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Aurobindo Pharma - Milpharm Ltd.

Odyssey Business Park, Ares Block, West End Road, South Ruislip, Middlesex, HA4 6QD
Telephone: + 44 (0)208 845 8811
Fax: +44 (0)208 845 8735
WWW: http://www.aurobindo.com
Medical Information Direct Line: +44 (0)208 839 0959
Medical Information e-mail: medinfo@aurobindo.com
Customer Care direct line: +44 (0)208 845 8811
Medical Information Fax: +44 (0)208 845 8795

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Summary of Product Characteristics last updated on the eMC: 29/05/2012
SPC Domperidone 10mg Tablets


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1. Name of the medicinal product

Domperidone 10mg Tablets


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2. Qualitative and quantitative composition

Each tablet contains Domperidone maleate equivalent to 10mg domperidone base.

For a full list of excipients see section 6.1.


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3. Pharmaceutical form

Tablets

Domperidone 10mg Tablet is presented as a white round biconvex tablet with “Dm 10” inscription on one side.


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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.

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


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4.2 Posology and method of administration

Domperidone 10mg Tablets are for oral administration.

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

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.

See section 4.4


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4.3 Contraindications

• Known hypersensitivity to domperidone or any of the excipients.

• Prolactin-releasing pituitary tumour (prolactinoma.)

• Hepatic and/or renal impairment

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


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4.4 Special warnings and precautions for use

Precautions for use

Domperidone tablets contain lactose and may be unsuitable for patients with lactose intolerance, galactosaemia or glucose/galactose malabsorption.

Use during lactation

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 breast-feeding is not recommended for mothers who are taking domperidone.

Use in infants

Neurological side effects are rare (see "Undesirable effects" section). Since metabolic functions and the blood-brain barrier are not fully developed in the first months of life the risk of neurological side effects is higher in young children. 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, domperidone should be not be used in patients with hepatic impairment

Renal insufficiency

In patients with severe renal insufficiency (serum creatinine > 6 mg/100 mL, i.e. > 0.6 m mol/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 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).

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.) Use is therefore contraindicated in patients with underlying cardiac disease (see sections 4.3 and 4.8)

The risk may be higher in patients older than 60 years or at daily doses of more than 30 mg. Domperidone should be used at the lowest effective dose in adults (see section 4.2) and children. Domperidone is not recommended for those under 16 years of age (see section 4.2).

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 (see section 4.3).

The label will include:

Do not take if you are pregnant.


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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 CYP3A4 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 (200mg twice 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, domperidone 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 800ng/ml after oral and i.v administration of 2.5mg/kg respectively). Domperidone concentrations in breast milk of lactating women are 10 to 50% of the corresponding plasma concentrations and expected not to exceed 10ng/ml. The total amount of domperidone excreted in human breast milk is expected to be less than 7micrograms per day at the highest recommended dosing regimen. It is not known whether this is harmful to the newborn. Therefore breast-feeding is not recommended for mothers who are taking domperidone.


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4.7 Effects on ability to drive and use machines

Domperidone has no or negligible influence on the ability to drive or use machines.


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4.8 Undesirable effects

The following frequencies are used for the description of the occurrence of adverse reactions:

Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), unknown (cannot be estimated from the available data).

Where frequency cannot 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

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 Disorder:

Not know: anaphylactic reactions including anaphylactic shock, angioedema, allergic reaction

Psychiatric System Disorder:

Not known: agitation, nervousness

Nervous system disorders:

Not known; extrapyramidal disorder, convulsions,

Eye disorders: Not known: Oculogyric crisis

Skin and subcutaneous tissue disorders:

Not known: urticaria, angioedema

Reproductive system and breast disorders:

Not known:, gynaecomastia, amenorrhoea.

Cardiac disorders:

Unknown; ventricular arrhythmias QTc prolongation and sudden cardiac death (See sections 4.3 and 4.4).

Investigations:

Not known: liver function test abnormal, blood prolactin increased

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.


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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, convulsions, 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.


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5. Pharmacological properties

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5.1 Pharmacodynamic properties

Pharmacotherapeutic Group: Propulsives, ATC code: A03F A03

Domperidone is a dopamine antagonist with anti-emetic properties domperidone does not readily cross the bloodbrain 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 gastrointestinal 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.

Distribution

Oral domperidone does not appear to accumulate or induce its own metabolism; a peak plasma level after 90 minutes of 21ng/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.


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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 and in vitro and in in vivo pro-arrhythmic models (isolated Langendorff perfused heart)and in vivo models (dog, guinea pig, rabbits sensitised for torsades de pointes) 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 excipients

Microcrystalline cellulose

Lactose monohydrate

Maize starch

Povidone K30

Sodium lauryl sulphate

Silica colloidal, anhydrous

Magnesium stearate


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6.2 Incompatibilities

Not Applicable


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6.3 Shelf life

24 months.


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6.4 Special precautions for storage

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


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6.5 Nature and contents of container

The tablets are packed in blisters constituted from a PVC and aluminium foil in packs of 30 and 100.


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6.6 Special precautions for disposal and other handling

None


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7. Marketing authorisation holder

Milpharm Limited,

Ares,

Odyssey Business Park,

West End Road,

South Ruislip HA4 6QD,

United Kingdom


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8. Marketing authorisation number(s)

PL 16363/0106


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9. Date of first authorisation/renewal of the authorisation

3 February 2003


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10. Date of revision of the text

25/05/2012



More information about this product

Link to this document from your website: http://www.medicines.org.uk/emc/medicine/23098/SPC/


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