public assessment report decentralised procedure aripiprazole

PAR Aripiprazole 2mg, 5mg, 10mg, 15mg, 20mg and 30 mg Tablets UK/H/5758/01-06/DC

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Public Assessment Report

Decentralised Procedure

Aripiprazole 2mg Tablets Aripiprazole 5mg Tablets Aripiprazole 10mg Tablets Aripiprazole 15mg Tablets Aripiprazole 20mg Tablets Aripiprazole 30mg Tablets

(aripiprazole)

Procedure No: UK/H/5758/001-006/DC

UK Licence No: PL 24668/0277-282

Caduceus Pharma Limited


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LAY SUMMARY

Aripiprazole 2mg, 5mg, 10mg, 15mg, 20mg and 30mg Tablets (aripiprazole, tablets, 2mg, 5mg, 10mg, 15mg, 20mg and 30 mg)

This is a summary of the Public Assessment Report (PAR) for Aripiprazole 2mg, 5mg, 10mg, 15mg, 20mg and 30mg Tablets (PL 24668/0277-0282; UK/H/5758/01-06/DC). It explains how Aripiprazole 2mg, 5mg, 10mg, 15mg, 20mg and 30mg Tablets 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 Aripiprazole 2mg, 5mg, 10mg, 15mg, 20mg and 30mg Tablets. These products will collectively be referred to as Aripiprazole Tablets throughout the remainder of this public assessment report (PAR). For practical information about using Aripiprazole Tablets, patients should read the package leaflet or contact their doctor or pharmacist. What are Aripiprazole Tablets and what are they used for? Aripiprazole 5mg, 10mg, 15mg and 30mg Tablets are ‘generic medicines’. This means that Aripiprazole 5mg, 10mg, 15mg and 30mg Tablets are similar to a ‘reference medicine’ already authorised in the European Union (EU) called Abilify 5mg, 10 mg, 15 mg and 30 mg Tablets (Otsuka Pharmaceutical Europe Ltd). Aripiprazole 2mg and 20mg Tablets are ‘hybrid generic medicines’. This means they are similar to a reference medicine called Abilify 5mg Tablet (Otsuka Pharmaceutical Europe Ltd) but are a change in strength of the active substance, aripiprazole (2mg and 20mg strength) to the reference medicine. Aripiprazole Tablets are used to treat adults and adolescents aged 15 years and older who suffer from a disease characterised by symptoms such as hearing, seeing or sensing things which are not there, suspiciousness, mistaken beliefs, incoherent speech and behaviour and emotional flatness. People with this condition may also feel depressed, guilty, anxious or tense. Aripiprazole Tablets are used to treat adults and adolescents aged 13 years and older who suffer from a condition with symptoms such as feeling “high”, having excessive amounts of energy, needing much less sleep than usual, talking very quickly with racing ideas and sometimes severe irritability. In adults it also prevents this condition from returning in patients who have responded to the treatment with Aripiprazole Tablets. How do Aripiprazole Tablets work? Aripiprazole Tablets contain the active ingredient aripiprazole, which belongs to a group of medicines called antipsycotics. These medicines work by affecting the activity of some key brain chemicals. How are Aripiprazole Tablets used? The pharmaceutical form of Aripiprazole Tablets is a tablet and the route of administration is by mouth (oral). The patient must always take Aripiprazole Tablets exactly as their doctor has told them to. The patient must check with their doctor or pharmacist if they are not sure. The recommended dose for adults is 15 mg once a day. However, the patient’s doctor may prescribe a lower or higher dose to a maximum of 30 mg once a day.


