public assessment report decentralised procedure practical information about using domperidone 1...

Public Assessment Report

Decentralised Procedure

Domperidone 1mg/ml Oral Suspension

Procedure No: UK/H/5247/001/DC

UK Licence No: PL 29831/0522

Wockhardt UK Ltd

Domper idone 1 mg/ml Oral Suspension UK/H/5247/001/DC

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Lay Summary

Domperidone 1 mg/ml Oral Suspension (domperidone)

This is a summary of the public assessment report (PAR) for Domperidone 1 mg/ml Oral Suspension (PL 29831/0522; UK/H/5247/001/DC). It explains how Domperidone 1 mg/ml Oral Suspension was assessed and its authorisation recommended, as well as its conditions of use. It is not intended to provide practical advice on how to use Domperidone 1 mg/ml Oral Suspension. For practical information about using Domperidone 1 mg/ml Oral Suspension, patients should read the Patient Information Leaflet (PIL) or contact their doctor or pharmacist. What is Domperidone 1 mg/ml Oral Suspension and what is it used for? Domperidone 1 mg/ml Oral Suspension is a ‘generic medicine’. This means that it is similar to a ‘reference medicine’, already authorised in the European Union (EU) called Motilium 1 mg/ml suspension. Domperidone 1 mg/ml Oral Suspension is used in adults and in children to treat nausea (feeling sick) and vomiting (being sick). How does Domperidone 1 mg/ml Oral Suspension work? Domperidone 1 mg/ml Oral Suspension contains the active substance domperidone. Domperidone belongs to a group of medicines called ‘dopamine antagonists’. It is not clear exactly how domperidone works to treat nausea and vomiting but its effect may be due to a combination of affecting the motility within the gut and blocking signals to a particular part of the brain that regulates the vomiting reflex. How is Domperidone 1 mg/ml Oral Suspension used? Domperidone 1 mg/ml Oral Suspension should be taken by mouth, using the oral syringe provided to measure the dose. This medicine should be taken 15 to 30 minutes before a meal and, if needed, before going to bed. Please read Section 3 of the PIL for detailed information on dosing recommendations, the route of administration, and the duration of treatment. In adults and teenagers (12 years of age and older, with a body weight of 35 kg or more) the usual dose is 10 mg taken up to three times a day. In children and adolescents (weighing less than 35 kg) the prescribing doctor will work out the dose, which will depend on the weight of the child. The medicine can only be obtained with a prescription. What benefits of Domperidone 1 mg/ml Oral Suspension have been shown in studies? Because Domperidone 1 mg/ml Oral Suspension is a generic medicine, studies in patients have been limited to tests to determine that it is bioequivalent to the reference medicine, Motilium 1 mg/ml suspension. Two medicines are bioequivalent when they produce the same levels of the active substance in the body.


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What are the possible side effects of Domperidone 1 mg/ml Oral Suspension? Because Domperidone 1 mg/ml Oral Suspension is a generic medicine and is bioequivalent to the reference medicine, its benefits and possible side effects are taken as being the same as the reference medicine. For information about side effects that may occur with using Domperidone 1 mg/ml Oral Suspension, please refer to the PIL or the Summary of Product Characteristics (SmPC) available on the Medicines and Healthcare products Regulatory Agency (MHRA) website. Why is Domperidone 1 mg/ml Oral Suspension approved? It was concluded that, in accordance with EU requirements, Domperidone 1 mg/ml Oral Suspension has been shown to have comparable quality and to be bioequivalent to Motilium 1 mg/ml suspension. It was, therefore, decided that, as for Motilium 1 mg/ml suspension, the benefits are greater than its risk and recommended that it can be approved for use. What measures are being taken to ensure the safe and effective use of Domperidone 1 mg/ml Oral Suspension? A Risk Management Plan (RMP) has been developed to ensure that Domperidone 1 mg/ml Oral Suspension is used as safely as possible. Based on this plan, safety information has been included in the SmPC and the PIL for this product, including the appropriate precautions to be followed by healthcare professionals and patients. Known side effects are continuously monitored. Furthermore new safety signals reported by patients and healthcare professionals will be monitored and reviewed continuously as well.

Other information about Domperidone 1 mg/ml Oral Suspension Ireland and the UK agreed to grant a marketing authorisation for Domperidone 1 mg/ml Oral Suspension on 05 November 2014. The marketing authorisation in the UK was granted on 03 December 2014. The full PAR for Domperidone 1 mg/ml Oral Suspension follows this summary. For more information about treatment with Domperidone 1 mg/ml Oral Suspension, read the PIL or contact your doctor or pharmacist. This summary was last updated in February 2015.


