annex i list of the names, pharmaceutical...

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ANNEX I

LIST OF THE NAMES, PHARMACEUTICAL FORM, STRENGTHS OF THE MEDICINAL

PRODUCT, ROUTE OF ADMINISTRATION, MARKETING AUTHORISATION HOLDERS,PACKAGING AND PACKAGE SIZES IN THE MEMBER STATES

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Annex I

MAH Address(Contact Person)

Trade Name/Name

Strengths PharmaceuticalForms

Routes ofAdministration

Packaging Content/Concentration

Package Sizes

AUSTRIAJanssen-Cilag PharmaGmbH, Pfarrgasse 75,A-1232 Wien

Motilium 10 mg

1 mg/ml

10 mg

30 mg

60 mg

Film-coated tablet

Oral suspension

Suppository

Suppository

Suppository

Oral

Oral

rectal

rectal

rectal

blister

flask

strip

strip

strip

10 mg /tablet

1 mg / ml

10 mg / suppository

30 mg / suppository

60mg / suppository

10, 50 tablets

200 ml

6 suppositories

6 suppositories

6 suppositories

BELGIUMJanssen-Cilag N.V.Roderveldlaan 12600 BerchemBelgium

Motilium 10 mg

10 mg

10 mg

1 mg/ml

10 mg,

30 mg.

60 mg

Tablet

Instant melt tablet

Effervescent granule

Drinkable suspension

Suppository

Suppository

Suppository

Oral

Oral

Oral

Oral

Rectal

Rectal

Rectal

blister

blister

sachet

bottle

strip

strip

strip

10 mg / tablet

10 mg / tablet

10 mg / sachet

1 mg/ml

10 mg/suppository

30 mg/suppository.

60 mg/suppository

30, 100 tablets

10, 20, 30tablets

20 sachets

100 ml, 200ml

6 suppositories

6 suppositories

6 suppositories

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DENMARKJanssen-Cilag A/SHammerbakken 19Dk-3460 Birkerød

Motilium 10 mg

30 mg

60 mg

Tablet

Suppository

Suppository

Oral

Rectal

Rectal

strips

strips

Strips

10 mg / tablet

30 mg/suppository

60 mg / suppository

30 tablets

6 suppositories

6 suppositories

FRANCEJanssen-Cilag1, Rue CamilleDesmoulinsTSA 9100392787 Issy LesMoulineaux Cedex 9

Motilium 10 mg

10mg

1mg/ml

10 mg

30 mg

60 mg

10 mg

Tablet


Oral suspension

Suppository

Suppository

Suppository

Oral Lyophilisate

Oral

Oral

Oral

Rectal

Rectal

Rectal

Oral

blister

sachet

flask

Strips

Strips

Strips

blister

10 mg / tablet

10 mg per sachet of 3 g

1 mg / ml

10 mg / suppository

30 mg suppository

60 mg suppository

10 mg / lyophilisate

40 tablets

30 sachets

200 ml

5 suppositories

5 suppositories

5 suppositories

10, 30, 40Lyophilisates

Pierre FabreMedicament45, Place Abel-Gance92100 Boulogne

Peridys 10 mg

1 mg/ml

Tablet

Oral suspension

Oral

Oral

blister

flask

10 mg / tablet

1 mg / ml

40 tablets

200 ml

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GERMANYByk Gulden LombergChemische FabrikGmbH Byk-Gulden-Str. 2 78467Konstanz

Motilium

Motilium K

MotiliumGranulat

10 mg

10 mg/ml

10 mg /ml

10 mg

Tablet

Suspension

Suspension

effervescent granule

Oral

Oral

Oral

Oral

Blister

dropperbottledropperbottlesachets

10 mg/tablet

10 mg/ml

10 mg/ml

10 mg/sachet

20, 50,100,400tablets30 and 100 ml

HP 1 x 10 x 30ml10 ml20, 50, 100sachets

GREECEJanssen-CilagPharmaceutical S.A.C.I.56, Eirinis Avenue, 15121 Pefki, Athens,GREECE

