Decentralised Procedure Public Assessment Report L-Polamidon 2.5 / 5 / 20 mg Tablets Levomethadone hydrochloride DE/H/3528/001-003/DC Applicant: Sanofi-Aventis Deutschland GmbH Reference Member State DE
TABLE OF CONTENTS I. INTRODUCTION... 4 II. EXECUTIVE SUMMARY... 4 II.1 About the product... 4 II.2 General comments on the submitted dossier... 4 II.3 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.. 4 III. SCIENTIFIC OVERVIEW AND DISCUSSION... 4 III.1 Quality aspects... 4 III.2 Non-clinical aspects... 6 III.3 Clinical aspects... 6 IV. BENEFIT RISK ASSESSMENT... 8 DE/H/3528/001-003/DC Public AR Page 2/8
ADMINISTRATIVE INFORMATION Proposed name of the medicinal product(s) in the RMS INN (or common name) of the active substance(s): Pharmaco-therapeutic group (ATC Code): Pharmaceutical form(s) and strength(s): Reference Number(s) for the Decentralised Procedure Reference Member State: Member States concerned: Applicant (name and address) L-Polamidon 2,5 / 5 / 20 mg Tabletten Levomethadone hydrochloride N07BC05 tablet, 2.5 / 5 / 20 mg DE/H/3528/001-003/DC DE AT Sanofi-Aventis Deutschland GmbH Industriepark Höchst, Geb. K703 65929 Frankfurt am Main, Germany DE/H/3528/001-003/DC Public AR Page 3/8
I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for L-Polamidon 2.5 / 5 / 20 mg Tablets, in the treatment of Zur oralen Substitutionsbehandlung bei Opiatabhängigkeit im Rahmen medizinischer, sozialer und psychotherapeutischer Maßnahmen bei Erwachsenen. is approved. II. EXECUTIVE SUMMARY II.1 About the product Levomethadone HCl is the active substance of L-Polamidon. L-Polamidon was registered as drop formulation and solution for injection in Germany in 1963 and marketed since 1965 as an analgesic for severe pain. An oral solution was approved and introduced in 2001 indicated for substitution therapy in opioid addicted subjects. Levomethadone reduces withdrawal symptoms in people addicted to heroin or other narcotic drugs without causing the high associated with the drug addiction. Levomethadone treatment is an integral part of detoxification and maintenance programs in case of opioid addiction. II.2 General comments on the submitted dossier This applications concern a line extension to the approved L-Polamidon Lösung zur Substitution (5 mg/ml, MA-no.: 45583.00.00) containing the same active substance for the same indication (substitution therapy in opioid addicted subjects) to register levomethadone as immediate release tablets in three strengths (2.5 mg, 5 mg and 20 mg). The legal basis of the application is Article 8(3) for known active substances considered as "full, but mixed application". Active substance of these products is levomethadone HCl [(R)-6-(dimethylamino)-4,4-diphenyl-3- heptanone HCl, CAS No 125-58-6]. Thus, these preparations contain the same active substance and have same indications as the reference product L-Polamidon Lösung zur Substitution (5 mg/ml), which has been approved and marketed in Germany since 2001 (MA-no.: 45583.00.00) and was regularly renewed in 2008. The applicant, Sanofi-Aventis Deutschland GmbH, Germany, applies through the Decentralised Procedure with Germany acting as reference member state (RMS) and AT as concerned member states (CMS). II.3 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. The applicant has confirmed that study LEVOM_L_05558 / 1245lev10ct, EudraCT 2011-002206-78 was conducted in accordance with the standards of GCP. III. III.1 SCIENTIFIC OVERVIEW AND DISCUSSION Quality aspects Drug substance The active substance in L-Polamidon tablets is Levomethadone hydrochloride, micronized. Drug substance Levomethadone hydrochloride, micronized is produced by additional milling of Levomethadone hydrochloride. Drug substance is covered by a granted CEP (R0-CEP 2008-306-Rev 00 dated February 22 nd, 2010) valid for a period of five years. The additional milling step has been detailed by further information about manufacturing process and process controls. A retest period for Levomethadone hydrochloride, micronized of 9 months is accepted. DE/H/3528/001-003/DC Public AR Page 4/8
Drug Product L-Polamidon tablets are white to off-white tablets available in three strengths containing 2.5 mg, 5.0 mg and 20.0 mg Levomethadone hydrochloride, micronized. Drug product is produced in three different shapes provided with a break line on the one side and with a gravure on the other side illustrating the respective strength. Total weight of each strength is 100.0 mg. Drug product is packed into blisters with additional childproof aluminium support. All excipients used such as Mannitol, Lactose monohydrate, Croscarmellose sodium, Cellulose powder, Silica gel anhydrous and Magnesium stearate are well-known pharmaceutical ingredients and their quality is described in Ph. Eur. monographs. With the exception of Lactose monohydrate all dosages of drug product contain constant amounts of excipients. The content of Lactose monohydrate is decreased in the same measure as the content of drug substance is increased. The rationale of pharmaceutical development is described sufficiently. Properties of drug product and its dosage form as well as the derived measures to control the process have been elaborated thoroughly. All ingredients as well as the manufacturing process of the immediate release tablet, comprising of standard blending and compression, are considered suitable to produce a pharmaceutical product of the proposed quality. Release specification includes tests for appearance, identification, assay, uniformity of dosage unit, related