Decentralised Procedure Public Assessment Report Valproat AL 300 Mg/Ml Lösung Zum Einnehmen Sodium Valproate DE/H/6803/001/DC A
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
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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
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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;
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.
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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
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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 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.
GMP active substance Regarding the statement on GMP for the active substance a statement/declaration is provided from the manufacturer(s) responsible for manufacture of the finished product and batch release situated in the EU.
III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance Sodium valproate 300 mg/mL Oral solution contains 300 mg of sodium valproate generated in situ from Valproic Acid Ph. Eur. per millilitre sweetened, orange flavoured aqueous solution.
The active substance valproic acid is described in the European Pharmacopoeia. The quality of the valproic acid is controlled in compliance with the corresponding monograph of the European Pharmacopoeia. The certificate of suitability of the EDQM has been submitted.
Katwijk Chemie BV The CEP does not include any re-test period. Detailed information on stability studies have been presented. The re-test date of the substance valproic acid is set to 60 months. Stability studies have been performed with the drug substance. No significant changes in any parameters were observed. The proposed re-test period of 5 years is justified.
Drug Product The development of the product has been described, the choice of excipients is justified and their functions explained. The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Furthermore, batch analyses data of three batches of Sodium valproate 300 mg/mL Oral solution containing drug substance manufactured by manufacturer A. Drug substance manufactured by manufacturer A is not part of the dossier. Manufacturer A has been removed from Module 3.2.S previously, as this API manufacturer has stopped supplying valproic acid in 2017. The conditions used in the stability studies are according to the ICH stability guideline. The control tests and specifications for drug product are adequately drawn up. The proposed shelf-life of 60 months and the proposed shelf-life after the first opening (in-use stability) of 6 months are justified based on presented stability data.
III.2 Non clinical aspects Pharmacodynamic, pharmacokinetic and toxicological properties of valproate are well known. As valproate is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate.
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The non-clinical overview is dated 02.08.2019. The report refers 29 publications up to year 2018. The non- clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate.
The non-clinical sections of the SmPC are in accordance with the German reference product Ergenyl oral solution and the amendments adopted via Referral under Article 31 of Directive 2001/83/EC.
Environmental Risk Assessment (ERA) Since “Valproat AL 300 mg/ml Lösung zum Einnehmen” is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary.
III.3 Clinical aspects Pharmacokinetics To support this application, the applicant has submitted no bioequivalence study. According to the EMA Guideline on the Investigation of Bioequivalence (EMA, CPMP/EWP/QWP/1401/98 Rev. 1/Corr, 2010) for oral solutions a biowaiver approach is acceptable.
Valproate is considered to have well established use due to satisfactory level of safety and recognised efficacy. This is widely reflected in the published scientific literature and the coherence of scientific assessments.
In terms of pharmaceutical/clinical equivalence it is necessary to show that the finished product is essentially similar to the innovator finished product. Therefore, also several bioavailability studies were performed to show bioequivalence of several valproate preparations manufactured by G.L. Pharma versus the reference valproate product Depakin (also marketed under the trade names Depakine, Ergenyl and Epilim) and thus to prove the surrogate of equivalent efficacy and safety for the products.
Sodium valproate 300 mg/mL Oral solution (this application) claims bioequivalence with Ergenyl-Lösung and Depakine Tropfen of Sanofi (containing sodium valproate in the same concentration, i.e. 300 mg/mL) justified by the following:
- aqueous oral valproic acid liquid formulations are approximately 100% bioavailable - the intended and the reference oral solution contain the active substance in the same concentration - the other excipients of the intended product in the concentrations used do not affect bioavailability of the actives substance from the product.
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 (see Table 1 below), - 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 see below).
The reference medicinal product is Ergenyl-Lösung (DE) from Sanofi-Aventis which was first approved in 17.02.1999 (DE). 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.
Sodium Valproate 300 mg/ml Oral Solution is administered orally. The pharmacokinetic behaviour of valproate after oral administration is reported in detail in the published literature.