Cilroton 10mg

5mg/5ml

10mg

60mg

Film coated tablet

Oral solution


Suppository

Oral

Oral

Oral

Rectal

Blisters

Bottle

Sachets

foil

10 mg / tablet

1mg /ml

10mg / sachet

60mg / suppository

Box of 30 (blister 3x10)200ml

30 sachets

6 suppositories

IRELANDJanssen-Cilag LimitedSaundertonHigh WycombeBuckinghamshireHP14 4HJUK

Motilium 10 mg

30 mg

10 mg

60 mg

1 mg/ml

Suppository

Suppository

Tablet

Suppository

Oral suspension

Rectal

Rectal

Oral

Rectal

Oral

blister.

blister

Blister

blisterstrips.bottle

10 mg /tablet

30 mg / suppository

10 mg / tablet

60 mg /suppository

1 mg/ml.

6 suppositories

6 suppositories

10, 20 & 100 tablets

6 suppositories

200 ml

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ITALYItalchimici SPAv.Pontina Km 29,Civ.500040 Pomezia(Roma)

Peridon 10 mg

1 mg/ml

60 mg

30 mg

10 mg

Tablet

oral solution

Suppository

Suppository


Oral

Oral

Rectal

Rectal

Oral

Blister

bottle

strip

strip

sachets

10 mg/tablet

1 mg/ml

60 mg/suppository

30 mg/suppository

10 mg/sachet

30 tablets

200 ml

6 suppositories

6 suppositories

30 sachets

Janssen-Cilag SpAv.M.Buonarroti 2320093 ColognoMonzese (MI)

Gastronorm

Gastronorm*

Motilium

5 mg

5 mg

10 mg

1 mg/ml

10 mg

effervescent granulechewable tablet

tablet

oral solution

effervescentgranule

Oral

Oral

Oral

Oral

Oral

sachet

blister

blister

glass bottle

sachets

5 mg/sachet

5 mg/tablet

10 mg/ tablet

1 mg/ml

10 mg/sachet

20 sachets

10 tablets

30 tablets

200 ml

30 sachets* registration suspended by Ministry of Health as product not marketed within 12 months of liccensing

LUXEMBOURGJanssen-Cilag N.V.Roderveldlaan 12600 BerchemBelgium

Motilium 10 mg

10 mg

10 mg

1 mg/ml

10 mg

30 mg.

60 mg

tablet

Instant melt tablet


drinkable suspension

Suppository

Suppository

Suppository

Oral

Oral

Oral

Oral

Rectal

Rectal

Rectal

Blister

Blister

Sachet

Glass bottle

Strip

Strip

Strip

10 mg / tablet

10 mg / tablet

10 mg / sachet

1 mg/ml

10 mg / suppository

30 mg / suppository

60 mg / suppository

30, 100 tablets

20, 30 tablets

20, 30, 40 sachets

100 ml, 200 ml

6 suppositories

6 suppositories

6 suppositories

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NETHERLANDSJanssen-Cilag B.V.Postbus 902405000 LT Tilburgthe Netherlands

Motilium 10 mg

10 mg

1 mg/ml

10 mg

30 mg

60 mg

Film coated tablet

lingual tablet

oral suspension

Suppository

Suppository

Suppository

Oral

Oral

Oral

Rectal

Rectal

Rectal

Blister

Blister

Bottle

Blister

Blister

Blister

10 mg /tablet

10 mg /lingual tablet

1 mg/ml

10 mg /suppository

30 mg/ suppository

60 mg /suppository

60 tablets, 50 tablets(hospital)10 and 30 tablets

200 ml

6 suppositories

6 suppositories

6 suppositories

TaxandriaPharmaceutica B.V.Postbus 902415000 LV TilburgThe Netherlands

Gastrocure 10 mg Film coated tablet Oral Blister 10 mg /ablets 10 tablets

PORTUGALJanssen FarmacêuticaPortugal, Lda.

