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(Levomethadone) DE/H/4849/005/DC Applicant Decentralised Procedure Public Assessment Report Levomethadone Aristo 7.5 mg tablets (Levomethadone) DE/H/4849/005/DC Applicant: Aristo Pharma GmbH Date: 03rd March 2021 This module reflects the scientific discussion for the approval of the above-mentioned product. The procedure was finalised on 15th February 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 ........................................................................ 4 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. 5 III. SCIENTIFIC OVERVIEW AND DISCUSSION ................................................................. 5 III.1 Quality aspects ......................................................................................................................... 5 III.2 Non-clinical aspects ................................................................................................................. 6 III.3 Clinical aspects ........................................................................................................................ 6 IV. BENEFIT RISK ASSESSMENT ........................................................................................... 8 Levomethadone, DE/H/4849/005/DC Public AR 2/8 ADMINISTRATIVE INFORMATION Proposed name of the medicinal product Levomethadon Aristo 7,5 mg Tabletten in the RMS Name of the drug substance (INN Levomethadone name): Pharmaco-therapeutic group N07BC05 (ATC Code): Pharmaceutical form(s) and strength(s): Tablet, 7,5 mg Reference Number(s) for the DE/H/4849/005/DC Decentralised Procedure Reference Member State: DE Concerned Member States: LU (withdrawn) Legal basis of application: Article 10(3) hybrid application Applicant (name and address) Aristo Pharma GmbH Wallenroder Str. 8-10 13435 Berlin Germany Names and addresses of all proposed Aristo Pharma GmbH manufacturer(s) responsible for batch Wallenroder Str. 8-10 release in the EEA 13435 Berlin Germany Levomethadone, DE/H/4849/005/DC Public AR 3/8 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for “Levomethadon Aristo 7,5 mg Tabletten”, used in adults for treatment of severe pain is approved. II. EXECUTIVE SUMMARY II.1 Problem statement N/A II.2 About the product Levomethadon HCl immediate release 7.5 mg tablets containing levomethadone hydrochloride as active substance are intended for oral use. The product is a line extension to the already approved 2.5 mg, 5 mg, 20 mg and 30 mg dose strengths (DE/H/4849/001-004/DC). Levomethadone is the active R-enantiomer of racemic methadone. Methadone is a synthetic μ-opioid receptor agonist and contains a single chiral carbon atom. Levomethadone has a 10-fold higher affinity to both the μ and δ opioid receptors, and possesses up to 50 times the analgesic activity of dextromethadone. Levomethadone primarily acts via agonism at the μ-opioid receptors but in addition also, as a NMDA receptor antagonist and serotonin and norepinephrine re-uptake inhibitor. This multi-modal analgesic action renders levomethadone a particularly attractive option in patients with severe refractory pain. The use of levomethadone instead of racemic methadone for the treatment of severe pain is largely restricted to German-speaking regions and levomethadone for the indication of severe pain is approved in Germany for over 10 years. The proposed indication is: Severe pain in adults II.3 General comments on the submitted dossier The applicant, Aristo Pharma GmbH, Germany, applies through the Decentralised Procedure with DE acting as reference member state (RMS). Although the product under discussion is an IR tablet formulation whereas the reference product is an oral aqueous solution both formulations show the same pharmaceutical form within the definition of a generic medicinal product for the purposes of Article 10 of Directive 2001/83/EC, as amended. However, Levomethadone HCl Tablets is an immediate release tablet formulation developed in five distinct dosage strengths in comparison to L-Polamidon® Tropfen 5 mg/ml, Tropfen zum Einnehmen, which is an oral solution of a defined concentration (5 mg/ml) but without exactly defined strengths. Hence, this application is filed with reference to Article 10.3 of Directive 2001/83/EC, as amended. The originator product, L-Polamidon® Tropfen 5 mg/ml, Tropfen zum Einnehmen, was approved in an EU Member State in 2001 (4th February 2003 in DE; Reg. No. 6196782.00.00). Accordingly, the authorisation of the originator product dates back at least 10 years. The applicant provides no further bioavailability study, since the requested product is a line extension to the already approved strengths of procedure DE/H/4849/001-004/DC. The following BE study was carried out in the course of the aforementioned procedure: Comparative bioavailability study with Levomethadone HCl 5 mg IR tablets and the clinical reference product L-Polamidon®, Lösung zur Substitution, Lösung zum Einnehmen (Sanofi-Aventis Deutschland GmbH, Germany) in order to ensure that test and reference formulations are bioequivalent. Of note, the outcome of this study is considered meaningful also for the originator Levomethadone, DE/H/4849/005/DC Public AR 4/8 product L-Polamidon® Tropfen 5 mg/ml, Tropfen zum Einnehmen since both L-Polamidon® oral solutions show the same qualitative and quantitative composition with regard to the active substance (levomethadone HCl 5 mg/ml) and an identical qualitative composition of the remaining ingredients (methyl parahydroxybenzoate, betaine hydrochloride, glycerol 85%, purified water). 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 (here: Switzerland). GMP active substance Regarding the statement on GMP for the drug 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 The drug substance is described in the Ph. Eur. The quality of the drug substance as supplied, is sufficiently stated. The stability results indicated that levomethadone hydrochloride is stable for five years (re test period stated by EDQM) when the drug substance is stored in the proposed PE bags. The quality of the drug substance is sufficiently controlled by the EDQM The stability results indicated that the drug is stable for 48 months (EDQM proposed re test period) when the drug substance is stored in the chosen PE bags. Drug substance´s quality is sufficiently stated by the EDQM certificate. The stability results indicated that levomethadone HCl is stable for 36 months (re test period EDQM based) when the drug substance is stored in the proposed PE bags. Drug Product The finished product is manufactured by manufacturer A and manufacturer B. This product is a generic formulation. BE study, respective bio waiver approach is carried out for the 7.5 mg strength. The excipients used in the product are conventional pharmaceutical ingredients. The function of each ingredient (only for oral use) included in the product has been described detailed. The manufacturing process is sufficiently described for the pilot batches. The analytical methods are described and complete validation reports referred to ICH are submitted. The finished product specifications (for release and shelf life) are in compliance with the general pharmacopoeial requirements and the batch data submitted are controlled with valid ICH conform methods. The batch results are within the specification limits set. The specification limits are justified for this type of solid dosage form. The genotoxic aspects and the analysis of elemental impurities regarding ICH Q 3D are part of this dossier. Details to nitrosamines risks and regarding ICH Q 3D assessment are part of the dossier. All used analytical methods are validated based on the current ICH requirements. Reference materials used are described. Levomethadone, DE/H/4849/005/DC Public AR 5/8 The chosen container closure systems are PVC-Al- blisters and HDPE bottles with a child resistant screw cap (made
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