Decentralised Procedure Public Assessment Report Valproat AL 300 mg/ml Lösung zum Einnehmen Sodium valproate DE/H/6803/001/DC Applicant: STADA Arzneimittel AG Date: 06th July 2021 This module reflects the scientific discussion for the approval of the above-mentioned product. The procedure was finalised on 1st June 2021. TABLE OF CONTENTS I INTRODUCTION ................................................................................................................................. 4 II EXECUTIVE SUMMARY .................................................................................................................. 4 II.1 PROBLEM STATEMENT....................................................................................................................... 4 II.2 ABOUT THE PRODUCT ........................................................................................................................ 4 II.3 GENERAL COMMENTS ON THE SUBMITTED DOSSIER ....................................................................... 5 II.4 GENERAL COMMENTS ON COMPLIANCE WITH GMP, GLP, GCP AND AGREED ETHICAL PRINCIPLES. .................................................................................................................................................. 6 III SCIENTIFIC OVERVIEW AND DISCUSSION ............................................................................ 6 III.1 QUALITY ASPECTS ............................................................................................................................ 6 III.2 NON CLINICAL ASPECTS ................................................................................................................... 6 III.3 CLINICAL ASPECTS ........................................................................................................................... 7 IV BENEFIT RISK ASSESSMENT ..................................................................................................... 20 IV.1 CONDITIONS PURSUANT TO ARTICLE 21A OR SPECIFIC OBLIGATIONS PURSUANT TO ARTICLE 22 OF DIRECTIVE 2001/83/EC ................................................................................................................... 20 DE/H/6803/001/DC, Sodium valproate Public AR Page 2/22 ADMINISTRATIVE INFORMATION Proposed name of the medicinal Valproat AL 300 mg/ml Lösung zum Einnehmen product in the RMS Name of the drug substance (INN Sodium valproate name): Pharmaco-therapeutic group N03AG01 (ATC Code): Pharmaceutical form(s) and Oral solution, 300 mg/ml strength(s): Reference Number(s) for the DE/H/6803/001/DC Decentralised Procedure Reference Member State: DE Concerned Member States: LU Legal basis of application: Article 10(1) Generic application Applicant (name and address) STADA Arzneimittel AG Stadastrase 2-18 61118 Bad Vilbel, Germany Names and addresses of all proposed STADA Arzneimittel AG manufacturer(s) responsible for Stadastrase 2-18 batch release in the EEA 61118 Bad Vilbel, Germany G.L. Pharma GmbH Schlossplatz 1 8502 Lannach, Austria DE/H/6803/001/DC, Sodium valproate Public AR Page 3/22 I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for “Valproat AL 300 mg/ml Lösung zum Einnehmen” with the following indication: For the treatment of: • generalised seizures in the form of absences, myoclonic seizures and tonic-clonic seizures, • focal and secondary generalised seizures, and for the combined therapy in the case of other forms of seizure, e.g. focal seizures with simple and complex symptoms as well as focal seizures with secondary generalisation, when these seizure forms do not respond to the standard antiepileptic treatment. Notes Valproic acid containing medicinal products are the first-line therapy for infants in exceptional cases only; <Product name> should be used with extreme caution, if the benefits outweigh the risks, and, if possible, monotherapy should be preferred. For use during pregnancy, see sections 4.4 and 4.6. is approved. II EXECUTIVE SUMMARY II.1 Problem statement N/A II.2 About the product Pharmacological class and proposed clinical use Valproic acid (VPA) is an eight-carbon branched-chain fatty acid with unique anticonvulsant properties and is also used in bipolar disorder and for the prophylaxis of migraine. Sodium valproate belongs to the pharmacotherapeutic class ‘Antiepileptics, fatty acid derivatives’, ATC code: N03A G01. With its anticonvulsant properties it has been used since decades as an antiepileptic, particularly in the treatment of primary generalised seizures. It provides notable benefit in absence and myoclonic seizures, and is also used for partial seizures. Its actions are complex and its mode of action in epilepsy is not fully understood. Sodium valproate is also used in bipolar disorder and for the prophylaxis of migraine. Mode of action The most likely mode of action is potentiation of the inhibitory action of gamma amino butyric acid (GABA) through an action on the further synthesis or further metabolism of GABA. The activation of glutamic acid decarboxylase and the inhibition of GABA transaminase result in a strong increase in GABA concentrations in the synaptosomes and in the intersynaptic cleft. As an inhibitory neurotransmitter, GABA impedes pre- and postsynaptic discharges and thus prevents convulsive activity from spreading. DE/H/6803/001/DC, Sodium valproate Public AR Page 4/22 Pharmacokinetic properties VPA and its sodium salts are rapidly and completely absorbed from the gastrointestinal tract; the rate, but not the extent of absorption, is delayed by administration with or after food. VPA is extensively metabolised in the liver, a large part by glucuronidation and the remainder by a variety of complex pathways. It does not appear to enhance its own metabolism, but metabolism may be enhanced by other drugs which induce hepatic microsomal enzymes. It is excreted in the urine almost entirely in the form of its metabolites; small amounts are excreted in faeces and expired air. VPA is extensively bound to plasma proteins. The extent of protein binding is concentration dependent and is stated to be about 90 to 95 % at total concentrations of 50 mg/l, falling to about 80 to 85 % at 100 mg/l. The elimination half-life of valproate is critically dependent on comedication and age. Reported half-lives for VPA have ranged from about 5 to 20 hours, the shorter half-lives have generally been recorded in epileptic patients receiving multiple drug therapy. The 'target' range of total plasma-VPA is usually quoted as being 40 to 100 mg/l (280 to 700 μmol/l) but routine monitoring of plasma concentrations is not generally considered to be of use as an aid to assessing control. The bioavailability of standard oral preparations of valproate is fast and virtually complete as compared to the intravenous form. VPA crosses the placental barrier and small amounts are distributed into breast milk depending on the fraction unbound to plasma proteins. II.3 General comments on the submitted dossier This decentralised application concerns a generic version of sodium valproate, under the trade name Valproat AL 300 mg/ml Lösung zum Einnehmen. In this Assessment Report, the name valproate is used. The originator product is Ergenyl 300 mg/ml Lösung, oral solution by Sanofi Aventis Germany, registered since 17.02.1999. With Germany as the Reference Member State in this Decentralized Procedure, Stada Arzneimittel AG is applying for the Marketing Authorisations for Valproat AL 300 mg/ml Lösung zum Einnehmen. The MAA in LU has been withdrawn during clock stop. The present applications of Valproic Acid 300 mg/ml oral solution comply with the definition of a generic medicinal product as stated in Article 10(1) of Directive 2001/83/EC as amended, as it has: - the same qualitative and quantitative composition in active substances as the reference medicinal product (please refer to Module 2.7.1 and 3.2.P.2), - the same pharmaceutical form as the reference medicinal product (oral solution), - and whose bioequivalence with the reference medicinal product has been demonstrated in a biowaiver with information as mentioned below (for more detailed information, please refer to Module 2.7.1 and 3.2.P.2). The reference medicinal products are Ergenyl-Lösung (DE) and Depakine Tropfen (AT) from Sanofi- Aventis which were first approved in 17.02.1999 (DE) and 30.05.1975 (AT). Thus, the application complies with Article 10(1) of Directive 2001/83/EC as amended, as the reference medicinal product is authorized in a Member State for more than ten years. Assessment of similarity with authorised orphan medicinal product(s) under market exclusivity Potential similarity with orphan medicinal products N/A DE/H/6803/001/DC, Sodium valproate Public AR Page 5/22 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product. 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 of 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