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The following applies for oral solutions according to the EMA Guideline on the Investigation of Bioequivalence (EMA, CPMP/EWP/QWP/1401/98 Rev. 1/Corr, 2010) (page 23, chapter ‘Oral solutions’): - “If the test product is an aqueous oral solution at time of administration and contains an active substance in the same concentration as an approved oral solution, bioequivalence studies may be waived.” This applies to the test product. - “However if the excipients may affect gastrointestinal transit (e.g. sorbitol, mannitol, etc.), absorption (e.g. surfactants or excipients that may affect transport proteins), in vivo solubility (e.g. co-solvents) or in vivo stability of the active substance, a bioequivalence study should be conducted, unless the differences in the amounts of these excipients can be adequately justified by reference to other data. The same requirements for similarity in excipients apply for oral solutions as for Biowaivers (see Appendix III, Section IV.2 Excipients).”
Legal Status Medicinal product subject to medical prescription.
User Testing The package leaflet of
Considering all information: According to the readability index (RI) a high percentage (98.7%) of the information requested in the questions was found and understood correctly. 296 out of 300 pieces of information were found and understood.
Considering each test subject: According to the RI-Rating 17 test subjects (85%) found and understood all pieces of information requested.
Considering each question: The lowest RI rating (finding + understanding) of any requested information was 18/20 (90.0%) for questions no. 5 and 12. This test result meets the corresponding success criteria of the “Guideline on the readability of the labelling and package leaflet of medicinal products for human use”, Annex, 2009 “A satisfactory test outcome for the method outlined above is when the information requested within the package leaflet can be found by 90% of test participants, of whom 90% can show that they understand it. That means to have 16 out of 20 participants able to find the information and answer each question correctly and act appropriately”.
No further test round is required.
The applicability of this PL is high because the test subjects were able to answer the questions within a few cognitive steps. The PL is therefore considered to be user friendly. Overall the test subjects were satisfied with the readability of the text. They were also satisfied with the clarity of the text, the graphical layout, and the font style and size.
Summary Pharmacovigilance system The Applicant has submitted a signed Summary of the Applicant's and/or Proposed Future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable.
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Risk Management Plan The MAH has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Valproat AL 300 mg/ml Lösung zum Einnehmen.
Summary of safety concerns The Applicant proposed the following summary of safety concerns:
Summary of safety concerns Important identified risks Teratogenicity Important potential risks Risks to unborn children via third generation and paternal exposure Missing information None
Pharmacovigilance Plan The Applicant provided the following summary of additional pharmacovigilance activities:
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Additional risk minimization measures: The Applicant provided the following summary of additional risk minimization measures:
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Periodic Safety Update Report (PSUR) With regard to PSUR submission, the MAH should take the following into account:
• PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR. • For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list. • In case the active substance will be removed in the future from the EURD list because the MAs have been withdrawn in all but one MS, the MAH shall contact that MS and propose DLP and frequency for further PSUR submissions together with a justification
IV BENEFIT RISK ASSESSMENT The presented chemical-pharmaceutical documentation of drug substance valproic acid and drug product Valproat AL 300 mg/ml Lösung zum Einnehmen (Sodium valproate 300 mg/mL Oral solution) is of acceptable quality. Approval is recommended from quality point of view. The application contains an adequate review of published clinical data and the bioequivalence has been shown. The waiver of a bioequivalence study appears justified. Bioequivalence of the intended product, Sodium valproate 300 mg/ml oral solution (this application) with the reference product Ergenyl-Lösung of Sanofi can be concluded. It is confirmed that no excipients of Sodium valproate 300 mg/ml oral solution interact with or affect the gastrointestinal transit, absorption, in vivo solubility or in vivo stability of the contained active substance. Approval is recommended from the clinical point of view. Approval is also recommended from the nonclinical point of view. The application is approved. For intermediate amendments see current product information.
IV.1 Conditions pursuant to Article 21a or specific obligations pursuant to article 22 of Directive 2001/83/EC
Additional risk minimisation measures (including educational material) The educational material should contain the following key elements:
The Marketing Authorisation Holder shall ensure that Healthcare professionals who intend to prescribe or dispense Valproate are provided or have access to the most recent version of SmPC and Valproate Educational Materials for HCPs and Patients.