Motilium

MotiliumRapid

10 mg

10 mg

30 mg

60 mg

1 mg/ml

10 mg

10 mg

Tablet

Suppository

Suppository

Suppository

oral solution


Oral lyophilisate

Oral

Rectal

Rectal

Rectal

Oral

Oral

Oral

Blister

Strips

Strips

Strips

Bottles

Sachets

Blister

10 mg/tablet

10 mg/ suppository

30 mg/ suppository

60 mg/ suppository

1 mg/ml

10 mg/sachet

10 mg/sachet

20 and 60 tablets

6 suppositories

6 suppositories

6 suppositories

100, 200 ml

10, 20 Sachets

10, 30, 40 tablets

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Nauzelin 10mg/tablet

Film coated tablet Oral Blister 10 mg/tablet 30 tabletsSPAINJanssen-Cilag, S.A.Paseo de Las DoceEstrellas, 5-728042-Madrid (Spain)

1 mg/ml Oral suspension Oral Bottle 1 mg/ml 200 ml

Dr. Esteve, S.A.Av. Mare de Deu deMontserrat, 22108041-Barcelona(Spain)

Motilium 10mg/tablet1 mg/ml

30 mg

60 mg

Film coated tablet

Oral suspension

Suppository

suppository

Oral

Oral

Rectal

Rectal

Blister

Bottle

Blister

Blister

10 mg/tablet

1mg/ml

30 mg/ suppository

60 mg/ suppository

30 tablets

200 ml

12 suppositories

12 suppositoriesUKSanofi Winthrop LtdOne Onslow StreetGuildfordSurrey GU1 4YS

Motilium 30mg

5mg

10mg

60mg

50mg

20mg

Suppository

Suspension

Tablet

Suppository

Suspension

Tablet

Rectal

Oral

Oral

Rectal

Oral

Oral

Strips

Bottles

Blisters,

HDPEcontainersStrips

Bottles

Blister

30mg/suppository

1mg/ml

12.72mg equivalent to10mg domperidone

60mg/suppository

10mg/ml

Domperidone maleate25.45mg equivalent to20mg domperidone

3 and 10suppositories

100 and 200ml

4, 10, 28, 30 and100 tablets500 tablets10 suppositories

30 and 100ml bottles

30 and 100 tablets

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Janssen-Cilag LimitedSaundertonHigh WycombeBuckinghamshireHP14 4HJUK

Domperidone

Domperidone(Maleate)Tablets

Domperidone

Domperidone

Domperidone

Domperidone

60 mg

20 mg

1 mg/ml

30 mg

10 mg

10 mg

Suppository

Tablet

Oral suspension

Suppository

Suppository

Tablet

Rectal

Oral

Oral

Rectal

Rectal

Oral

Strips

Blisters

Flasks

Strips

Strips

Blisters

60 mg / suppository

Domperidone maleate25.45 mg, equivalent todomperidone base 20 mg.

1 mg /1ml

30 mg / suppositoriy

10 mg / suppository

10 mg./ tablet

10 and 21suppositories

28, 30, 100 and 250tablets

30 and 200 ml

3 or 10 suppositories

10 suppositories

28, 30, 100 and 250tablets

Johnson & JohnsonMSDHigh WycombeBuckinghamshireHP14 4HJ, UK

Motilium 10

DomperidoneMaleateTablets 10mg

10mg

10mg

Film coated tablet

Film coated tablet

Oral

Oral

Blisters

Blisters

Tubs

Domperidone maleateequivalent to 10mgdomperidone base.

