Venlafaxine Teva XL 225 mg Prolonged release Capsules, Hard

Public Assessment Report

Decentralised Procedure

Venlafaxine Teva XL 225 mg Prolonged-release Capsules, Hard

(Venlafaxine hydrochloride)

Procedure No: UK/H/6165-6166/001/DC

UK Licence No: PL 00289/2049-2050

Teva UK Limited

Venlafaxine Teva XL 225 mg Prolonged-Release Capsules, Hard UK/H/6165-6166/001/DC

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LAY SUMMARY

Venlafaxine Teva XL 225 mg Prolonged-release Capsules, Hard

(venlafaxine hydrochloride) This is a summary of the Public Assessment Report (PAR) for Venlafaxine Teva XL 225 mg Prolonged-release Capsules, Hard (PL 00289/2049-2050; UK/H/6165-6166/001/DC). It explains how the applications for Venlafaxine Teva XL 225 mg Prolonged-release Capsules, Hard were assessed and their authorisation recommended, as well as the conditions of use. It is not intended to provide practical advice on how to use Venlafaxine Teva XL 225 mg Prolonged-release Capsules. The product may be referred to as ‘Venlafaxine XL 225 mg’ in this Lay summary For practical information about using Venlafaxine XL 225 mg, patients should read the package leaflet or contact their doctor or pharmacist. What is Venlafaxine XL 225 mg and what is it used for? Venlafaxine XL 225 mg is a generic medicine. This means that Venlafaxine XL 225 mg is similar to a ‘reference medicine’ already authorised in the UK called Efexor XL 225 mg prolonged-release capsules, hard (PL 00057/1512; Pfizer Limited, UK). Venlafaxine XL 225 mg is used for the treatment of major depression. The patient’s doctor may also use Venlafaxine XL 225 mg to treat other illnesses. How does Venlafaxine XL 225 mg work? Venlafaxine XL 225 mg contains the active ingredient venlafaxine hydrochloride, which is an antidepressant that belongs to group of medicines called serotonin and norepinephrine reuptake inhibitors (SNRIs). This group of medicine is used to treat depression and other conditions such as anxiety disorders. It is thought that people who are depressed and/or anxious have lower levels of serotonin and noradrenaline in the brain. It is not fully understood how antidepressants work, but they may help by increasing the levels of serotonin and noradrenaline in the brain. Venlafaxine XL 225 mg is a treatment for adults with depression. It is also a treatment for adults with the following anxiety disorders: generalised anxiety disorder, social anxiety disorder (fear or avoidance of social situations) and panic disorder (panic attacks). Treating depression or anxiety disorders properly is important to help you get better. If it is not treated, your condition may not go away and may become more serious and more difficult to treat. Venlafaxine XL 225 mg is made to release the drug slowly in the body and therefore is different to other immediate release tablets containing venlafaxine. How is Venlafaxine XL 225 mg used? Venlafaxine XL 225 mg is available as prolonged release hard capsules and is taken by mouth. The capsules should be swallowed whole with liquid and not opened, crushed, chewed or dissolved. The patient should always take Venlafaxine XL 225 mg exactly as his/her doctor has advised. The patient should check with his/her doctor or pharmacist if not sure. The usual recommended starting dose for treatment of depression, generalised anxiety disorder and social anxiety disorder is 75 mg per day.


