Annex I. Routes of Administration Oral. Oral. rectal. rectal. rectal. Oral. Oral. Effervescent granule. Oral. Oral. Drinkable suspension.

Transcription

1 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 1

2 Annex I MAH Address (Contact Person) AUSTRIA Janssen-Cilag Pharma GmbH, Pfarrgasse 75, A-1232 Wien Trade Name /Name Strengths Pharmaceutical Forms Film-coated tablet suspension Routes of Administration rectal Packaging blister flask strip Content/ Concentration /tablet 1 mg / ml / suppository Package Sizes 10, 50 tablets 200 ml 30 mg rectal strip 30 mg / suppository 60 mg rectal strip 60mg / suppository BELGIUM Janssen-Cilag N.V. Roderveldlaan Berchem Belgium, Tablet Instant melt tablet Effervescent granule Drinkable suspension blister blister sachet bottle strip / tablet / tablet / sachet /suppository 30, 100 tablets 10, 20, 30 tablets 20 sachets 100 ml, 200 ml 30 mg. strip 30 mg/suppository. 60 mg strip 60 mg/suppository 2

3 DENMARK Janssen-Cilag A/S Hammerbakken 19 Dk-3460 Birkerød 30 mg 60 mg Tablet strips strips Strips / tablet 30 mg/suppository 60 mg / suppository 30 tablets FRANCE Janssen-Cilag 1, Rue Camille Desmoulins TSA Issy Les Moulineaux Cedex 9 10mg 1mg/ml Tablet Effervescent granule suspension blister sachet flask Strips / tablet per sachet of 3 g 1 mg / ml / suppository 40 tablets 30 sachets 200 ml 5 suppositories 30 mg Strips 30 mg suppository 5 suppositories 60 mg Strips 60 mg suppository 5 suppositories Lyophilisate blister / lyophilisate 10, 30, 40 Lyophilisates Pierre Fabre Medicament 45, Place Abel-Gance Boulogne Peridys Tablet suspension blister flask / tablet 1 mg / ml 40 tablets 200 ml 3

4 GERMANY Byk Gulden Lomberg Chemische Fabrik GmbH Byk-Gulden- Str Konstanz GREECE Janssen-Cilag Pharmaceutical S.A.C.I. 56, Eirinis Avenue, Pefki, Athens, GREECE K Granulat Cilroton /ml /ml 10mg 5mg/5ml 10mg 60mg Tablet Suspension Suspension effervescent granule Film coated tablet solution Effervescent granule dropper bottle dropper bottle sachets s Bottle Sachets foil /tablet /ml /ml /sachet / tablet 1mg /ml 10mg / sachet 60mg / suppository 20, 50,100,400 tablets 30 and 100 ml HP 1 x 10 x 30 ml 10 ml 20, 50, 100 sachets Box of 30 (blister 3 x10) 200ml 30 sachets IRELAND Janssen-Cilag Limited Saunderton High Wycombe Buckinghamshire HP14 4HJ UK 30 mg 60 mg Tablet suspension blister. blister blister strips. bottle /tablet 30 mg / suppository / tablet 60 mg /suppository. 10, 20 & 100 tablets 200 ml 4

5 ITALY Italchimici SPA v.pontina Km 29, Civ Pomezia (Roma) Peridon 60 mg 30 mg Tablet oral solution bottle strip strip /tablet 60 mg/suppository 30 mg/suppository 30 tablets 200 ml effervescent granule sachets /sachet 30 sachets Janssen-Cilag SpA v.m.buonarroti Cologno Monzese (MI) Gastronorm Gastronorm* 5 mg 5 mg effervescent granule chewable tablet tablet oral solution effervescent granule sachet blister blister glass bottle sachets * registration suspended by Ministry of Health as product not marketed within 12 months of liccensing 5 mg/sachet 5 mg/tablet / tablet /sachet 20 sachets 10 tablets 30 tablets 200 ml 30 sachets LUXEMBOURG Janssen-Cilag N.V. Roderveldlaan Berchem Belgium tablet Instant melt tablet effervescent granule Sachet / tablet / tablet / sachet 30, 100 tablets 20, 30 tablets 20, 30, 40 sachets drinkable suspension Glass bottle 100 ml, 200 ml Strip / suppository 30 mg. Strip 30 mg / suppository 60 mg Strip 60 mg / suppository 5

