Public Assessment Report UK National Procedure … · Fluoxetine 10 mg hard capsules . Fluoxetine...

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Fluoxetine 10 mg, 30 mg, 40 mg and 60 mg hard capsules PL 21880/0153-0156 1 Public Assessment Report UK National Procedure Fluoxetine 10 mg hard capsules Fluoxetine 30 mg hard capsules Fluoxetine 40 mg hard capsules Fluoxetine 60 mg hard capsules PL 21880/0153-0156 Medreich Plc

Transcript of Public Assessment Report UK National Procedure … · Fluoxetine 10 mg hard capsules . Fluoxetine...

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Fluoxetine 10 mg, 30 mg, 40 mg and 60 mg hard capsules PL 21880/0153-0156

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Public Assessment Report

UK National Procedure

Fluoxetine 10 mg hard capsules

Fluoxetine 30 mg hard capsules

Fluoxetine 40 mg hard capsules

Fluoxetine 60 mg hard capsules

PL 21880/0153-0156

Medreich Plc

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LAY SUMMARY This is a summary of the public assessment report (PAR) for Fluoxetine 10 mg, 30 mg, 40 mg and 60 mg hard capsules. It explains how Fluoxetine 10 mg, 30 mg, 40 mg and 60 mg hard capsules were assessed and their authorisation recommended, as well as their conditions of use. It is not intended to provide practical advice on how to use Fluoxetine 10 mg, 30 mg, 40 mg and 60 mg hard capsules. These medicinal products will be collectively referred to as Fluoxetine hard capsules in this summary. For practical information about using Fluoxetine hard capsules, patients should read the package leaflet or contact their doctor or pharmacist. What are Fluoxetine hard capsules and what are they used for? Fluoxetine 60 mg hard capsules is a generic medicine. This means that Fluoxetine 60 mg hard capsules are similar to a reference medicine already authorised in the European Union (EU) called Prozac 60 mg hard capsules. Fluoxetine 10 mg, 30 mg and 40 mg hard capsules are hybrid medicines. They are similar to a ‘reference medicine’ containing the same active substance (fluoxetine) but are available at lower strengths to the reference medicine, Prozac 60 mg hard capsules. Fluoxetine hard capsules are used to treat major depressive episodes, obsessive-compulsive disorder and the eating disorder bulimia nervosa in adults and moderate to severe major depressive disorder in children and adolescents aged 8 years and above. How are Fluoxetine hard capsules used? Fluoxetine hard capsules should be swallowed with a drink of water. The recommended dose in adults with depression is 20 mg daily. A doctor will review and adjust the dosage if necessary within 3 to 4 weeks of the start of treatment. If required, the dosage can be gradually increased up to a maximum of 60 mg daily. The recommended dose in adults with bulimia is 60 mg daily. The recommended dose in adults with obsessive-compulsive disorder is 20 mg daily. A doctor will review and adjust the dosage if necessary after 2 weeks of treatment. If required, the dosage can be gradually increased up to a maximum of 60 mg daily. The starting dose in children and adolescents aged 8 to 18 years with depression is 10 mg/day. After 1 to 2 weeks, a doctor may increase the dose to 20 mg/day. Lower weight children may need lower doses. Treatment should be started and be supervised by a specialist. How do Fluoxetine hard capsules work? Fluoxetine is a type of antidepressant known as a selective serotonin reuptake inhibitor (SSRI). Serotonin is a compound that exists naturally in the brain where it acts as a chemical messenger between the nerve cells. When serotonin is released from nerve cells in the brain it improves mood. When it is reabsorbed into the nerve cells, it no longer has an effect on mood. SSRIs work by preventing serotonin from being reabsorbed back into the nerve cells in the brain. This helps to improve mood and relieves depression.

It is not fully understood how fluoxetine works in the treatment of bulimia nervosa and obsessive compulsive disorder in adults.

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How have Fluoxetine hard capsules been studied? Because Fluoxetine 60 mg hard capsules is a generic medicine, studies in patients have been limited to tests to determine that this medicine is bioequivalent to the reference medicine. Two medicines are bioequivalent when they produce the same levels of the active substance in the body. Because the lower strength capsules are proportionally similar to the 60 mg capsules, the results from this study can be applied to Fluoxetine 10 mg, 30 mg and 40 mg hard capsules. What benefit have Fluoxetine hard capsules shown during studies? Because Fluoxetine hard capsules are generic medicines their benefits are taken as being the same as those of the reference medicine. What is the risk associated with Fluoxetine hard capsules? The most common side effects with Fluoxetine hard capsules, which affect more than 1 in 10 people, are insomnia, headache, diarrhoea, feeling sick (nausea) and fatigue. For the full list of all side effects reported with Fluoxetine hard capsules, see section 4 of the package leaflet. For the full list of restrictions, see the package leaflet. Why are Fluoxetine hard capsules approved? It was considered that the benefits of using Fluoxetine hard capsules to treat major depressive episodes, obsessive-compulsive disorder and bulimia nervosa in adults and moderate to severe major depressive disorder in children and adolescents aged 8 years and above outweigh the risks and the grant of Marketing Authorisations was recommended. What measures are being taken to ensure the safe and effective use of Fluoxetine hard capsules? A Risk Management Plan has been developed to ensure Fluoxetine hard capsules are used as safely as possible. Based on this plan, safety information has been included in the Summaries of Product Characteristics and the package leaflet for Fluoxetine hard capsules, 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 Fluoxetine hard capsules The MHRA agreed to grant Marketing Authorisations for Fluoxetine hard capsules on 27 November 2014. For more information about treatment with Fluoxetine hard capsules, read the package leaflet, or contact your doctor or pharmacist. This summary was last updated in January 2015.

