apclaven xl 37.5 mg, 75 mg and 150 mg prolonged release capsule

MHRA PAR – Apclaven XL 37.5 mg, 75 mg and 150 mg Prolonged release capsule (PL 33410/0125-7) 1 -

APCLAVEN XL 37.5 MG PROLONGED RELEASE CAPSULE APCLAVEN XL 75 MG PROLONGED-RELEASE CAPSULE APCLAVEN XL 150 MG PROLONGED-RELEASE CAPSULE

(Venlafaxine hydrochloride)

PL 33410/0125-7

UKPAR

TABLE OF CONTENTS Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

6

Steps taken after authorisation – summary

Page 17

Summary of Product Characteristics

Page 18

Product Information Leaflet

Page 19

Labelling Page 20


PL 33410/0125-7

LAY SUMMARY The MHRA granted Apsla Limited Marketing Authorisations (licences) for the medicinal products Apclaven XL 37.5 mg, 75 mg and 150 mg Prolonged release capsules on 27 November 2012. These products are prescription-only medicines (POM) used to treat adults with depression, generalised anxiety disorders, social anxiety disorders (fear or avoidance of social situations) and panic disorder (panic attacks). Apclaven XL 37.5 mg, 75 mg and 150 mg Prolonged release capsules contain the active ingredient venlafaxine which is an antidepressant and belongs to a group of medicines called serotonin-noradrenaline re-uptake inhibitors (SNRIs). It is thought that people who are depressed may have lower levels of serotonin and noradrenaline in their brain. Whilst it is not fully understood how antidepressants work, Apclaven XL 37.5 mg, 75 mg and 150 mg Prolonged release capsules may help to relieve the symptoms of depression by increasing the levels of these substances in the brain. No new or unexpected safety concerns arose from these applications and it was, therefore, judged that the benefits of taking Apclaven XL 37.5 mg, 75 mg and 150 mg Prolonged release capsules outweigh the risks, hence Marketing Authorisations have been granted.



PL 33410/0125-7

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS Introduction

Page 4

Pharmaceutical assessment

Page 6

Non-clinical assessment

Page 9

Clinical assessment

Page 10

Overall conclusions and risk benefit assessment Page 15


INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the MHRA granted Apsla Limited, Marketing Authorisations for the medicinal products Apclaven XL 37.5 mg, 75 mg and 150 mg Prolonged release capsules (PL 33410/0125-7) on 27 November 2012. These products are prescription-only medicines (POM) indicated for

treatment of major depressive episodes. prevention of recurrence of major depressive episodes. treatment of generalised anxiety disorder. treatment of social anxiety disorder. treatment of panic disorder, with or without agoraphobia.

These abridged applications submitted under Article 10(1) of Directive 2001/83/EC as amended, are for Apclaven XL 37.5 mg, 75 mg and 150 mg Prolonged release capsules. Apclaven 37.5 mg XL prolonged release capsules claims to be a generic version of the European Reference Product (ERP) Effexor LP 37.5 mg granted on 15 April 1998 in France to Wyeth Laboratoires. Apclaven 75 mg and 150 mg Prolonged release capsules claim to be generic versions of the UK reference products Efexor XL 75 mg and 150 mg Prolonged Release Capsules (PL 00011/0223-4) granted to John Wyeth and Brother Limited on 05 August 1997. These licences underwent a Change of Ownership (CoA) procedure on 25 October 2011 and are currently authorised to Pfizer Limited. The reference products have been authorised in the EU for more than 10 years, thus the period of exclusivity has expired. Venlafaxine is a structurally novel antidepressant that is chemically unrelated to tricyclic, tetracyclic, or other available antidepressants. It is a racemate with two active enantiomers. The mechanism of venlafaxine’s antidepressant action in humans is believed to be associated with its potentiation of neurotransmitter activity in the central nervous system. Preclinical studies have shown that venlafaxine and its major metabolite, O-desmethyl venlafaxine (ODV), are potent inhibitors of serotonin and noradrenaline reuptake. Venlafaxine also weakly inhibits dopamine reuptake. No new non-clinical data have been submitted, which is acceptable given that the applications were based on being generic medicinal products of originator products that have been in clinical use for over 10 years. Three bioequivalence studies (two single-dose in the fed and fasted state and one multiple dose in the fed state) were submitted to support these applications, comparing the test product Apclaven XL 75 mg Prolonged release capsules (Apsla Limited) and the reference product Efexor® XL 75 mg modified release capsules (Wyeth UK) for the studies under fed conditions and the reference product Trevilor Retard 75 mg Capsules (Wyeth Pharma GmbH) for the study under fasting conditions. The reference product used in the fasted state study was taken from the German market. It has been confirmed that this can be considered equivalent to the same product from the UK market. The bioequivalence studies were carried out in accordance with Good Clinical Practice (GCP). With the exception of the bioequivalence studies, no new clinical studies were performed, which is acceptable given that the applications were based on being generic medicinal products of originator products that have been in clinical use for over 10 years.