6 NETHERLANDS Janssen-Cilag B.V. Postbus LT Tilburg the Netherlands Film coated tablet lingual tablet oral suspension Bottle /tablet /lingual tablet 60 tablets, 50 tablets (hospital) 10 and 30 tablets 200 ml /suppository 30 mg 30 mg/ suppository 60 mg 60 mg /suppository Taxandria Pharmaceutica B.V. Postbus LV Tilburg The Netherlands Gastrocure Film coated tablet /ablets 10 tablets PORTUGAL Janssen Farmacêutica Portugal, Lda. Tablet Strips /tablet / suppository 20 and 60 tablets 30 mg Strips 30 mg/ suppository 60 mg Strips 60 mg/ suppository oral solution Bottles 100, 200 ml effervescent granule Sachets /sachet 10, 20 Sachets Rapid lyophilisate /sachet 10, 30, 40 tablets 6

7 SPAIN Janssen-Cilag, S.A. Paseo de Las Doce Estrellas, Madrid (Spain) Nauzelin 10 mg/tablet Film coated tablet /tablet 30 tablets suspension Bottle 200 ml Dr. Esteve, S.A. Av. Mare de Deu de Montserrat, Barcelona (Spain) 10 mg/tablet 30 mg Film coated tablet suspension Bottle /tablet 1mg/ml 30 mg/ suppository 30 tablets 200 ml 12 suppositories UK Sanofi Winthrop Ltd One Onslow Street Guildford Surrey GU1 4YS 60 mg 30mg 5mg 10mg 60mg suppository Suspension Tablet Strips Bottles s, HDPE containers Strips 60 mg/ suppository 30mg/suppository 1mg/ml 12.72mg equivalent to 10mg domperidone 60mg/suppository 12 suppositories 3 and 10 suppositories 100 and 200ml 4, 10, 28, 30 and 100 tablets 500 tablets 10 suppositories 50mg Suspension Bottles 10mg/ml 30 and 100ml bottles 20mg Tablet Domperidone maleate 25.45mg equivalent to 20mg domperidone 30 and 100 tablets 7

8 Janssen-Cilag Limited Saunderton High Wycombe Buckinghamshire HP14 4HJ UK Domperidone Domperidone (Maleate) Tablets Domperidone 60 mg 20 mg Tablet suspension Strips s Flasks 60 mg / suppository Domperidone maleate mg, equivalent to domperidone base 20 mg. 1 mg /1ml 10 and 21 suppositories 28, 30, 100 and 250 tablets 30 and 200 ml Domperidone 30 mg Strips 30 mg / suppositoriy 3 or 10 suppositories Domperidone Strips / suppository 10 suppositories Johnson & Johnson MSD High Wycombe Buckinghamshire HP14 4HJ, UK Domperidone 10 Domperidone Maleate Tablets 10mg 10mg 10mg Tablet Film coated tablet Film coated tablet s s s Tubs./ tablet Domperidone maleate equivalent to 10mg domperidone base. 28, 30, 100 and 250 tablets 10 tablets 10, 28 and 30 tablets 84, 100 and 250 tabs 8

9 ANNEX II SCIENTIFIC CONCLUSIONS AND GROUNDS FOR AMENDMENT OF THE SUMMARIES OF PRODUCT CHARACTERISTICS PRESENTED BY THE EMEA 9

