Public Assessment Report. Scientific discussion. Amoxiclav Aristo 500 mg/125 mg and 875 mg/125 mg film-coated tablets

Transcription

1 Public Assessment Report Scientific discussion C Amoxiclav Aristo 500 mg/125 mg and 875 mg/125 mg film-coated tablets (amoxicillin triydrate and potassium clavulanate) NL/H/3468/ /DC Date: 12 July 2016 Tis module reflects te scientific discussion for te approval of Amoxiclav Aristo 500 mg/125 mg and 875 mg/125 mg film-coated tablets. Te procedure was finalised on 9 July For information on canges after tis date please refer to te steps taken after finalisation at te end of tis PAR.

2 List of abbreviations C CEP CHMP CMD() CMS EDMF EDQM EEA ERA ICH MAH P.Eur. PL RH RMP SmPC TSE Certificate of Suitability to te monograps of te European Parmacopoeia Committee for Medicinal Products for Human Use Coordination group for Mutual recognition and Decentralised procedure for uman medicinal products Concerned Member State European Drug Master File European Directorate for te Quality of Medicines European Economic Area Environmental Risk Assessment International Conference of Harmonisation Marketing Autorisation Holder European Parmacopoeia Package Leaflet Relative Humidity Risk Management Plan Summary of Product Caracteristics Transmissible Spongiform Encepalopaty 2/13

3 I. INTRODUCTION Based on te review of te quality, safety and efficacy data, te Member States ave granted a marketing autorisation for Amoxiclav Aristo 500 mg/125 mg and 875 mg/125 mg film-coated tablets, from Aristo Parma GmbH. Te product is indicated for te treatment of te following infections in adults and cildren: Acute bacterial sinusitis (adequately diagnosed) Acute otitis media Acute exacerbations of cronic broncitis (adequately diagnosed) Community acquired pneumonia Cystitis Pyelonepritis Skin and soft tissue infections in particular cellulitis, animal bites, severe dental abscess wit spreading cellulitis Bone and joint infections, in particular osteomyelitis Consideration sould be given to official guidance on te appropriate use of antibacterial agents. A compreensive description of te indications and posology is given in te SmPC. Tis decentralised procedure concerns a generic application claiming essential similarity wit te innovator products Augmentin 500 mg/125 mg and 875 mg/125 mg, film-coated tablets (NL License RVG and 18553) wic were registered in te Neterlands by GlaxoSmitKline B.V. on respectively 2 December 1983 (500 mg/125 mg strengt) and 22 August 1996 (875 mg/125 mg strengt). Te iger strengt is no longer registered in te Neterlands. Te concerned member state (CMS) involved in tis procedure was Germany. Te marketing autorisation as been granted pursuant to Article 10(1) of Directive 2001/83/EC. II. QUALITY ASPECTS II.1 Introduction Bot Amoxiclav Aristo 500 mg/125 mg and 875 mg/125 mg are wite to off wite oblong film-coated tablets wit a non-functional score line. Tis line is to facilitate breaking for te ease of swallowing and not to divide te tablet into two equal doses. Te 500 mg/125 mg strengt tablet contains as active substances mg of amoxicillin triydrate (equivalent to 500 mg amoxicillin) and mg potassium clavulanate diluted wit microcrystalline cellulose in te ratio 1:1 (equivalent to 125 mg clavulanic acid). Te 875 mg/125 mg strengt tablet contains as active substances mg of amoxicillin triydrate (equivalent to 875 mg amoxicillin) and mg potassium clavulanate diluted wit microcrystalline cellulose in te ratio 1:1 (equivalent to 125 clavulanic acid). Te film-coated tablets are packed in OPA/Al/PVC-Al blisters. Te excipients are: tablet core - cellulose, microcrystalline (E460), crospovidone type A (E1202), croscarmellose sodium (E468), silica, colloidal anydrous (E551) and magnesium stearate (E470b) tablet coating basic butylated metacrylate copolymer, titanium dioxide (E171), talc (E553b) and macrogol II.2 Drug Substances Te active substances are amoxicillin triydrate and potassium clavulanate diluted wit microcrystalline cellulose in te ratio 1:1. Bot are establised active substances described in te 3/13

