public assessment report decentralised procedure ... · par dipyridamole 200mg/5ml oral suspension...

PAR Dipyr idamole 200mg/5ml Oral Suspension

UK/H/5767/003/DC

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Public Assessment Report

Decentralised Procedure

Dipyridamole 200mg/5ml Oral Suspension

(dipyridamole)

Procedure No: UK/H/5767/003/DC

UK Licence No: PL 39307/0041

Syri Limited (trading as Thame Laboratories).


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LAY SUMMARY

Dipyridamole 200mg/5ml Oral Suspension

(dipyridamole, oral suspension, 200mg/5ml).

This is a summary of the Public Assessment Report (PAR) for Dipyridamole 200mg/5ml Oral Suspension (PL 39307/0041; UK/H/5767/003/DC). It explains how Dipyridamole 200mg/5ml 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 Dipyridamole 200mg/5ml Oral Suspension. For practical information about using Dipyridamole 200mg/5ml Oral Suspension, patients should read the package leaflet or contact their doctor or pharmacist. The product will be referred to as Dipyridamole throughout the remainder of this PAR. What is Dipyridamole and what is it used for? Dipyridamole is a ‘hybrid generic medicine’. This means that it is similar to a ‘reference medicine’ containing the same active substance but is available as an oral suspension (200mg/5ml) instead of a tablet (100mg). The company (Syri Limited) has provided additional own data to demonstrate the safety and efficacy of Dipyridamole regarding this difference from the reference medicine. The reference medicine for Dipyridamole is Persantin Tablets 100 mg (Boehringer Ingelheim Limited). Dipyridamole helps stop blood clots which may occur if a patient has had their heart valves replaced. How does Dipyridamole work? Dipyridamole belongs to a group of medicines called ‘anti-thrombotic agents’, which are used to help stop blood clots forming. How is Dipyridamole used? The pharmaceutical form of this medicine is an oral suspension. The route of administration of this medicine is oral (by mouth). The patient must always take this medicine exactly as their doctor has told them. The patient should check with their doctor or pharmacist if they are not sure. The usual dose is 300-600mg each day. This is taken in three or four separate doses. The maximum daily dose is 600 mg. It is best to take Dipyridamole before meals. This medicine must not be given to children. Please read section 3 of the package leaflet for detailed information on dosing recommendations, the route of administration, and the duration of treatment. This medicine can only be obtained with a prescription.


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What benefits of Dipyridamole have been shown in studies? Because Dipyridamole is a hybrid application of Persantin Tablets 100 mg (Boehringer Ingelheim Limited), a clinical study has been provided for Dipyridamole to show the efficacy for the difference of Dipyridamole from the reference product Persantin Tablets 100 mg (Boehringer Ingelheim Limited). What are the possible side effects of Dipyridamole? Like all medicines, Dipyridamole can cause side effects, although not everybody gets them. The most common side effects with Dipyridamole (which may affect more than 1 in 10 people) are headache, feeling dizzy, feeling sick (nausea) and diarrhoea. For the full list of all side effects reported with Dipyridamole, see section 4 of the package leaflet available on the MHRA website. For the full list of restrictions, see the package leaflet. Why was Dipyridamole approved? The MHRA decided that Dipyridamole’s benefits are greater than its risks and recommended that it be approved for use. What measures are being taken to ensure the safe and effective use of Dipyridamole? A risk management plan (RMP) has been developed to ensure that Dipyridamole is used as safely as possible. Based on this plan, safety information has been included in the Summary of Product Characteristics and the package leaflet for Dipyridamole 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/healthcare professionals will be monitored/reviewed continuously. Other information about Dipyridamole Ireland and the UK agreed to grant a Marketing Authorisation for Dipyridamole on 10 December 2015. A Marketing Authorisation was granted in the UK on 06 January 2016. The full PAR for Dipyridamole follows this summary. For more information about treatment with Dipyridamole, read the package leaflet, or contact your doctor or pharmacist. This summary was last updated in February 2016.