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Use in children and adolescents Aripiprazole Tablets may be started at a low dose with the oral solution (liquid) form. The dose may be gradually increased to the recommended dose for adolescents of 10 mg once a day. However the patient’s doctor may prescribe a lower or higher dose to a maximum of 30 mg once a day. If the patient has the impression that the effect of Aripiprazole Tablets is too strong or too weak, the patient should talk to their doctor or pharmacist. Try to take the Aripiprazole Tablet at the same time each day. It does not matter whether the patient takes it with or without food. The patient should always take the tablet with water and swallow it whole. Even if the patient feels better, do not alter or discontinue the daily dose of Aripiprazole Tablets without first consulting the patient’s doctor. Please read section 3 of the package leaflet for detailed information on dosing recommendations, the route of administration, and the duration of treatment. This medicine can only be obtained with a prescription. What benefits of Aripiprazole Tablets have been shown in studies? The company provided data from studies to determine that this medicine is bioequivalent to the reference medicine, Abilify tablets. Two medicines are bioequivalent when they produce the same levels of the active substance in the body. What are the possible side effects of Aripiprazole Tablets? Because Aripiprazole Tablets are generic and hybrid generic medicines, their benefits and possible side effects are taken as being the same as the reference medicine. For the full list of all side effects reported with Aripiprazole Tablets, see section 4 of the package leaflet available on the MHRA website. Why was Aripiprazole Tablets approved? It was concluded that, in accordance with EU requirements, Aripiprazole Tablets have been shown to have comparable quality and to be bioequivalent to Abilify 5mg, 10mg, 15mg and 30mg Tablets (Otsuka Pharmaceutical Europe Ltd). Therefore, the MHRA decided that, as for Abilify 5mg, 10mg, 15mg and 30mg Tablets (Otsuka Pharmaceutical Europe Ltd), the benefits are greater than the risks and recommended that they can be approved for use. What measures are being taken to ensure the safe and effective use of Aripiprazole Tablets? A risk management plan (RMP) has been developed to ensure that Aripiprazole Tablets are used as safely as possible. Based on this plan, safety information has been included in the Summary of Product Characteristics and the package leaflet for Aripiprazole Tablets 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.


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Other information about Aripiprazole Tablets The marketing authorisations for Aripiprazole Tablets were granted in the UK on 21 January 2015. The full PAR for Aripiprazole Tablets follows this summary. For more information about use of Aripiprazole Tablets, read the package leaflet, or contact your doctor or pharmacist. This summary was last updated in March 2015. .


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TABLE OF CONTENTS

I Introduction Page 6 II Quality aspects Page 7 III Non-clinical aspects Page 9 IV Clinical aspects Page 9 V User consultation Page 15 VI Overall conclusion, benefit/risk assessment and

recommendation Page 15


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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) granted Caduceus Pharma Ltd, Marketing Authorisations for the medicinal products Aripiprazole 2mg, 5mg, 10mg, 15mg, 20mg and 30 mg Tablets (PL 24668/0277-0282; UK/H/5758/01-06/DC) on 21 January 2015. The products are prescription-only (POM) medicines indicated for:

• The treatment of schizophrenia in adults and in adolescents aged 15 years and older. • The treatment of moderate to severe manic episodes in Bipolar I Disorder and for the prevention

of a new manic episode in adults who experienced predominantly manic episodes and whose manic episodes responded to aripiprazole treatment (see section 5.1 of the summary of product characteristics).

• The treatment up to 12 weeks of moderate to severe manic episodes in Bipolar I Disorder in adolescents aged 13 years and older (see section 5.1 of the summary of product characteristics).