substances and impurities, dissolution and microbial contamination. Shelf life specification comprises investigations on appearance, disintegration, hardness, identification, assay, related substances and impurities, dissolution and microbial contamination. Determination of microbial stability has been performed externally. Specified limits of both product specifications are justified. The proposed release and shelf life specification are considered sufficient. All analytical procedures and test methods have been described adequately and the validation data presented is basically acceptable. Covering all dosages results from batch analysis on overall seven pilot batches demonstrate conformity with release specification. Drug product has been investigated under forced stress conditions with special regard to photo stability confirming the well-known photo degradation of dissolved and solid Levomethadone hydrochloride and demonstrating the requested selectivity of the HPLC method. Stability data is available for a total of seven pilot batches representing all dosages. Samples from these batches packed in the proposed primary packaging material have been stored under long-term (25 C / 60 % RH), intermediate (30 C / 65 % RH) and accelerated conditions (40 C / 75 % RH). All tests were performed in accordance to the proposed shelf life specification and correspond to validated analytical procedures. Identification of drug substance was co-determined by assay while microbial contamination was substituted by loss on drying and water activity. Due to reduced hardness of tablets under accelerated conditions slightly deviating from shelf life specification, a storage recommendation of below 30 C is given. Drug product is protected by the immediate pack against UV-light sufficiently while degradation of L-Polamidon tablets outside the immediate pack has been detected. As a consequence of these properties statements have been included in SmPC and PL to take tablets immediately after removing from the blister and to avoid storage of the tablets outside the immediate pack. The presented results indicate sufficient chemical and physical stability of drug product. A shelf life of 36 months is accepted. DE/H/3528/001-003/DC Public AR Page 5/8
III.2 Non-clinical aspects Pharmacology, pharmacokinetics and toxicology Nonclinical pharmacodynamic, pharmacokinetic and toxicological properties of levomethadone are well known. As levomethadon is a widely used, well-known active substance, no further nonclinical studies are required and the applicant provides none. Overview based on literature review is, thus, appropriate. The submitted nonclinical overview on the nonclinical pharmacology, pharmacokinetics and toxicology of levomethadone is considered adequate. The dosage form excipients, namely lactose monohydrate, mannitol, cellulose powdered, croscarmellose sodium, silica colloidal anhydrous and magnesium stearate, are approved and well established agents in widespread use in the pharmaceutical industry. No known toxicity is attached to their use as presented. SmPC and PL are essentially in line with the innovator s text and considered acceptable. Environmental risk assessment A specific environmental risk assessment was not provided. The applicant states that, based on the assumption that this medicinal product is intended to substitute for other similar medicinal products on the market; the approval of the referred medicinal product should not result in an increase of the total quantity of levomethadone released into the environment. The applicant concludes that, therefore it should not result in increase of risk to the environment during storage, distribution, use and disposal. Taking into account that L-Polamidon 2,5 / 5 / 20 mg Tabletten will be used as a prescription-only medicinal product, this conclusion is accepted. There are no objections to approval of L-Polamidon 2,5 / 5 / 20 mg Tabletten from a non-clinical point of view. III.3 Clinical aspects Pharmacokinetics The following effects are known for the µ-receptor agonist levomethadone: considerable inter-subject variability in pharmacokinetics rapid and (nearly) complete absorption after oral administration large volume of distribution, which increases under long term treatment with the consequence of decreased clearance metabolism by various CYP isoenzymes (of deviating relevance depending on the enantiomer), however, the majority of a dose can be found unchanged in the urine excretion by both major routes, i.e. via urine (ph-dependently) and faeces high variability in terminal half-life (9 to 87 h) and, thus, in time needed to achieve steady state (4 to 5 days or even longer) some indication for dose linearity; however this has not conclusively been tested crossing of the placenta and excretion into breast milk potential for drug-drug interactions due to CYP metabolism DE/H/3528/001-003/DC Public AR Page 6/8
