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McNeil Healthcare (Ireland) Ltd

Airton Road, Tallaght, Dublin 24, Ireland
Telephone: +353 1 466 5200
Fax: +353 1 466 5316


Summary of Product Characteristics last updated on medicines.ie: 08/01/2014
SPC Motilium Oral Suspension



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1. NAME OF THE MEDICINAL PRODUCT

Motilium 1mg/ml Oral Suspension


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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

The oral suspension contains domperidone 1 mg per ml.

For a full list of excipients, see section 6.1.


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3. PHARMACEUTICAL FORM

Oral suspension.

White homogeneous suspension.


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4. CLINICAL PARTICULARS

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4.1 Therapeutic indications

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.


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4.2 Posology and method of administration

It is recommended to take oral Motilium before meals. If taken after meals, absorption of the drug is somewhat delayed.

The initial duration of treatment is four weeks. Patients should be re-evaluated after four weeks and the need for continued treatment re-assessed. Therapy should not exceed 14 days of continuous treatment without medical consultation.

See section 4.4 for further information.

Adults and adolescents (over 12 years and weighting35 kg or more)

10 ml to 20 ml of oral suspension (containing domperidone 1 mg per ml) three to four times per day with a maximum daily dose of 80 ml.

Infants and Children under 12 years of age and weighing less than 35kg

0.25-0.5 mg/kg three to four times per day with a maximum daily dose of 2.4 mg/kg (but do not exceed 80 mg per day).

Hepatic Impairment

Motilium is contraindicated in moderate or severe hepatic impairment (see section 4.3). Dose modification in mild hepatic impairment is however not needed (see section 5.2).

Renal Impairment

Since the elimination half-life of domperidone is prolonged in severe renal impairment, on repeated administration, the dosing frequency of Motilium 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 (see sections 4.4 and 5.2)


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4.3 Contraindications

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, e.g. in patients with gastro-intestinal haemorrhage, mechanical obstruction or perforation.

• In patients with moderate or severe hepatic impairment (see section 5.2).


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4.4 Special warnings and precautions for use

Precautions for use

The oral suspension contains sorbitol and may be unsuitable for patients with sorbitol intolerance.

Use during lactation

The total amount of domperidone excreted in human breast milk is expected to be less than 7 µg 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.

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

Renal impairment

Since the elimination half-life of domperidone is prolonged in severe renal impairment, , on repeated administration, the dosing frequency of Motilium 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 (see section 5.2).

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).

Cardiovascular 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 or with daily doses 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, and patients with significant electrolyte disturbances or underlying cardiac diseases such as congestive heart failure.


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4.5 Interaction with other medicinal products and other forms of interaction

When antacids or antisecretory drugs are used concomitantly, they should not be taken simultaneously with oral formulations of Motilium (domperidone base), i.e., they should be taken after meals and not before meals.

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.


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4.6 Pregnancy and lactation

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 µg 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.


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4.7 Effects on ability to drive and use machines

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


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4.8 Undesirable effects

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 can not be estimated from clinical trials data, it is recorded as “Not known”.

System Organ Class

Adverse Drug Reaction

Frequency

 

Common

Uncommon

Psychiatric disorders

 

Loss of libido

Anxiety

Nervous system disorders

 

Somnolence

Headache

Gastrointestinal disorders

Dry mouth

Diarrhoea

Skin and subcutaneous tissue disorder

 

Rash

Pruritus

Reproductive system and breast disorders

 

Galactorrhoea

Breast pain

Breast tenderness

General disorders and administration site conditions

 

Asthenia

In 45 studies where domperidone was used at higher dosages, for longer duration and for additional indications including diabetic gastroparesis, the frequency of adverse events (apart from dry mouth) was considerably higher. This was particularly evident for pharmacologically predictable events related to increased prolactin. In addition to the reactions listed above, akathisia, breast discharge, breast enlargement, breast swelling, depression, hypersensitivity, lactation disorder, and irregular menstruation were also noted.

