Public Assessment Report - GOV.UK the full list of all side effects reported with Tacni capsules see section 4 of the ... (Astellas Pharma Limited ... read the package leaflet or contact

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Public Assessment Report

Repeat-Use Mutual Recognition Procedure

Tacni 0.5 mg hard capsules Tacni 1 mg hard capsules Tacni 5 mg hard capsules

(tacrolimus)

Procedure No: UK/H/3029/001-003/E01

UK Licence No: PL 00289/1620-1622

Teva (UK) Limited

PAR Tacni 0.5 mg, 1 mg, 5 mg hard capsules PL 00289/1620-1622; UK/H/3029/001-003/E01

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LAY SUMMARY

Tacni 0.5 mg, 1 mg and 5 mg hard capsules (tacrolimus)

This is a summary of the Public Assessment Report (PAR) for Tacni 0.5 mg, 1 mg and 5 mg hard capsules (PL 00289/1620-1622, formerly PL 23022/0068-70; UK/H/3029/001-003/E01). It explains how the applications for Tacni 0.5 mg, 1 mg and 5 mg hard capsules 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 Tacni 0.5 mg, 1 mg and 5 mg hard capsules. For practical information about using Tacni 0.5 mg, 1 mg and 5 mg hard capsules, patients should read the package leaflet or contact their doctor or pharmacist. The product may be referred to as ‘Tacni’ or ‘Tacni capsules’ in this report. What are Tacni capsules and what are they used for? Tacni 0.5 mg, 1 mg and 5 mg hard capsules are‘generic medicines’. This means that Tacni 0.5 mg, 1 mg and 5 mg hard capsules are similar to ‘reference medicines’ already authorised in the UK called Prograf 0.5 mg, 1 mg and 5 mg hard capsules (PL 00166/0206, 0203 and 0204 respectively; Astellas Pharma Limited). Tacni capsules are used to suppress the immune system following an organ transplant. Tacni capsules are often used in combination with other medicines that also suppress the immune system. Tacni capsules may also be given for an ongoing rejection of a transplanted liver, kidney, heart or other organ when any previous treatment has been unable to control this immune response after organ transplantation. How do Tacni capsules work? Tacni capsules contain the active ingredient tacrolimus, which is an immunosuppressant. Following an organ transplant (e.g. liver, kidney, heart), the body’s immune system will try to reject the new organ. Tacni is used to control the body’s immune response enabling the body to accept the transplanted organ. How are Tacni capsules used? Each Tacni 0.5 mg, 1 mg and 5 mg hard capsule contain 0.5 mg, 1 mg and 5 mg tacrolimus, respectively. The capsules should be swallowed whole with a glass of water. The patient should always take these medicines exactly as advised by the doctor. The patient should check with the doctor or pharmacist if unsure. Tacni capsules are taken orally twice daily, usually in the morning and evening. The patient should generally take Tacni capsules on an empty stomach or at least 1 hour before or 2 to 3 hours after the meal. The patient should avoid grapefruit and grapefruit juice while taking Tacni capsules. Please read section 3 of the package leaflet for detailed information on dosing recommendations, the route of administration, the duration of treatment and the need for any specific monitoring of certain parameters or for diagnostic tests.