These applications were submitted using the Decentralised Procedure, with the UK as Reference Member State (RMS) and Iceland as Concerned Member State (CMS). The applicant subsequently withdrew the applications in Iceland during the procedure, leaving no CMS. The applications were submitted under Article 10(1) of Directive 2001/83/EC, as amended, as generic applications (5mg strength, PL 24668/0278; 10mg strength, PL 24668/0279; 15mg strength, PL 247668/0280 and 30mg strength, PL 24668/0282) and Article 10(3) as amended, as hybrid applications for a change in strength (2mg strength, PL 24668/0277 and 20mg strength; PL 24668/0281). The reference medicinal products for Aripiprazole 5mg, 10mg, 15mg and 30 mg Tablets applications are Abilify 5mg, 10mg, 15mg and 30mg Tablets, respectively, which were first licenced to Otsuka Pharmaceutical Europe Ltd on 04 June 2004 via the Centralised Procedure. The reference medicinal product for the 2mg and 20mg strengths (hybrid applications) is Abilify 5mg Tablets. It has been proposed that aripiprazole’s efficacy in schizophrenia and Bipolar I Disorder is mediated through a combination of partial agonism at dopamine D2 and serotonin 5HT1a receptors and antagonism of serotonin 5HT2a receptors. Aripiprazole exhibited antagonist properties in animal models of dopaminergic hyperactivity and agonist properties in animal models of dopaminergic hypoactivity. Aripiprazole exhibited high binding affinity in vitro for dopamine D2 and D3, serotonin 5HT1a and 5HT2a receptors and moderate affinity for dopamine D4, serotonin 5HT2c and 5HT7, alpha-1 adrenergic and histamine H1 receptors. Aripiprazole also exhibited moderate binding affinity for the serotonin reuptake site and no appreciable affinity for muscarinic receptors. Interaction with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole. Two bioequivalence studies were submitted to support these applications comparing the applicant’s test product strengths Aripiprazole 2mg and 10mg Tablets (Caduceus Pharma Limited) with the reference products Abilify 5mg and 10mg Tablets (Otsuka Pharmaceutical Europe Ltd, UK) under fasting conditions. The applicant has stated that the bioequivalence studies were conducted in compliance with ICH, Good Clinical Practices (GCP) requirements and the Declaration of Helsinki. With the exception of the bioequivalence studies, no new non-clinical or clinical data were submitted, which is acceptable given that these applications were based on a product being a hybrid generic/generic medicinal product of an originator product that has been in clinical use for over 10 years. The MHRA has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place for this product type at all sites responsible for the manufacture and assembly of this product.


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II QUALITY ASPECTS II.1 Introduction Each tablet contains 2mg, 5mg, 10mg, 15mg, 20mg or 30mg of the active ingredient aripiprazole. Other ingredients consist of the pharmaceutical excipients microcrystalline cellulose, lactose monohydrate, maize starch, hydroxypropyl cellulose type EF (E463), magnesium stearate and purified water. All strengths of the finished product are packed into aluminium/aluminium blister packs with push-through foil containing 28 tablets. Not all pack sizes may be marketed. Satisfactory specifications and Certificates of Analysis have been provided for all packaging components. II.2. Drug Substance INN: Aripiprazole. Chemical names: 7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-3,4- dihydroquinolin-2-(1H)-

one Structural formula:

Molecular formula: C23H27Cl2N3O2. Molecular mass: 448.4 g/mol Appearance: A white or almost white crystals or crystalline powder. Solubility: Practically insoluble in water, soluble in methylene chloride and very slightly

soluble in ethanol (96%). Aripiprazole is the subject of a European Pharmacopoeia monograph. Synthesis of the active substance from the designated starting materials has been adequately described and appropriate in-process controls and intermediate specifications are applied. Satisfactory specification tests are in place for all starting materials and reagents, and these are supported by relevant Certificates of Analysis. Appropriate proof-of-structure data have been supplied for the active substance. All potential known impurities have been identified and characterised. An appropriate specification is provided for the active substance. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. Satisfactory certificates of analysis have been provided for all working standards. Batch analyses data are provided that comply with the proposed specification. Suitable specifications have been provided for all packaging used. The primary packaging has been shown to comply with current guidelines concerning contact with food. Appropriate stability data have been generated supporting a suitable retest period when stored in the proposed packaging. II.3. Medicinal Product Pharmaceutical Development The objective of the development programme was to formulate safe, efficacious, tablets containing 2mg, 5mg, 10mg, 15mg, 20mg or 30mg aripiprazole per tablet that are generics/hybrid of the reference