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TABLE OF CONTENTS

I Introduction Page 5 II Quality aspects Page 7 III Non-clinical aspects Page 8 IV Clinical aspects Page 9 V User consultation Page 13 VI Overall conclusion, benefit/risk assessment

and recommendation Page 13

Table of content of the PAR update for

MRP and DCP

Page 17


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I Introduction Based on the review of the data on quality, safety and efficacy, the member states have granted a marketing authorisation (MA) for the medicinal product Domperidone 1 mg/ml Oral Suspension. The application was submitted using the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS) and Ireland as a Concerned Member State (CMS). Domperidone 1 mg/ml Oral Suspension is a prescription-only medicine (POM), indicated in adults and children for the relief of the symptoms of nausea and vomiting. This application was made under Article 10(1) of Directive 2001/83/EC, as amended, claiming to be a generic medicinal product. The reference medicinal product, which has been authorised in accordance with Community provisions in force for not less than 10 years in the European Economic Area, is Motilium 1 mg/ml Suspension (PL 17780/0299), authorised to Winthrop Pharmaceuticals UK Limited (Trading as Zentiva). This marketing authorisation was originally granted to Smithkline Beecham (SWG) Limited in UK on 07 April 1987 (PL 00071/0292) but subsequently underwent a change of ownership to Sanofi Winthrop Limited on 02 January 1994 (PL 11723/0054), before undergoing a change of ownership to the current MA holder, Winthrop Pharmaceuticals UK Limited (Trading as Zentiva), on 02 July 2007. The medicinal product contains the active substance domperidone, which is a dopamine antagonist with anti-emetic properties. 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. No new non-clinical studies were conducted, which is acceptable given that the application was based on being a generic medicinal product of an originator product that has been licensed for over 10 years. Since Domperidone 1 mg/ml Oral Suspension is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is, therefore, not deemed necessary. With the exception of bioequivalence data, no new clinical data were provided with this application. One bioequivalence study was performed, which compared the pharmacokinetics of the applicant’s Domperidone 1 mg/ml Oral Suspension with those of the reference product, Motilium 1 mg/ml Oral Suspension, in healthy subjects under fasting conditions. The applicant has stated that the bioequivalence study was conducted in line with current Good Clinical Practice (GCP). The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place for this product type at all sites responsible for the manufacture and assembly of this product. For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites.


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A Risk Management Plan (RMP) and a summary of the pharmacovigilance system have been provided with this application and are satisfactory. The RMS and CMS considered that the application could be approved at the end of procedure (Day 210) on 05 November 2014. The marketing authorisation in the UK was granted on 03 December 2014.


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II Quality aspects II.1 Introduction The application is submitted according to Article 10(1) of Directive 2001/83/EC, as amended. The applicant has specified Motilium 1 mg/ml Oral Suspension, (PL 17780/0299), as the reference medicinal product for the purpose of determining the expiry period of data exclusivity (MA holder: Winthrop Pharmaceuticals UK Limited). The product is formulated as a white to off-white, opaque homogenous suspension containing the active substance domperidone at a concentration of 1 mg/ml. The excipients present are liquid sorbitol (non-crystallising, E420), microcrystalline cellulose (E460), carmellose sodium, saccharin sodium (E954), methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216), polysorbate 20 (E432) and purified water. The oral suspension is presented in a 200 ml conventional amber soda glass (Type III) bottle, fitted with 28 mm child resistant tamper-evident cap. In addition, the product is supplied with a 5 ml oral dosing syringe and bottle adaptor, and packed in an outer cardboard carton. II.2 Drug Substance Domperidone rINN: Domperidone Chemical Name: 5-Chloro-1-[1-[3-(2-oxo-2,3-dihydro-1H-benzimidazol-1

yl)propyl]piperidin-4-yl]-1,3-dihydro-2Hbenzimidazol-2-one Structure:

Molecular formula: C22H24ClN5O2 Molecular weight: 425.9 Appearance: White or almost white powder. Solubility: Practically insoluble in water, soluble in dimethylformamide, slightly

soluble in ethanol (96 per cent) and in methanol. Domperidone is the subject of a European Pharmacopoeia monograph. All aspects of the manufacture and control of the active substance, domperidone, are covered by a European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificate of Suitability.


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II.3 Medicinal Product Pharmaceutical development The objective was to develop a product that is comparable to the UK reference product Motilium 1 mg/ml Oral Suspension (PL 17780/0299). All the excipients used in the manufacture of the proposed formulation comply with their respective European Pharmacopoeia monographs. Satisfactory certificates of analysis have been provided for all excipients showing compliance with their proposed specifications. None of the excipients used contain material of animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of these excipients.