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The dose can be increased by the patient’s doctor gradually, and if needed, even up to a maximum dose of 375 mg daily for depression. If the patient is being treated for panic disorder, the doctor will start with a lower dose (37.5 mg) and then increase the dose gradually. The maximum dose for generalised anxiety disorder, social anxiety disorder and panic disorder is 225 mg/day. Venlafaxine XL 225mg capsules should be taken at approximately the same time each day, either in the morning or in the evening. Venlafaxine XL 225 mg should be taken with food. Please read section 3 of the package leaflet for detailed information on dosing recommendations, the route of administration and the duration of treatment. Venlafaxine XL 225 mg can only be obtained with a prescription. What benefits of Venlafaxine XL 225 mg have been shown in studies? Studies have been limited to tests to determine that Venlafaxine XL 150 mg is bioequivalent to the reference medicine, Trevilor retard 150 mg prolonged release capsules (Pfizer Pharma GmbH, Germany). As Efexor XL 150 mg prolonged-release capsules, hard (PL 00057/1281; Pfizer Limited, UK) is considered identical to Trevilor retard 150 mg prolonged release capsules (Pfizer GmbH, Germany), bioequivalence has also been shown between Venlafaxine XL 150 mg and Efexor XL 150 mg prolonged-release capsules, hard (PL 00057/1281; Pfizer Limited, UK). Two medicines are bioequivalent when they produce the same levels of the active substance in the body. A biowaiver for the 225 mg strength product was accepted on clinical and quality grounds. What are the possible side effects of Venlafaxine XL 225 mg? As Venlafaxine XL 225 mg is a generic medicine of the reference medicine Efexor XL 225 mg prolonged-release capsules, hard (Pfizer Limited, UK), the benefits and possible side effects are taken as being the same as those of the reference medicine. Very common and common side effects are listed below: Very common (may affect more than 1 in 10 people) • dizziness; headache • nausea; dry mouth • sweating (including night sweats). Common (may affect up to 1 in 10 people) • appetite decreased • confusion; feeling separated (or detached) from yourself; lack of orgasm; decreased libido;

nervousness; insomnia; abnormal dreams • drowsiness; tremor; pins and needles; increased muscle tonus • visual disturbance including blurred vision; dilated pupils; inability of the eye to automatically change

focus from distant to near objects • ringing in the ears (tinnitus) • palpitations • increase in blood pressure; flushing • yawning • vomiting; constipation; diarrhoea • increased frequency in urination; difficulties passing urine • menstrual irregularities such as increased bleeding or increased irregular bleeding; abnormal


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ejaculation/orgasm (males); erectile dysfunction, (impotence) • weakness (asthenia); fatigue; chills • increased cholesterol. For the full list of all side effects reported with Venlafaxine XL 225 mg, see section 4 of the package leaflet. For the full list of restrictions, see the package leaflet. Why is Venlafaxine XL 225 mg approved? In accordance with the EU requirements, Venlafaxine XL 225 mg has been shown to have comparable quality and bioequivalent to the originator Efexor XL 225 mg prolonged-release capsules, hard (Pfizer Limited, UK). Based on this evaluation, the MHRA concluded that the benefits of Venlafaxine XL 225 mg outweigh the identified risks and recommended Venlafaxine XL 225 mg for approval. What measures are being taken to ensure the safe and effective use of Venlafaxine XL 225 mg? A Risk Management Plan has been developed to ensure that Venlafaxine XL 225 mg is used as safely as possible. The relevant safety information has been included in the Summary of Product Characteristics and the package leaflet for Venlafaxine XL 225 mg, 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 Venlafaxine XL 225 mg Spain, the Netherlands, Portugal and the UK agreed to grant Marketing Authorisations for Venlafaxine XL 225 mg on 05 September 2016. Marketing Authorisations were granted in the UK on 16 September 2016. The full PAR for Venlafaxine XL 225 mg follows this summary. For more information about treatment with Venlafaxine XL 225 mg read the package leaflet, or contact your doctor or pharmacist. This summary was last updated in November 2016.


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SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

I Introduction Page 6 II Quality aspects Page 7 III Non-clinical aspects Page 15 IV Clinical aspects Page 16 V User consultation Page 22 VI Overall conclusion, benefit/risk assessment and recommendation Page 22 Annex 1- Table of content of the PAR update for MRP and DCP Page 23


