Public Assessment Report. Scientific discussion

Transcription

1 Public Assessment Report Scientific discussion Valbanatan 320 mg/25 mg; 160 mg/12,5 mg; 160 mg/25 mg; 320 mg/12,5 mg; 320 mg/25 mg Filmtabletten Valbacomp 320 mg/25 mg; 160 mg/12,5 mg; 160 mg/25 mg; 320 mg/12,5 mg; 320 mg/25 mg Filmtabletten Valsartan/Hydrochlorothiazide This module reflects the scientific discussion for the approval of Valbanatan/Valbacomp. The procedure was finalised at For information on changes after this date please refer to the module Update. 1/7

2 I. INTRODUCTION The application through the Decentralised Procedure concerns Valsartan/Hydrochlorothiazide (HCT) 80 mg/12.5 mg; 160 mg/12.5 mg; 160 mg/25 mg; 320 mg/12,5 mg and 320 mg/25 mg film-coated tablets with Austria acting as RMS. The tablets are a generic version of Co-Diovan (forte), marketed by Novartis, which is available in the same strengths and had been authorised through an MR procedure (SE/H/0565/ ). II. QUALITY ASPECTS II.1 Introduction Valbanatan/Valbacomp is a Film-coated tablet which is presented in a PVC/PVDC aluminium blister. II.2 Drug Substance The active substances in Valbanatan/Valbacomp are Valsartan and Hydrochlorothiazide (HCT). The specification of the active substances meets the current scientific requirements. The adequate quality of the active substances has been shown by submitting the appropriate control data. The stability of the active substances has been tested under ICH conditions. The results of the stability studies support the established retest-period. II.3 Medicinal Product Valbanatan/Valbacomp contains the following active subtance/s and excipients: Core: Lactose monohydrate Cellulose, powdered Hypromellose Croscarmellose sodium Silica, colloidal anhydrous Magnesium stearate Film-Coat: Hypromellose Macrogol 8000 Talc 80 mg/12.5 mg and 320 mg/12.5 mg film-coated tablets contain: Titanium dioxide (E171) Iron Oxide Red (E172) 160 mg/12.5 mg film-coated tablets contain: Iron Oxide Yellow (E172) Iron Oxide Red (E172) Iron Oxide Black (E172) 160 mg/25 mg film-coated tablets contain: Titanium dioxide (E171) Iron Oxide Yellow (E172) Iron Oxide Red (E172) 2/7

3 Iron Oxide Black (E172) 320 mg/25 mg film-coated tablets contain: Titanium dioxide (E171) Iron Oxide Yellow (E172) The manufacturers responsible for batch release are: For Valbanatan: Centrafarm Services BV Nieuwe Donk 9, 4879 AC Etten Leur; The Netherlands Clonmel Healthcare Ltd. Waterford Road, Clonmel, Co. Tipperary; Ireland Eurogenerics N.V. Heizel Esplanade Heysel b 22, B-1020 Brussels; Belgium LAMP S. Prospero S.p.A. Via della Pace, 25/A, I San Prospero (Modena); Italy PharmaCoDane ApS Marielundvej 46A, DK-2730 Herlev; Denmark STADA Arzneimittel AG Stadastr. 2-18, Bad Vilbel; Germany STADA Arzneimittel GmbH Muthgasse 36/2, A-1190 Wien; Austria STADA Production Ireland Waterford Road, Clonmel, Co. Tipperary; Ireland For Valbacomp: Centrafarm Services BV Nieuwe Donk 9, 4879 AC Etten Leur; The Netherlands ALIUD PHARMA GmbH Gottlieb-Daimler-Str. 18, Laichingen; Germany Eurogenerics N.V. Heizel Esplanade Heysel b 22, B-1020 Brussels; Belgium LAMP S. Prospero S.p.A. Via della Pace, 25/A, I San Prospero (Modena); Italy PharmaCoDane ApS Marielundvej 46A, DK-2730 Herlev; Denmark 3/7