Postmarketing experience

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

Immune system disorders

Not known

Anaphylactic reaction (including anaphylactic shock)

Psychiatric disorders

Not known

Agitation, nervousness

Nervous system disorders

Not known

Convulsion, extrapyramidal disorder

Eye disorders

 

Not known

Oculogyric crisis

Cardiac disorders (see section 4.4)

Not Known

Ventricular arrhythmias, sudden cardiac death, QTc prolongation

Skin and subcutaneous tissue disorders

Not known

Urticaria, angioedema

Renal and urinary disorders

Not known

Urinary retention

Reproductive system and breast disorders

Not known

Gynaecomastia, amenorrhoea

Investigations

Not known

Liver function test abnormal, blood prolactin increased

Extrapyramidal disorder occurs primarily in neonates and infants..

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


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4.9 Overdose

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 is recommended. Anticholinergic, anti-parkinson drugsmay be helpful in controlling the extrapyramidal reactions.


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5. PHARMACOLOGICAL PROPERTIES

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5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Propulsives, ATC code: A03F A 03

Domperidone is a dopamine antagonist with anti-emetic properties. Dopamine 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.


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5.2 Pharmacokinetic properties

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 administration of cimetidine or sodium bicarbonate. The time of peak absorption is slightly delayed and the AUC somewhat increased when the drug is taken after a meal.

The bioavailability of a 60 mg suppository after single or repeated dosing is approximately 65% of 80 mg of oral tablets, given over 24 hours. After rectal administration of 60 mg domperidone suppositories, mean domperidone plasma concentrations between 20 and 40 ng/ml are maintained from approximately 0.5 to 5 hours after single- and multiple-dose administration. Following single-dose administration, mean peak plasma levels of 60 mg suppositories 88% of that of two oral tablets, but the mean dose normalized rectal bioavailability relative to oral bioavailability is 64%. Following multiple-dose administration, peak plasma levels and dose-normalized bioavailability of 60 mg suppositories administered every 12 hours are 63% and 66%, respectively, of two 10 mg oral tablets administered every 6 hours.

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 dose is 7-9 hours in healthy subjects but is prolonged in patients with severe renal insufficiency.

Hepatic impairment

In subjects with moderate hepatic impairment (Pugh score 7 to 9, Child-Pugh rating B), the AUC and Cmax of domperidone is 2.9- and 1.5-fold higher, respectively, than in healthy subjects. The unbound fraction is increased by 25%, and the terminal elimination half-life is prolonged from 15 to 23 hours. Subjects with mild hepatic impairment have a somewhat lower systemic exposure than healthy subjects based on Cmax and AUC, with no change in protein binding or terminal half-life. Subjects with severe hepatic impairment were not studied.

Renal impairment

In subjects with severe renal insufficiency (serum creatinine > 6 mg/100 ml, i.e. > 0.6 mmol/L) the half-life of domperidone is increased from 7.4 to 20.8 hours, but plasma drug levels are lower than in subjects with normal renal function. Very little unchanged drug (approximately 1%) is excreted via the kidneys (see section 4.4).

Paediatric population

No pharmacokinetic data are available in the paediatric population.


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5.3 Preclinical safety data

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 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.


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6. PHARMACEUTICAL PARTICULARS

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6.1 List of excipient(s)

Microcrystalline cellulose and carboxymethylcellulose sodium

Sorbitol

Methylparahydroxybenzoate

Propylparahydroxybenzoate

Sodium saccharin

Polysorbate 20

Sodium hydroxide

Purified water qs ad


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6.2 Incompatibilities

None.


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6.3 Shelf life

3 years.

In-use shelf life after first opening: 3 months


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6.4 Special precautions for storage

Do not store above 30°C. Do not refrigerate or freeze. Keep container in the outer carton to protect from light.


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6.5 Nature and contents of container

200 ml amber glass Type III bottle with a tamper-resistant screw cap coated on the inside with PVC or child resistant cap of PP with a LDPE liner and a separate measuring cup, packed in a cardboard carton.


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6.6 Special precautions for disposal and other handling

Mix the contents of the bottle completely using a gentle tilting motion to avoid the formation of foam


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7. MARKETING AUTHORISATION HOLDER

McNeil Healthcare (Ireland) Ltd.

Airton Road

Tallaght

Dublin 24

Ireland


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8. MARKETING AUTHORISATION NUMBER(S)

PA 823/51/6


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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authoridation: 3 December 1990

Date of last renewal: 30 June 2005


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10. DATE OF REVISION OF THE TEXT

December 2013



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Active Ingredients

 
   Domperidone