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Scientific discussion I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the Member States considered that the applications for Venlafaxine Teva XL 225 mg Prolonged-Release Capsules, Hard (PL 0289/2049-2050; UK/H/6165-6166/001/DC) could be approved. The product may be referred to as Venlafaxine XL 225 mg Prolonged-release Capsules in this Scientific Discussion. The product is a Prescription Only Medicine (POM) indicated in the following: • Treatment of major depressive episodes. • For 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 applications were submitted using the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS) and Spain, the Netherlands and Portugal as Concerned Member States (CMS) for procedure UK/H/6165/001/DC, and Spain as the only CMS in procedure UK/H/6166/001/DC. The applications for Venlafaxine XL 225 mg Prolonged-release Capsules were submitted under Article 10(1) of Directive 2001/83/EC, as amended, as generic applications. The reference product for the purposes of data exclusivity is Efexor 150 mg prolonged-release capsules, (Pfizer Limited, UK), which was first authorised on 05 August 1997 to John Wyeth & Brother Ltd (PL 00011/0224). The Marketing Authorisation for Efexor 150 mg prolonged-release capsules, (Pfizer Limited, UK) is currently part of a Mutual recognition Procedure (SE/H/0936/003) with Spain, the Netherlands, Portugal and the UK among the CMS. The cross reference product in the UK is Efexor XL 225 mg prolonged-release capsules, authorised on 31 October 2014 to Pfizer Ltd (PL 00057/1512) via a Decentralised Procedure (SE/H/0936/004/DC) with Spain, Portugal and the UK among the CMS.

Venlafaxine XL 225 mg Prolonged-release Capsules contain the active ingredient, venlafaxine hydrochloride, which is a phenethylamine bicyclic derivative, chemically unrelated to tricyclic, tetracyclic or other available antidepressant agents. The mechanism of venlafaxine's antidepressant action in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its major metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine also weakly inhibits dopamine uptake. Venlafaxine and its active metabolite reduce β adrenergic responsiveness after both acute (single dose) and chronic administration. Venlafaxine and ODV are very similar with respect to their overall action on neurotransmitter reuptake and receptor binding. Three bioequivalence studies were submitted to support these applications, comparing the applicant’s test product Venlafaxine Hydrochloride Extended Release Capsules 150 mg with the reference product Trevilor retard 150 mg prolonged release capsules (Pfizer Pharma GmbH, Germany) under fasting, fed and steady-state conditions. During product development, Venlafaxine Hydrochloride Extended Release Capsules 150 mg was the name used for Venlafaxine XL 150 mg Prolonged-release Capsules. The bioequivalence studies are stated to have been conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP) guidelines.


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With the exception of the bioequivalence studies, no new non-clinical or clinical data were submitted, which is acceptable given that the applications were based on the product being a generic medicinal product of an originator product that has been in clinical use for over 10 years. The RMS has been assured that acceptable standards of 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. For manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites. The Member States considered that the applications could be approved at the end of procedure (Day 210) on 05 September 2016. After a subsequent national phase, Marketing Authorisations were granted on 16 September 2016 in the UK to Teva UK Limited. II QUALITY ASPECTS II.1 Introduction The submitted documentation concerning the proposed product is of sufficient quality and meets the current EU regulatory requirements. The quality overall summary has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical aspects of the dossier. Venlafaxine XL 225 mg Prolonged-Release Capsules are pink opaque, size ‘00’, hard gelatin capsules, with blue thick and thin radial circular bands on the body and cap, filled with mini tablets. Each capsule contains 225 mg of venlafaxine, as venlafaxine hydrochloride. The product also contain the pharmaceutical excipients in the capsule fill and capsule shell, namely microcrystalline cellulose, Povidone K-90, talc, colloidal silicon dioxide, magnesium stearate, ethyl cellulose, copovidone, gelatin, carmoisine (E122), titanium dioxide (E171), water and printing ink (contains shellac, propylene glycol, strong ammonia solution (E527) and indigo carmine aluminium lake (E 132)). Appropriate justification for the inclusion of each excipient has been provided. The finished product is supplied in:

1. Cold-forming aluminium (Oriented polyamide/aluminium/polyvinylchloride (OPA/Al/PVC)) and aluminium foil blisters, in pack sizes of 28, 30 and 30 x 1 prolonged-release hard capsules.

2. White opaque polyvinylchloride/polyvinylidene chloride (PVC/PVdc) and aluminium foil blisters, in pack sizes of 28, 30 and 30 x 1 prolonged-release hard capsules.

3. White opaque PVC/Aclar) and aluminium foil blisters, in pack sizes of 28, 30 and 30 x 1 prolonged-release hard capsules.

Not all pack sizes may be marketed. Satisfactory specifications and Certificates of Analysis for the primary packaging materials have been provided. All primary packaging complies with current European regulations concerning materials in contact with foodstuff.