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Tacni capsules can only be obtained with a prescription. The patient should ensure that he/she receives the same tacrolimus medicine every time he/she collects his/her prescription, unless the transplant specialist has agreed to change to a different tacrolimus medicine. What benefits of Tacni capsules have been shown in studies? As Tacni capsules are generic medicines, studies in patients have been limited to tests to determine that Tacni capsules are bioequivalent to the reference medicines, Prograf 0.5 mg, 1 mg and 5 mg hard capsules (PL 00166/0206, 0203 and 0204 respectively; Astellas Pharma Limited). Two medicines are bioequivalent when they produce the same levels of the active substance in the body. In addition, the Marketing Authorisation Holder (Teva UK Limited) has provided data from the published literature on tacrolimus. What are the possible side effects of Tacni capsules? Because Tacni 0.5 mg, 1 mg and 5 mg hard capsules are generic medicines and are bioequivalent to the reference medicines Prograf 0.5 mg, 1 mg and 5 mg hard capsules (Astellas Pharma Limited), the benefits and possible side effects are taken as being the same as those of the reference medicines. For the full list of all side effects reported with Tacni capsules see section 4 of the package leaflet. For the full list of restrictions, see the package leaflet. Why are Tacni capsules approved? It was concluded that, in accordance with EU requirements, Tacni capsules have been shown to have comparable quality and to be comparable to Prograf 0.5 mg, 1 mg and 5 mg hard capsules (Astellas Pharma Limited). Therefore, the MHRA decided that, as for Prograf 0.5 mg, 1 mg and 5 mg hard capsules (Astellas Pharma Limited), the benefits outweigh the identified risks and recommended that Tacni capsules can be approved for use. What measures are being taken to ensure the safe and effective use of Tacni capsules? A risk management plan has been developed to ensure that Tacni capsules are used as safely as possible. Based on this plan, safety information has been included in the Summary of Product Characteristics and the package leaflets for Tacni 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 Tacni Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, The Netherlands, Norway, Poland, Portugal, Romania, Sweden, Slovenia, Slovakia, Spain and the UK agreed to Marketing Authorisations for Tacni 0.5 mg, 1 mg and 5 mg hard capsules on16 October 2010. Marketing Authorisations for Tacni 0.5 mg, 1 mg and 5 mg hard capsules) were granted in the UK to PharOS - Pharmaceutical Oriented Services Ltd on 28 October 2010 (PL 23022/0068-70). Subsequent to Change of Ownership procedures, the Marketing Authorisations for Tacni 0.5 mg, 1 mg and 5 mg hard capsules were granted to Teva (UK) Limited on 24 March 2011 (PL 00289/1620-1622). Iceland agreed to grant Marketing Authorisations for Tacni 0.5 mg, 1 mg and 5 mg hard capsules on 04 July 2013.


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The full PAR for Tacni capsules follows this summary. For more information about treatment with Tacni capsules, read the package leaflet or contact your doctor or pharmacist. This summary was last updated in September 2015.


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SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

I Introduction Page 6 II Quality aspects Page 7 III Non-clinical aspects Page 16 IV Clinical aspects Page 17 V User consultation Page 19 VI Overall conclusion, benefit/risk assessment and

recommendation Page 19

Annex 1 - Table of content of the PAR update for MRP and DCP

Page 21


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Module 5

Scientific discussion during initial procedure I INTRODUCTION Based on the review of the data on quality, safety and efficacy Iceland considered that the applications for Tacni 0.5 mg, 1 mg and 5 mg hard capsules (PL 00289/1620-1622, formerly PL 23022/0068-70) could be approved via the Mutual Recognition Procedure (UK/H/3029/001-003/E01). The products are prescription-only medicines. These are generic applications for Tacni 0.5 mg, 1 mg and 5 mg hard capsules, three strengths of tacrolimus, submitted under Article 10.1 of 2001/83 EC, as amended. The applications refer to the UK originator products, Prograf 0.5 mg, 1 mg and 5 mg hard capsules, originally licensed to Fujisawa Ltd (PL 13424/0004, 0001 and 0002) on 15 September 1999, 7 June 1994 and 7 June 1994 respectively. These licences underwent Change of Ownership (CoA) procedures in November 2005 and are currently authorised to Astellas Pharma Ltd (PL 00166/0206, 0203 and 0204 respectively). Prograf 0.5 mg, 1 mg and 5 mg hard capsules have been authorised in the UK for more than 10 years; thus the period of data exclusivity has expired. The products went through Decentralised procedure (UK/H/3029/01-03/DC) involving the UK as Reference Member State and Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, The Netherlands, Norway, Poland, Portugal, Romania, Sweden, Slovenia, Slovakia, Spain as Concerned Member States (CMS). The procedure was completed on 16 October 2010. Marketing Authorisations (PL 23022/0068-70) were granted in the UK to PharOS - Pharmaceutical Oriented Services Ltd on 28 October 2010. Subsequent to Change of Ownership procedures, the Marketing Authorisations Tacni 0.5 mg, 1 mg and 5 mg hard capsules (PL 00289/0068-0070) were granted to Teva (UK) Limited) on 24 March 2011. A second-wave Mutual Recognition Procedure (UK/H/3029/01-03/E01) involving the Concerned Member State, Iceland, was concluded on 04 July 2013. Tacni 0.5 mg, 1 mg and 5 mg hard capsules are indicated for:

• prophylaxis of transplant rejection in liver, kidney or heart allograft recipients • treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal

products. Tacrolimus is a calcineurin inhibitor (ATC code: L04A D02). It is derived from the fungus, Streptomyces tsukubaensis, and has a macrolide structure. At the molecular level, the effects of tacrolimus appear to be mediated by binding to a cytosolic protein (FKBP12) which is responsible for the intracellular accumulation of the compound. The FKBP12-tacrolimus complex specifically and competitively binds to and inhibits calcineurin, leading to a calcium-dependent inhibition of T-cell signal transduction pathways, thereby preventing transcription of a discrete set of cytokine genes. Tacrolimus is a highly potent immunosuppressive agent and has proven activity in both in vitro and in vivo experiments. In particular, tacrolimus inhibits the formation of cytotoxic lymphocytes, which are mainly responsible for graft rejection. Tacrolimus suppresses T-cell activation and T-helper-cell dependent B-cell proliferation, as well as the formation of lymphokines (such as interleukins-2, -3, and γ-interferon) and the expression of the interleukin-2 receptor. No new non-clinical or clinical efficacy studies were conducted for these applications, which is acceptable given that the applications were for generic versions of products that have been licensed for over 10 years.


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The applications are supported by the bioequivalence study presented by the applicant comparing the pharmacokinetic profile of the test product, Tacni 5 mg hard capsules, to that of the reference product, Prograf 5 mg hard capsules (Astellas Pharma Ltd, sourced from Ireland). The bioequivalence study was carried out in accordance with Good Clinical Practice (GCP). The Reference Member State (RMS) 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 these products. Evidence of compliance with GMP has been provided for the named manufacturing and assembly sites. 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 or 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. II. QUALITY ASPECTS II.1 Introduction The submitted documentation concerning the proposed products 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. Tacni 0.5 mg, 1 mg and 5 mg hard capsules are presented as hard shell capsules (ivory, white, and red respectively) containing white powder. The capsules contain 0.5 mg, 1 mg or 5 mg of the active ingredient, tacrolimus. Full descriptions of the individual capsules may be found by referring to the SmPCs or patient information leaflet text. Other ingredients consist of pharmaceutical excipients, namely povidone K-30, croscarmellose sodium (E468), lactose anhydrous and magnesium stearate making up the capsule contents; and gelatin and titanium dioxide (E171) making up the capsule shell. The 0.5 mg strength capsules additionally contain yellow iron oxide (E172) and the 5 mg strength capsules additionally contain red iron oxide (E172). Appropriate justification for the inclusion of each excipient has been provided. The finished products are supplied in polyvinylchloride/polyvinylidene chloride-aluminium (PVC/PVdC-aluminium) blister strips. The blister strips, each containing 10 capsules, are placed with a desiccant into aluminium foil sachets which are packaged with the Patient Information Leaflet (PIL) into cardboard outer cartons in pack sizes of 20, 30, 50, 50x1, 60, 90 and 100 hard capsules. The Marketing Authorisation Holder (MAH) has stated that not all pack sizes may be marketed. The MAH has committed to submitting mock-ups for unmarketed pack sizes to the relevant regulatory authorities for approval before those packs are commercially marketed. Satisfactory specifications and Certificates of Analysis for all packaging components used have been provided. All primary product packaging complies with EU legislation, Directive 2002/72/EC (as amended), and is suitable for contact with foodstuffs.