The full PAR for Fluoxetine hard capsules follows this summary.

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TABLE OF CONTENTS

I Introduction Page 5

II Quality aspects Page 6

III Non-clinical aspects Page 10 IV Clinical aspects Page 11

V User consultation Page 15

VI Overall conclusion, benefit/risk assessment and recommendation Page 15 VII Steps taken for assessment Page 16 VIII Steps taken after initial authorisation Page 16

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I Introduction Based on the review of the data on quality, safety and efficacy, the Medicines and Healthcare products Regulatory Agency (MHRA) considered that the applications for Fluoxetine 10 mg, 30 mg, 40 mg and 60 mg hard capsules could be approved. These prescription only medicines (POM) are used for the treatment of major depressive episodes, obsessive-compulsive disorder and bulimia nervosa in adults and moderate to severe major depressive disorder in children and adolescents aged 8 years and above. The applications for Fluoxetine 10 mg, 30 mg and 40 mg hard capsules were made under Article 10(3) of Directive 2001/83/EC, as amended, as so-called hybrid applications. The application for Fluoxetine 60 mg hard capsules was made under Article 10(1) of Directive 2001/83/EC, as amended, as a so-called generic application. The reference medicinal product for these applications is Prozac 60 mg hard capsules (Eli Lilly & Company Ltd; PL 00006/0198), first authorised 25 Nov 1988. As this reference product has been authorised in the EEA for at least 10 years the legal basis of these applications is acceptable. Fluoxetine is a selective inhibitor of serotonin reuptake, and this probably accounts for the mechanism of action. Fluoxetine has practically no affinity to other receptors such as α1-, α2-, and β-adrenergic; serotonergic; dopaminergic; histaminergic; muscarinic; and GABA receptors. A bioequivalence study comparing the 60 mg proposed product to Prozac 20 mg hard capsules (Eli Lilly & Company Ltd; PL 00006/0195) which were administered as three capsules in a 60 mg dose, was submitted with the applications. Assurance has been provided that the study has been conducted according to the principles of Good Clinical Practice (GCP). No new non-clinical data were submitted, which is acceptable given that the applications are for generic versions of an originator product that has been in clinical use for over 10 years. The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place for these product types 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 RMS considers that the pharmacovigilance system, as described by the MA holder, fulfils the requirements and provides adequate evidence that the MA holder 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. The MA holder has provided a Risk Management Plan (RMP).

Since Fluoxetine 10 mg, 30 mg, 40 mg and 60 mg hard capsules are intended for generic substitution, their use will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary. The MHRA considered that the applications could be approved and Marketing Authorisations

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were granted on 27 November 2014. II Quality aspects II.1 Introduction Fluoxetine 10 mg, 30 mg, 40 mg and 60 mg hard capsules contain fluoxetine hydrochloride equivalent to 10 mg, 30 mg, 40 mg and 60 mg fluoxetine, respectively and the excipients pregelatinised starch, iron oxide yellow (E 172), patent blue V (E 131), titanium dioxide (E 171) and gelatin. The 10 mg tablets also contain sodium lauryl sulphate. The 10mg capsules are size ‘4’ with an off white opaque body marked ‘F10’ and a dark green opaque cap marked ‘F10’. The 30mg capsules are size ‘3’ with an off white opaque body marked ‘F30’ and a green opaque cap marked ‘F30’. The 40mg capsules are size ‘2’ with an off white opaque body marked ‘F40’ and a green opaque cap marked ‘F40’. The 60mg capsules are size ‘1’ with an off white opaque body marked ‘F60’ and a green opaque cap marked ‘F60’. The capsules are presented in Alu-PVC blister packs of 10, 28 and 30 capsules available in a carton. II.2 Drug Substance INN: Fluoxetine hydrochloride Chemical name: (3RS)-N-Methyl-3-phenyl-3-[4-(trifluoromethyl) phenoxy]-propan-1-

amine hydrochloride Structure:

Molecular formula: C17H19 ClF3NO Molecular weight: 345.8 All aspects of the manufacture and control of the active substance, fluoxetine hydrochloride, are covered by European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificates of Suitability. II.3 Medicinal Product

Pharmaceutical development The aim of the pharmaceutical development of Fluoxetine 10 mg, 30 mg, 40 mg and 60 mg hard capsules was to develop generic/hybrid versions of the innovator product. The proposed and the reference products were tested for a number of parameters to support the claim that the products were comparable. All excipients comply with their pharmacopoeia monographs. Satisfactory certificates of analysis have been provided for all excipients showing compliance with their proposed specifications. The gelatin is sourced in compliance with current guidelines concerning the minimisation of risk of transmission of TSE/BSE. None of the other excipients are of animal or human origin.