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products Abilify 5mg, 10mg, 15mg and 30mg Tablets (Otsuka Pharmaceutical Europe Ltd). A satisfactory account of the pharmaceutical development has been provided. Comparative impurity and in-vitro dissolution profiles have been provided for the proposed and originator products. All excipients comply with their respective European Pharmacopoeia monographs. Satisfactory Certificates of Analysis have been provided for all excipients. Suitable batch analysis data have been provided for each excipient. With the exception of lactose monohydrate none of the excipients used contain material of animal or human origin. The supplier of lactose monohydrate has confirmed that it is sourced from healthy animals under the same conditions as milk for human consumption. No genetically modified organisms (GMO) have been used in the preparation of these products. No genetically modified organisms (GMO) have been used in the preparation of these products. Manufacture of the product Satisfactory batch formulae have been provided for the manufacture of the products, along with an appropriate account of the manufacturing process. The manufacturing process has been validated at pilot-scale batch sizes and shown satisfactory results. The marketing authorisation holder (MAH) has committed to perform additional process validation on future commercial-scale batches. Finished Product Specification The finished product specifications proposed are acceptable. Test methods have been described that have been adequately validated. Batch data have been provided that comply with the release specifications. Certificates of Analysis have been provided for all working standards used. Stability of the Product Finished product stability studies were performed in accordance with current guidelines on batches of finished products in the packaging proposed for marketing. The data from these studies support a shelf-life of 2 years with no special storage conditions. Suitable post approval stability commitments have been provided to continue stability testing on batches of finished products. II.4 Discussion on chemical, pharmaceutical and biological aspects There are no objections to the approval of these applications from a pharmaceutical viewpoint.


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III NON-CLINICAL ASPECTS III.1 Introduction As the pharmacodynamic, pharmacokinetic and toxicological properties of aripiprazole are well-known, no new non-clinical studies are required and none have been provided. An overview based on the literature review is, thus, appropriate. The applicant’s non-clinical expert report has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the relevant non-clinical pharmacology, pharmacokinetics and toxicology. III.2 Pharmacology Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above. III.3 Pharmacokinetics Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above. III.4 Toxicology Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above. III.5 Ecotoxicity/environmental risk assessment (ERA) Since Aripiprazole Tablets are intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary. III.6 Discussion on the non-clinical aspects No new non-clinical studies were conducted, which is acceptable given that the applications were based on being generic and hybrid generic medicinal products of originator products that have been licensed for over 10 years. There are no objections to the approval of these applications from a non-clinical viewpoint. IV CLINICAL ASPECTS IV.1 Introduction The clinical pharmacology of aripiprazole is well-known. With the exception of data from the bioequivalence studies detailed below, no new pharmacodynamics or pharmacokinetic data are provided or are required for these applications. No new efficacy or safety studies have been performed and none are required for this type of application. A comprehensive review of the published literature has been provided by the applicant, citing the well-established clinical pharmacology, efficacy and safety of aripiprazole. To support a biowaiver for all strengths applied for, the applicant included data from published literature in the review submitted which demonstrates that the kinetics of the active substance aripiprazole is linear over the therapeutic range. Based on the data provided, Aripiprazole Tablets can be considered bioequivalent to Abilify 5mg, 10mg, 15mg and 30mg Tablets (Otsuka Pharmaceutical Europe Ltd).


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IV.2 Pharmacokinetics In support of these applications, the applicant submitted the following bioequivalence studies: STUDY 1 An open label, randomised, two-period, two-treatment, two-sequence, single dose, crossover study to compare the pharmacokinetics of the applicant’s test product, 5 x Aripiprazole 2mg Tablets (Caduceus Pharma Limited), versus the reference product, 2 x Abilify 5mg Tablets (Otsuka Pharmaceutical Europe Ltd, UK), in healthy adult subjects under fasting conditions. The subjects were administered a single dose (10 mg) of either the test (5 x 2mg tablet) or the reference product (2 x 5mg tablet) after an overnight fast with 240 ml of water. Blood samples were collected for plasma levels before dosing and up to and including 72 hours after each administration. The washout period between the treatment phases was 36 days. The pharmacokinetic results are presented below: Table: Summary of geometric means and 90% confidence intervals for test and reference product for aripiprazole.

