Decentralised Procedure. Public Assessment Report. ALGOTRA 37.5 mg/325 mg überzogene Tabletten Tramadol/Paracetamol DE/H/3688/001/DC

Transcription

1 Decentralised Procedure Public Assessment Report ALGOTRA 37.5 mg/325 mg überzogene Tabletten Tramadol/Paracetamol DE/H/3688/001/DC Applicant: Laboratoires SMB S.A. Reference Member State DE

2 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.. 4 III. SCIENTIFIC OVERVIEW AND DISCUSSION... 5 III.1 Quality aspects... 5 III.2 Non-clinical aspects... 5 III.3 Clinical aspects... 5 IV. BENEFIT RISK ASSESSMENT... 6 ALGO TRA, DE/H/3688/001/DC Public AR Page 2/6

3 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) ALGOCID 37,5 mg/325 mg überzogene Tabletten Tramadol hydrochloride Paracetamol N02AX52 Coated tablet, 37.5 mg/325 mg DE/H/3688/001/DC DE BE, BG, CY, EL, LU, RO Laboratoires SMB S.A. Rue de la pastorale 26-28, B-1080 Brussels, Belgium ALGO TRA, DE/H/3688/001/DC Public AR Page 3/6

4 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for ALGO TRA 37.5 mg/325 mg film-coated tablets for the symptomatic treatment of moderate to severe pain, is approved. II. EXECUTIVE SUMMARY II.1 Problem statement This decentralised applications concern two generic versions of tramadol hydrochloride/paracetamol, under ALGO TRA 37.5 mg/325 mg film-coated tablets and 37.5 mg/325 mg effervescent tablets trade name. The application for ALGO TRA 37.5 mg/325 mg effervescent tablets was withdrawn. In this Assessment Report, the name Tramadol/Paracetamol is used. The originator products are Zaldiar 37.5 mg mg film-coated tablets / effervescent tablets by Laboratoires Grunenthal, registered since With Germany as the Reference Member State in this Decentralised Procedure, Laboratoires SMB S.A. is applying for the Marketing Authorisations for ALGO TRA 37.5 mg/325 mg film-coated tablets in BE, BG, CY, EL, LU and RO. The application for ALGO TRA 37.5 mg/325 mg effervescent tablet was withdrawn. II.2 About the product Tramadol and paracetamol (acetaminophen) are two analgesics combined in fixed-dose tablet as they have complimentary mechanisms of action (opioid plus non-opioid), presenting the additional advantage of the rapid onset of action of paracetamol and the long-acting nature of tramadol. The combination of Tramadol hydrochloride/ paracetamol is considered to be a step II analgesic according to the WHO pain ladder guidance. Tramadol and paracetamol are two analgesics that have shown efficacy in several clinical conditions (it was studied for acute and chronic pain) and have been combined together in a fixed-dose combination tablet (tramadol 37.5mg/ paracetamol 325mg) in two dosage forms (coated tablet and effervescent tablet). The products were developed with the aim of obtaining medicinal products essentially similar to the originator, Zaldiar. The indication applied for is the symptomatic treatment of moderate to severe pain, restricted to patients whose moderate to severe pain is considered to require a combination of tramadol and paracetamol. II.3 General comments on the submitted dossier Being a generic application, the dossier is based on demonstration of bioequivalence with the originator product. From the clinical perspective, the Modules 2.5, 2.7 and 5 are well structured, and of acceptable quality. 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. ALGO TRA, DE/H/3688/001/DC Public AR Page 4/6

5 III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance (Paracetamol and Tramadol hydrochloride) The active substances paracetamol and tramadol hydrochloride are described in the European Pharmacopoeia (Ph. Eur.). The quality of the drug substance paracetamol is controlled in compliance with the corresponding monograph of the European Pharmacopoeia (Ph. Eur.). The quality of the drug substance tramadol hydrochloride is controlled in compliance with the corresponding monograph of the European Pharmacopoeia (Ph. Eur.). The suitability of the monograph to test the drug substances has been verified by EDQM and is documented by the issue of certificates of suitability. Drug Product Film-coated tablets: The ingredients and the manufacturing process of the drug product are considered suitable to produce a pharmaceutical product of the proposed quality. All relevant quality characteristics of the drug substance and the drug product (release and shelf-life) are specified. The proposed limits are accepted. The description of the analytical methods used to analyse the drug substance and drug product are adequate, the validation results are plausible. The stability results do justify a shelf-life of 24 months (without label claim). III.2 Non-clinical aspects Pharmacology, Pharmacokinetics, Toxicology Pharmacodynamic, pharmacokinetic and toxicological properties of tramadol and of paracetamol as well as those of their combination are well known. As tramadol and paracetamol are widely used, well-known active substances, 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 pre-clinical pharmacology, pharmacokinetics and toxicology of tramadol/paracetamol is adequate. Environmental Risk Assessment (ERA) Since the medicinal products submitted for marketing authorisation are 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 The pharmacodynamic and pharmacokinetic properties as well as the efficacy and safety of Tramadol/Paracetamol are adequately summarised in the clinical expert report. Pharmacokinetics Coated tablet Bioequivalence between the new TRAMADOL/PARACETAMOL formulation and the reference product Zaldiar film-coated tablet marketed by Grünenthal SA, Belgium was demonstrated in an open-label, randomized, two-treatment, two-period, two-way crossover, single dose study conducted in healthy subjects under fasting conditions (Study Code: SMB-PATRA-SD111/ EudraCT number: ). Pharmacodynamics / Clinical efficacy / Clinical safety N/A ALGO TRA, DE/H/3688/001/DC Public AR Page 5/6

6 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 90% of the subjects being able to locate the requested information, and of those, 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 positive. In conclusion, the user test is acceptable. 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 following safety concerns have been proposed by the applicant: Summary of safety concerns Important identified risks Hepatic failure Respiratory depression Convulsion Serotonin syndrome Drug abuse, misuse and diversion Drug dependence and Withdrawal Important potential risks Use by elderly (> 75 years) Important missing information Use by children (< 12 years) Use during pregnancy and lactation No additional pharmacovigilance or risk minimisation measures have been proposed. Periodic Safety Update Report (PSUR) The PSUR cycle should follow the list of union reference dates and frequency of submission of periodic safety update reports (EURD-list). Currently the PSUR submission frequency is 3 years with the next DLP on 1 August PSURs are also required for products referred to in Articles 10(1), 10a, 14, 16a of Directive 2001/83/EC as amended. IV. BENEFIT RISK ASSESSMENT The combination of Tramadol and Paracetamol have a well-recognised efficacy and an acceptable level of safety in the indications approved for the proposed tablets, and corresponding products have been widely used. The application contains an adequate review of published non-clinical and clinical data. Bioequivalence has been shown for the coated tablets. Therefore, the benefit-risk-balance is considered positive for this dosage form. The application is approved. For intermediate amendments see current product information. ALGO TRA, DE/H/3688/001/DC Public AR Page 6/6