Mutual Recognition Procedure. Public Assessment Report. Valproat Orion 300 / 500 mg Retardtabletten. Sodium valproate DE/H/1910/ /MR

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1 Mutual Recognition Procedure Public Assessment Report Valproat Orion 300 / 500 mg Retardtabletten Sodium valproate DE/H/1910/ /MR (former FI/H/0608/ /MR) Applicant: Orion Corporation Date: This module reflects the scientific discussion for the approval of Valproat Orion 300 / 500 mg Retardtabletten. The procedure was finalised on

2 TABLE OF CONTENTS I. INTRODUCTION... 4 II. QUALITY ASPECTS... 4 II.1 Introduction... 4 II.2 Drug substance... 4 II.3 Medicinal product... 4 II.4 Discussion on chemical, pharmaceutical and biological aspects... 5 III. NON-CLINICAL ASPECTS... 5 III.1 Introduction... 5 III.2 Pharmacology... 5 III.3 Toxicology... 5 III.4 Environmental Risk Assessment (ERA)... 5 III.5 Discussion on the non-clinical aspects... 5 IV. CLINICAL ASPECTS... 6 IV.1 Pharmacokinetics... 6 IV.2 Pharmacodynamics... 7 IV.3 Clinical efficacy... 7 IV.4 Clinical safety... 7 IV.5 Discussion on the clinical aspects... 8 V. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION... 8 Valproat Orion 300 / 500 mg Retardtabletten, DE/H/1910/ /MR Public AR 2/8

3 ADMINISTRATIVE INFORMATION Proposed name of the medicinal product in the RMS Name of the drug substance (INN name): Pharmaco-therapeutic group (ATC Code): Pharmaceutical form(s) and strength(s): Reference Number(s) for the Decentralised Procedure Reference Member State: Concerned Member States: Applicant (name and address) Valproat Orion 300 / 500 mg Retardtabletten Sodium valproate N03AG01 Prolonged release tablet; 300 / 500 mg DE/H/1910/ /MR (former FI/H/0608/ /MR) DE (former FI) CZ, EE, FI, HU, LT, LV, PL, SK Orion Corporation Orionintie ESPOO Finnland Valproat Orion 300 / 500 mg Retardtabletten, DE/H/1910/ /MR Public AR 3/8

4 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the applications of Sodium Valproate Orion Pharma 300 mg and 500 mg modified release tablets were approved for the following indications: Generalised epileptic seizures, such as tonic-clonic seizures (grand mal), absence seizures (petit mal), myoclonic and atonic seizures. As a secondary medication also in the treatment of partial, focal seizures. A comprehensive description of the indications and posology is given in the SmPC. The product is sold by medical prescription only. With FI as RMS, the marketing authorisations were granted pursuant to Article of Directive 2001/83/EC. The concerned member states were CZ, DE, EE, HU, PL, LT, LV, and SK. This application concerns a generic version of sodium valproate. Sodium valproate has been on the market in Finland and in Sweden under the name Absenor and in Denmark under the name Delepsine since The originator product is Depakine Chrono (300 mg and 500 mg modified release tablet) by Sanofi- Synthelabo France. After changing the RMS, Germany is the new RMS. The former procedure number was FI/H/0608/ /MR. II. QUALITY ASPECTS II.1 Introduction Sodium Valproate Orion Pharma 300 mg and 500 mg modified release tablets are packed into an amber glass jar closed with a tamper-evident closure lined with expanded polyethylene. There is a desiccant capsule in each jar. Amber glass jars are further packed into cardboard boxes. II.2 Drug substance The active substance, sodium valproate, is described in the European Pharamcopoeia and the certificate of suitability granted by European Directorate for Quality of Medicines (EDQM) was presented for the substance. The specifications, analytical procedures used in the testing of sodium valproate are those described in monograph 0678 sodium valproate of the current European Pharmacopoeia. All the batch analysis results provided complied within the specifications limits. Stability studies were conducted under ICH conditions and a suitable retest period could be agreed for sodium valproate based on the data provided. According to the stability data at 40 C/75 % RH sodium valproate should be stored below 25 C. II.3 Medicinal product The aim of the development work was to formulate a modified release tablets containing 300 mg and 500 mg of sodium valproate. The formulation development aimed at a product that was intended to be bioequivalent with Ergenyl Retard 300 mg and 500 mg depot tablets of Sanofi Winthrop AB, Solna, Sweden. Sodium valproate Orion Pharma 300 mg and 500 mg modified release tablets are film-coated tablets. The products have been on the market in Finland since 1995 with the trade name Absenor 300 mg and 500 mg modified release tablet. The tablets were uncoated. In 1998 a moisture-protective coating was developed and added to the products. The compatibility of the drug substance with the excipients was studied and the substance was confirmed compatible with the excipients chosen. All excipients used in the modified release tablet except for Opadry OY-B comply with the current specifications of the European Pharmacopoeia. The TSE risks of the excipients have been adequately addressed. Comparative Valproat Orion 300 / 500 mg Retardtabletten, DE/H/1910/ /MR Public AR 4/8