AUC0-72 area under the plasma concentration-time curve from time zero to 72 hours Cmax maximum plasma concentration The 90% confidence intervals of the test/reference formulations for AUCO-72 and Cmax values lie within the acceptable limits of 80.00% to 125.00%, in line with the ‘Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/Corr**). Thus, the data support the claim that the applicant’s tablets, administered as 5 x 2mg tablets are bioequivalent to the reference products Abilify Tablets, administered as 2 x 5mg Tablets (Otsuka Pharmaceutical Europe Ltd, UK). STUDY 2 An open label, randomised, two-period, two-treatment, two-sequence, single dose, crossover study to compare the pharmacokinetics of the applicant’s test product Aripiprazole 10mg Tablets (Caduceus Pharma Limited) versus the reference product, Abilify 10mg Tablets (Otsuka Pharmaceutical Europe Ltd, UK), in healthy adult subjects under fasting conditions.


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The subjects were administered a single dose (10 mg) of either the test or the reference product after an overnight fast with 240 ml of water. Blood samples were collected for plasma levels before dosing and up to and including 72 hours after each administration. The washout period between the treatment phases was 35 days. The pharmacokinetic results are presented below: Table: Summary of geometric means and 90% confidence intervals for test and reference product for aripiprazole.

AUC0-72 area under the plasma concentration-time curve from time zero to 72 hours Cmax maximum plasma concentration The 90% confidence intervals of the test/reference formulations for AUCO-72 and Cmax values lie within the acceptable limits of 80.00% to 125.00%, in line with the ‘Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/Corr**). Thus, the data support the claim that the applicant’s 10mg test products are bioequivalent to the reference products Abilify 10mg Tablets (Otsuka Pharmaceutical Europe Ltd, UK). Biowaiver As the 5mg, 10mg, 15mg, 20mg and 30mg strength test products meet the biowaiver criteria specified in the current bioequivalence guidance, the results and conclusions of the bioequivalence studies with the 10mg tablet strength can be extrapolated to the 5mg, 15mg, 20mg and 30 mg strength tablets. IV.3 Pharmacodynamics No new pharmacodynamic data were submitted and none were required for an application of this type. IV.4 Clinical efficacy No new efficacy data were submitted and none were required for an application of this type. IV.5 Clinical safety No new safety data were submitted and none were required for this application. IV.6 Risk Management Plan (RMP) and Pharmacovigilance System The marketing authorisation holder (MAH) has submitted a risk management plan (RMP), in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities


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and interventions designed to identify, characterise, prevent or minimise risks relating to Aripiprazole Tablets. A summary of safety concerns and planned risk minimisation activities, as approved in the RMP, are listed below: Summary table of safety concerns:

Summary table of risk minimisation measures:


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Routine pharmacovigilance is proposed for all safety concerns. Routine risk minimisation is proposed for all safety concerns with the exception of ‘extrapyramidal symptoms, including tardive dyskinesia’, ‘weight gain’ and ‘somnolence/fatigue’. For these, an information pack containing the SmPC, PIL, educational materials for patients and care givers and educational materials for healthcare professionals is proposed. This is consistent with the additional risk minimisation measures of the reference product for the indication “treatment of up to 12 weeks of moderate to severe manic episodes in Bipolar I disorder in adolescents aged 13 years and older”. In each Member State where the indication of the treatment up to 12 weeks of moderate to severe manic episodes in Bipolar I Disorder in adolescents aged 13 years and older is launched for this product, the Marketing Authorisation Holder (MAH) shall agree an educational programme with the National