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II.2 DRUG SUBSTANCE Venlafaxine hydrochloride INN: Venlafaxine hydrochloride Chemical name: 1-[(1RS)-2-(Dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol

hydrochloride Structure:

Molecular formula: C17H27NO2HCl Molecular weight: 313.86 Appearance: White or almost white powder. Solubility: Freely soluble in methanol and water, soluble in anhydrous ethanol and slightly

soluble or practically insoluble in acetone. Isomerism: Venlafaxine hydrochloride contains one chiral carbon in its structure and exists as

(+) and (-) enantiomers. Polymorphism Venlafaxine hydrochloride exhibits polymorphism. 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 and Healthcare (EDQM) Certificate of Suitability. II.3 MEDICINAL PRODUCT Pharmaceutical Development The objective of the development programme was to formulate a safe, efficacious, stable, prolonged-release capsule (using the tablet-in-capsule technology platform) that was bioequivalent to 3 x 75mg capsules of the reference product Trevilor retard capsules (Pfizer Pharma GmbH, Germany). Suitable pharmaceutical development data have been provided for these applications. Comparative in-vitro dissolution profiles have been provided for this product and the reference product. The dissolution profiles were satisfactory. The use of 3 x 75 mg capsules of the reference product rather than 1 x 225 mg reference product is acceptable since (i) at the time of development the 225 mg reference product was not marketed, (ii) the reference product uses modified release spheres, with different capsule fill weights, for the different capsule strengths and (iii) the posology of the reference products Summary of Product Characteristics (75 mg and 225 mg) do not differ. With the exception of carmoisine (E122), titanium dioxide (E171) and printing ink, all the excipients comply with their respective European Pharmacopoeia monographs. Carmoisine (E122) and titanium dioxide (E171) are controlled to suitable in-house specification. Carmoisine (E122) and titanium dioxide (E171) are also compliant with current EU Directive requirements concerning colouring agents in medicines. Satisfactory Certificates of Analysis have been provided for all excipients. With the exception of gelatin, none of the excipients contain materials of animal or human origin. The suppliers of gelatin have provided Certificates of Suitability from the European Directorate for the Quality of Medicines and Healthcare (EDQM) to show that it is manufactured in line with current European guidelines concerning the minimising of risk of transmission of Bovine Spongiform Encephalopathy/Transmissible Spongiform Encephalopathies (BSE/TSE).


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No genetically modified organisms (GMO) have been used in the preparation of these excipients. Manufacturing Process A satisfactory batch formula has been provided for the manufacture of the product, along with an appropriate description of the manufacturing process. The manufacturing process has been validated with pilot-scale batches and has shown satisfactory results. The Marketing Authorisation Holder has committed to performing process validation studies on the first three full-scale production batches. Control of Finished Product The finished product specification is acceptable. Test methods have been described and have been validated adequately. Batch data have been provided that complies with the release specification. 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. Based on the results, a shelf-life of 2 years, with no special storage conditions has been accepted. Suitable post approval stability commitments have been provided to continue stability testing on batches of finished product. Bioequivalence/Bioavailability Satisfactory Certificates of Analysis have been provided for the test and reference batches used in the bioequivalence studies. The bioequivalence studies are discussed in Section IV, Clinical Aspects. II.4 Discussion on chemical, pharmaceutical and biological aspects It is recommended that a Marketing Authorisations are granted, from a quality point of view. II.5 Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels The SmPCs, PILs and labelling are satisfactory and, where appropriate, in line with current guidance. In accordance with Directive 2010/84/EU, the current version of the SmPCs and PILs are available on the MHRA website. The current labelling is presented below:


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Venlafaxine XL 225 mg Prolonged-release Capsules, Hard (PL 00289/2049):


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Venlafaxine XL 225 mg Prolonged-release Capsules, Hard (PL 00289/2050): The labelling text below is that agreed at the end of the Decentralised Procedure (UK/H/6166/001/DC). The Marketing Authorisation Holder has committed to submit the UK labelling for review to the regulatory authority before marketing any pack size.


