plasma levels are generally higher due to a moderate prolongation of the elimination half-life. Therapeutic doses, however are similar to those used in younger patients.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
In case of overdosage, the administration of activated charcoal and dose observation of the patient are recommended. The symptoms that occur most frequently after overdosing are abdominal cramping and increased stool frequency. In infants, mild sedation, apathy and atony were observed.

IDENTIFICATION
White, circular, biconvex, slightly arched tablet with "CIS" above 10 inscription on one side and "JANSSEN" on the other side.

PRESENTATION
Cartons containing one or more blister packs of 10, 20 or 25 tablets.

STORAGE INSTRUCTIONS
Store below 25°C. Store in a dry place. Protect from light.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER
V/11/144

NAME AND BUSINESS ADDRESS OF THE APPLICANT
JANSSEN
PHARMACEUTICA
Janssen Pharmaceutica (Pty) Ltd.,
(Reg. No 80/11122/07)
15th Road, HALFWAY HOUSE, 1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT

26 July 1993.

Code No.: 022745
94D