10 tablets

10, 28 and 30 tablets

84, 100 and 250 tabs

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ANNEX II

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR AMENDMENT OF THE SUMMARIESOF PRODUCT CHARACTERISTICS PRESENTED BY THE EMEA

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SCIENTIFIC CONCLUSIONS

Rationale for the article 30 referral

Due to the fact that the original product Motilium and associated names, does not have the sameSummary of Product Characteristics (SPC) in the various Member States in the European Union dueto divergent national decisions, a harmonisation of the SPC for Motilium and associated names,throughout Europe was necessary.

Background

Domperidone is a peripheral dopamine D2-receptor antagonist with gastrokinetic and anti-emeticproperties. It is used in the treatment of symptoms of dyspepsia, and of nausea and vomiting ofvariable origin. It exerts its actions via inhibition of dopamine receptors in the human gut, and in thechemoreceptor trigger zone (CTZ), which lies outside the blood-brain barrier in the area postrema.Unlike other dopamine antagonists with similar properties, domperidone does not readily cross theblood-brain barrier, thereby considerably reducing the risk for central and especially extrapyramidaladverse effects. The active substance is available as domperidone and as domperidone maleate.

Domperidone was first authorised in Belgium in 1978 and is now approved in over 80 countriesworldwide. It is approved and marketed in 13 out of 15 European Union Member States and isavailable in a number of oral (tablets, suspension, effervescent granules) and rectal formulations(suppositories). However, no marketing authorisation application for domperidone has been submittedin Finland, Sweden, Iceland or Norway. “Over the counter” (OTC) status has been granted in severalcountries, including Belgium, Ireland, Italy, Netherlands, UK, Switzerland and South Africa.

Overall Summary of the Scientific Evaluation of Motilium and associated names

- Quality issues

No significant issues relating to Quality were identified. The pharmaceutical particulars of the SPC were harmonised, except the sections, which need to beintroduced nationally by the Member States when implementing the harmonised SPC (section 6).

- Efficacy issues

The divergences that previously existed across the SPCs of EU Member States included:

Section 4.1. Therapeutic indications

For the majority of the European Union Member States, the approved indications for Motilium aretreatment of nausea and vomiting and treatment of the symptoms of dyspepsia, however there was adisharmony in the labelling relating to;

� The indication “for up to 12 weeks treatment of nausea and vomiting caused by L-dopa andbromocriptine” exists in the UK, but this is not approved in France.

� The indication of “gastro-oesophageal reflux disease” is approved in France whereas thisindication does not exist in UK.

After an assessment of the documentation provided by the MAH and an evaluation of the current EU-wide clinical practices relating to the use of Motilium, the following was considered to be the mostsuitable harmonised Section 4.1 indications text:

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4.1 Therapeutic indicationsAdultsThe relief of the symptoms of nausea and vomiting, epigastric sense of fullness, upper abdominaldiscomfort and regurgitation of gastric contents.

Children

� The relief of the symptoms of nausea and vomiting.

Section 4.2. Posology and method of administration

The MAH was requested to substantiate scientifically the divergent information across member statesand justify a proposed common wording, especially with regard to recommendations in the treatmentof nausea and vomiting where the maximum dosage varies across EU states.

After an assessment of the documentation provided by the MAH and an evaluation of the current EU-wide clinical practices relating to the use of Motilium the following was considered to be the mostsuitable harmonised Section 4.2 Posology text:

4.2 Posology and method of administrationIt is recommended to take oral Motilium before meals. If taken after meals, absorption of the drug issomewhat delayed.

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

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

1 to 2 of the 10-mg tablets three to four times per day with a maximum daily dose of 80 mg.

� Oral suspension

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

� Effervescent granules

1 to 2 sachets (containing domperidone 10 mg per sachet) three to four times per day with amaximum daily dose of 8 sachets.

� Suppositories

60-mg suppositories two times per day.

Infants and children

� Tablets, Oral Suspension

0.25 – 0.5 mg/kg three to four times per day with a maximum daily dose of 2.4 mg/kg (but donot exceed 80 mg per day).

Tablets are unsuitable for use in children weighing less than 35 kg.