4 STADA Arzneimittel AG Stadastr. 2-18, Bad Vilbel; Germany STADA Arzneimittel GmbH Muthgasse 36/2, A-1190 Wien; Austria STADA Production Ireland Waterford Road, Clonmel, Co. Tipperary; Ireland The development of the product has been sufficiently made and deemed appropriate. The usage of all the excipients has been described. The release specification includes the check of all parameters relevant to this pharmaceutical form. Appropriate data concerning the control of the finished product support the compliance with the release specifications. The packaging of the medicinal product complies with the current legal requirements. Stability studies under ICH conditions have been performed and data presented support the shelf life claimed in the SmPC, with a shelf life of 24 months when stored below 30 C. The pharmaceutical quality of Valbanatan/Valbacomp has been adequately shown. III. III.1 NON-CLINICAL ASPECTS Introduction Pharmacodynamic, pharmacokinetic and toxicological properties of both valsartan and hydrochlorothiazide are well known. As valsartan + hydrochlorothiazide is a widely used, wellknown combination, no further studies are required and the applicant provides none. Overview based on literature review is, thus, appropriate. III.2 Ecotoxicity/environmental risk assessment These products are intended to substitute for other identical products on the market. The approval of these products does not result in an increase of the total quantity of valsartan or hydrochlorothiazide released into the environment. They do not contain any component which would result in an additional hazard to the environment during storage, distribution, use and disposal. IV. CLINICAL ASPECTS IV.1 Pharmacokinetics Valsartan Following oral administration valsartan is rapidly absorbed and the absolute bioavailability is approximately 23%. 4/7

5 The pharmacokinetics of valsartan are linear in the dose range tested. Valsartan shows a multi-exponential degradation kinetic (primary half-life < 1 hour and terminal halflife about 9 hours). Valsartan is highly bound to serum proteins (94 97%), mainly albumin. Valsartan is excreted mainly in unchanged form via the bile and urine. A hydroxymetabolite has been identified in plasma at low concentrations (less than 10% of the AUC of valsartan). This metabolite is pharmacologically inactive. Following oral administration of valsartan, 83% is excreted with the faeces and 13% via the urine, mainly in unchanged form. Hydrochlorothiazide After oral application, hydrochlorothiazide is resorbed quickly (tmax approx. 2 hours) and the absolute bioavailability is 60-80%. Within the therapeutic range, the increase in the mean AUC is linear and proportional to the dose. The distribution and elimination follow a bi-exponential kinetic with a terminal half-life of 6-15 hours. Circulating hydrochlorothiazide is bound to serum proteins (40-70%), and mainly to albumin. More than 95% of the resorbed amount is excreted via the kidney in unchanged form. Valsartan/Hydrochlorothiazide An observed reduction in the systemic availability of hydrochlorothiazide by about 30% upon simultaneous application with valsartan does not have a clinical impact, since in controlled clinical studies with the combination valsartan+hydrochlorothiazide a clear hypotensive effect was shown which was greater than that produced by either of the individual substances or placebo administration. IV.2 Clinical efficacy and safety Bioequivalence studies The main objective of the first bioequivalence study was to assess bioequivalence of the test product Valsartan/HCT 160 mg/25 mg film-coated tablets (STADA Arzneimittel AG, Germany) compared to the reference product CoDiovan forte 160 mg/25 mg film-coated tablets (Novartis Pharma GmbH, Germany). The secondary objective was to investigate safety on the basis of clinical and laboratory examinations (at the beginning and at the end of the trial) and registration of adverse events. The study was conducted as a monocentric, open, randomized, single-dose, two-period crossover trial in 85 healthy male volunteers, with a wash-out period of 7 days. AUC0-tlast and Cmax of valsartan and hydrochlorothiazide were defined as primary endpoints, tmax of valsartan and hydrochlorothiazide as a secondary and AUC0-inf, MRT, and t½ of valsartan and hydrochlorothiazide as additional endpoints. Bioequivalence was determined through comparison of the 90% confidence intervals of logtransformed values for the intra-individual ratio (test vs. Reference) for AUC0-tlast and Cmax of valsartan and hydrochlorothiazide. 5/7