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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


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I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the Member States considered that the application for Dipyridamole (PL 39307/0041; UK/H/5767/003/DC) could be approved. The product is a prescription-only medicine (POM) and is indicated as an adjunct to oral anti-coagulation for prophylaxis of thrombo-embolism associated with prosthetic heart valves. The application was submitted using the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS), and Ireland as Concerned Member State (CMS). The application was submitted under Article 10.3 of Directive 2001/83/EC, as amended, as a hybrid application. The reference medicinal product for this application is Persantin Tablets 100 mg, which was originally authorised to Boehringer Ingelheim Limited (PL 00015/5016R), on 24 November 1988. A CE marked 2.5/5ml double ended dosing spoon, is included in the pack, which is suitable for delivering the therapeutic dose range [2.5 ml three times a day (tds) to 5 ml tds] and appropriately validated. Following approval, there will be 3 different strengths of oral dipyridamole suspension licensed, i.e. 50 mg per 5 ml, 100 mg per 5 ml and with this application, a more concentrated strength of 200 mg per 5 ml. The Applicant has taken adequate steps to minimise the risk of resulting dosing error, as outlined in the Risk Management Plan (RMP) [refer to section IV.6 of this report; Summary table of risk minimisation measures]. The packaging has been compared in relation to the other 3 UK licenced products, and there is good differentiation in colour and pack style. In addition, during the UK national phase, the Applicant has highlighted the dose and made the dose font size larger to further increase differentiation to the other licenced products. Dipyridamole inhibits the uptake of adenosine into erythrocytes, platelets and endothelial cells in vitro and in vivo; the inhibition amounts to 80% at its maximum and occurs dose-dependently at therapeutic concentrations (0.5 - 2 μg/mL). Consequently, there is an increased concentration of adenosine locally to act on the platelet A2-receptor, stimulating platelet adenylate cyclase, thereby increasing platelet cAMP levels. Thus, platelet aggregation in response to various stimuli such as PAF, collagen and ADP is inhibited. Reduced platelet aggregation reduces platelet consumption towards normal levels. In addition, adenosine has a vasodilator effect and this is one of the mechanisms by which dipyridamole produces vasodilation. Dipyridamole inhibits phosphodiesterase (PDE) in various tissues. Whilst the inhibition of cAMP-PDE is weak, therapeutic levels inhibit cGMP-PDE, thereby augmenting the increase in cGMP produced by EDRF (endothelium derived relaxing factor, identified as NO). Dipyridamole also stimulates the biosynthesis and release of prostacyclin by the endothelium. Dipyridamole reduces the thrombogenicity of subendothelial structures by increasing the concentration of the protective mediator 13-HODE (13-hydroxyoctadecadienic acid). One bioequivalence study was submitted to support this application conducted under fasting conditions. The Applicant has stated that the bioequivalence study was conducted in accordance with the clinical research guidelines established by the basic principles defined in the ICH-GCP guidelines, Schedule Y (as amended) of Central Drugs Standard Control Organization (CDSCO); 2005, Ethical Guidelines for Biomedical Research on Human Participants, ICMR (Indian Council of Medical Research; 2006), Declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil, October 2013), ICH (Step 5) 'Guidance on Good Clinical Practice', Guideline on the Investigation of Bioequivalence


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CPMP/EWP/QWP/1401/98 Rev. 1/ Corr**, January 2010 and Good Laboratory Practice and applicable regulatory requirements. The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place at all sites responsible for the manufacture, assembly and batch release 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. The RMS and CMS considered that the application could be approved at the end of procedure (Day 210) on 10 December 2015. After a subsequent national phase, a licence was granted in the UK on 06 January 2016.