� Suppositories

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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.

- Safety issues

Section 4.3. Contra-indications

The MAH was requested to propose and scientifically justify a common EU wide approach as thecontraindications text was considered to differ to a large extent between Member States especiallyrelating to:

� History of iatrogenic dyskinesia� Prolactinaemia� Patients at risk of gastrointestinal haemorrhages, mechanic obstruction, digestive

perforation due to hyperstimulation of gastrointestinal motility.

After an assessment of the documentation provided by the MAH and an evaluation of the current EU-wide clinical practices relating to the use of Motilium, the most suitable harmonised Section 4.3Contraindications text was approved (See Annex III). The text approved in the harmonised SPC is notso dissimilar to the currently approved SPCs that it will significantly change clinical practices.

Section 4.4. Special warnings and precautions for use

After an assessment of the documentation provided by the MAH and an evaluation of the current EU-wide clinical practices relating to the use of Motilium, the most suitable harmonised Section 4.4Special Warnings and Precautions for Use text was approved (See Annex III). The text in theharmonised SPC is not so dissimilar to the currently approved SPCs that it will significantly changeclinical practices

All other sections of the SPC were harmonised as a result of the referral procedure (except See Below;Administrative Issues).

- Administrative issues

Other sections of the SPC which were not harmonised and which need to be introduced nationally bythe Member States when implementing the harmonised SPC are the following: MAH, MA number,date of first authorisation/renewal of authorisation, Date of revision of the text.

Benefit/Risk considerationsBased on the documentation submitted by the MAH and the scientific discussion within theCommittee, the CPMP considered that the benefit/risk ratio of Motilium is favourable for use relatingto relief of the symptoms of nausea and vomiting, epigastric sense of fullness, upper abdominaldiscomfort and regurgitation of gastric contents.

GROUNDS FOR AMENDMENT OF THE SUMMARIES OF PRODUCT CHARACTERISTICS Whereas,

� the scope of the referral was the harmonisation of the Summaries of Products Characteristics,� the Summary of Products Characteristic proposed by the Marketing Authorisation Holders has

been assessed based on the documentation submitted and the scientific discussion within theCommittee,

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the CPMP has recommended the amendment of the Marketing Authorisations for which the Summaryof Product Characteristics is set out in Annex III of the Opinion. The major divergences identified atthe start of the referral have been resolved.

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ANNEX III

SUMMARY OF PRODUCT CHARACTERISTICS

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1. NAME OF THE MEDICINAL PRODUCT

<Motilium and associated names – see Annex I> <strength> <pharmaceutical form>.

(To be implemented nationally)

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One tablet contains domperidone 10 mg.

One film-coated tablet contains domperidone 10 mg.

Effervescent granules contain domperidone 10 mg per sachet.

The oral suspension contains domperidone 1 mg per ml.

One suppository contains domperidone 10 mg, 30 mg or 60 mg.

For excipients, see 6.1.

3. PHARMACEUTICAL FORM

Film coated tablets - white to faintly cream coloured, circular, biconvex tablets

Effervescent granules - white granular powder with characteristic odour and flavour

Oral suspension - white homogenous suspension

Oral Lyophilisate - white to off white, circular, freeze dried units

Suppositories - white to slightly yellow suppositories

4. CLINICAL PARTICULARS

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.

4.2 Posology and method of administration

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

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

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

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� Tablets

1 to 2 of the 10-mg tablets three to four times per day with a maximum daily dose of 80 mg.

� Oral suspension

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

� Effervescent granules

1 to 2 sachets (containing domperidone 10 mg per sachet) three to four times per day with amaximum daily dose of 8 sachets.

� Suppositories

60-mg suppositories two times per day.


� Tablets, Oral Suspension

0.25 – 0.5 mg/kg three to four times per day with a maximum daily dose of 2.4 mg/kg (but do notexceed 80 mg per day).


� Suppositories

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.