4 European Parmacopoeia (P.Eur.). Amoxicillin triydrate is a wite or almost wite crystalline powder wic is sligtly soluble in water. Potassium clavulanate is a wite or almost wite crystalline powder, wic is freely soluble in water. No polymorpism or isomerism is described for eiter active substance. Te CEP procedure is used for bot active substances. Under te official Certification Procedures of te EDQM of te Council of Europe, manufacturers or suppliers of substances for parmaceutical use can apply for a certificate of suitability concerning te control of te cemical purity and microbiological quality of teir substance according to te corresponding specific monograp, or te evaluation of reduction of Transmissible Spongiform Encepalopaty (TSE) risk, according to te general monograp, or bot. Tis procedure is meant to ensure tat te quality of substances is guaranteed and tat tese substances comply wit te P.Eur. Manufacturing process CEPs as been submitted; terefore no details on te manufacturing process ave been included. Quality control of drug substances Te drug substance specifications are in line wit te P.Eur and additional requirements are laid down on te CEPs. Te specifications are acceptable in view of te route of syntesis and te various European guidelines. Batc analytical data demonstrating compliance wit te drug substance specifications ave been provided for tree batces for amoxicillin triydrate. For potassium clavulanate sufficient data ave been provided. Stability of drug substances Te active substance amoxicillin triydrate is stable for 6 years wen stored under te stated conditions. Potassium clavulanate is stable for 48 monts at te stated conditions. Assessment tereof was part of granting te CEP and as been granted by te EDQM. II.3 Medicinal Product Parmaceutical development Te product is an establised parmaceutical form and its development is adequately described in accordance wit te relevant European guidelines. Te development of te product as been described, te coice of excipients is justified and teir functions explained. It as been explained tat tere is very limited impact of particle size of bot actives on te performance of te product. Tis explanation being a justification of absence of drug substance particle size specifications for bot actives is additionally supported by te tigt dissolution specifications on bot actives: NLT 85% (Q) in 30 min. It as been sown tat te dissolution metod as sufficiently discriminating ability. Te two strengts for bot te reference product and te test products are not dose-weigt proportional, terefore bioequivalence studies ave been performed for bot strengts. Manufacturing process Te manufacturing process consist of a repeating sequence of weiging, blending, compacting, sieving, final blending, compression and film-coating. It is considered a standard process. Full process validation will be performed on tree consecutive batces of eac strengt of te product for commercial batc size. Control of excipients Te specifications for te excipients are considered acceptable. For te tablet coating ingredient basic butylated metacrylate copolymer adequate specifications were proposed, for all oter excipients P. Eur. monograp requirements are applicable and erewit acceptable. Quality control of drug product Te finised product specifications are adequate to control te relevant parameters for te dosage form. Te specification includes tests for appearance, identification, uniformity of dosage units (CU), dissolution, assay, degradation products, residual solvents (acetone, 2-propanol), water content and microbiological purity. Limits in te specification ave been justified and are considered appropriate for adequate quality control of te product. Satisfactory validation data for te analytical metods ave been provided. Batc analytical data from 4 batces of te 500 mg/125 mg strengt and 3 batces of 4/13

5 te 875/125 mg from te proposed production site ave been provided, demonstrating compliance wit te specification. Stability of drug product Stability data on te product ave been provided for 2 batces of eac strengt in accordance wit applicable European guidelines. Te batces were stored for 24 monts at 25 C/60% RH, 12 monts at 30 C/65% RH and 3 or 6 monts at 40 C/75% RH. Stability results in bot te accelerated and intermediate studies were not satisfactory. Te MAH improved te stability beaviour of te drug product by introducing new Alu-Alu blisters aving ticker Aluminium layers. Wit te new stability batces (2 batces per strengt) 12 monts data at 25 C/60% RH and 30 C/65% RH, and 3 monts at 40 C/75% RH ave become available. On basis of te data submitted, a self life was granted of 24 monts for bot strengts wen stored in te original package in order to protect from moisture. Protection from ligt is not necessary. Specific measures concerning te prevention of te transmission of animal spongiform encepalopaties Tere are no substances of ruminant animal origin present in te product nor ave any been used in te manufacturing of tis product, so a teoretical risk of transmitting TSE can be excluded. II.4 Discussion on cemical, parmaceutical and biological aspects Based on te submitted dossier, te member states consider tat Amoxiclav Aristo as a proven cemical-parmaceutical quality. Sufficient controls ave been laid down for te active substances and finised product. No post-approval commitments were made. III. III.1 NON-CLINICAL ASPECTS Ecotoxicity/environmental risk assessment (ERA) Since Amoxiclav Aristo is intended for generic substitution, tis will not lead to an increased exposure to te environment. An environmental risk assessment is terefore not deemed necessary. III.2 Discussion on te non-clinical aspects Tese products are generic formulations of Augmentin wic is available on te European market. is made to te preclinical data obtained wit te innovator product. A non-clinical overview on te parmacology, parmacokinetics and toxicology as been provided, wic is based on up-todate and adequate scientific literature. Te overview justifies wy tere is no need to generate additional non-clinical parmacology, parmacokinetics and toxicology data. Terefore, te member states agreed tat no furter non-clinical studies are required. IV. IV.1 CLINICAL ASPECTS Introduction Amoxicillin triydrate and potassium clavulanate are a well-known active substance wit establised efficacy and tolerability. A clinical overview as been provided, wic is based on scientific literature. Te overview justifies wy tere is no need to generate additional clinical data. Terefore, te member states agreed tat no furter clinical studies are required. For tis generic application, te MAH initially submitted two bioequivalence studies (one for eac strengt) under fasting conditions. However, as stated in te SmPC of Augmentin, te dose sould be administered at te start of a meal to minimise potential gastrointestinal intolerance and optimise absorption of amoxicillin/clavulanic acid. As stated in te EMA guideline on te investigation of Bioequivalence, for products were te SmPC recommends intake of te reference medicinal product only in fed state, te bioequivalence study sould generally be conducted under fed conditions. 5/13