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III NON-CLINICAL ASPECTS III.1 Introduction The pharmacodynamic, pharmacokinetic and toxicological properties of venlafaxine hydrochloride are well known. No new non-clinical data have been submitted for these applications and none are required. The applicant has provided an overview based on published literature. The non-clinical overview 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 No new data have been submitted and none are required for applications of this type. Refer to Section III.1, Introduction, above. III.3 Pharmacokinetics No new data have been submitted and none are required for applications of this type. Refer to Section III.1, Introduction, above. III.4 Toxicology No new data have been submitted and none are required for applications of this type. Refer to Section III.1, Introduction, above. III.5 Ecotoxicity/Environmental Risk Assessment (ERA) Suitable justification has been provided for non-submission of an Environmental Risk Assessment. As the product is intended for generic substitution with a product that is already marketed, no increase in environmental exposure to venlafaxine hydrochloride is anticipated. Thus, the justification for non-submission of an Environmental Risk Assessment is accepted.


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III.6 Discussion of the non-clinical aspects It is recommended that Marketing Authorisations are granted, from a non-clinical point of view. IV. CLINICAL ASPECTS IV.1 Introduction. The clinical pharmacology of venlafaxine hydrochloride is well-known. In accordance with the regulatory requirements for a modified release generic product claiming to be bioequivalent to a reference product (CPMP/EWP/QWP/280/96 Corr1), the applicant submitted three bioequivalence studies (single dose fasted, single dose fed and multiple dose):

1. Fasting bioequivalence study of Venlafaxine Hydrochloride Prolonged Release Capsules 150 mg in healthy volunteers

2. Fed bioequivalence study of Venlafaxine Hydrochloride Prolonged Release Capsules 150 mg in healthy volunteers

3. Fed steady state bioequivalence study of Venlafaxine Hydrochloride Prolonged Release Capsules 150 mg in healthy volunteers.

Due to dose related known undesirable effects and the limited literature data available on the 225 mg strength in healthy human volunteers, the studies were performed on the 150 mg product, rather than on the higher 225 mg strength product. The use of Trevilor retard 150 mg prolonged release capsules from the German market as the reference product is acceptable and has been confirmed to be identical to the UK reference product. A biowaiver for the 225mg strength product has been applied for, cross-referring to the bioequivalence studies carried out on the 150mg product. The biowaiver can be accepted. With the exception of data from the bioequivalence studies detailed in Section IV.2, Pharmacokinetics below, no new pharmacodynamic or pharmacokinetic data are provided and none are required for these applications. IV.2 Pharmacokinetics In support of the application, the applicant submitted the following bioequivalence studies: Study 1 An open-label, randomised, two-treatment, two-sequence, two-period, two-way crossover, single-dose, oral bioequivalence study comparing the pharmacokinetics of the applicant’s test product Venlafaxine Hydrochloride Extended Release Capsules 150 mg versus the reference product Trevilor retard 150 mg prolonged -release capsules (Pfizer Pharma GmbH, Germany) in healthy adult male subjects, under fasting conditions. The subjects were administered a single dose of either treatment with 240 ml of water, after at least a 10-hour overnight fast. Blood samples were collected before, up to and including 72 hours after each administration. The washout period between the treatment phases was 8 days. The pharmacokinetic results are presented below.


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Results Pharmacokinetic (PK) parameters of venlafaxine

AUC0-t Area under the plasma concentration curve from administration to last observed concentration at time t. AUC0-inf Area under the plasma concentration curve extrapolated to infinite time. Cmax Maximum plasma concentration

Bioequivalence analyses:

AUC0-t Area under the plasma concentration curve from administration to last observed concentration at time t. Cmax Maximum plasma concentration No new or unexpected safety or tolerability issues were identified. Conclusion The 90% confidence intervals of the test/reference ratio for AUC0-t, and Cmax 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, these data support the claim that the applicant’s 150 mg strength test product is bioequivalent to the reference product Trevilor retard 150 mg prolonged release capsules (Pfizer Pharma GmbH, Germany) under fasting conditions. Study 2 An open-label, randomised, two-treatment, two-sequence, two-period, two-way crossover, single-dose bioequivalence study comparing the pharmacokinetics of the applicants test product Venlafaxine Hydrochloride Extended Release Capsules 150mg versus the reference product Trevilor retard 150mg prolonged release capsules (Pfizer Pharma GmbH, Germany) in healthy adult male subjects, under fed conditions. The subjects were administered a single dose of either treatment with 240 ml of water 30 minutes after a high fat, high calorie breakfast (about 1000 Kcal), after at least a 10 hour overnight fast. Blood samples were collected before, up to and including 72 hours after each administration. The washout period between the treatment phases was 8 days. The pharmacokinetic results are presented below.


