Decentralised Procedure Public Assessment Report Levomethadon Develco 2,5 / 5 / 20 / 30 mg Tabletten Levomethadon Develco Pharma 2,5 / 5 / 20 / 30 mg Tabletten Levomethadone hydrochloride DE/H/4848-49/001-004/DC Applicant: Develco Pharma GmbH, Germany Date: 05.10.2017 This module reflects the scientific discussion for the approval of Levomethadon Tabletten. The procedure was finalised at 12.07.2017. 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 ............................................................. 6 III.1 Quality aspects................................................................................................................. 6 III.2 Non clinical aspects .......................................................................................................... 6 III.3 Clinical aspects ................................................................................................................ 6 IV BENEFIT RISK ASSESSMENT ..................................................................................... 8 Levomethadon, DE/H/4848-49/001-004/DC Public AR 2/8 ADMINISTRATIVE INFORMATION Levomethadon Develco Proposed name of the medicinal Levomethadon Develco Pharma product in the RMS 2,5 / 5 / 20 / 30 mg Tabletten Name of the drug substance (INN Levomethadone hydrochloride name): Pharmaco-therapeutic group N07BC05 and N02AC06 (ATC Code): Pharmaceutical form(s) and Tablets; 2,5 / 5 / 20 / 30 mg strength(s): Reference Number(s) for the DE/H/4848-49/001-004/DC Decentralised Procedure Reference Member State: DE Concerned Member States: LU Develco Pharma GmbH Grienmatt 27 Applicant (name and address) 79650 Schopfheim Germany Levomethadon, DE/H/4848-49/001-004/DC Public AR 3/8 I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for “Levomethadon Develco2,5 / 5 / 20 / 30 mg Tabletten and Levomethadon Develco Pharma 2,5 / 5 / 20 / 30 mg Tabletten”, used in adults for oral substitution treatment of opioid dependence within a framework of medical, social and psychological treatment (DE/H/4848/001-004/DC) and indicated for severe pain (DE/H/4849/001-004/DC), is approved. II EXECUTIVE SUMMARY II.1 Problem statement N/A II.2 About the product Levomethadon HCl immediate release 2.5, 5, 20, and 30 mg tablets containing levomethadone hydrochloride as active substance are intended for oral use. 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. DE/H/4848/001-004/DC Methadone maintainance therapy was introduced in Germany in 1988 and recemic methadone was not aproved until 1994, therefore in Germany until the mid-1990 only levomethadone was used. Levomethadone is primary responsible for the opioid agonist and desired substitution effect in opiod- dependent patients, while dextromethadone does not contribute to the efficacy and has been related to undesired effects such as sweating and gastrointestinal disturbances. The goals of maintenance treatment with opioid agonists are a reduction or cessation of illicit opioids, of injecti ng and associated risk of blood borne virus transmission, of overdose risk, of criminal activity and improvement in psychological and physical health. Therapeutic indication: is used in adults for oral substitution treatment of opioid dependence within a framework of medical, social and psychological treatment. DE/H/4849/001-004/DC 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. Therapeutic indication: Severe pain II.3 General comments on the submitted dossier The applicant, Develco Pharma GmbH, Germany, applies through the Decentralised Procedure with DE acting as reference member state (RMS) and LU as concerned member states (CMS). Levomethadon, DE/H/4848-49/001-004/DC Public AR 4/8 DE/H/4848/001-004/DC The active substance, proposed therapeutic indications, pharmaceutical form and route of administration of the applicant’s product vis-à-vis the reference medicinal product is identical. However, Levomethadone HCl Tablets is an immediate release tablet formulation presented in 4 distinct dosage strengths in comparison to L-Polamidon® Lösung zur Substitution 5 mg/ml, Lösung zum Einnehmen which is an oral solution of a defined concentration (5 mg/ml) but without exactly defined strengths. Consequently, this application is filed in accordance with Article 10.3 of Directive 2001/83/EC (so called “hybrid” application) due to the formal mismatch of the dosage strengths between the applicant’s formulation compared to the reference drug product, and is suitably supported via a bioequivalence study between test and reference product. The originator product, L-Polamidon ® Lösung zur Substitution 5 mg/ml, Lösung zum Einnehmen, was approved in an EU Member State in 2001 (5th January 2001 in DE; Reg. No. 45583.00.00). Accordingly, the authorisation of the originator product dates back at least 10 years. DE/H/4849/001-004/DC 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 four 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 a 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 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 GMP 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. 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. GCP/GLP The applicant states that the study was conducted in accordance with GCP and under consideration of relevant legal guidelines and recommendations. The study sites for clinics, bioanalytics and pharmacokinetics/statistics was audited by the Czech Regulatory Authority (SUKL) in 2014. The staff of the CRO had no access to the randomisation details before the pharmacokinetic data evaluation and all non-clinical parts were performed in accordance with GLP. Levomethadon, DE/H/4848-49/001-004/DC Public AR 5/8 III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance The drug substances used for the manufacture of the drug product levomethadone HCl IR tablets, levomethadone is monographed in the Ph. Eur.. The quality of the drug substances from both manufacturer. is controlled in compliance with