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Competent Authority. The MAH shall ensure that, following discussions and agreement with the National Competent Authorities in each Member State where the indication the treatment up to 12 weeks of moderate to severe manic episodes in Bipolar I Disorder in adolescents aged 13 years and older is launched for this product, the following are made available:

1. Educational material for healthcare professionals 2. Educational material for the patients and their caregivers

• Brief introduction to aripiprazole indication and the purpose of the tool

Key elements of the Healthcare Professional FAQ Brochure (Q&A form) intended for Healthcare Providers treating adolescent patients with bipolar mania:

• Instructions reinforcing that the intended age range is 13-17 years and that aripiprazole is not recommended for use in patients below 13 years of age due to safety concerns

• Instructions that the recommended dose is 10 mg/day and that enhanced efficacy at higher doses has not been demonstrated

• Information regarding the safety and tolerability profile of aripiprazole, in particular potential consequences regarding adverse effects at doses higher than 10 mg/day, in particular with respect to:

o Weight gain, including a recommendation to monitor patients o Extrapyramidal symptoms o Somnolence o Fatigue

• Reminder to educate patients/caregivers and provide the Patient/Caregiver Information Brochure

• Brief introduction to aripiprazole indication and the purpose of the tool Key elements of the Patients/Caregiver Information Brochure:

• Information that the indicated age range is 13-17 years and that aripiprazole is not recommended for use in patients below 13 years of age

• Information that aripiprazole can cause adverse effects at doses higher than 10 mg/day, in particular with respect to: - Weight gain, including a recommendation to monitor patients - Extrapyramidal symptoms - Somnolence - Fatigue

• Request to inform the physician of all medical conditions before treatment • The importance of not attempting to self-treat any symptoms without consulting their Healthcare

professional IV.7 Discussion on the clinical aspects With the exception of the bioequivalence studies, no new clinical studies were conducted, which is acceptable given that the applications were based on being a generic and hybrid generic medicinal products of originator products that have been licensed for over 10 years. Bioequivalence has been demonstrated between the applicant’s Aripiprazole 2mg Tablets, administered as 5 x 2mg tablets, and the reference product Abilify 5mg Tablets, administered as 2 x 5mg tablets, under fasting conditions. Bioequivalence has been demonstrated between the applicant’s Aripiprazole 10mgTablets and the reference product, Abilify 10mg Tablets under fasting conditions.


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As the 10 mg, 15 mg, 20 mg and 30 mg strength test products meet the biowaiver criteria specified in the current bioequivalence guidance, the results and conclusions of the bioequivalence studies with the 10 mg tablet strength can be extrapolated to the 15 mg, 20 mg and 30 mg strength tablets. The grant of marketing authorisations is recommended for these applications. V User consultation The package leaflet has been evaluated via a user consultation study, in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose of user testing the PIL was English. The results show that the package leaflet meets the criteria for readability, as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use. VI Overall conclusion, benefit/risk assessment and recommendation The quality of the products is acceptable, and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with aripiprazole is considered to have demonstrated the therapeutic value of the compound. The benefit-risk is, therefore, considered to be positive.


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Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPC) and Patient Information Leaflets (PIL) for products granted Marketing Authorisations at a national level are available on the MHRA website. The approved labelling for Aripiprazole Tablets is presented below: PL 24668/0277; Aripiprazole 2mg Tablets: The following text is the approved label text for the product. No label mock-ups have been provided. In accordance with medicines legislation, the product shall not be marketed in the UK until approval of the label mock-ups has been obtained.


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PL 24668/0281; Aripiprazole 20mg Tablets: The following text is the approved label text for the product. No label mock-ups have been provided. In accordance with medicines legislation, the product shall not be marketed in the UK until approval of the label mock-ups has been obtained.


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public assessment report decentralised procedure aripiprazole

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