Public Assessment Report. Scientific discussion. Euplix 20 mg/20 drops (33.1 mg/ml) oral drops, solution. Paroxetine (as paroxetine mesilate)

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1 Public Assessment Report Scientific discussion Euplix 20 mg/20 drops (33.1 mg/ml) oral drops, solution Paroxetine (as paroxetine mesilate) DK/H/0240/002/MR This module reflects the scientific discussion for the approval of Euplix. The procedure was finalised on 18 December For information on changes after this date please refer to the module Update. 1/6

2 I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Euplix 20 mg/20 drops (33.1 mg/ml) oral drops, solution, from Synthon BV. The product was authorised in Denmark on 30 August The product is indicated for: Major Depressive Episode Obsessive Compulsive Disorder Panic Disorder with and without agoraphobia Social Anxiety Disorders/Social phobia Generalised Anxiety Disorder Post-traumatic Stress Disorder In 1999 the applicant Synthon B.V submitted an abbridged application for Euplix film-coated tablets containing 20 mg paroxetine as paroxentine mesilate claiming essential similarity with the Brand Leader Seroxat marketed by GlaxoSmithKline as film-coated tablets containing 20 mg paroxetine as paroxetine hydrochloride hemihydrate. The Danish license was granted in 2000 and the mutual recognition procedure DK/H/0240/001/MR ended in May This mutual recognition procedure concerns oral drops, solution of 20 mg paroxetine as paroxentine mesilate per 20 drops and is a change of the existing marketing authorisation for Euplix 20 mg filmcoated tablets. The legal basis for this abbridged application is Article 10 of directive 2001/83/EEC as amended, claiming essential similarity with the Brand Leader Seroxat marketed by GlaxoSmithKline as filmcoated tablets containing 20 mg paroxetine as paroxetine hydrochloride hemihydrate. II. II.1 QUALITY ASPECTS Introduction 1 drop contains 1 mg paroxetine (as paroxetine mesilate). 1 ml contains 33.1 mg paroxetine (as paroxetine mesilate). The solution for oral use is stored in a 20 ml brown glass bottle (type III), which contains a LDPE dropper. The bottle is packed in a carton box and contains a HDPE child-resistant closure. The excipients are: Sodium saccharine (E954); Acesulfame-K (E950); Mint aroma; Polysorbate 80 (E433); Ethanol 96% (v/v) and Propyleneglycol (E1520). Compliance with Good Manufacturing Practice The RMS has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place for this product type at all sites responsible for the manufacturing of the active substance as well as for the manufacturing and assembly of this product prior to granting its national authorisation. II.2 Drug Substance INN: Paroxetine mesylate. Chemical name(s): a) (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-piperidine methane sulphonic acid b) (-)-trans-4-(4 -fluorophenyl)-3-(3,4 -methylenedioxyphenoxymethyl)piperidine methane sulphonic acid. 2/6

3 c) (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine methane sulphonic acid. d) (1)-trans-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine methane sulphonic acid. Molecular formula: C 19 H 20 FNO 3 (paroxetine); C 19 H 20 FNO 3.CH 3 SO 3 H (paroxetine mesylate). Molecular mass: (paroxetine); (paroxetine mesylate). Molecular structure: F O O O N H CH 3 SO 3 H The active substance, paroxetine mesilate, is not described in the European Pharmacopoeia. It is a white to almost white powder and is very soluble in water, 0.1 M HCl, acetone and ethanol. Paroxetine mesilate is optically active with the (-) isomer expressing therapeutic activity. Enantiomeric purity is ensured by limiting the presence of the (+) isomer in the starting material and by the manufacturing process chosen. The stereochemistry of all batches is controlled by determination of optical rotation. The documentation on the active substance is presented as an EDMF/ASMF. Based on the documentation submitted an appropriate retest period has been set. II.3 Medicinal Product The dossier complies with relevant EU guidelines and directives. Manufacture is performed in accordance with cgmp and a product of consistent quality and homogeneity is guaranteed. The product is stable when stored in the original container. Based on the stability data provided a shelf-life of 24 months without special storage precautions has been accepted. An in-use shelf-life period of 56 days can be accepted based on satisfactory data obtained on 24 month old batches. III. NON-CLINICAL ASPECTS This product is a generic formulation of Seroxat, which is available on the European market. No new preclinical data have been submitted, and therefore the application has not undergone preclinical assessment. This is acceptable for this type of application Environmental risk assessment The product is intended as a substitute for other identical products on the market. The approval of this product will not result in an increase in the total quantity of paroxetine released into the environment. It does not contain any component, which results in an additional hazard to the environment during storage, distribution, use and disposal. 3/6