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II.2 DRUG SUBSTANCE - TACROLIMUS Nomenclature: INN: Tacrolimus (as monohydrate) Chemical names: i) [3S,4R,5S,8R,9E, 12S18R, 19R, 26aS)

5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-Hexadecahydro- 5,19-dihydroxy-3-[(1E)-2-[(lR,3R,4R) - 4 - hydroxy-3-methoxycyclohexyl]-1 -methylethenyl]- 14,16-dimethoxy- 4,10,12,18 – tetramethyl-8-(2-propenyl) -15,19-epoxy-3H-pyrido [2,1-c] [1,4]oxaazacyclotricosine-1,7,-2O,21 (4H,23H) tetrone monohydrate; ii) 17-allyl- 1,14-dihydroxy- 12-[2-(4-hydroxy-3 methoxycyclohexyl)-1 - methylvinyl]-23,25- dimethoxy- 13,19,21,27-tetramethyl- 11,28 – dioxa -4- azatricyclo[22.3.1.04,9]octacos-18-ene- 2,3,10,16-tetraone monohydrate.

Structure:

Molecular formula: C44H69NO12.H2O Molecular weight: 822.0 g/mol CAS No: 104987-11-3 Physical form: White crystalline powder Solubility: Soluble in methanol, ethanol, ethyl acetate, acetone, chloroform and diethyl ether.

Sparingly soluble in hexane and petroleum ether. Insoluble in water and known to degrade in alkali buffer.

Melting point: 123.5°C – 127.5°C The active substance, tacrolimus, is not the subject of a European Pharmacopeia (Ph. Eur.) or British Pharmacopeia (B.P.) 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 specifications are in place for all starting materials and reagents and these are supported by relevant Certificates of Analysis. Confirmation has been provided that the raw materials, intermediates and auxiliary agents used in synthesis of the active are not of animal, biological or genetically modified origin. Appropriate specifications have been provided for the active substance. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. Batch analysis data are provided and comply with the proposed specifications. Satisfactory Certificates of Analysis have been provided for any reference standards used by the active substance manufacturer during validation studies. The active substance is stored in appropriate packaging. The container closure system used consists of 2-ply polyethylene bags sealed in an aluminium foil bag. The foil bags are placed into aluminium containers. Specifications and Certificates of Analysis have been provided for the packaging materials


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used. The primary polyethylene bags in direct contact with the active substance satisfy Directive 2002/72/EC (as amended), and are suitable for contact with foodstuffs. Appropriate stability data have been generated for active substance stored in the proposed commercial packaging. Based on the data, a retest period of 36 months has been set with the storage instruction “Store in the original container to protect from moisture and light”; this is satisfactory. II.3 MEDICINAL PRODUCT Pharmaceutical development Details of the pharmaceutical development of the medicinal products have been supplied and are satisfactory. The objective was to develop stable, generic formulations, with similar physical and chemical characteristics to the innovator products, Prograf 0.5 mg, 1 mg and 5 mg hard capsules (PL 00166/0206, 0203 and 0204; Astellas Pharma Ltd). Comparative dissolution and impurity data were provided for batches of the test products and appropriate reference products. The dissolution and impurity profiles were satisfactory. All excipients used comply with their respective European Pharmacopoeia monographs, with the exception of the colourants, iron oxide yellow (E172) and iron oxide red (E172). It is stated that iron oxide yellow and iron oxide red comply with the EU food colouring regulation 95/45/EC. Satisfactory Certificates of Analysis have been provided for all excipients. The magnesium stearate has been confirmed as being of plant origin. Excipients used that contain material of animal or human origin are lactose anhydrous and gelatin. The applicant has provided a declaration that milk used in the production of lactose anhydrous is sourced from healthy animals under the same conditions as that for human consumption. Satisfactory documentation has been provided by the gelatin suppliers stating that the gelatin they provide complies with the criteria described in the current version of the monograph ‘Products with risk of transmitting agents of animal spongiform encephalopathies’. None of the excipients are sourced from genetically modified organisms. There were no novel excipients used and no overages. Manufacture A description and flow-chart of the manufacturing method has been provided. In-process controls are appropriate considering the nature of the products and the method of manufacture. Process validation studies were conducted and validation data provided for all the product strengths; the results were satisfactory. Control of Finished Product The finished product specifications are provided for both release and shelf-life and are satisfactory. Acceptance limits have been justified with respect to conventional pharmaceutical requirements and, where appropriate, safety. Test methods have been described and have been adequately validated, as appropriate. Satisfactory batch analysis data are provided for all strengths of the medicinal product, and accepted. The data demonstrate that the batches are compliant with the proposed specifications. Certificates of Analysis have been provided for any reference standards used. Stability Finished product stability studies have been conducted in accordance with current guidelines, using product stored in the packaging proposed for marketing. Based on the results, a shelf-life of 27 months has been set for the unopened product, and a shelf-life of 1 year has been set for the blisters, once the