6 Terefore te MAH submitted two additional bioequivalence studies, one for eac strengt conducted under fed conditions. Te four studies are discussed below. IV.2 Parmacokinetics Te MAH conducted bioequivalence studies in wic te parmacokinetic profile of te test product Amoxiclav Aristo tablets (Aristo Parma GmbH, Germany) is compared wit te parmacokinetic profile of te reference product Augmentin tablets (GlaxoSmitKline S.A., Belgium): Study I - A bioequivalence study under fasting conditions wit te 500 mg/125 mg strengt Study II - A bioequivalence study under fasting conditions wit te 875 mg/125 mg strengt Study III - A bioequivalence study under fed conditions wit te 500 mg/125 mg strengt Study IV - A bioequivalence study under fed conditions wit te 875 mg/125 mg strengt Te coice of te reference products in te four bioequivalence studies as been justified. Te formula and preparation of te bioequivalence batc is identical to te formula proposed for marketing. Te designs of te studies is acceptable. Analytical/statistical metods Te analytical metod as been adequately validated and is considered acceptable for analysis of te plasma samples. Te metods used in tis study for te parmacokinetic calculations and statistical evaluation are considered acceptable. Bioequivalence studies Bioequivalence study I - Amoxiclav Aristo 500 mg/125 mg vs Augmentin under fasted conditions Design A single-dose, randomised, balanced, open-label, two-period, two-sequence, crossover bioequivalence study was carried out under fed conditions in 40 ealty male subjects, aged years. After an overnigt fast eac subject received a single dose (500 mg amoxicillin/125 clavulanic acid mg) of one of te 2 formulations. Te tablets were administered in solid form wit 240 ml. Tere were 2 dosing periods, separated by a wasout period of 7 days. Blood samples were collected pre-dose and at 0.17, 0.33, 0.5, 0.67, 0.83, 1.0, 1.33, 1.67, 1.83, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 9.0, 10.0 and 12.0 ours after administration of te products. Te design of te study is acceptable. Results Four subjects did not return for te second period of te study. Terefore, 36 subjects completed te study and were included in te statistical analysis. Table 1. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, (median, range)) of amoxicillin triydrate under fasted conditions. N=36 ng./ml ng./ml ± ± ± ± ± ± ( ) 0.99 ( ) 1.83 ( ) 1.92 ( ) 1.6 ± ± /13

7 area under te plasma concentration-time curve from time zero to infinity area under te plasma concentration-time curve from time zero to t ours alf-life C Table 2. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, (median, range)) of clavulanic acid under fasted conditions. N=36 ng./ml ng./ml 7886 ± ± ± ± ± ± ( ) 0.96 ( ) 1.5 ( ) 1.42 ( ) 1.1 ± ± area under te plasma concentration-time curve from time zero to infinity area under te plasma concentration-time curve from time zero to t ours alf-life Bioequivalence study II Amoxiclav Aristo 875 mg/125 mg vs Augmentin under fasted conditions Design A single-dose, randomised, balanced, open-label, two-period, two-sequence, crossover bioequivalence study was carried out under fasted conditions in 40 ealty male subjects, aged years. After an overnigt fast eac subject received a single dose (875 amoxicillin/125 clavulanic acid mg) of one of te 2 formulations. Te tablets were administered in solid form wit 240 ml. Tere were 2 dosing periods, separated by a wasout period of 7 days. Blood samples were collected pre-dose and at 0.17, 0.33, 0.5, 0.67, 0.83, 1.0, 1.33, 1.67, 1.83, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 9.0, 10.0 and 12.0 ours after administration of te products. Te design of te study is acceptable. Results One subject did not return for te second period of te study. One subjects was excluded for parmacokinetic analysis due to very low plasma concentrations for amoxicillin as well as for clavulanic acid. As te AUC t value of tis subject was below 5% of te geometric mean of te total population witout tis subject, it is acceptable to exclude te data of tis subject from parmacokinetic and statistical analysis. Terefore, 38 subjects completed te study and were included in te statistical analysis. Table 3. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, (median, range)) of amoxicillin triydrate under fasted conditions. N=38 ng./ml ng./ml 7/13