4 IV. CLINICAL ASPECTS IV.1 Introduction Paroxetine is a well-known active substance with established efficacy and tolerability. For this generic application, the MAH has submitted one bioequivalence study in which the pharmacokinetic profile of the test product Euplix 20 mg/20 drops (33.1 mg/ml) oral drops, solution is compared with the pharmacokinetic profile of the reference product Seroxat 20 mg film-coated tablets, GlaxoSmithKline, from the Dutch market. The study was an open-label, randomized, single-dose, two-way, two-sequence crossover, laboratory blind bioequivalence study conducted under fasting conditions with a wash out period of 20 days between the two administrations. The test product was administered as a single dose of 20 mg paroxetine as 20 oral drops in 100 ml of water. Then the glass was rinsed with another 100 ml of water, which was drunk as well. Reference product was administered as a single tablet with 200 ml water. The subjects were fasted for 10 hours before and 4 hours post drug administration. Meals were standardised for the first 32 hours after drug administration. Water was allowed ad libitum from 4 hours after drug administration. The subjects were confined at the study centre until collection of the 32 hour post-dose blood sample. Blood sampling was performed predosing and at various time-points post administration in each period. 48 (including 4 alternates) healthy Caucasian subjects (26 men/22 women, years) participated in the study and 46 subjects completed. The volunteers were divided into two subgroups and the administration of the study drugs to each subgroup was performed on separate days. Plasma samples of 44 subjects were analysed, as was prescribed in the protocol. There were two dropouts, both subjects withdrawn prior to period 2 due to adverse events during the wash out period. The two drop outs were substituted by alternates before the analytical part of the study. The pharmacokinetic variables evaluated were: Primary variables: AUC 0-t, AUC 0- and C max Secondary parameters: t max, K el, and t ½. Safety was also analysed. In order to conclude bioequivalence, 90% CIs for AUC 0-t, AUC 0- and C max should be within %. Results 4/6

5 Parameter Intra-subject variation Inter-subject variation AUC 0-t % % ln AUC 0-t % % AUC % % ln AUC % % C max % % ln C max % % The 90% confidence intervals for all three primary parameters AUC 0-t, AUC 0- and C max are within the acceptance range of %. The statistical power achieved was good and above 90%. The inter-subject variability was very high (119% for AUC 0-t and 89% for C max using ln-transformed data) while medium intra-subject variability was observed (23% for AUC 0- and 24% for C max using ln-transformed data). This is characteristic for paroxetine and does not affect the bioequivalence results. Euplix 20 mg/20 drops (33.1 mg/ml) oral drops, solution is considered bioequivalent with Seroxat 20 mg film-coated tablets. Tolerability of the test product is acceptable and not significantly different from reference product. The RMS has been assured that the bioequivalence study has been conducted in accordance with acceptable standards of Good Clinical Practice (GCP, see Directive 2005/28/EC) and Good Laboratory Practice (GLP, see Directives 2004/9/EC and 2004/10/EC). IV.2 Risk management plan & Pharmacovigilance system Paroxetine was first approved in 1990, and there is now more than 10 years post-authorisation experience with the active substance. The safety profile of paroxetine can be considered to be well established and no product specific pharmacovigilance issues were identified pre- or postauthorisation which are not adequately covered by the current SPC. Additional risk minimisation activities have not been identified for the reference medicinal product. The MAH has a pharmacovigilance system at their disposal, which is based on the current European legislation. The Pharmacovigilance system described fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the identification and notification of any potential risks occurring either in the Community or in a third country. V. PRODUCT INFORMATION SmPC and Package leaflet 5/6

6 The content of the SmPC and package leaflet approved during the mutual recognition procedure is in accordance with that accepted for the reference product Seroxat marketed by GlaxoSmithKline and with that accepted for the Euplix film-coated tablets. Readability test 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 test consisted of a pilot test with 2 participants, followed by two rounds with 10 participants each. The questions covered the following areas sufficiently: traceability, comprehensibility and applicability. 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 Euplix 20 mg/20 drops (33.1 mg/ml) oral drops, solution has a proven chemical-pharmaceutical quality and is a generic form of Seroxat. Seroxat is a well-known medicinal product with an established favourable efficacy and safety profile. Bioequivalence has been shown to be in compliance with the requirements of European guidance documents. The MAH has provided written confirmation that systems and services are in place to ensure compliance with their pharmacovigilance obligations. The SmPC, package leaflet and labelling are in the agreed templates and are in agreement with other paroxetine containing products and with the Euplix film-coated tablets. Agreement between Member States was reached during a written procedure. There was no discussion in the CMD(h). The Concerned Member States, on the basis of the data submitted, considered that essential similarity has been demonstrated for Euplix 20 mg/20 drops (33.1 mg/ml) oral drops, solution with the reference product, and have therefore granted a marketing authorisation. The mutual recognition procedure was finalised on 18 December The date for the first renewal will be: 23 October 2010 (in line with Euplix film-coated tablets). The following post-approval commitments have been made during the procedure: To submit a variation application to add the presentation of a bottle without dropper device and to update the SPC, package leaflet and labelling reflecting this change. Process validation will be performed on the first three batches of the maximum batch size. 1 batch of product will be put on stability per year. At least the first batch will be of the maximum batch size. Antimicrobial preservative efficacy testing will be performed on batches stored for 36 months and the results submitted when available. 6/6