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:gastro-intestinal haemorrhage, mechanical obstruction or perforation.

4.4 Special warnings and special precautions for use

Precautions for use

The film-coated tablets contain lactose and may be unsuitable for patients with lactose intolerance,galactosaemia or glucose/galactose malabsorption.The oral suspension contains sorbitol and may be unsuitable for patients with sorbitol intolerance.The effervescent granules contain fructose and may be unsuitable for patients with fructoseintolerance.

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Use in patients with risk of hyperphenylalaninaemiaThe effervescent granules contain aspartame. Do not use in patients with a risk ofhyperphenylalaninaemia.

Use during lactationThe total amount of domperidone excreted in human breast milk is expected to be less than 7�g perday at the highest recommended dosing regimen. It is not known whether this is harmful to thenewborn. Therefore breast-feeding is not recommended for mothers who are taking Motilium.

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

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

Use in liver disorders:Since domperidone is highly metabolised in the liver, Motilium should be not be used in patients withhepatic impairment.

Renal insufficiency:In patients with severe renal insufficiency (serum creatinine > 6 mg/100 mL, i.e. > 0.6 m mol/L) theelimination half-life of domperidone was increased from 7.4 to 20.8 hours, but plasma drug levelswere lower than in healthy volunteers. Since very little unchanged drug is excreted via the kidneys, itis unlikely that the dose of a single administration needs to be adjusted in patients with renalinsufficiency. However, on repeated administration, the dosing frequency should be reduced to once ortwice daily depending on the severity of the impairment, and the dose may need to be reduced. Suchpatients on prolonged therapy should be reviewed regularly.

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 theconcomitant use of drugs that significantly inhibit this enzyme may result in increased plasma levelsof domperidone. In vivo interaction studies with ketoconazole revealed a marked inhibition ofdomperidone’s CYP3A4 mediated first pass metabolism by ketoconazole.

4.6 Pregnancy and lactation

There are limited post-marketing data on the use of domperidone in pregnant women. A study in ratshas shown reproductive toxicity at a high, maternally toxic dose. The potential risk for humans isunknown. Therefore, Motilium should only be used during pregnancy when justified by theanticipated therapeutic benefit.

The drug is excreted in breast milk of lactating rats (mostly as metabolites: peak concentration of 40and 800 ng/mL after oral and i.v. administration of 2.5 mg/kg respectively). Domperidoneconcentrations in breast milk of lactating women are 10 to 50% of the corresponding plasmaconcentrations and expected not to exceed 10ng/ml. The total amount of domperidone excreted inhuman breast milk is expected to be less than 7�g per day at the highest recommended dosingregimen. It is not known whether this is harmful to the newborn. Therefore breast-feeding is notrecommended for mothers who are taking Motilium.

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

� Immune System Disorder: Very rare; Allergic reaction� Endocrine disorder: Rare; increased prolactin levels� Nervous system disorders: Very rare; extrapyramidal side effects� Gastrointestinal disorders: Rare; gastro-intestinal disorders, including very rare transient

intestinal cramps� Skin and subcutaneous tissue disorders: Very rare; urticaria� Reproductive system and breast disorders: Rare; galactorrhoea, gynaecomastia, amenorrhea

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

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

4.9 Overdose

SymptomsSymptoms of overdosage may include drowsiness, disorientation and extrapyramidal reactions,especially in children.

TreatmentThere is no specific antidote to domperidone, but in the event of overdose, gastric lavage as well as theadministration of activated charcoal, may be useful. Close medical supervision and supportive therapyis recommended.