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Manufacture of the product A satisfactory batch formula has been provided for the manufacture of the products, along with an appropriate account of the manufacturing process. The manufacturing process has been validated and has shown satisfactory results.

Finished Product Specification The finished product specifications proposed for the products are acceptable. 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. Stability of the product Stability studies were performed in accordance with current guidelines on batches of the finished products, stored in the packaging proposed for marketing. The data from these studies support a shelf-life of 2 years. These medicinal products do not require any special storage conditions. II.4 Discussion on chemical, pharmaceutical and biological aspects The grant of marketing authorisations is recommended.

II.5 SmPCs, PIL and labelling 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 following text is the approved label text for the 10mg capsules. The label text for the other product strengths is essentially identical, apart from differences related to the difference in product strength. No label mock-ups have been provided for any of the product strengths. In accordance with medicines legislation, the products shall not be marketed in the UK until approval of the label mock-ups has been obtained.

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III Non-clinical aspects III.1 Introduction No new non-clinical data have been submitted and none are required for applications of this type. The applicant’s non-clinical overview has been written by an appropriately qualified person and is satisfactory. III.2 Pharmacology No new pharmacology data are required for these applications and none have been submitted. III.3 Pharmacokinetics No new pharmacokinetic data are required for these applications and none have been submitted. III.4 Toxicology No new toxicology data are required for these applications and none have been submitted. III.5 Ecotoxicity/environmental risk assessment (ERA) Since the formulations of Fluoxetine 10 mg, 30 mg, 40 mg and 60 mg hard capsules are intended for generic substitution, they 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 The grant of marketing authorisations is recommended.

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IV Clinical aspects IV.1 Introduction The applicant has submitted a report of a bioequivalence study in support of these applications. The applicant’s clinical overview has been written by an appropriately qualified person and is considered acceptable. IV.2 Pharmacokinetics Bioequivalence study Study design The study was an open label, balanced, randomised, two-sequence, two-treatment, two period, single oral dose, crossover, bioequivalence study in healthy, adult, human subjects under fasting conditions comparing Fluoxetine 60 mg capsules to the reference product Prozac 20 mg hard capsules. After an overnight fast a single oral dose (60 mg) of either the test product (60 mg capsule) or the reference product (3 x 20 mg capsules) was administered. The washout period was 45 days. Blood samples were collected from each subject in each period at pre-dose and at intervals up to 72 hours following drug administration. The plasma samples from the subjects were analysed for fluoxetine using a validated method. Samples from 26 subjects were considered in the PK analysis and the results are presented below:

The 90% confidence intervals for AUC and Cmax were within the acceptance range of 80.00 to 125.00 %. Bioequivalence between the test product and reference product has been adequately demonstrated. Biowaiver The applicant has submitted a single bioequivalence study using the 60 mg dose strength only. The requirements of the guideline on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/Corr) have been met with regards to a claim for a biowaiver for the 10 mg, 30 mg and 40 mg strength capsules. The dissolution data and other biowaiver criteria are acceptable. IV.3 Pharmacodynamics No new pharmacodynamic data are required for these applications and none have been submitted.

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IV.4 Clinical efficacy No new clinical efficacy data are required for these applications and none have been submitted. IV.5 Clinical safety With the exception of the data generated during the bioequivalence study, no new safety data are presented for these applications and none are required. No new or unexpected safety issues arose during the bioequivalence study. IV.6 Risk Management Plan The applicant has submitted an RMP, in accordance with the requirements of Directive 2001/83/EC, as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Fluoxetine 10 mg, 30 mg, 40 mg and 60 mg hard capsules. Routine pharmacovigilance activities and risk minimisation measures should be adequate for this product, which contains a widely used active substance with a well-established safety profile. A summary of safety concerns and planned risk minimisation activities, as approved in the RMP, is listed below:

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IV.7 Discussion on the clinical aspects The grant of Marketing Authorisations is recommended for these applications. V User consultation In accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC, the package leaflet will be evaluated via a user consultation study. The products will not be marketed until the package leaflet and user consultation study are approved by the MHRA. VI Overall conclusion, benefit/risk assessment and recommendation The quality of the products is acceptable and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with fluoxetine is considered to have demonstrated the therapeutic value of the compound. The benefit/risk balance is, therefore, considered to be positive.

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VII Steps taken for assessment

VIII Steps taken after initial authorisation

Date submitted

Application type

Scope Outcome

1 The MHRA received the Marketing Authorisation applications on 29 May 2013. 2 Following standard checks and communication with the applicant the MHRA

considered the applications valid on 13 December 2013. 3 Following assessment of the applications the MHRA requested further

information relating to the dossier on 24 March 2014. 4 The applicant responded to the MHRA’s requests, providing further information

on 27 June 2014. 5 The applications were granted on 27 November 2014.