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II QUALITY ASPECTS II.1 Introduction Each 5ml of oral suspension contains 200mg dipyridamole. Other ingredients consist of the pharmaceutical excipients methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216), polysorbate 80 (E433), simeticone emulsion 30% (containing polydimethylsiloxane, sorbitan monostearate, polyoxyethylene 20 sorbitan, silicon dioxide, xanthan gum, benzoic acid, sorbic acid, potassium hydroxide, hydrogen chloride and deionised water), liquid maltitol (E965), xanthan gum (E415), aluminium magnesium silicate (E553a), citric acid monohydrate (E330), disodium phosphate anhydrous (E339), ammonium glycyrrhizinate, propylene glycol (E1520), orange flavour [containing propylene glycol (E1520)] and purified water. Dipyridamole is available in Ph.Eur Type III amber glass bottles with a tamper evident, child resistant, plastic (polypropylene/polyethylene) cap with an EPE liner in pack sizes of 150ml and 300ml. Not all pack sizes may be marketed. Each bottle of finished product is packed into a cardboard outer carton with a dosing device (double ended white polypropylene plastic spoon with 2.5ml and 5ml measuring ends). Satisfactory specifications and Certificates of Analysis have been provided for all packaging components. II.2. Drug Substance INN: Dipyridamole Chemical name: 2,2',2'',2'''-[(4,8-di(piperidin-1-yl)pyrimido[5,4-d]pyrimidine-2,6- diyl)dinitrilo]

tetraethanol

Structural formula:

Molecular formula: C24H40N8O4 Molecular mass: 504.6 g/mol Appearance: A bright yellow crystalline powder. Solubility: Practically insoluble in water and in ether, freely soluble in acetone, soluble in

ethanol. It dissolves in dilute mineral acids. Dipyridamole is the subject of a European Pharmacopoeia monograph. All aspects of the manufacture and control of the active substance, dipyridamole, are covered by the European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificate of Suitability. II.3. Medicinal Product Pharmaceutical Development The objective of the development programme was to formulate a hybrid generic product containing 200mg dipyridamole per 5ml of oral suspension that is safe, efficacious, and bioequivalent to the reference product Persantin Tablets 100 mg (Boehringer Ingelheim Limited).


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A satisfactory account of the pharmaceutical development has been provided. All excipients comply with their respective European Pharmacopoeia monographs with the exception of simeticone emulsion 30% and the orange flavour which comply with suitable in-house specifications. In addition the Applicant has provided a statement of regulatory compliance to EC Regulation 1334/2008 on flavourings and certain food ingredients with flavouring properties for use in and on foods for the orange flavouring. Satisfactory Certificates of Analysis have been provided for all excipients. Suitable batch analysis data have been provided for each excipient. None of the excipients contain materials of animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of this product. Manufacture of the product A satisfactory batch formula has been provided for the manufacture of the product, along with an appropriate account of the manufacturing process. The manufacturing process has been validated at commercial-scale batch size and shown satisfactory results. Finished Product Specification The finished product specification proposed is acceptable. Test methods have been described that have been adequately validated. Batch data have been provided that comply with the release specifications. Certificates of Analysis have been provided for all working standards used. Stability of the Product Finished product stability studies were performed in accordance with current guidelines on batches of finished product in the packaging proposed for marketing. The data from these studies support a shelf-life of 12 months for the unopened, bottle with the storage conditions ‘Do not store above 25°C.’ the in-use shelf life of the product is 60 days after first opening. After which time the content must be discarded. In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. This product may settle during storage. Shake the bottle well before use. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Suitable post approval stability commitments have been provided to continue stability testing on batches of finished product. II.4 Discussion on chemical, pharmaceutical and biological aspects There are no objections to the approval of this application from a pharmaceutical viewpoint. III NON-CLINICAL ASPECTS III.1 Introduction As the pharmacodynamic, pharmacokinetic and toxicological properties of dipyridamole are well-known, no new non-clinical studies are required and none have been provided. An overview based on the literature review is, thus, appropriate.


