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MOTILIUM� tablets

SCHEDULING STATUS
Schedule 2.

PROPRIETARY NAME
(and dosage form)

MOTILIUM� tablets

COMPOSITION
Each tablet contains 10 mg domperidone.

PHARMACOLOGICAL CLASSIFICATION
A.5.7.2 Anti-emetics and anti-vertigo preparations.

PHARMACOLOGICAL ACTION
Domperidone is a dopamine-receptor blocking agent. Its action on the dopamine-receptors in the chemo-emetic trigger zone produces an anti-emetic effect.
Domperidone does not cross the blood-brain barrier to any appreciable degree and so exerts relatively little effect on cerebral dopaminergic receptors.
Domperidone has been shown to increase the duration of antral and duodenal contractions to increase gastric emptying.
Domperidone does not alter gastric secretions and has no effect on intracranial pressure or on the cardiovascular system.
Domperidone is rapidly absorbed, with peak plasma concentrations at approximately 1 hour after oral administration.
The absolute bio-availability of oral domperidone is low (approximately 15%) due to first-pass hepatic and intestinal metabolism.
Domperidone is 91 to 93% bound to plasma proteins. The plasma half-life after a single oral dose is 7 to 9 hours in healthy subjects but is prolonged in patients with severe renal insufficiency.
Domperidone undergoes rapid and extensive hepatic metabolism by hydroxylation and N-dealkylation. In vitro metabolism experiments with diagnostic inhibitors revealed that CYP3A4 is a major form of cytochrome P-450 involved in the N-dealkylation of domperidone, whereas CYP3A4, CYP1A2 and CYP2E1 are involved in domperidone aromatic hydroxylation.
Urinary and faecal excretion amount to 31% and 66% of the oral dose, respectively. The proportion of drug excreted unchanged is small (approximately 1% of urinary and 10% of faecal excretion).

INDICATIONS
MOTILIUM is indicated for:
- Delayed gastric emptying of functional origin with gastro-oesophageal reflux and/or dyspepsia.
- Control of nausea and vomiting of central or local origin.
- As an anti-emetic in patients receiving cytostatic and radiation therapy.
- Facilitates radiological examination of the upper gastro-intestinal tract.

CONTRA-INDICATIONS
MOTILIUM is contra-indicated in patients with known hypersensitivity to domperidone.
MOTILIUM should not be used whenever stimulation of gastric motility is to be avoided or could be harmful, eg. in the presence of gastro-intestinal haemorrhage, obstruction or perforation.
MOTILIUM is also contra-indicated in patients with a prolactin-releasing pituitary tumour (prolactinoma).
The safety of use during pregnancy and lactation has not been established.

DOSAGE AND DIRECTIONS FOR USE
Acute conditions (mainly nausea, vomiting, hiccup)
Adults: Two tablets (20 mg) 3 to 4 times per day, 15 to 30 minutes before meals and, if necessary, before retiring.
Children 5 to 12 years old: One tablet (10 mg) 3 to 4 times per day, 15 to 30 minutes before meals and, if necessary, before retiring.
Chronic conditions (mainly dyspepsia)
Adults: One tablet (10 mg) taken 3 times per day, 15 to 30 minutes before meals and, if necessary, before retiring. The dosage may be doubled.
Children 5 to 12 years old: � tablet (5 mg) 3 to 4 times per day, 15 to 30 minutes before meals and if necessary, before retiring.
This formulation is not suited for children under the age of 5 years, but for this group of patients the suspension is available.
MOTILIUM should be used with caution in patients with renal impairment or in those at risk of fluid retention. In patients with severe renal insufficiency ( serum creatinine more than 6 mg/100 mL, ie. more than 0,6 mmol/L) the elimination half-life of domperidone was increased from 7,4 to 20,8 hours. The dosing frequency should be reduced to once or twice daily, depending on the severity of impairment, and the dose may need to be reduced. Patients on prolonged therapy should be reviewed regularly.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-effects
Allergic reactions, such as rash or urticaria, have been reported.
Abdominal cramps have been reported.
Dystonic reactions (extrapyramidal phenomena) may occur.
Reversible raised serum prolactin levels have been observed which may lead to galactorrhoea and gynaecomastia.
Hypertensive crises in patients with phaeochromocytoma may occur with administration of domperidone.
Where the blood brain barrier is not fully developed (mainly in young babies) or is impaired, the possible occurrence of neurological side-effects cannot be totally excluded.
Special precautions
Since domperidone is highly metabolised in the liver, MOTILIUM should be used with caution in patients with hepatic impairment (and in the elderly).
Interactions
Concomitant administration of anti-cholinergic drugs may inhibit the anti-dyspeptic effects of MOTILIUM.
Anti-muscarinic agents and opioid analgesics may antagonise the effect of MOTILIUM.
MOTILIUM suppresses the peripheral effects (digestive disorders, nausea and vomiting) of dopaminergic agonists.
Since MOTILIUM has gastro-kinetic effects, it could influence the absorption of concomitant orally administered medicines, particularly those with sustained release or enteric coated formulations.
As MOTILIUM interferes with serum prolactin levels, it may interfere with other hypoprolactinaemic agents and with some diagnostic tests.
Antacids and anti-secretory agents lower the oral bioavailability of domperidone. They should be taken after meals and not before meals, i.e. they should not be taken simultaneously with MOTILIUM.
Reduced gastric acidity impairs the absorption of domperidone.
Oral bioavailability is decreased by prior administration of cimetidine or sodium bicarbonate.
The main metabolic pathway of domperidone is through CYP3A4. In vitro data suggests that concomitant use of drugs that significantly inhibit this enzyme may result in increased plasma levels of domperidone. Examples of CYP3A4 inhibitors include the following:
- azole antifungals
- macrolide antibiotics
- HIV protease inhibitors
- nefazodone

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Symptoms of overdosage may include drowsiness, disorientation and extrapyramidal reactions especially in children.
Anticholinergic, anti-Parkinson medicines or antihistamines with anticholinergic properties may be helpful in controlling the extrapyramidal reactions. There is no specific antidote to domperidone but in the event of overdosage, gastric lavage as well as the administration of activated charcoal may be useful. Symptomatic and supportive measures are recommended.

IDENTIFICATION
White circular, biconvex, film-coated tablet with a 6,5 mm diameter engraved "M" above "10" on one side and "JANSSEN" on the other side.

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

STORAGE INSTRUCTIONS
Store below 25�C. Protect from light.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER
K/5.7.2/261

NAME AND BUSINESS ADDRESS OF THE APPLICANT
JANSSEN - CILAG logo

JANSSEN PHARMACEUTICA (PTY) LTD
(Reg. No. 1980/011122/07)
15th Road
HALFWAY HOUSE
1685
� JPH (PTY) LTD SA 1990

DATE OF PUBLICATION OF THIS PACKAGE INSERT
30 July 1990
Code No.:024092
2001C
Britepak

� =Trademark

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