No new or unexpected safety concerns were raised during the assessment of these applications and it was, therefore, judged that the benefits of taking Apclaven XL 37.5 mg, 75 mg and 150 mg Prolonged release capsules outweigh the risks; hence Marketing Authorisations have been granted.


PHARMACEUTICAL ASSESSMENT

ACTIVE SUBSTANCE INN: Venlafaxine hydrochloride. Chemical name: 1-[(1RS)-2-Dimethylamino)-1-(4-

methoxyphenyl)ethyl]cyclohexanol hydrochloride Structure:

Molecular formula: C17H27NO2.HCl Molecular weight: 313.9 Appearance: Venlafaxine hydrochloride is a white to almost white powder. Solubility: Venlafaxine hydrochloride is freely soluble in methanol and water,

soluble in anhydrous ethanol and slightly soluble or practically insoluble in acetone.

Venlafaxine hydrochloride is the subject of a European Pharmacopoeia monograph. All aspects of the manufacture and control of the active substance venlafaxine hydrochloride are covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability. MEDICINAL PRODUCT Other ingredients Other ingredients consist of pharmaceutical excipients sugar spheres (contains sucrose), Surelease E-7-7050 (contains ethyl cellulose (E462), dibutyl sebacate, oleic acid, purified water and colloidal anhydrous silica), hydroxypropylcellulose, hypromellose (E464) and talc (E553b). In addition:

The 37.5 mg strength also contains the capsule shell components gelatin, sodium lauril sulphate, ponceau 4R red (E124), quinoline yellow (E104) and titanium dioxide (E171).

The 75 mg strength also contains the capsule shell components gelatin, sodium lauril sulphate, sunset yellow (E110), quinoline yellow (E104) and titanium dioxide (E171).

The 150 mg strength contains the capsule shell components gelatin, sodium lauril sulphate, sunset yellow (E110), quinoline yellow (E104), patent blue (E 131) and titanium dioxide (E171).

Appropriate justification for the inclusion of each excipient has been provided. All excipients used comply with their respective European Pharmacopoeia monograph with the exception of Surelease E-7-7050, ponceau 4R red (E124), quinoline yellow (E104),


sunset yellow (E110) and patent blue (E 131) which are controlled to suitable in-house specifications. Satisfactory Certificates of Analysis have been provided for all excipients. With the exception of gelatin and oleic acid, none of the excipients contain materials of animal or human origin. The suppliers of gelatin and oleic acid have provided Certificates of Suitability from the European Directorate for the Quality of Medicines (EDQM) to show that they are manufactured in-line with current European guidelines concerning the minimising of risk of transmission of Bovine Spongiform Encephalopathy/transmissible Spongiform Encephalopathies (BSE/TSE). No genetically modified organisms (GMO) have been used in the preparation of these products. Pharmaceutical development The aim of the development programme was to formulate safe, efficacious,capsules that could be considered generic medicinal products of the innovator’s products Effexor 37.5 mg LP (France) and Efexor XL 75 mg and 150 mg Prolonged Release Capsules (UK). Suitable pharmaceutical development data have been provided for these applications. Comparable in vitro dissolution profiles have been provided for the proposed and originator products. The impurity profiles for the proposed products have been provided and are in line with ICH requirements. Manufacture A description and flow-chart of the manufacturing method has been provided. Satisfactory batch formulae have been provided for the manufacture of all strengths of the product, along with an appropriate account of the manufacturing process. The manufacturing process has been validated at commercial scale and has shown satisfactory results. Finished product specification The finished product specifications are satisfactory. Test methods have been described and have been adequately validated, as appropriate. Batch data have been provided and comply with the release specification. Certificates of Analysis have been provided for any working standards used. Container Closure System All strengths of the finished product are packaged in:

polyvinyl chloride/aluminium blister strips and are available in pack sizes of 14, 28 and 30 capsules.

High density polyethylene (HDPE) bottles with HDPE screw cap and a sachet of silica gel (desiccant) in pack sizes of 100 capsules.

It has been stated that not all pack sizes may be marketed, however, the marketing authorisation holder has committed to submitting the mock-ups for any pack size to the relevant regulatory authorities for approval before marketing.


