Decentralised Procedure

Public Assessment Report

Levomethadone Aristo 7.5 mg tablets

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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Number(s) for the DE/H/4849/005/DC Decentralised Procedure Reference Member State: DE Concerned Member States: LU (withdrawn) Legal basis of application: Article 10(3) hybrid application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

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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 is a synthetic μ- 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.

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The chosen container closure systems are PVC-Al- blisters and HDPE bottles with a child resistant screw cap (made of polypropylene). Statements for the suitability for food contact and pharmaceutical use according national / EU requirements are included. The stability studies undertaken do support a shelf life of 48 months (with labelling statement on storage conditions “protect from light”) for both proposed container closure systems. Both studies (for blister and bottles) are in line with the current ICH requirements. The application is now approvable.

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. An Overview based on an up-to-date literature review is thus, in principle appropriate. On request of the RMS, the Applicant has provided an up-to-date Non-clinical Overview on the non- clinical pharmacodynamic, pharmacokinetic and toxicological properties of levomethadone that is considered adequate and has provided information on name, educational background and specific expertise and qualification of the involved expert.

Environmental Risk Assessment (ERA) Since the medicinal product 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 In the course of procedure DE/H/4849/001-004/DC:

5mg 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.

2.5mg, 20mg and 30mg strengths Adequate justification to extrapolate the BE results of the 5 mg strength to the 2.5, 20 mg and 30mg 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.

The 7,5 mg dose strength, now applied for, is completely identical (dose proportional) to the 2,5 and 5 mg strengths. The tablet shows similar dissolution profiles in all test media (see Quality AR) confirming the adequacy of waiving additional in vivo bioequivalence testing.

Pharmacodynamics N/A

Clinical efficacy N/A

Clinical safety N/A

Legal Status Medicinal product subject to restricted medical prescription.

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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). 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 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.

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 the medicinal product(s) applied for authorisation.

Safety specification According to the Applicant the safety specification is in full accordance with the current safety specification agreed and published for a similar product which is acceptable.

Pharmacovigilance Plan Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant, which is endorsed.

Risk minimisation measures Routine risk minimisation is suggested and no additional risk minimisation activities are proposed by the applicant, which is endorsed.

Summary of the RMP The submitted Risk Management Plan is considered acceptable.

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.

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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. • 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 non-clinical and clinical data and the bioequivalence (with the proportional 5mg strength) has been shown. Approval is recommended from the non-clinical and clinical point of view. The application is approved. For intermediate amendments see current product information.

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