8 40883 ± ± ± ± ± ± ( ) 0.96 ( ) C 2.0 ( ) 2.5 ( ) 1.6 ± ± area under te plasma concentration-time curve from time zero to infinity area under te plasma concentration-time curve from time zero to t ours alf-life Table 4. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, (median, range)) of Clavulanic acid under fed conditions. N=39 ng./ml ng./ml 8812 ± ± ± ± ± ± ( ) 0.99 ( ) 1.6 ( ) 1.5 ( ) 1.2 ± ± area under te plasma concentration-time curve from time zero to infinity area under te plasma concentration-time curve from time zero to t ours alf-life Bioequivalence study III - Amoxiclav Aristo 500 mg/125 mg vs Augmentin under conditions Design A single-dose, randomised, balanced, open-label, two-period, two-treatment, two-sequence, crossover bioequivalence study was carried out under fed conditions in 40 ealty male subjects, aged years. In eac study period, subjects were fasted overnigt for at least 10 ours prior to start of a ig fat, ig calorie, non-vegetarian breakfast (911 kcal). After 30 minutes eac subject received a single dose (500 mg amoxicillin/125 clavulanic acid mg) of one of te 2 formulations. Te tablets were administered in solid form wit 240 ml. Tere were 2 dosing periods, separated by a wasout period of 7 days. Blood samples were collected pre-dose and at 0.17, 0.33, 0.5, 0.67, 0.83, 1.0, 1.33, 1.67, 1.83, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 9.0, 10.0 and 12.0 ours after administration of te products. Te design of te study is acceptable. Instead of at te start of a meal, te formulation was administered 30 min after te start of intake of a meal. Altoug not fully in accordance wit te SmPC, it is considered acceptable. 8/13

9 Results Two subjects witdrew by not sowing up for te second period and one witdrew on is own accord. Terefore, a total of 37 subjects completed te study and were included in te statistical analysis. Table 5. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, (median, range)) of amoxicillin triydrate under fed conditions. N=37 ng./ml ng./ml ± ± ± ± ± ± ( ) 0.99 ( ) 2.0 ( ) 2.0 ( ) 1.6 ± ± area under te plasma concentration-time curve from time zero to infinity area under te plasma concentration-time curve from time zero to t ours alf-life Table 6. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, (median, range)) of clavulanic acid under fed conditions. N=37 ng./ml ng./ml 5450 ± ± ± ± ± ± ( ) 0.98 ( ) 1.83 ( ) 1.83 ( ) 1.1 ± ± area under te plasma concentration-time curve from time zero to infinity area under te plasma concentration-time curve from time zero to t ours alf-life Bioequivalence study IV Amoxiclav Aristo 875 mg/125 mg vs Augmentin under fed conditions Design A single-dose, randomised, balanced, open-label, two-period, two-treatment, two-sequence, crossover bioequivalence study was carried out under fed conditions in 40 ealty male subjects, aged years. In eac study period, subjects were fasted overnigt for at least 10 ours prior to start of a ig fat, ig calorie, non-vegetarian breakfast (911 kcal). After 30 minutes eac subject received a single dose (875 amoxicillin/125 clavulanic acid mg) of one of te 2 formulations. Te tablets were administered in solid form wit 240 ml. Tere were 2 dosing periods, separated by a wasout period of 7 days. 9/13