Satisfactory specifications and certificates of analysis have been provided for all packaging components. All primary packaging complies with the current European regulations concerning materials in contact with food. Stability Stability studies were performed in accordance with current guidelines on batches of all strengths of finished product packed in the packaging proposed for marketing. The data from these studies support a shelf-life of 3 years (blister pack and bottle presentations) which reduces to 100 days after first opening for the bottles only with the storage conditions ‘Store below 30°C and store in the original container to protect from moisture’. Bioequivalence/Bioavailability Satisfactory Certificates of Analysis have been provided for the test and reference batches used in the bioequivalence studies. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labelling The SmPCs, PILs and labelling are satisfactory. A package leaflet has been submitted to the MHRA along with results of consultations with target patient groups ("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC, as amended. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains. Marketing Authorisation Application (MAA) Forms The MAA forms are satisfactory. Expert Report A quality overall summary has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical aspects of the dossier. Conclusion It is recommended that marketing authorisations are granted for these applications.


NON-CLINICAL ASSESSMENT PHARMACODYNAMICS, PHARMACOKINETICS AND TOXICOLOGY No new non-clinical data were submitted, which is acceptable given that the proposed products are generic medicinal products of originator products that have been licensed for over 10 years. NON-CLINICAL EXPERT REPORT The non-clinical overview has been written by an appropriately qualified person and is a suitable summary of the non-clinical aspects of the dossier. ENVIRONMENTAL RISK ASSESSMENT Since Apclaven XL 37.5 mg, 75 mg and 150 mg Prolonged release capsules are intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment (ERA) is therefore not deemed necessary. CONCLUSION It is recommended that marketing authorisations are granted for these applications.


CLINICAL ASSESSMENT

CLINICAL PHARMACOLOGY The clinical pharmacology of venlafaxine hydrochloride is well-known. With the exception of the bioequivalence studies, no pharmacokinetic or pharmacodynamic data were submitted for these applications, and none were required for applications of this type. Three bioequivalence studies were submitted. The MAH has studied the 75 mg strength (middle dose) of the three proposed for marketing. According to the guideline, CPMP/EWP/280/96, studies should normally be conducted on the highest strength (in this case 150 mg). However, due to dose-related undesirable effects, the studies were performed on the 75mg product, rather than on the highest strength. This is acceptable and appropriate for safety and tolerability reasons. The following three bioequivalence studies were submitted: STUDY 1. A comparative, randomised, two-way, two-period, single dose, crossover study to compare the pharmacokinetics of the test product Apclaven XL 75 mg Prolonged release capsules (Apsla Limited) versus the reference product Efexor® XL 75 mg modified release capsules (Wyeth UK) in healthy adult volunteers in the fed state. All volunteers received a single oral dose of either the test or the reference product administered 30 minutes after completing a standardised high-fat, high calorie breakfast. Blood samples were taken for the measurement of pharmacokinetic parameters at pre- and up to 60 hours post dose. The washout period between treatment periods was at least 7 days. The pharmacokinetic results for parent drug venlafaxine and O-desmethylvenlafaxine (active metabolite), for the test product versus the reference product following a 75 mg venlafaxine single dose in the fed state are presented below (non-transformed values, arithmetic mean values with ratios of geometric means):


AUC0-t area under the plasma concentration-time curve from time zero to t hours AUC0-∞ area under the plasma concentration-time curve from time zero to infinity Cmax maximum plasma concentration 90% CI* 90% Geometric Confidence Interval using log-transformed data ODV= O-desmethylvenlafaxine (active metabolite)

STUDY 2. An open label, laboratory blind, multiple dose, randomised, two-period crossover study to compare the pharmacokinetics of the test product Apclaven XL 75 mg Prolonged release capsules (Apsla Limited) versus the reference product Efexor® XL 75 mg modified release capsules (Wyeth UK) given once daily in healthy adult volunteers in the fed state. All volunteers received a single oral dose of either the test or the reference product administered 10 minutes after completing a standardised high-fat, high calorie breakfast. From days 1 to 5 subjects received the first randomised treatment given once every 24 hours, and from days 6 to 9 subjects received the second randomised treatment. Blood samples were taken for the measurement of pharmacokinetic parameters at pre- and up to 24 hours post dose. There was no washout period between treatment phases. The pharmacokinetic results for parent drug venlafaxine and O-desmethylvenlafaxine (active metabolite), for the test product versus the reference product after multiple doses of 75 mg venlafaxine are presented below (non-transformed values, arithmetic mean values with ratios of geometric means):


AUC0-t area under the plasma concentration-time curve from time zero to t hours AUC0-∞ area under the plasma concentration-time curve from time zero to infinity Cmax maximum plasma concentration 90% CI* 90% Geometric Confidence Interval using log-transformed data ODV= O-desmethylvenlafaxine (active metabolite)