Anticholinergic, anti-parkinson drugs may be helpful in controlling the extrapyramidal reactions.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Propulsives, ATC code: A03F A 03

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

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

5.2 Pharmacokinetic properties

AbsorptionIn fasting subjects, domperidone is rapidly absorbed after oral administration, with peak plasmaconcentrations 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. Althoughdomperidone's bioavailability is enhanced in normal subjects when taken after a meal, patients withgastro-intestinal complaints should take domperidone 15-30 minutes before a meal. Reduced gastricacidity impairs the absorption of domperidone. Oral bioavailability is decreased by prior concomitant

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

After rectal administration of 60mg domperidone suppositories, a plateau is attained withdomperidone plasma concentrations of about 20ng/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 rectalbioavailability of 12.4% is quite similar to that after oral administration.

DistributionOral domperidone does not appear to accumulate or induce its own metabolism; a peak plasma levelafter 90 minutes of 21 ng/ml after two weeks oral administration of 30 mg per day was almost thesame 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 lowbrain concentration. Small amounts of drug cross the placenta in rats.

MetabolismDomperidone undergoes rapid and extensive hepatic metabolism by hydroxylation and N-dealkylation. In vitro metabolism experiments with diagnostic inhibitors revealed that CYP3A4 is amajor form of cytochrome P-450 involved in the N-dealkylation of domperidone, whereas CYP3A4,CYP1A2 and CYP2E1 are involved in domperidone aromatic hydroxylation.

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

5.3 Preclinical safety data

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

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

(to be implemented nationally)

6.2 Incompatibilities


6.3 Shelf life


6.4 Special precautions for storage


6.5 Nature and contents of container

(See Annex I - to be implemented nationally)

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6.6 Instructions for use and handling


7. MARKETING AUTHORISATION HOLDER


8. MARKETING AUTHORISATION NUMBER(S)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10. DATE OF REVISION OF THE TEXT

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1. NAME OF THE MEDICINAL PRODUCT

Motilium M 10mg tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One tablet contains domperidone maleate 12.72 mg equivalent to domperidone10 mg.

For excipients, see 6.1.

4. PHARMACEUTICAL FORM

Film coated tablets

Off white, biconvex, circular tablet

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Adults

� The relief of the symptoms of nausea and vomiting, epigastric sense of fullness, upper abdominaldiscomfort, regurgitation of gastric contents.

4.2 Posology and method of administration

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

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

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

1 to 2 of the 10 mg tablets three to four times per day with a maximum daily dose of 80 mg.



4.3 Contraindications

Motilium M is contraindicated in the following situations:

� Known hypersensitivity to domperidone or any of the excipients.� Prolactin-releasing pituitary tumour (prolactinoma).

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

4.4 Special warnings and special precautions for use

Precautions for use

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The film coated tablets contain lactose and they may be unsuitable for patients with lactoseintolerance, galactosaemia or glucose/galactose malabsorption.

Use during lactationThe total amount of domperidone excreted in human breast milk is expected to be less than 7�g perday at the highest recommended dosing regimen. It is not known whether this is harmful to thenewborn. Therefore breast-feeding is not recommended for mothers who are taking Motilium M.

Use in infants:Tablets are unsuitable for use in children weighing less than 35 kg.

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

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

Use in liver disorders:Since domperidone is highly metabolised in the liver, Motilium M should be not be used in patientswith hepatic impairment

Renal insufficiency:In patients with severe renal insufficiency (serum creatinine > 6 mg/100 mL, i.e. > 0.6 m mol/L) theelimination half-life of domperidone was increased from 7.4 to 20.8 hours, but plasma drug levelswere lower than in healthy volunteers. Since very little unchanged drug is excreted via the kidneys, itis unlikely that the dose of a single administration needs to be adjusted in patients with renalinsufficiency. However, on repeated administration, the dosing frequency should be reduced to once ortwice daily depending on the severity of the impairment, and the dose may need to be reduced. Suchpatients on prolonged therapy should be reviewed regularly.

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 theconcomitant use of drugs that significantly inhibit this enzyme may result in increased plasma levelsof domperidone. In vivo interaction studies with ketoconazole revealed a marked inhibition ofdomperidone’s CYP3A4 mediated first pass metabolism by ketoconazole.