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aluminium wrapper has been opened; this is satisfactory. Storage instructions are ‘Store below 30°C, in the original package, to protect from moisture & light’. Bioequivalence Study A bioequivalence study was presented comparing the test product, Tacni 5 mg hard capsules, to the reference product, Prograf 5 mg hard capsules (Astellas Pharma Ltd). An evaluation of the bioequivalence study is found in Section IV, Clinical Aspects. II.4 Discussion on chemical, pharmaceutical and biological aspects All pharmaceutical issues have been resolved and the quality grounds for these applications are considered adequate. There are no objections to approval of Tacni 0.5 mg, 1 mg and 5 mg hard capsules from a pharmaceutical point of view. II.5 Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels The SmPC, PIL and labelling are satisfactory and, where appropriate, in line with current guidance. In accordance with Directive 2010/84/EU, the current version of the SmPC and PIL are available on the MHRA website. The current labelling is presented below: Labelling for Tacni 0.5 mg hard capsules:


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Labelling for Tacni 1 mg hard capsules:


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III. NON-CLINICAL ASPECTS III.1 Introduction Specific non-clinical studies have not been performed, which is acceptable considering that these are applications for generic versions products that have been licensed for over 10 years. The non-clinical overview provides a satisfactory review of the pharmacodynamic, pharmacokinetic, and toxicological properties of tacrolimus, a widely used and well-known active substance. The overview, dated March 2008, cites 47 references from the published literature dated up to 2007. The CV of the non-clinical expert has been supplied. For generic applications of this nature, the need for repetitive tests on animals and humans is avoided. Reference is made to the innovator medicinal products, Prograf 0.5 mg, 1 mg and 5 mg hard capsules (Astellas Pharma Ltd). III.2 Pharmacology Not applicable, see Section III.1 Introduction, above. III.3 Pharmacokinetics Not applicable, see Section III.1 Introduction, above.


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III.4 Toxicology Not applicable, see Section III.1 Introduction, above. III.5 Ecotoxicity/Environmental Risk Assessment (ERA) The Marketing Authorisation Holder has provided adequate justification for not submitting an Environmental Risk Assessment (ERA). These were applications for generic products and there is no reason to conclude that marketing of these products will change the overall use pattern of the existing market. There are no environmental concerns associated with the method of manufacture or formulation of the products. III.6 Discussion of the non-clinical aspects There are no objections to approval of Tacni 0.5 mg, 1 mg and 5 mg hard capsules from a non-clinical point of view. IV. CLINICAL ASPECTS IV.1 Introduction. The clinical pharmacology of tacrolimus is well known. A satisfactory clinical overview is provided, and has been prepared by an appropriately qualified expert. The CV of the clinical expert has been supplied. With the exception of the bioequivalence study, no new pharmacodynamic or pharmacokinetic data are supplied and none are required for these applications. IV.2 Pharmacokinetics Pharmacokinetics – bioequivalence study The applications are supported by the bioequivalence study presented by the applicant comparing the pharmacokinetic profiles of Tacni 5 mg hard capsules (test) and Prograf 5 mg hard capsules, Astellas Pharma Ltd, Ireland (reference). The study was of an appropriate design and was conducted to principles of Good Clinical Practice (GCP). Certificates of Analysis have been provided for the test and reference products. This was a standard, randomised, open-label, two-treatment, two-period, single-dose, crossover, bioequivalence study conducted in 156 healthy adult male and female subjects under fasting conditions. Following an overnight fast of at least 10 hours, a single dose of the investigational products was administered orally, with 200ml water, to each subject in each period. A satisfactory washout period of 25 days was maintained between the two dosing days in each group. Blood samples were taken pre-dose (0.0) and at specified time points up to 144.0 hours after administration of test or reference product. The parent compound, tacrolimus, was analysed in whole blood using a validated HPLC-MS/MS analytical method. Analysis of the parent compound in whole blood was appropriate as the compound is extensively bound to erythrocytes, and metabolites are known not to contribute to pharmacological activity. The primary pharmacokinetic parameters for this study were Cmax, AUC0-t, and AUC0-∞. The CHMP (EWP) recommends that the bioequivalence acceptance criteria for tacrolimus should be [90-111%] for AUC and [80-125%] for Cmax (EMA/CHMP/EWP/731195/2009). Results: 156 subjects were enrolled in the study; 141 of these completed the study and were included in the pharmacokinetic evaluation and statistical analysis. The discontinuation, and non-inclusion in the pharmacokinetic analysis, of 15 subjects was satisfactorily justified.