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Results Pharmacokinetic (PK) parameters of venlafaxine

AUC0-t Area under the plasma concentration curve from administration to last observed concentration at time t. AUC0-inf Area under the plasma concentration curve extrapolated to infinite time. Cmax Maximum plasma concentration Bioequivalence analyses

AUC0-t Area under the plasma concentration curve from administration to last observed concentration at time t. Cmax Maximum plasma concentration Ratios and 90% confidence intervals calculated from ln-transformed data No new or unexpected safety or tolerability issues were identified. Conclusion of Study 2 The 90% confidence intervals of the test/reference ratio for AUC0-t, and Cmax 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, these data support the claim that the applicant’s 150 mg strength test product is bioequivalent to the reference product Trevilor retard 150 mg prolonged release capsules (Pfizer Pharma GmbH, Germany) under fed conditions. Study 3 An open-label, randomised, two-treatment, two-sequence, two -period, two -way crossover, multiple-dose, bioequivalence study comparing the pharmacokinetics of the applicants test product Venlafaxine Hydrochloride Extended Release Capsules 150 mg versus the reference product Trevilor retard 150 mg prolonged release capsules (Pfizer Pharma GmbH, Germany) in healthy male subjects, under fed conditions. The subjects were housed at the clinical facility from not less than 10.5 hours before Dose 1 of Period-1 until at least 24.0 hours post-dose of Dose 4 of Period-2 (i.e. total 9 consecutive nights). From not less than 10.5 hours before Dose 1 of Period-1 until 24.0 hours post dose of 4 (i.e. Day 0 to 5) was considered as Period-1. From Dose 1 of Period-2 until last sample of the study (i.e. Day 5 to 9) was considered as Period-2. After an overnight fast subjects were administered a single dose (one capsule) of either the test or the reference product with 240 mL of drinking water after a high fat, high calorie breakfast (about 1000 kilocalories). Dosing of dose 4 was done 30 minutes after the start of the breakfast in each period.


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Blood samples were collected within 05 minutes before dosing of Dose 2 to Dose 4 and up to and including 24 hours (within± 02 minutes) after dosing of Dose 4 in each period. A wash out period was not considered necessary. Carry over into the 24 hour sampling of the second study period would not be expected based on the known half-life of the drug. The pharmacokinetic results are presented below. Results Pharmacokinetic (PK) parameters of venlafaxine

AUC0-τ area under the plasma concentration-time curve to the time of the last quantifiable concentration during

dosing interval at steady state Cmax,ss maximum observed plasma concentration during dose interval at steady state Cτ,ss concentration at the end of the dosing interval at steady state Cav average concentration at steady state CV% coefficient of variation Tmax,ss time until Cmax,ss is reached Bioequivalence analyses (for all subjects):

Cmax,ss maximum observed plasma concentration during dose interval at steady state Cτ,ss concentrationat the end of the dosing interval at steady state Ratios and 90% confidence intervals calculated from ln-transformed data No new or unexpected safety or tolerability issues were identified. Additional analyses 3 subjects did not show steady state conditions for venlafaxine. Addition, statistical analysis was done excluding these subjects. The bioequivalence results for the modified population were as follows.