4.6 Pregnancy and lactation

There are limited post-marketing data on the use of domperidone in pregnant women. A study in ratshas shown reproductive toxicity at a high, maternally toxic dose. The potential risk for humans isunknown. Therefore, Motilium M should only be used during pregnancy when justified by theanticipated therapeutic benefit.

The drug is excreted in breast milk of lactating rats (mostly as metabolites: peak concentration of 40and 800 ng/mL after oral and i.v. administration of 2.5 mg/kg respectively). Domperidoneconcentrations in breast milk of lactating women are 10 to 50% of the corresponding plasmaconcentrations and expected not to exceed 10ng/ml. The total amount of domperidone excreted inhuman breast milk is expected to be less than 7�g per day at the highest recommended dosingregimen. It is not known whether this is harmful to the newborn. Therefore breast-feeding is notrecommended for mothers who are taking Motilium M.

4.7 Effects on ability to drive and use machines

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

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4.8 Undesirable effects

� Immune System Disorder: Very rare; Allergic reaction� Endocrine disorder: Rare; increased prolactin levels� Nervous system disorders: Very rare; extrapyramidal side effects� Gastrointestinal disorders: Rare; gastro-intestinal disorders, including very rare transient intestinal

cramps� Skin and subcutaneous tissue disorders: Very rare; urticaria� Reproductive system and breast disorders: Rare; galactorrhoea, gynaecomastia, amenorrhea

As the hypophysis is outside the blood brain barrier, domperidone may cause an increase inprolactinlevels. In rare cases this hyperprolactinaemia may lead to neuro endocrinological side effects such asgalactorrhoea, gynaecomastia and amenorrhoea.

4.9 Overdose

SymptomsSymptoms of overdosage may include drowsiness, disorientation and extrapyramidal reactions,especially in children.

TreatmentThere is no specific antidote to domperidone, but in the event of overdose, gastric lavage as well as theadministration of activated charcoal, may be useful. Close medical supervision and supportive therapyare recommended.

Anticholinergic, anti-parkinson drugs may be helpful in controlling the extrapyramidal reactions.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Propulsives, ATC code: A03F A 03

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

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

5.2 Pharmacokinetic properties

AbsorptionIn fasting subjects, domperidone is rapidly absorbed after oral administration, with peak plasmaconcentrations 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. Althoughdomperidone's bioavailability is enhanced in normal subjects when taken after a meal, patients withgastro-intestinal complaints should take domperidone 15-30 minutes before a meal. Reduced gastricacidity does not impair the absorption of domperidone. Oral bioavailability is not decreased by priorconcomitant administration of cimetidine and sodium bicarbonate. The time of peak absorption isslightly delayed and the AUC somewhat increased when the oral drug is taken after a meal.

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DistributionOral domperidone does not appear to accumulate or induce its own metabolism; a peak plasma levelafter 90 minutes of 21 ng/ml after two weeks oral administration of 30 mg per day was almost thesame 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 lowbrain concentration. Small amounts of drug cross the placenta in rats.

MetabolismDomperidone undergoes rapid and extensive hepatic metabolism by hydroxylation and N-dealkylation. In vitro metabolism experiments with diagnostic inhibitors revealed that CYP3A4 is amajor form of cytochrome P-450 involved in the N-dealkylation of domperidone, whereas CYP3A4,CYP1A2 and CYP2E1 are involved in domperidone aromatic hydroxylation.

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

5.3 Preclinical safety data

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

6. PHARMACEUTICAL PARTICULARS

6.2 List of excipients


6.2 Incompatibilities


6.6 Shelf life


6.7 Special precautions for storage(to be implemented nationally)

6.8 Nature and contents of container


6.6 Instructions for use and handling


7. MARKETING AUTHORISATION HOLDER


8. MARKETING AUTHORISATION NUMBER(S)

25

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10. DATE OF REVISION OF THE TEXT

annex i list of the names, pharmaceutical...

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