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Safety - The two formulations were well tolerated; a total of 10 post-dose adverse events were reported by 8 subjects. Two subjects were withdrawn as a result of adverse events. Of the remaining 6 subjects, 5 subjects experienced adverse events after taking the test product and one subject following the reference product (nausea and vomiting). There were no deaths or serious or significant adverse events. The summary of the results of the bioequivalence study are tabulated below. Pharmacokinetic results for tacrolimus for a randomised, two-treatment, two-period, single-dose crossover study between the test and reference products. n=141 healthy subjects, dosed fasted; t=144 hours. Wash-out period: 25 days.

Treatment Cmax

ng/ml AUC0-t

ng/ml/h AUC0-∞

ng/ml/h

Test 32.534 ± 11.509

260.236 ± 149.617

279.685 ± 155.996

Reference 29.526 ± 11.293

261.606 ± 160.329

281.575 ± 171.173

Ratio (90% CI) Point estimate and limits

111.574% (105.563-117.928)

98.728% (93.062-104.738)

99.009% (93.614-104.716)

AUC0-∞ area under the plasma concentration-time curve from time zero to infinity AUC0-t area under the plasma concentration-time curve from time zero to t hours Cmax maximum plasma concentration

Conclusion on Bioequivalence The results of the bioequivalence study show that the 5 mg strength test and reference products are bioequivalent, under fasting conditions, as the confidence intervals for Cmax, AUC0-t, and AUC0-∞ fall within the acceptance criteria ranges of 80.00-125.00% for Cmax, and 90.00-111.00% for AUC0-t and AUC0-∞, in line with current recommendations. Satisfactory justification is provided for a bio-waiver for Tacni 0.5 mg and 1 mg hard capsules. As Tacni 0.5 mg, 1 mg and 5 mg hard capsules meet 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 5 mg strength can be extrapolated to the 0.5 mg and 1 mg strength capsules IV.3 Pharmacodynamics The clinical pharmacodynamics properties of tacrolimus are well-known. No new pharmacodynamic data were submitted and none are required for applications of this type. IV.4 Clinical Efficacy No new data have been submitted and none are required. The reference products are established and the applications depend upon the ability to demonstrate bioequivalence. Efficacy is reviewed in the clinical overview. The efficacy of tacrolimus is well-established from its extensive use in clinical practice. IV.5 Clinical Safety No new data have been submitted and none are required for applications of this type. No new or unexpected safety concerns arose from these applications. Safety is reviewed in the clinical overview. The safety profile of tacrolimus is well-known.


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IV.6 Risk Management Plan The applications include a Risk Management Plan (RMP) to reduce the risks arising from switching formulations and medication error. The RMP is adequate and the MAH proposes appropriate optional risk-minimisation measures, in addition to routine pharmacovigilance activities, in order to minimise the identified risks. IV.7 Discussion of the clinical aspects All issues have been adequately addressed by the applicant. For generic applications of this nature, the need for repetitive tests on animals and humans is avoided. Reference is made to the innovator medicinal products, Prograf 0.5 mg, 1 mg and 5 mg hard capsules (Astellas Pharma Ltd). Sufficient clinical information has been submitted to support these applications. The risk-benefit of the benefit of the products is considered favourable from a clinical perspective. The grant of Marketing Authorisations was therefore recommended on medical grounds. 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, as amended. 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 AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Tacni 0.5 mg, 1 mg and 5 mg hard 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 Bioequivalence has been demonstrated between the applicant’s Tacni 5 mg hard capsules and the reference product, Prograf 5 mg hard capsules (Astellas Pharma Ltd). As the proposed products, Tacni 0.5 mg, 1 mg and 5 mg hard capsules, meet 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 5mg strength were extrapolated to the 0.5 mg and 1 mg strength capsules, and omission of further bioequivalence studies on the other strengths can be accepted. No new or unexpected safety concerns arise from these applications. PRODUCT LITERATURE The approved SmPCs are satisfactory. The PIL is in line with the SmPCs and is satisfactory. 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, as amended. 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.


