McNeil Healthcare (Ireland) Ltd

Motilium 10 mg Suppositories

One suppository contains domperidone 10 mg.

For excipients, see 6.1.

Suppositories

White to slightly yellow suppositories.

Adults

− The relief of the symptoms of nausea and vomiting, epigastric sense of fullness, upper abdominal discomfort and regurgitation of gastric contents.

Children

− The relief of the symptoms of nausea and vomiting.

The initial duration of treatment is four weeks. Patients should be re-evaluated after four weeks and the need for continued treatment re-assessed.

Adults and adolescents (over 12 years and weighing 35kg or more)

60 mg suppositories two times per day.

Infants and children

The total daily dose is dependent on the child's weight:

− for a child weighing 5-15 kg: 10 mg suppositories two times per day

− for a child weighing more than 15 kg: 30 mg suppositories two times per day

Suppositories are unsuitable for use in children weighing less than 5 kg.

Motilium is contraindicated in the following situations:

− known hypersensitivity to domperidone or any of the excipients

− prolactin-releasing pituitary tumour (prolactinoma).

Motilium should not be used when stimulation of the gastric motility could be harmful: gastro-intestinal haemorrhage, mechanical obstruction or perforation.

Precautions for use

The suppositories contain butylated hydroxyanisole which can irritate eyes, skin and the lining of the mouth and nose (mucous membranes).

Use during lactation

The total amount of domperidone excreted in human breast milk is expected to be less than 7μg per day at the highest recommended dosing regimen. It is not known whether this is harmful to the newborn. Therefore Motilium is not recommended in breast-feeding women.

Use in infants

Although neurological side effects are rare (see "Undesirable effects" section), the risk of neurological side effects is higher in young children since metabolic functions and the blood-brain barrier are not fully developed in the first months of life. Therefore, it is recommended that the dose be determined accurately and followed strictly in neonates, infants, toddlers and small children.

Overdosing may cause extrapyramidal symptoms in children, but other causes should be taken into consideration.

Use in liver disorders

Since domperidone is highly metabolised in the liver, Motilium should not be used in patients with hepatic impairment.

Renal insufficiency

In patients with severe renal insufficiency (serum creatinine> 6 mg/100 ml, ie> 0.6 mmol/l) the elimination half-life of domperidone was increased from 7.4 to 20.8 hours, but plasma drug levels were lower than in healthy volunteers. Since very little unchanged drug is excreted via the kidneys, it is unlikely that the dose of a single administration needs to be adjusted in patients with renal insufficiency. However, on repeated administration, the dosing frequency should be reduced to once or twice daily depending on the severity of the impairment, and the dose may need to be reduced. Such patients on prolonged therapy should be reviewed regularly.

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).

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 10mg four times daily and ketoconazole 200mg 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 10mg four times daily and oral erythromycin 500mg 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 10mg 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. A study in rats has shown reproductive toxicity at a high, maternally toxic dose. The potential risk for humans is unknown. Therefore, Motilium should only be used during pregnancy when justified by the anticipated therapeutic benefit.

The drug is excreted in breast milk of lactating rats (mostly as metabolites: peak concentration of 40 and 800 ng/ml after oral and i.v. administration of 2.5 mg/kg respectively). Domperidone concentrations in breast milk of lactating women are 10 to 50% of the corresponding plasma concentrations and expected not to exceed 10 ng/ml. The total amount of domperidone excreted in human breast milk is expected to be less than 7 micrograms per day at the highest recommended dosing regimen. It is not known whether this is harmful to the newborn. Therefore Motilium is not recommended in breast-feeding women.

Motilium has no, or negligible, influence on the ability to drive and use machines.

The adverse drug reactions are ranked below by frequency, using the following convention: very common (>1/10), common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000), including isolated reports.

− Immune System Disorder: Very rare :allergic reactions including anaphylaxis, anaphylactic shock, anaphylactic reaction, and angioedema.

− Endocrine disorder: Rare : increased prolactin levels.

− Psychiatric system disorders: Very rare: agitation, nervousness.

− Nervous system disorders: Very rare : extrapyramidal side-effects, convulsion, somnolence, headache.

− Cardiac disorders: QTc prolongation (frequency not known). Very rare : ventricular arrhythmias.

− Gastrointestinal disorders: Rare _ gastro-intestinal disorders, including very rare transient intestinal cramps; very rare : diarrhoea.

− Skin and subcutaneous tissue disorders: Very rare : uriticaria, pruritus, rash.

− Reproductive system and breast disorders: Rare : galactorrhoea, gynaecomastia, amenorrhoea

− Investigations: Very rare: liver function test abnormal.

As the hypophysis is outside the blood-brain barrier, domperidone may cause an increase in prolactin levels. In rare cases this hyperprolactinaemia may lead to neuro-endocrinological side effects such as galactorrhoea, gynaecomastia and amenorrhoea.

Extrapyramidal side effects are very rare in neonates and infants, and exceptional in adults. These side effects reverse spontaneously and completely as soon as the treatment is stopped.

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

Symptoms

Overdose has been reported primarily in infants and children. Symptoms of overdose 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 is 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 in 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 the oral drug is taken after a meal.

After rectal administration of 60 mg domperidone suppositories, a plateau is attained with domperidone plasma concentrations of about 20 ng/ml lasting from 1 to 5 hours after administration. Although peak plasma levels are only about one third of that of an oral dose, the mean rectal bioavailability of 12.4% is quite similar to that after oral administration.

Distribution

Oral domperidone does not appear to accumulate or 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 (20mg q.i.d.) by 17-fold. However, safety margins in in vitro 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 (20mg 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 rabbits.

Macrogol 4000

Macrogol 1000

Macrogol 400

Tartaric acid

Butylated hydroxyanisole

None.

Two years.

Do not store above 25°C. Do not refrigerate or freeze. Keep container in the outer carton to protect from light.

Aluminium/polyethylene blister strips consisting of printing primer, aluminium (45 micrometre) and polyethylene (inner layer) containing 6 suppositories, packed in a cardboard carton.

Not applicable.

McNeil Healthcare (Ireland) Ltd

Airton road

Tallaght

Dublin 24

Ireland

PA 823/51/3

Date if first authorisation: 3 December 1990

Date of last renewal: 30 June 2005

May 2010