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

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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 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

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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 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 is a synthetic μ- 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 , 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).

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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.

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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 the corresponding monograph of the Ph. Eur.. The suitability of the monograph to test the drug substance has been verified by EDQM respectively. The certificates of suitability have been granted and copies of the current version of the certificates are provided. A declaration that no starting materials derived from human or animal origin are used during the drug substance manufacturing process is stated on the CEPs, respectively.

Drug product Levomethadone HCl IR tablets are an oral immediate release tablet formulation of levomethadone hydrochloride obtained by compression of active granules into a tablet. The formulation will be available in multiple strengths, i.e. containing 2.5 mg, 5 mg, 20 mg, and 30 mg levomethadone hydrochloride.

Objective of this development was to obtain an immediate release formulation bioequivalent to the relevant originator product approved and marketed in Germany under the trade name “L-Polamidon® Lösung zur Substitution (5 mg/mL)”. The ingredients and the manufacturing process of the drug are considered suitable to produce a pharmaceutical product of the proposed quality.

All relevant quality characteristics of the drug product (release and shelf-life) are specified. Specifications are justified and conform to ICH guidelines. A risk assesment in line with ICH Q3D guideline has been included in the dossier. The description of the analytical methods used to analyse the drug product are adequate, the validation results are plausible.

The container closure system consists of aluminium /PVC-PE-PVDC blisters and HDP bottles with child-resistant polypropylene twist-off caps. All relevant certificates of the container closure systems are provided.

In the light of the provided stability data, a shelf life of 24 months is accepted.

III.2 Non clinical aspects Pharmacology, Pharmacokinetics, Toxicology Pharmacodynamic, pharmacokinetic and toxicological properties of levomethadone are well known. As levomethadone is a widely used, well-known active substance, the applicant has not provided additional non-clinical studies and further non-clinical studies are not required. Overview based on literature review is, thus, appropriate.

The submitted non-clinical overview on the non-clinical pharmacology, pharmacokinetics and toxicology of levomethadone is considered adequate.

Environmental Risk Assessment (ERA) Since “Levomethadon Develco/Levomethadon Develco Pharma 2,5 / 5 / 20 / 30 mg Tabletten” 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 5 mg strength Bioequivalence of the test product was assessed in comparison to the reference product L- Polamidon® Lösung zur Substitution (Sanofi-Aventis Deutschland GmbH, Germany), with 5 mg levomethadone HCl per ml in a 2-period crossover study (ID CPA 456-14, EudraCT No.: 2014- 005414-31) after single dose fasted administration to 34 healthy male subjects.

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The point estimators and 90% confidence intervals for the primary PK parameters AUC(0-72h) (107.65%; 90% CI: 103.39-112.09) and Cmax (104.01%; 90% CI: 99.23-109.02) were entirely within the conventional bioequivalence acceptance margins (80.00% to 125.00%). Additionally, the tmax was not significantly different between treatments.

2.5 mg, 20 mg and 30 mg strengths Adequate justification to extrapolate the BE results of the 5 mg strength to the 2.5, 20 mg and 30 mg strength has been provided. Tablets of all dose strengths showed similar dissolution profiles in all test media confirming the adequacy of waiving additional in vivo bioequivalence testing.

Pharmacodynamics / Clinical efficacy / Clinical safety N/A

Legal Status Prescription only medicine

User Testing Overall, the test methodology follows the guidelines of the European Commission (Guideline on the readability of the label and package leaflet of medicinal products for human use, Revision January 2009; Update of Directive 2001/83/EC as amended by Directive 2004/27/EC / Guidance concerning consultations with target patient groups for the packet leaflet, May 2006). Both the first and the second test round met the success criteria of more than 90% of the subjects being able to locate the requested information, and of those, more than 90% being able to give the correct answer, to indicate that they understood the information presented. The general impression of the PL (Content, language and layout) was mostly positive. In conclusion, the user test is considered acceptable.

Summary Pharmacovigilance system The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/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.

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 levomethdadone.

- Summary table of safety concerns as approved in RMP

Summary of safety concerns Important identified risks  Hepatic impairment  Renal impairment  Respiratory depression  Drug dependence  Drug abuse/misuse  Interactions with:  CYP 3A4 acting substances  MAOI  CNS depressants  QT-prolongating agents  Others  Drug withdrawal  Constipation  Fatal Overdose  QT-prolongation / Torsade de Pointes

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 CNS depression  Off label use Important potential risks None Missing information  Use in children and adolescents  Use during pregnancy and lactation

No additional pharmacovigilance activities or risk minimisation measures have been included in the RMP.

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted: - At the request of the RMS; - Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures.

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. • For medicinal products that do not fall within the categories waived of the obligation to submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow the DLP according to the EURD list.

IV BENEFIT RISK ASSESSMENT The application contains an adequate review of published clinical data and the bioequivalence has been shown. The application is approved. For intermediate amendments see current product information.

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