10 SCIENTIFIC CONCLUSIONS Rationale for the article 30 referral Due to the fact that the original product and associated names, does not have the same Summary of Product Characteristics (SPC) in the various Member States in the European Union due to divergent national decisions, a harmonisation of the SPC for and associated names, throughout Europe was necessary. Background Domperidone is a peripheral dopamine D 2 -receptor antagonist with gastrokinetic and anti-emetic properties. It is used in the treatment of symptoms of dyspepsia, and of nausea and vomiting of variable origin. It exerts its actions via inhibition of dopamine receptors in the human gut, and in the chemoreceptor 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 the blood-brain barrier, thereby considerably reducing the risk for central and especially extrapyramidal adverse 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 countries worldwide. It is approved and marketed in 13 out of 15 European Union Member States and is available in a number of oral (tablets, suspension, effervescent granules) and rectal formulations (suppositories). However, no marketing authorisation application for domperidone has been submitted in Finland, Sweden, Iceland or Norway. Over the counter (OTC) status has been granted in several countries, including Belgium, Ireland, Italy, Netherlands, UK, Switzerland and South Africa. Overall Summary of the Scientific Evaluation of 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 be introduced 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 are treatment of nausea and vomiting and treatment of the symptoms of dyspepsia, however there was a disharmony in the labelling relating to; The indication for up to 12 weeks treatment of nausea and vomiting caused by L-dopa and bromocriptine exists in the UK, but this is not approved in France. The indication of gastro-oesophageal reflux disease is approved in France whereas this indication does not exist in UK. After an assessment of the documentation provided by the MAH and an evaluation of the current EUwide clinical practices relating to the use of, the following was considered to be the most suitable harmonised Section 4.1 indications text: 10

11 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. Section 4.2. Posology and method of administration The MAH was requested to substantiate scientifically the divergent information across member states and justify a proposed common wording, especially with regard to recommendations in the treatment of 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 EUwide clinical practices relating to the use of the following was considered to be the most suitable harmonised Section 4.2 Posology text: 4.2 Posology and method of administration It is recommended to take oral 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. 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. suspension 10 ml to 20 ml (of oral suspension containing domperidone 1mg per ml) three to four times per day with a maximum daily dose of 80 ml. Effervescent granules 1 to 2 sachets (containing domperidone per sachet) three to four times per day with a maximum daily dose of 8 sachets. Suppositories 60-mg suppositories two times per day. Infants and children Tablets, Suspension 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). Tablets are unsuitable for use in children weighing less than 35 kg. Suppositories 11

12 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 the contraindications text was considered to differ to a large extent between Member States especially relating 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 EUwide clinical practices relating to the use of, the most suitable harmonised Section 4.3 Contraindications text was approved (See Annex III). The text approved in the harmonised SPC is not so 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 EUwide clinical practices relating to the use of, the most suitable harmonised Section 4.4 Special Warnings and Precautions for Use text was approved (See Annex III). The text in the harmonised SPC is not so dissimilar to the currently approved SPCs that it will significantly change clinical 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 by the 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 considerations Based on the documentation submitted by the MAH and the scientific discussion within the Committee, the CPMP considered that the benefit/risk ratio of is favourable for use relating to relief of the symptoms of nausea and vomiting, epigastric sense of fullness, upper abdominal discomfort 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 the Committee, 12

13 the CPMP has recommended the amendment of the Marketing Authorisations for which the Summary of Product Characteristics is set out in Annex III of the Opinion. The major divergences identified at the start of the referral have been resolved. 13

14 ANNEX III SUMMARY OF PRODUCT CHARACTERISTICS 14

15 1. NAME OF THE MEDICINAL PRODUCT < and associated names see Annex I> <strength> <pharmaceutical form>. (To be implemented nationally) 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One tablet contains domperidone. One film-coated tablet contains domperidone. Effervescent granules contain domperidone per sachet. The oral suspension contains domperidone 1 mg per ml. One suppository contains domperidone, 30 mg or 60 mg. For excipients, see PHARMACEUTICAL FORM Film coated tablets - white to faintly cream coloured, circular, biconvex tablets Effervescent granules - white granular powder with characteristic odour and flavour suspension - white homogenous suspension 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 before meals. If taken after meals, absorption of the drug is somewhat 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 the need for continued treatment re-assessed. 15

16 Tablets 1 to 2 of the 10-mg tablets three to four times per day with a maximum daily dose of 80 mg. suspension 10 ml to 20 ml (of oral suspension containing domperidone 1mg per ml) three to four times per day with a maximum daily dose of 80 ml. Effervescent granules 1 to 2 sachets (containing domperidone per sachet) three to four times per day with a maximum daily dose of 8 sachets. Suppositories 60-mg suppositories two times per day. Infants and children Tablets, Suspension 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). Tablets are unsuitable for use in children weighing less than 35 kg. 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 is contraindicated in the following situations: Known hypersensitivity to domperidone or any of the excipients. Prolactin-releasing pituitary tumour (prolactinoma). 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 fructose intolerance. 16