5 dissolution results on Absenor 300 mg and 500 mg modified release tablets and Deprakine 300 mg and 500 mg depot tablets used in bioequivalence studies were performed. The reference products for the dissolution studies were purchased from Finland and some other countries. Commonly used manufacturing methods and equipment were chosen for the manufacturing process of the modified release tablets. The flowcharts of the manufacturing process were thoroughly presented by the applicant. The process controls included operating parameters, process tests and inprocess material tests. Process validation studies had been conducted for the manufacturing process of the uncoated tablet and the film-coating. The finished product specifications of Sodium Valproate Orion Pharma 300 mg and 500 mg modified release tablets have been set in order to adequately control the physical, chemical, biopharmaceutical and microbiological quality of the product at the time of manufacture and throughout the shelf life. The proposed specifications and limits of finished products were acceptable in the view of the batch data presented. The batches presented complied with the proposed specifications. The analytical procedures were adequately described and validated for their intended purpose. Stability studies for the finished product packed in the propose container closure system had been conducted stored in standard ICH storage conditions. The results of the stability studies substantiated storage in a glass jar with a desiccant capsule and a shelf life of 3 years. The container should be kept tightly closed because the product is sensitive to moisture. II.4 Discussion on chemical, pharmaceutical and biological aspects Overall, the quality of the pharmaceutical data was acceptable and was presented in line with current European regulatory requirements with no principal deviations from EU and ICH quality guidelines. Chemical and pharmaceutical quality of Sodium Valproate Orion Pharma 300 mg and 500 mg modified release tablets was considered as acceptable during the procedure. III. NON-CLINICAL ASPECTS III.1 Introduction Pharmacodynamic and pharmacokinetic properties as well as toxicity of sodium valproate are well known. III.2 Pharmacology Pharmacodynamic and pharmacokinetic properties as well as toxicity of sodium valproate are well known. III.3 Toxicology The acute toxicity of sodium valproate in animals is low, i.e. in rats the oral LD50 is 1500 mg/kg. Chronic toxicity studies show effects on liver and in carcinogenicity studies increased incidence of fibrosarcoma has been reported. In reproductive toxicity studies reduced spermatogenesis and testicular atrophy was detected in male rats and dogs. In female rats, increased numbers of follicular cysts in ovaries was found. Sodium valproate passes through placenta and into milk. Both embryotoxic and teratogenic effects have been shown in animals and in humans. Neural tube defects and skeletal malformations have been seen. In juvenile animals impaired spatial learning has been detected. III.4 Environmental Risk Assessment (ERA) Since Sodium Valproate Orion Pharma 300 mg and 500 mg modified release tablets were intended for generic substitution, this did not lead to an increased exposure to the environment. An environmental risk assessment was therefore not deemed necessary. III.5 Discussion on the non-clinical aspects Abridged applications for generics avoid the need for repetitive tests on animals and humans. As Sodium Valproate is not a new chemical entity, published scientific literature review was considered sufficient to evaluate non-clinical aspects of the product. Approval was recommended from the nonclinical point of view. Valproat Orion 300 / 500 mg Retardtabletten, DE/H/1910/ /MR Public AR 5/8

6 IV. CLINICAL ASPECTS IV.1 Pharmacokinetics Sodium valproate is converted to valproic acid in the gastrointestinal tract and absorbed almost completely, bioavailability being %. Valproic acid is 90% bound to plasma proteins, mainly albumin. It is mainly eliminated by glucuronic acid conjugation and β-oxidation in the liver and excreted to urine. Half-life varies with age; in healthy adults it is hours, in neonates up to 60 hours and in epileptic patients about 9 hours. The pharmacokinetics is linear at steady state. The effective plasma levels of valproic acid are μg/ml. To support the application, the applicant had submitted four reports of steady-state bioequivalence trials: Study , Study , FR and Study FR Study was a comparison between Absenor 500 mg modified release tablet by Orion Corporation as a test product, and reference products Absenor 500 mg modified release tablet, new formulation, by Orion Corporation, and Ergenyl 500 mg prolonged release tablet from the Swedish market, by Sanofi Winthrop in a single dose and at steady state studies. The results of this study are shown in table 1 and table 2. The bioequivalence of the two 500 mg products had been considered shown under the steady state. Table 1. Study with 500 mg test product Absenor 500 mg modified release tablet (by Orion Corporation) v. Ergenyl 500 mg prolonged release tablet (by Sanofi Winthrop). Single dose pharmacokinetic parameters, fasting conditions (non-transformed values; mean ± SD, t max mean and range) Treatment N = 16 AUC0-t AUC0- Cmax μg/ml tmax h Test 523,93 84,61 837,52 350,30 29,31 4,27 8, Reference 480,25 95,86 837,08 284,77 26,85 4,56 7, *Ratio (90% CI) 1, ,4-117,9 0,994 84,2-117,2 1, ,4-117,2 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 24 hours Cmax maximum plasma concentration Tmax time for maximum concentration *ln-transformed values Table 2. Study : Steady state pharmacokinetic parameters, fasting conditions (nontransformed values; mean ± SD, t max mean and range) Treatment N=16 ss-auct ss-cav PTF ss-cmax μg/ml tmax h ss-cmin μg/ml Test 798,15 140,80 66,51 11,73 21,98 7,77 74,69 12,41 5, ,94 11,99 Reference 812,89 177,31 67,74 14,78 13,90 7,24 74,17 17,08 5, ,28 15,39 *Ratio (90% CI) 0,993 92,7-106,4 1,022 95,5-110,0 ss-auct area under the plasma concentration-time curve over the dose interval 12 h at steadystate sscavt average steady-state plasma concentration-time during the dosage interval PTF percent fluctuation index ss-cmax maximum plasma concentration tmax time for maximum concentration ss-cmin trough, day 4 *ln-transformed values Valproat Orion 300 / 500 mg Retardtabletten, DE/H/1910/ /MR Public AR 6/8