10 Blood samples were collected pre-dose and at 0.17, 0.33, 0.5, 0.67, 0.83, 1.0, 1.33, 1.67, 1.83, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 9.0, 10.0 and 12.0 ours after administration of te products. Te design of te study is acceptable. Instead of at te start of a meal, te formulation was administered 30 min after te start of intake of a meal. Altoug not fully in accordance wit te SmPC, it is considered acceptable. Results One subject did not return to te facility witout clarification. Terefore, a total of 39 subjects were eligible for parmacokinetic analysis. Table 7. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, (median, range)) of amoxicillin triydrate under fed conditions. N=39 ng./ml ng./ml ± ± ± ± ± ± ( ) 0.94 ( ) 2.25 ( ) 2.5 ( ) 1.6 ± ± area under te plasma concentration-time curve from time zero to infinity area under te plasma concentration-time curve from time zero to t ours alf-life Table 8. Parmacokinetic parameters (non-transformed values; aritmetic mean ± SD, (median, range)) of Clavulanic acid under fed conditions. N=39 ng./ml ng./ml 10/ ± ± ± ± ± ± ( ) 1.02 ( ) 2.0 ( ) 2.0 ( ) 1.2 ± ± area under te plasma concentration-time curve from time zero to infinity area under te plasma concentration-time curve from time zero to t ours alf-life Conclusion on bioequivalence studies Te 90% confidence intervals calculated for and are witin te bioequivalence acceptance range of Based on te submitted bioequivalence studies Amoxiclav Aristo 500 mg/125 mg

11 and 875 mg/125 mg, film-coated tablets are considered bioequivalent wit Augmentin 500 mg/125 mg and 875 mg/125 mg film-coated tablets under fed conditions. Te MEB as been assured tat te bioequivalence studies ave been conducted in accordance wit acceptable standards of Good Clinical Practice (GCP, see Directive 2005/28/EC) and Good Laboratory Practice (GLP, see Directives 2004/9/EC and 2004/10/EC). IV.3 Risk Management Plan Te MAH as submitted a risk management plan, in accordance wit te requirements of Directive 2001/83/EC as amended, describing te parmacovigilance activities and interventions designed to identify, caracterise, prevent or minimise risks relating to Amoxiclav Aristo. - Summary table of safety concerns as approved in RMP Important identified risks Hypersensitivity Hepatic impairment Important potential risks Acute generalised exantemous pustulosis Antibiotic-associated colitis Increased risk of neonatal necrotizing enterocolitis (wen amoxicillin/clavulanic acid is used propylactically in women wit preterm, premature rupture of te foetal membrane) Lack of efficacy due to resistance Missing information Exposure during pregnancy Exposure troug uman milk Exposure in cildren under 2 years Te member states agreed tat routine parmacovigilance activities and routine risk minimisation measures are sufficient for te risks and areas of missing information. IV.4 Discussion on te clinical aspects For tis autorisation, reference is made to te clinical studies and experience wit te innovator product Augmentin. No new clinical studies were conducted. Te MAH demonstrated troug bioequivalence studies tat te parmacokinetic profile of te product is similar to te parmacokinetic profile of tis reference product. Risk management is adequately addressed. Tis generic medicinal product can be used instead of te reference product. V. USER CONSULTATION For tis autorisation, a full user testing report for te 875 mg/125 mg strengt and a bridging report for te 500 mg/125 mg strengt were provided for te package leaflet (PL). Te user testing as been adequately performed and te overall readability/quality of te PL is acceptable. Te final PL reflects te results of testing wit patients to make sure it meets teir needs and can enable te patient to use te medicinal product safely and effectively. Furtermore, tere were no problems identified regarding compreensibility and usefulness of information. Te bridging report ad been prepared in accordance wit te guidance on readability testing and it is acceptable. 11/13

12 VI. C OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Amoxiclav Aristo 500 mg/125 mg and 875/125 mg film-coated tablets ave a proven cemicalparmaceutical quality and are generic forms of Augmentin 500 mg/125 mg and 875/125 mg filmcoated tablets. Augmentin is a well-known medicinal product wit an establised favourable efficacy and safety profile Bioequivalence as been sown to be in compliance wit te requirements of European guidance documents, bot under fasting and fed conditions. Te Board followed te advice of te assessors. Tere was no discussion in te CMD(). Agreement between member states was reaced during a written procedure. Te member states, on te basis of te data submitted, considered tat essential similarity as been demonstrated for Amoxiclav Aristo 500 mg/125 mg and 875 mg/125 mg film-coated tables wit te reference product, and ave terefore granted a marketing autorisation. Te decentralised procedure was finalised wit a positive outcome on 9 July /13

13 STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE - SUMMARY Scope Procedure number Type of modification Date of start of te procedure Date of end of te procedure Approval/ non approval Assessmen t report attaced 13/13