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The Applicant’s non-clinical expert report has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the relevant non-clinical pharmacology, pharmacokinetics and toxicology. III.2 Pharmacology Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above. III.3 Pharmacokinetics Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above. III.4 Toxicology Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above. III.5 Ecotoxicity/environmental risk assessment (ERA) Since Dipyridamole 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. III.6 Discussion on the non-clinical aspects No new non-clinical studies were conducted or necessary for this type of application. There are no objections to the approval of this application from a non-clinical viewpoint. IV CLINICAL ASPECTS IV.1 Introduction The clinical pharmacology of dipyridamole is well-known. With the exception of data from the bioequivalence study detailed below, no new pharmacodynamics or pharmacokinetic data are provided or are required for this application. The Applicant submitted one bioequivalence study to support this application to demonstrate bioequivalence with the reference product. This is acceptable. No new efficacy or safety studies have been performed and none are required for this type of application. A comprehensive review of the published literature has been provided by the Applicant, citing the well-established clinical pharmacology, efficacy and safety of dipyridamole. Based on the data provided, Dipyridamole can be considered bioequivalent to Persantin Tablets 100 mg (Boehringer Ingelheim Limited). IV.2 Pharmacokinetics In support of this application, the Applicant submitted the following bioequivalence study: STUDY An open label, randomised, single dose, crossover study to compare the pharmacokinetics of the Applicant’s test product Dipyridamole (Syri Limited) versus the reference product, Persantin Tablets 100 mg (Boehringer Ingelheim Limited), in healthy adult subjects under fasting conditions. The subjects were administered a single 100mg dose of either the test (100mg as 2.5ml of oral suspension) or the reference product (1 x 100mg tablet) under fasting conditions. Blood samples were collected for plasma levels before dosing and up to and including 36 hours after each administration. The washout period between the treatment phases was 7 days. The pharmacokinetic results are presented below:


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Table: Summary statistics for dipyridamole are as follows:

Table: Ratios of least square means for log transformed pharmacokinetic parameters and 90% Confidence interval for dipyridamole are given below:

Conclusion The 90% confidence intervals of the test/reference ratio for AUC, and Cmax values for dipyridamole lie within the acceptable limits of 80.00% to 125.00%, in line with the ‘Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/Corr**). Thus, the data support the claim that the Applicant’s test product, Dipyridamole (Syri Limited), is bioequivalent to the reference product Persantin Tablets 100 mg (Boehringer Ingelheim Limited). IV.3 Pharmacodynamics No new pharmacodynamics data were submitted and none were required for an application of this type. IV.4 Clinical efficacy No new efficacy data were submitted and none were required for an application of this type. IV.5 Clinical safety No new safety data were submitted and none were required for this application. IV.6 Risk Management Plan (RMP) The marketing authorisation holder (MAH) has submitted a risk management plan (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 Dipyridamole.


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A summary of safety concerns and planned risk minimisation activities, as approved in the RMP, are listed below: Summary table of safety concerns:

Summary table of risk minimisation measures:


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IV.7 Discussion on the clinical aspects With the exception of the bioequivalence study, no new clinical studies were conducted, which is acceptable given that the application was based on being a hybrid generic medicinal product of an originator product that has been licensed for over 10 years. Bioequivalence has been demonstrated between the Applicant’s test product, Dipyridamole (Syri Limited), versus the reference product, Persantin Tablets 100 mg (Boehringer Ingelheim Limited). The grant of a marketing authorisation is recommended for this application. V User consultation The package leaflet has been evaluated via a user consultation study, in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose of user testing the PIL was English. The results show that the package leaflet meets the criteria for readability, as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use. 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. Extensive clinical experience with dipyridamole is considered to have demonstrated the therapeutic value of the compound. The benefit-risk is, therefore, considered to be positive.


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Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPC) and Patient Information Leaflets (PIL) for products granted Marketing Authorisations at a national level are available on the MHRA website. The approved labelling for Dipyridamole is presented below:


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