Manufacture of the product A satisfactory batch formula has been provided for the manufacture of the finished product, together with an appropriate account of the manufacturing process. A satisfactory manufacturing process has been validated with production scale batches. Finished Product Specification The finished product specification is satisfactory. Test methods have been described that have been adequately validated, as appropriate. Batch data have been provided from two batches that comply with the release specification. Certificates of analysis have been provided for all working standards used. Stability of the product Stability studies were performed in accordance with current guidelines on batches of the finished product, packed in the packaging proposed for marketing. The data from these studies support a shelf-life of 18 months unopened and 3 months opened, with special storage conditions of “Do not store above 25°C” and “Keep the bottle in the outer carton in order to protect from light”. Suitable post approval stability commitments have been provided. II.4 Discussion on chemical, pharmaceutical and biological aspects The grant of a marketing authorisation is recommended. III Non-clinical aspects The pharmacodynamic, pharmacokinetic and toxicological properties of domperidone are well-established. As domperidone is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are not required. An overview based on a literature review is, thus, appropriate. Suitable justification has been provided for non-submission of an Environmental Risk Assessment (ERA). As the application is for a generic version of an already authorised product, it is not expected that environmental exposure will increase following approval of the marketing authorisation for the proposed product.


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IV Clinical aspects IV.1 Introduction No new clinical data have been submitted for this application. The applicant’s clinical overview on the clinical pharmacology, efficacy and safety of the product has been written by an appropriately qualified person and is adequate. IV. 2 Pharmacokinetics In support of this application, the marketing authorisation holder has submitted the following bioequivalence study: An open, randomised, 2-way crossover, bioequivalence study in healthy male and female subjects to compare the fasted bioavailability of 20 mg domperidone from the test investigational medicinal product (IMP), Domperidone Oral Suspension (1 mg/mL) with that from the reference IMP, Motilium® Oral Suspension (1mg/mL), following single dose administration. Twenty-two (22) subjects were randomised and completed the study. Volunteers received the test or reference treatment after an overnight fast. Blood samples were taken for the measurement of pharmacokinetic parameters pre-dose and up to 48 hours post-dose. The two treatment periods were separated by a minimum 7-day washout period. The main pharmacokinetic results are presented below: Summary of derived pharmacokinetic parameters following 20 mg Domperidone administered as Domperidone Oral Suspension (Test IMP) and Motilium® Oral Suspension (Reference IMP)


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Summary of the statistical analysis of bioequivalence following 20 mg domperidone administered as Domperidone Oral Suspension (Test IMP) and Motilium® Oral Suspension (Reference IMP)

The 90% confidence intervals were within the acceptance criteria of 80.00%-125.00%. Based on these results, the proposed product, Domperidone 1 mg/ml Oral Suspension, can be considered to be bioequivalent with the reference product Motilium 1 mg/ml Oral Suspension. IV.3 Pharmacodynamics No new pharmacodynamic data are required for this application and none have been submitted. An adequate clinical overview has been provided. IV.4 Clinical efficacy No new efficacy data were submitted with this application and none were required. An adequate clinical overview has been provided. IV.5 Clinical safety No new safety data were submitted with this application and none were required. An adequate clinical overview has been provided. IV.6 Risk Management Plan (RMP) The marketing authorisation holder has submitted an RMP, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Domperidone 1 mg/ml Oral Suspension. A summary of safety concerns and planned risk minimisation activities, as approved in the


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RMP, are listed below: Summary of safety concerns

Important identified risks • Cardiac events (QTc prolongation, Torsades de Pointes, serious ventricular arrhythmia and sudden cardiac death)

• Hypersensitivity (including anaphylaxis) • Off-label use (e.g. stimulation of lactation in breast

feeding women, gastroesophageal reflux disease, diabetic and non-diabetic gastroparesis, symptoms of postural hypotension in patients with Parkinson’s disease)

Important potential risks n/a Missing information • Risks during pregnancy and lactation

• Risks in patients with hepatic impairment Summary table of risk management measures


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IV.7 Discussion on the clinical aspects The grant of a marketing authorisation is recommended for this application. V User consultation A user consultation with target patient groups on the PIL has been performed on the basis of a bridging report making reference to Amitriptyline Oral Solution, which has been user-tested (PL 29831/0356 and PL 29831/0439, United Kingdom). The bridging report submitted by the applicant is acceptable. VI Overall conclusion, benefit/risk assessment and recommendation The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been identified. The application includes an adequate review of published non-clinical and clinical data concerning the efficacy and safety of domperidone. The test product Domperidone 1 mg/ml Oral Suspension can be considered bioequivalent with the reference


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product Motilium 1 mg/ml Oral Suspension. The benefit/risk assessment is, therefore, considered to be positive. The Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and labelling are satisfactory, in line with current guidelines and consistent with the reference product. In accordance with Directive 2012/84/EU, the current approved UK version of the SmPC and PIL for this product are available on the MHRA website. The currently approved labels are listed below:


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Table of content of the PAR update for MRP and DCP

Steps taken after the initial procedure with an influence on the Public Assessment Report (Type II variations, PSURs, commitments)

Scope Procedure

number Product information affected

Date of start of the procedure

Date of end of procedure

Approval/ non approval

Assessment report attached Y/N (version)

public assessment report decentralised procedure practical information about using domperidone 1...

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