MOTILIUM INSTANTS

One tablet contains 10 mg domperidone.

Excipients include 0.75 mg aspartame.

For a full list of excipients, see section 6.1.

Orodispersible tablet.

White to off-white circular tablet.

For the relief of nausea and vomiting of less than 48 hours duration.

See section 4.4.

For the relief of symptoms of post prandial stomach discomfort

Adults and children 16 years of age and older

Up to 10 mg three times daily and at night.

Maximum duration of course of treatment 2 weeks.

For the relief of nausea and vomiting

Adults and children 16 years of age and older

Up to 10 mg three times daily and at night.

Maximum duration of course of treatment 48 hours.

Use in children under 16 years of age

Not recommended.

Method of administration

For oral use.

Allow the tablet to disintegrate on the tongue then swallow the medication.

• Known hypersensitivity to domperidone or any of the excipients.

• Prolactin-releasing pituitary tumour (prolactinoma).

• When stimulation of the gastric motility could be harmful: gastro-intestinal haemorrhage, mechanical obstruction or perforation.

• Hepatic and/or renal impairment.

Motilium Instants should only be taken according to the above posology (see section 4.2).

Patients who find they have post-prandial symptoms that persist, and are having to take domperidone continuously for more than 2 weeks should be referred to their GP.

Patients who find that their nausea and vomiting persist for more than 48 hours should be referred to their doctor.

The patient should be advised that Motilium Instants is not recommended for the treatment of motion sickness.

Motilium Instants is not recommended for use in patients with underlying cardiac disease, without medical supervision.

Motilium Instants contain aspartame (E951) a source of phenylalanine. May be harmful for people with phenylketonuria.

Use with Potent CYP3A4 Inhibitors

Co-administration with oral ketoconazole, erythromycin or other potent CYP3A4 inhibitors that prolong the QTc interval should be avoided (see section 4.5 Interaction with other medicinal products and other forms of interaction).

Cardiac effects

Some epidemiological studies showed that domperidone may be associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death (see section 4.8). The risk may be higher in patients older than 60 years and at daily doses of more than 30 mg. Domperidone should be used at the lowest effective dose in adults and children.

Use of domperidone and other drugs which prolong QTc intervals requires that caution be exercised in patients who have existing prolongation of cardiac conduction intervals, particularly QTc, patients with significant electrolyte disturbances or underlying cardiac diseases such as congestive heart failure.

The label will include: Do not take if you are pregnant.

When antacids or antisecretory drugs are used concomitantly, they should not be taken simultaneously with oral formulations of Motilium Instants.

Concomitant administration of anticholinergic drugs may antagonise the anti-dyspeptic effect of Motilium Instants.

The main metabolic pathway of domperidone is through CYP3A4. In vitro data suggest that the concomitant use of drugs that significantly inhibit this enzyme may result in increased plasma levels of domperidone.

Separate in vivo pharmacokinetic/pharmacodynamic interaction studies with oral ketoconazole or oral erythromycin in healthy subjects confirmed a marked inhibition of domperidone's CYP3 A4 mediated first pass metabolism by these drugs. With the combination of oral domperidone 10 mg four times daily and ketoconazole 200 mg twice daily, a mean QTc prolongation of 9.8 msec was seen over the observation period, with changes at individual time points ranging from 1.2 to 17.5 msec. With the combination of domperidone 10 mg four times daily and oral erythromycin 500 mg three times daily, mean QTc over the observation period was prolonged by 9.9 msec, with changes at individual time points ranging from 1.6 to 14.3 msec. Both the Cmax and AUC of domperidone at steady state were increased approximately three-fold in each of these interaction studies. In these studies domperidone monotherapy at 10 mg given orally four times daily resulted in increases in mean QTc of 1.6 msec (ketoconazole study) and 2.5 msec (erythromycin study), while ketoconazole monotherapy (200 mg twice daily) and erythromycin monotherapy (500 mg three times daily) led to increases in QTc of 3.8 and 4.9 msec, respectively, over the observation period.

There are limited post-marketing data on the use of domperidone in pregnant women. Therefore, Motilium Instants should only be used during pregnancy when justified by the anticipated therapeutic benefit. Studies have shown that domperidone enters breast milk. It is not known whether this is harmful to the newborn. Therefore, breast feeding is not recommended for mothers who are taking Motilium Instants.

Motilium Instants have no or negligible influence on the ability to drive and use machines.

The safety of Motilium was evaluated in 1275 patients with dyspepsia, gastro-oesophageal reflux disorder (GERD), Irritable Bowel Syndrome (IBS), nausea and vomiting or other related conditions in 31 double-blind, placebo-controlled studies. All patients were at least 15 years old and received at least one dose of Motilium (domperidone base). The median total daily dose was 30 mg (range 10 to 80 mg), and median duration of exposure was 28 days (range 1 to 28 days).

Studies in diabetic gastroparesis or symptoms secondary to chemotherapy or parkinsonism were excluded.