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Mock-ups of the labelling have been provided. The approved labelling artwork complies with statutory requirements. In line with current legislation, the name of the product in Braille appears on the outer packaging and sufficient space has been included for a standard UK pharmacy dispensing label. The MAH has committed to submitting mock-ups for unmarketed pack sizes to the relevant regulatory authorities for approval before those packs are marketed. BENEFIT-RISK ASSESSMENT The quality of the products is acceptable and no new non-clinical or clinical safety concerns have been identified. The bioequivalence study and its conclusions support the claim that the applicant’s Tacni 0.5 mg, 1 mg and 5 mg hard capsules are generics of the reference products, Prograf 0.5 mg, 1 mg and 5 mg hard capsules (Astellas Pharma Ltd). Extensive clinical experience with tacrolimus is considered to have demonstrated the therapeutic value of the active substance. The benefit: risk ratio is considered to be positive.


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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 (Type Ib/II variations, PSURs, commitments)

The following table lists a non-safety update to the Marketing Authorisations that are of clinical significance for these products. This may not be a complete list of the post authorisation changes that have been made to these Marketing Authorisations. Scope Procedure number Product

Information affected

Date of start of the procedure

Date of end of procedure

Approval/non approval

Assessment report attached

To reduce the shelf life of the finished product from 27 months to 24 months based on stability results being within specification at the 24 months time point.

UK/H/3029/001-003/IB/001 SmPC 04/11/2011 09/11/2011 Yes No

To update sections 4.2 - 4.9 and 5.1 - 5.2 of the SmPC in line the reference product 'Prograf'. As a consequence, the PIL has been updated

UK/H/3029/001-003/IB/001 SmPC and PIL 06/07/2012 16/11/2012 Yes No

To update sections 2, 4.2, 4.3, 4.6, 4.8, 5.1, 5.2 and 6.6 of the SPC in line with the current Quality Review of Documents template (QRD) template. Consequentially the label and leaflet will be updated.

UK/H/3029/001-003/IB/008 SmPC, label and PIL

19/05/2015 28/07/2015 Approval Yes (Annex 1.1)


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ANNEX 1.1

Our Reference: PL 00289/1620 - 0027 Product: Tacni 0.5 mg hard capsules Marketing Authorisation Holder: Teva UK Limited Active Ingredient(s): Tacrolimus Type of Procedure: Mutual Recognition Submission Type: Variation Submission Category: Type IB Submission Complexity: Standard EU Procedure Number (if applicable): UK/H/3029/001-003/IB/008 Reason: To update sections 2, 4.2, 4.3, 4.6, 4.8, 5.1, 5.2 and 6.6 of the SmPC in line with the QRD template.Consequentially the label and leaflet will be updated. Linked / Related Variation(s) or Case(s): The Assessment Report refers to the Collection ID 163714 and covers the following submissions PL 00289/1621 - 0028, PL 00289/1622 - 0027. Supporting Evidence Revised SmPC fragments (sections) updated leaflet and labelling have been provided. Evaluation The updated sections of the SmPC and leaflet are acceptable. The updated labelling is acceptable. Conclusion The updated sections of the SmPC, the updated leaflet and labelling are satisfactory and there are no objections to approval. In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPCs) and Patient Information Leaflets (PILs) for products granted Marketing Authorisations at a national level are available on the MHRA website. The current labelling is presented below:


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Labelling for Tacni 0.5 mg hard capsules:


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25


26


27



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Decision – Approved on 28 July 2015.