7 The supportive study compared the pharmacokinetics of the test product Sodium Valproate Orion Pharma 500 mg modified release tablet by Orion Corporation and reference product Ergenyl 500 mg gastro-resistant (enteric coated) tablet from the Swedish market, by Orion Corporation, in steady state fasting versus fed conditions. Analytical method and handling of samples were found adequate. The AUC ss and C ss point estimates were in the confidence interval limits. Study FR was a comparison of pharmacokinetics. In this study the test product was Sodium Valproate Orion Pharma 500 mg modified release tablet by Orion Corporation and the reference product was Deprakine Depot 500 mg by Sanofi Synthelabo, France, purchased from Finland. The bioequivalence between the two 500 mg test and reference formulations was shown under fasting conditions. Study FR was performed to show the single-dose bioequivalence of the 300 mg products. The test product was Sodium Valproate Orion Pharma 300 mg modified release tablet by Orion Corporation and the reference product was Deprakine Depot 300 mg by Sanofi Synthelabo, France, purchased from Finland. The bioequivalence between the 300 mg test and reference formulation was shown under fasting conditions. Table 3. Study FR with the test product Sodium Valproate Orion Pharma 300 mg modified release tablet versus the reference product Deprakine Depot 500 mg by Sanofi Synthelabo. Single dose pharmacokinetic parameters, fasting conditions (non-transformed values; mean ± SD, t max mean and range) Treatment AUC0-t AUC0- Cmax tmax Test Reference Ln ratio 103,8 90% CI 99,34-108, ,3 97,66-107,22 μg/ml 18,9 3,07 15,9 3,12 119,5 115,10-124,06 h 13,37 2,00 10,7 3,37 AUC0- AUC0-t Cmax Tmax area under the plasma concentration-time curve from time zero to infinity area under the plasma concentration-time curve from time zero to 24 hours maximum plasma concentration time for maximum concentration Conclusion on bioequivalence studies: Based on the bioequivalence studies presented above, Sodium valproate Orion Pharma 300 mg and 500 mg modified release tablets were considered bioequivalent. IV.2 Pharmacodynamics Studies on pharmacodynamics were not applicable. IV.3 Clinical efficacy Sodium valproate has a well-recognised efficacy. IV.4 Clinical safety Sodium valproate is contraindicated in patients with severe hepatic or pancreatic dysfunction and bleeding disorders. Valproic acid inhibits the metabolism of several drugs, especially other antiepileptics. In addition, the metabolism of valproic acid is enhanced by several other antiepileptics. Dose adjustments are usually required. Competitive protein binding is another mechanism of interactions. Valproic acid is considered teratogenic. A foetal valproate syndrome has been described. Valproic acid is also excreted to milk in small amounts, but not regarded harmful for the child. Valproat Orion 300 / 500 mg Retardtabletten, DE/H/1910/ /MR Public AR 7/8

8 IV.5 Discussion on the clinical aspects Bioequivalence between Sodium valproate Orion Pharma and reference product was demonstrated. Abridged applications for generics avoid the need for repetitive tests on animals and humans. Approval was recommended from the clinical and pharmacokinetic point of view. V. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Overall, the quality of the pharmaceutical data was acceptable and was presented in line with current European regulatory requirements with no principal deviations from EU and ICH quality guidelines. Chemical and pharmaceutical quality of Sodium Valproate Orion Pharma 300 mg and 500 mg modified release tablets was considered as acceptable during the procedure. The application contained an adequate review of published non-clinical data and clinical data. Bioequivalence with the originator product has been adequately shown. The application is approved. For intermediate amendments see current product information. Valproat Orion 300 / 500 mg Retardtabletten, DE/H/1910/ /MR Public AR 8/8