17 Use in patients with risk of hyperphenylalaninaemia The effervescent granules contain aspartame. Do not use in patients with a risk of hyperphenylalaninaemia. Use during lactation The total amount of domperidone excreted in human breast milk is expected to be less than 7g 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. 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, 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. 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. In vivo interaction studies with ketoconazole revealed a marked inhibition of domperidone 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 rats has shown reproductive toxicity at a high, maternally toxic dose. The potential risk for humans is unknown. Therefore, 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 10ng/ml. The total amount of domperidone excreted in human breast milk is expected to be less than 7g 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. 4.7 Effects on ability to drive and use machines has no or negligible influence on the ability to drive and use machines 17

18 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 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. 4.9 Overdose Symptoms Symptoms of overdosage may include drowsiness, disorientation and extrapyramidal reactions, especially in children. 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. 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 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 oesophaegeal pressure, improve antroduodenal motility and accelerate gastric emptying. There is no effect on gastric secretion. 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 minutes before a meal. Reduced gastric acidity impairs the absorption of domperidone. bioavailability is decreased by prior concomitant 18

19 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 60mg domperidone suppositories, a plateau is attained with domperidone 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 rectal bioavailability of 12.4% is quite similar to that after oral administration. Distribution 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. 5.3 Preclinical safety data 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. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients (to be implemented nationally) 6.2 Incompatibilities (to be implemented nationally) 6.3 Shelf life (to be implemented nationally) 6.4 Special precautions for storage (to be implemented nationally) 6.5 Nature and contents of container (See Annex I - to be implemented nationally) 19

20 6.6 Instructions for use and handling (to be implemented nationally) 7. MARKETING AUTHORISATION HOLDER (See Annex I - to be implemented nationally) 8. MARKETING AUTHORISATION NUMBER(S) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF THE TEXT 20

21 1. NAME OF THE MEDICINAL PRODUCT M 10mg tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One tablet contains domperidone maleate mg equivalent to domperidone. For excipients, see 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 abdominal discomfort, regurgitation of gastric contents. 4.2 Posology and method of administration It is recommended to take oral M 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. Adults and adolescents (over 12 years and weighing 35 kg or more) 1 to 2 of the tablets three to four times per day with a maximum daily dose of 80 mg. Infants and children Tablets are unsuitable for use in children weighing less than 35 kg. 4.3 Contraindications M is contraindicated in the following situations: Known hypersensitivity to domperidone or any of the excipients. Prolactin-releasing pituitary tumour (prolactinoma). 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 21

22 The film coated tablets contain lactose and they 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 7g 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 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 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, M 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. 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. In vivo interaction studies with ketoconazole revealed a marked inhibition of domperidone 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 rats has shown reproductive toxicity at a high, maternally toxic dose. The potential risk for humans is unknown. Therefore, M 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 10ng/ml. The total amount of domperidone excreted in human breast milk is expected to be less than 7g 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 M. 4.7 Effects on ability to drive and use machines M has no or negligible influence on the ability to drive and use machines 22

23 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 inprolactin levels. In rare cases this hyperprolactinaemia may lead to neuro endocrinological side effects such as galactorrhoea, gynaecomastia and amenorrhoea. 4.9 Overdose Symptoms Symptoms of overdosage may include drowsiness, disorientation and extrapyramidal reactions, especially in children. 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. 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 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 oesophaegeal pressure, improve antroduodenal motility and accelerate gastric emptying. There is no effect on gastric secretion. 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 minutes before a meal. Reduced gastric acidity does not impair the absorption of domperidone. bioavailability is not 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. 23

24 Distribution 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. 5.3 Preclinical safety data 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. 6. PHARMACEUTICAL PARTICULARS 6.2 List of excipients (to be implemented nationally) 6.2 Incompatibilities (to be implemented nationally) 6.6 Shelf life (to be implemented nationally) 6.7 Special precautions for storage (to be implemented nationally) 6.8 Nature and contents of container (See Annex I - to be implemented nationally) 6.6 Instructions for use and handling (to be implemented nationally) 7. MARKETING AUTHORISATION HOLDER (See Annex I - to be implemented nationally) 8. MARKETING AUTHORISATION NUMBER(S) 24

25 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF THE TEXT 25