STUDY 3. An open label, randomised, balanced, two-treatment, two-sequence, two-period, single dose, crossover study to compare the pharmacokinetics of the test product Apclaven XL 75 mg Prolonged release capsules (Apsla Limited) versus the reference product Trevilor Retard 75 mg Capsules (Wyeth Pharma GmbH, Germany) in healthy adult volunteers under fasting conditions. All volunteers received a single oral dose of either the test or the reference product administered with 240 ml of water following a fast of at least 10 hours. Blood samples were taken for the measurement of pharmacokinetic parameters at pre- and up to 96 hours post dose. The washout period between treatment periods was at least 16 days. The pharmacokinetic results for parent drug venlafaxine and O-desmethylvenlafaxine (active metabolite), for the test product versus the reference product following a 75 mg


venlafaxine single dose under fasting conditions are presented below (non-transformed values, arithmetic mean values with ratios of geometric means):

AUC0-t area under the plasma concentration-time curve from time zero to t hours AUC0-∞ area under the plasma concentration-time curve from time zero to infinity Cmax maximum plasma concentration 90% CI* 90% Geometric Confidence Interval using log-transformed data ODV= O-desmethylvenlafaxine (active metabolite) Tmax =time when maximum plasma concntration is reached

The 90% confidence intervals for AUC and Cmax for test versus reference product for parent drug venlalafaxine and active metabolite O-desmethylvenlafaxine for all studies are within predefined acceptance criteria specified in ”Guideline on the Investigation of Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev 1/, Corr**). Thus, the data support the claim that the test product is bioequivalent to the reference product. As the 37.5 mg, 75 mg and 150 mg capsule strengths meets the criteria specified in the ”Guideline on the Investigation of Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev 1/, Corr**), the results and conclusions of the bioequivalence study on the 75 mg strength can be extrapolated to the 37.5 mg and 150 mg capsule strengths.


Pharmacodynamics No new pharmacodynamic data were submitted and none were required for these applications. Efficacy No new efficacy data were submitted and none were required for these applications. Safety With the exception of the data generated during the bioequivalence studies, no new safety data were submitted and none were required for these applications. No new or unexpected safety issues were raised by the bioequivalence data.

Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL), Labels The SmPCs, PIL and labels are acceptable. The SmPC for each strength is consistent with that for its’ respective originator product. The PIL is consistent with the SmPC and in-line current guidelines. The labelling is in-line with current guidelines. Clinical Expert Report The clinical expert report has been written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier. Pharmacovigilance System and Risk Management Plan The pharmacovigilance system, as described by the applicant, 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 notification of any adverse reaction suspected of occurring either in the Community or in a third country. A suitable justification has been provided for not submitting a Risk Management Plan for these products. Conclusion There are no objections to the approval of these products from a clinical viewpoint.


IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Apclaven XL 37.5 mg, 75 mg and 150 mg Prolonged release capsules are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit-risk balance. NON-CLINICAL No new non-clinical data were submitted and none are required for applications of this type. EFFICACY With the exception of the bioequivalence studies, no new data were submitted and none are required for applications of this type. Bioequivalence has been demonstrated between the applicant’s Apclaven XL 75 mg Prolonged release capsules and its respective reference product. As the 37.5 mg, 75 mg and 150 mg capsule strengths of the product meets the biowaiver criteria specified in the ”Guideline on the Investigation of Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev 1/, Corr**), the results and conclusions of the bioequivalence studies on the 75 mg strength can be extrapolated to the 37.5 mg and 150 mg capsule strengths. SAFETY With the exception of the bioequivalence studies, no new data were submitted and none are required for applications of this type. As the safety profile of venlafaxine is well-known, no additional data were required. No new or unexpected safety concerns arose from the safety data from the bioequivalence studies. PRODUCT LITERATURE The SmPCs, PIL and labelling are satisfactory and consistent with that for the reference products, where appropriate. BENEFIT-RISK ASSESSMENT The quality of the products is acceptable, and no new non-clinical or clinical safety concerns have been identified. The bioequivalence studies support the claim that the applicant’s products and the originator products are interchangeable. Extensive clinical experience with venlafaxine is considered to have demonstrated the therapeutic value of the compound. The benefit-risk is, therefore, considered to be positive.



PL 33410/0125-7

STEPS TAKEN FOR ASSESMENT

1 The MHRA received the marketing authorisation applications on 29 April 2010.

2 Following standard checks and communication with the applicant the MHRA

considered the applications valid on 25 May 2010.

3 Following assessment of the applications the MHRA requested further information relating to the quality dossier on 02 July 2010 and 24 August 2011 and the clinical dossier on 25 June 2010.

4 The applicant responded to the MHRA’s requests, providing further information on the quality dossier on 23 December 2010, 21 March 2011, 22 February 2012 and 9 May 2012 and the clinical dossier on 11 November 2010.

5 The applications were determined on 27 November 2012.



PL 33410/0125-7

STEPS TAKEN AFTER ASSESSMENT

Date submitted

Application type

Scope Outcome


SUMMARY OF PRODUCT CHARACTERISTICS 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.


Module 3 PATIENT INFORMATION LEAFLET

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.


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apclaven xl 37.5 mg, 75 mg and 150 mg prolonged release capsule

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