The content and format of the Valproate Educational Material, together with the communication and distribution plan, should be agreed with the National Competent Authority in each Member State prior to distribution.
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The following risk: • Teratogenicity is concerned by the additional minimization measures.
The MAH will implement a Pregnancy prevention programme (PPP). This Pregnancy prevention programme (PPP) is a set of interventions aiming to minimise pregnancy exposure during treatment with valproic acid due to the risk of teratogenicity. The following Educational materials are part of the Pregnancy prevention programme (PPP).
The Educational material consist of the following materials: Educational material for Health Care Professionals: - Healthcare professionals (HCPs) Guide - Annual risk acknowledgement form
Educational material for patients: - Patient Guide - Patient Card
Visual Reminder on the outer package: A visual reminder on the outer package is intended to warn the patient about the harm to an unborn baby and the need for effective contraception when using the medicinal product.
Key elements of the educational material: Healthcare professionals (HCPs) Guide aims to raise awareness of valproate prescribers of the risks associated with the use of this product in female children, women of childbearing potential and pregnant women.
It also provides information on the requirements prior to starting treatment with valproate and modalities for annual re-assessment of the need for valproate therapy and discontinuation and switching to alternative treatment options in female children who experienced menarche and women of childbearing potential. It includes the recommendation to inform the parents of young girls using valproate about the need to contact their specialist once their daughter has experienced menarche. Recommendations on switching or discontinuing valproate as well as recommendations on pregnancy planning are also included aiming at providing this information to the patients.
The guide includes the actions to mitigate the risks associated with the use of valproate in case of pregnancy.
This guide allows prescribers to familiarise themselves with the more recent data on disorders of development in the exposed child, provide information about the risks of valproate monotherapy and poly- therapy and a description of the roles of different HCPs. It also provides instructions to the prescribers on the distribution of the patient guide and the completion of the risk acknowledgement form.
Annual risk acknowledgement form – aims to support the transmission of the information to the patient and to support the dialogue between the prescriber and the patient to ensure that the patient has well understood this information. This form includes a checklist for prescribers and patients or carers. This checklist is intended to be used at time of treatment initiation and annual review by physicians experienced in the management of epilepsy, bipolar and migraine to facilitate a discussion with girls and WCBP patients and/or their carers about the suitability of treatment with valproate and its risks.
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Patient guide – is intended for women who are being prescribed valproate and are able to get pregnant. The guide provides comprehensive information on risks to the unborn child due to in utero exposure to valproate and related substances, the details of the pregnancy prevention programme and the required actions in terms of pregnancy or intention to become pregnant. In order to provide adequate information, it provides information for different situations in the life-time of a woman and is age-appropriate: the first prescription, women continuing valproate treatment and not trying to have a child, women of childbearing potential continuing valproate treatment and considering trying to have a child, pregnant women (unplanned pregnancy) whilst continuing valproate treatment.
Patient reminder card (the packaging is to be updated to include this on the outer carton) – is to be provided to all patients each time the medicine is dsispensed. Information on the patient card provides a brief and concise information regarding the efficacy of the valproate containing medicinal product but also the harm to the unborn baby when taken during pregnancy.
Obligation to conduct post-authorisation measures in accordance with Article 21a of Directive 2001/83
The MAH shall complete, within the stated timeframe, the below measures: Description Due date DUS of valproate and related substances, in Europe, using databases Final report (EMEA/H/N/PSA/J/0015) 2019 DUS extension VALNAC09343 (EMEA/H/N/PSP/J/0075 Final report June 2023 VALNAC09344 – Switch study (EMEA/H/N/J/0074) Final report November 2020 VALNAC09345 – retrospective observational study on risks in offspring paternally Final report exposed (EMEA/H/N/PSP/J/0072) Q4 2021 VALNAC09348 Survey among HCPs and patients (EMEA/H/N/PSP/J/0073) 12 months after protocol endorsement PASS using existing registries (WS Varition 354) Protocol submission until 9 March 2021
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