6 The 90% confidence interval of all primary endpoints (AUC0-t, Cmax) of Valsartan and Hydrochlorothiazide were within the % range. Therefore bioequivalence could be demonstrated in this study. But although bioequivalence could be proven in this trial involving the 160/25mg-strength, the results couldn t be extrapolated (via biowaiver) to the remaining strengths as the ratio of active substances and excipients is not the same for all strengths. Thus an additional, supportive bioequivalence study was carried out during the clock-stop. This was a single dose, randomized, 4-way replicate crossover study, this time with the 160/12.5 mg-strength. The 4-way replicate crossover design was chosen to demonstrate the high intrasubject variability of active substance valsartan. In addition to this, the applicant provided several references that support the high variability of active substance valsartan. The main objective of this second, supportive trial was to assess bioequivalence of 160/12.5 filmcoated tablets (STADA Arzneimittel AG, Germany) as compared to originator CoDiovan 160/12.5 mg film-coated tablets (Novartis Pharma GmbH, Germany). The secondary objective was to investigate the safety of both preparations on the basis of safety, clinical and laboratory examinations. AUC0-tlast and Cmax of valsartan and hydrochlorothiazide were defined as primary endpoints, tmax, AUC0-inf, AUCres, MRT and t½ as secondary or additional endpoints. The 90% confidence intervals of log-transformed values were calculated for the intra-individual ratio test vs. reference for AUC0-tlast and Cmax of valsartan and hydrochlorothiazide and then compared to the acceptance limits that had been predefined in the protocol. Based on the submitted references and the results of the two submitted bioequivalence studies, it could be concluded that valsartan in deed seems to be a highly variable drug. Results The 90% confidence interval of all primary endpoints (AUC0-t, Cmax) of Valsartan and Hydrochlorothiazide were within their protocol-defined limits. Based on the references and with regard to the results of the replicate design study (design chosen to demonstrate high intrasubject variability), the RMS was able to accept the pre-widening of cmax of Valsartan. Bioequivalence was demonstrated. Regarding the biowaiver (CPMP/EWP/QWP/1401/98) following criteria were clear and fulfilled from the beginning: - Same manufacturer and manufacturing - Both active substances are linear over therapeutic dose range - Same qualitative composition of all strengths - Similar dissolution profile for all strengths (see also question of PT). The only requirement initially causing difficulties in extrapolation was the same ratio between active substance and excipients or same ratio between the excipients in the case of drugs with a very low active substance (<5%), as in this case with HCT. 6/7

7 The 80/12.5mg and the 160/25mg strength (note: the first study was performed with 160/25mg) are exactly dose proportional. So are 160/12.5mg and 320/25mg. Note: The product contains less than 5% of the active substance HCT which is why it is sufficient that the excipients show the same ratio (CPMP/EWP/QWP/1401/98). 320/25mg differs from 320/12.5mg only in the amount of HCT, while the excipients remain the same. Therefore, the results from the 160/12.5mg study can safely be extrapolated to the 320/25mg and 320/12.5mg strengths. On the whole, bioequivalence between test and reference product was demonstrated in both studies and the results can now also be extrapolated to the remaining strengths. V. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Based on the documentation submitted the risk-benefit ratio for this application was considered positive and marketing authorisation was recommended. User consultation The Readability User Test was performed using Valbanatan 320 mg/25 mg film-coated tablets, Valbanatan 160 mg/25 mg film-coated tablets, as parent leaflet (leaflet with the highest concentrations of the active substances). Both leaflets share an identical set of key safety messages with highly similar or identical content. Minor differences exist in contraindications, general warnings, dosage information, kidney and liver problems, ingredients and appearance and content of the pack sections. These are however acceptable and obvious. Therefore the Readability User Test results obtained for the parent PIL can be bridged to the proposed daughter PIL. However meanwhile, the SPC and PIL have been adapted to the Art.30 referral outcome of the originator Co-Diovan. 7/7