5mg strength Bioequivalence of the development product L-Polamidon 5 mg Tabletten 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 (LEVOM_L_05558 / 1245lev10ct, EudraCT 2011-002206-78) after single dose fasted administration to 33 healthy male subjects. The point estimators for levomethadone with regard to AUC72h and Cmax are close to 1. The rate and extent of absorption of levomethadone from the reference product (L-Polamidon Lösung 5mg=1ml) and the test product (L-Polamidon 5 mg Tabletten) is similar since the 90% confidence interval is comprised in the predefined 80-125 % acceptance range for AUCt (96.63-101.84%) and Cmax (99.98-108.41%). Additionally, the tmax was not significantly different between treatments. 2.5mg and 20mg strengths Justification to extrapolate the BE results of the 5 mg strength to the 2.5 and 20 mg strength had been submitted to the BfArM and was favourably assessed during the written Scientific Advice in 2011. Tablets of all dose strengths showed similar dissolution profiles in all test media confirming the adequacy of waiving additional in vivo bioequivalence testing. Pharmacodynamics The following effects are known for the µ-receptor agonist levomethadone: considerable inter-subject variability in pharmacodynamics analgesic effects being shorter than expected from half-life respiratory depression with relatively early onset and long duration, thus, making countermeasures, i.e. administration of antagonists, difficult effects on the cardiovascular system which might be more attributed to d-methadone beneficial impact on the immune system probably due to avoidance of the suppressive effect of other opioids under substitution treatment occurrence of tolerance and dependence under long term treatment Clinical efficacy There are several relevant objectives of levomethadone maintenance therapy: to suppress signs and symptoms of opioid withdrawal, to extinguish opioid-drug craving, and to block the reinforcing effects of illicit opioids. Each of these objectives is accomplished in phases, rather than at once, relying on the administration of adequate levomethadone doses to achieve and sustain optimum blood levels. Although overdoses can be harmful, insufficient levomethadone treatment is largely ineffective and thus, needs to be avoided. Efficacy of levomethadone in the claimed indication has been proven by its use in this indication for over 10 years and is thus, well established in medical practice. Furthermore, efficacy data obtained for methadone can be transferred to levomethadone as there are no significant differences in efficacy between both drugs as confirmed by published data. Clinical safety As a full opioid agonist, levomethadone is associated with the entire spectrum of opioid effects. It is a well-known. When properly prescribed and used, levomethadone is an effective and safe medication with an established safety profile. Published information confirms a comparable safety profile of levomethadone and methadone. However, it appears that levomethadone confers advantages regarding cardiac safety and side effects for special patient groups due to the absence of d-methadone. DE/H/3528/001-003/DC Public AR Page 7/8
User Testing 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 90% of the participants are able to find the requested information in the PL, and of those, 90% being able to give the correct answer, to indicate that they can understand and properly interpret the information. The general impression of the PL (Content, language and layout) was mostly positive. In conclusion, the user test is considered acceptable. Pharmacovigilance system The applicant has provided documents that set out a detailed description of the sanofi aventis system of pharmacovigilance (Version 4.0 dated 27 January 2012). A statement signed by the applicant and the qualified person for pharmacovigilance, indicating that the applicant has the services of a qualified person responsible for pharmacovigilance and the necessary means for the notification of any adverse reaction occurring either in the Community or in a third country has been provided. The Pharmacovigilance system as described by the applicant fulfils the requirements as described in Volume 9A of the Rules Governing Medicinal Products in the European Union and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. Risk Management Plan No safety concerns requiring additional risk minimization activities have been identified with the reference medicinal product and no product-specific pharmacovigilance issues were identified from post-authorisation data and all safety issues are adequately covered by the current SmPC. Therefore, the safety profile of levomethadone can be considered well established and the introduction of the new tablet formulation is only been applied for reasons of distribution convenience compared to liquid formulation of the reference medicinal product. This formulation change has no further impact on safety relevant clinical properties, and the indication as well as recommended dosage remains identical. For these reasons, conducting routine pharmacovigilance for L-Polamidon tablets as already performed for L-Polamidon oral solution are sufficient to identify actual or potential risks and a detailed European Risk Management Plan (EU-RMP) is not considered necessary for this line extension. IV. BENEFIT RISK ASSESSMENT The use of levomethadone/methadone in maintenance treatment is suitable and effective for stabilising opioid dependent patients. As demonstrated throughout the clinical use of levomethadone for more than ten years levomethadone has a favourable and well characterized safety profile. The applicant has presented the results of study LEVOM_L_05558 / 1245lev10ct confirming bioequivalence of the development product L-Polamidon 5 mg Tabletten in comparison to the reference product L- Polamidon Lösung zur Substitution (Sanofi-Aventis Deutschland GmbH, Germany). Tablets of all dose strengths showed similar dissolution profiles in all test media confirming the adequacy of waiving additional in vivo bioequivalence testing. The application is approved. DE/H/3528/001-003/DC Public AR Page 8/8