The following terms and frequencies are applied: very common (1/10), common (1/100 to <1/10), uncommon (1/1000 to <1/100), rare (1/10,000 to <1/1000), and very rare (<1/10,000).

Where frequency cannot be estimated from clinical trials data, it is recorded as “Not known”.

Postmarketing experience

In addition to the adverse effects reported during clinical studies and listed above, the following adverse drug reactions have been reported.

Extrapyramidal disorder occurs primarily in neonates and infants.

Other central nervous system-related effects of convulsion and agitation also are primarily reported in infants and children.

Symptoms

Overdose has been reported primarily in infants and children. Symptoms of overdosage may include agitation, altered consciousness, convulsion, disorientation, somnolence and extrapyramidal reactions.

Treatment

There is no specific antidote to domperidone; but in the event of overdose, gastric lavage as well as the administration of activated charcoal may be useful. Close medical supervision and supportive therapy are recommended. Anticholinergic, anti-parkinson drugs may be helpful in controlling the extrapyramidal reactions.

Pharmacotherapeutic group: Propulsives. ATC Code: A03F A 03

Domperidone is a dopamine antagonist with anti-emetic properties. Domperidone does not readily cross the blood-brain barrier. In domperidone users, especially adults, extrapyramidal side effects are very rare, but domperidone promotes the release of prolactin from the pituitary. Its anti-emetic effect may be due to a combination of peripheral (gastrokinetic) effects and antagonism of dopamine receptors in the chemoreceptor trigger zone, which lies outside the blood-brain barrier in the area postrema. Animal studies, together with the low concentrations found in the brain, indicate a predominantly peripheral effect of domperidone on dopamine receptors.

Studies in man have shown oral domperidone to increase lower oesophageal pressure, improve antroduodenal motility and accelerate gastric emptying. There is no effect on gastric secretion.

Absorption

In fasting subjects, domperidone is rapidly absorbed after oral administration, with peak plasma concentrations at 30 to 60 minutes. The low absolute bioavailability of oral domperidone (approximately 15%) is due to an extensive first-pass metabolism in the gut wall and liver. Although domperidone's bioavailability is enhanced in normal subjects when taken after a meal, patients with gastro-intestinal complaints should take domperidone 15-30 minutes before a meal. Reduced gastric acidity impairs the absorption of domperidone. Oral bioavailability is decreased by prior concomitant administration of cimetidine and sodium bicarbonate. The time of peak absorption is slightly delayed and the AUC somewhat increased when domperidone is taken after a meal.

Distribution

Oral Domperidone does not appear to accumulate or to induce its own metabolism; a peak plasma level after 90 minutes of 21 ng/ml after two weeks oral administration of 30 mg per day was almost the same as that of 18 ng/ml after the first dose. Domperidone is 91-93% bound to plasma proteins. Distribution studies with radiolabelled drug in animals have shown wide tissue distribution, but low brain concentration. Small amounts of drug cross the placenta in rats.

Metabolism

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.

Excretion

Urinary and faecal excretions amount to 31 and 66% of the oral dose respectively. The proportion of the drug excreted unchanged is small (10% of faecal excretion and approximately 1% of urinary excretion). The plasma half-life after a single oral dose is 7-9 hours in healthy subjects but is prolonged in patients with severe renal insufficiency.

Electrophysiological in vitro and in vivo studies indicate an overall moderate risk of domperidone to prolong the QT interval in humans. In in vitro experiments on isolated cells transfected with HERG and on isolated guinea pig myocytes, exposure ratios ranged between 5- and 30-fold, based on IC50 values inhibiting currents through IKr ion channels in comparison to the free plasma concentrations in humans after administration of the maximum daily dose of 20 mg q.i.d. Exposure margins for prolongation of action potential duration in in vitro experiments on isolated cardiac tissues exceeded the free plasma concentrations in humans at maximum daily dose (20 mg q.i.d.) by 17-fold. However, safety margins in in vitro and in in vivo pro-arrhythmic models (isolated Langendorff perfused heart) and in in vivo models (dog, guinea pig, rabbits sensitised for torsades de points) exceeded the free plasma concentrations in humans at maximum daily dose (20 mg q.i.d) by more than 17-fold. In the presence of inhibition of the metabolism via CYP3A4 free plasma concentrations of domperidone can rise up to 10-fold.

At a high, maternally toxic dose (more than 40 times the recommended human dose), teratogenic effects were seen in the rat. No teratogenicity was observed in mice and rats.

Gelatin

Mannitol

Poloxamer 188

Aspartame

Mint flavour

Not applicable.

2 years.

Do not store above 25°C. Store in the original container.

Blister packs comprising PVDC/LDPE/PVC foil and heat seal lacquer/aluminium/PET/Kraft paper.

Pack size: 10 tablets.

No special requirements.

Any unused product or waste material should be disposed of in accordance with local requirements.

McNeil Products Limited

Foundation Park

Roxborough Way

Maidenhead

Berkshire

SL6 3UG

United Kingdom

PL 15513/0350

23/02/2010

24/04/2012