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Pharmacokinetics excluding 3 subjects:

AUC0-τ area under the plasma concentration-time curve to the time of the last quantifiable concentration during

dosing interval at steady state Cmax,ss maximum observed plasma concentration during dose interval at steady state Cτ,ss concentration at the end of the dosing interval at steady state CV% coefficient of variation Ratios and 90% confidence intervals calculated from ln-transformed data Conclusion for Study 3 The 90% confidence intervals of log-transformed pharmacokinetic parameter Cτ,ss, Cmax,ss and AUC0-τ for venlafaxine were within the bioequivalence acceptance limits of 80.00–125.00% both including and excluding 3 subjects for which steady state conditions were not demonstrated. The 90% confidence intervals of the test/reference ratio for Cτ,ss, Cmax,ss and AUC0-τ lie within the acceptable limits of 80.00% to 125.00%; irrespective of the analysis including or excluding three subjects for which steady state conditions were not demonstrated. Thus, these data support the claim that the applicant’s 150 mg strength test product is bioequivalent to the reference product Trevilor retard 150 mg prolonged release capsules (Pfizer Pharma GmbH, Germany) under steady state conditions. Overall bioequivalence conclusion The data support the claim that the applicant’s 150 mg strength test product is bioequivalent to the reference Trevilor retard 150 mg prolonged release capsules (Pfizer Pharma GmbH, Germany) under fasting, fed and steady-state conditions. As the German reference product used in the bioequivalence studies is considered comparable to the corresponding strength reference product in the UK, bioequivalence has also been shown between the applicant’s 150 mg strength product and the UK reference product Efexor XL 150 mg prolonged release capsules (PL 00057/1281; Pfizer Limited, UK) under fasting, fed and steady-state conditions. A biowaiver for the 225 mg strength product can be accepted on clinical and quality grounds. The drug input is linear over the therapeutic dosage range and other aspects of the biowaiver relating to the specific formulation are considered satisfactory. IV.3 Pharmacodynamics The clinical pharmacodynamics properties of venlafaxine hydrochloride are well-known. No new pharmacodynamic data were submitted and none are required for an application of this type. IV.4 Clinical Efficacy The clinical efficacy of venlafaxine hydrochloride is well-known. No new efficacy data are presented or are required for this type of application. IV.5 Clinical Safety


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With the exception of the safety data generated during the bioequivalence studies, no new safety data were submitted and none are required for this type of application. No new or unexpected safety issues arose during the bioequivalence studies. IV.6 Risk Management Plan The MAH has submitted a risk management plan, 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 Venlafaxine XL 225 mg Prolonged-release Capsules. A summary of safety concerns is listed in the table below:

Routine pharmacovigilance and risk minimisation activities are proposed for all safety concerns. IV.7 Discussion of the clinical aspects


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It is recommended that Marketing Authorisations are granted for Venlafaxine XL 225mg Prolonged-release Capsules, from a clinical point of view. V. USER CONSULTATION A 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 pack leaflet 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 QUALITY The important quality characteristics of Venlafaxine XL 225 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. As the pharmacokinetics, pharmacodynamics and toxicology of venlafaxine hydrochloride are well-known, no additional data were required. 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 product Venlafaxine XL 150mg Prolonged-Release Capsules (Venlafaxine Hydrochloride Extended Release Capsules 150mg) and the reference product Trevilor retard 150 mg prolonged release capsules (Pfizer Pharma GmbH, Germany) under fasting, fed and steady-state conditions. As the German reference product used in the bioequivalence studies is considered comparable to the corresponding strength reference product in the UK, bioequivalence has also been shown between the applicant’s Venlafaxine Hydrochloride Extended Release Capsules 150mg and the UK reference product Efexor XL 150mg prolonged release capsules (PL 00057/1281; Pfizer Limited, UK) under fasting, fed and steady-state conditions. A biowaiver for the 225 mg strength product can be accepted on clinical and quality grounds. The drug input is linear over the therapeutic dosage range and other aspects of the biowaiver relating to the specific formulation are considered satisfactory. SAFETY With the exception of the safety data from the bioequivalence studies, no new data were submitted and none are required for applications of this type. As the safety profile of venlafaxine hydrochloride is well-known, no additional data were required. No new or unexpected safety concerns arose from the safety data from the bioequivalence studies.


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PRODUCT LITERATURE The SmPC, PIL and labelling are satisfactory and, where appropriate, in line with current guidance. BENEFIT/RISK ASSESSMENT The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with venlafaxine hydrochloride is considered to have demonstrated the therapeutic value of the compound. The benefit/risk assessment is therefore considered to be positive. RECOMMENDATION The grant of Marketing Authorisations is recommended.


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Annex 1 - 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

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)

Documents

Venlafaxine Teva XL 225 mg Prolonged release Capsules, Hard