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Public Assessment Report Scientific Discussion Thiamazole Uni-Pharma

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Public Assessment Report Scientific Discussion Thiamazole Uni-Pharma Public Assessment Report Scientific discussion Thiamazole Uni-Pharma Thiamazole DK/H/2614/001/DC Date: 28-04-2017 This module reflects the scientific discussion for the approval of Thiamazole Uni-Pharma. The procedure was finalised on 08-03-2017. For information on changes after this date please refer to the module ‘Update’. I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Thiamazole Uni-Pharma, Tablet 5mg, from Uni-Pharma Kleon Tsetis Pharmaceutical Laboratories. The product is indicated for: the treatment of hyperthyroidism. A comprehensive description of the indications and posology is given in the SmPC. Thiamazole, mostly known as methimazole is an antithyroid drug and part of the thioamide group. Methimazole inhibits the enzyme thyroid-peroxidase, which normally acts in thyroid hormone synthesis by oxidizing the anion iodide (I-) to iodine (I), facilitating iodine's addition to tyrosine residues on the hormone precursor thyroglobulin, a necessary step in the synthesis of triiodothyronine (T3) and thyroxine (T4). The marketing authorisation has been granted pursuant to Article 10(1) of Directive 2001/83/EC. This decentralised procedure concerns a generic application claiming essential similarity with the reference product Thiamazol 5 mg HEXAL, Tabletten, by Hexal AG, Germany, which has been authorised based on a full dossier, under Article 8, for not less than eight years in the Community. Thiamazol 5 mg HEXAL contains 5 mg of thiamazole per tablet. A detailed biowaiver justification was included in Module 5, demonstrating that the requirements for in vivo demonstration of bioequivalence between the two medicinal products can be waived. The biowaiver approach is based on the Biopharmaceutics Classification System (BCS), which is meant to represent a surrogate for in vivo bioequivalence studies. The background of the biowaiver approach is developed in Appendix III (BCS-based biowaiver) of the guideline CPMP/EWP/QWP/1401/98 Rev. 1/Corr, “Guideline on the Investigation of Bioequivalence”, which sets the relevant criteria under which bioavailability studies need not be required. According to the above mentioned Guideline, in vivo bioequivalence studies may be exempted if an assumption of equivalence in in vivo performance can be justified by satisfactory in vitro data. II. QUALITY ASPECTS II.1 Introduction Each Thiamazole Uni-Pharma 5 mg tablet contains 5 mg thiamazole. The drug product is marketed in PVC/Aluminium blisters with a pack size of 100 tablets or 125 tablets. However, not all pack-sizes may be marketed Thiamazole Uni-Pharma 5 mg tablets are white, flat-faced bevel-edged, bisect on one side tablets, with a diameter of 8.06 mm PAR Scientific discussion 2/6 The excipients are: Lactose Monohydrate Sodium Starch Glycolate Talc Magnesium Stearate Compliance wih Good Manufacturing Practice The RMS has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place for this product type at all sites responsible for the manufacture and assembly of this product prior to granting its national authorisation. II.2 Drug Substance Active Substance The active substance thiamazole is described in the European Pharmacopoeia. It is a white or pale brown crystalline powder, freely soluble in water and in methylene chloride and in ethanol (96%). INN: Thiamazole Chemical name: 1-Metyl-1,3-dihydro-2H-imidazole-2-tione (Ph. Eur.) Molecular formula: C4-H6-N2-S Molecular mass: 114 Based on the presented stability studies, an appropriate re-test period has been set. The CEP procedure is used for the active substance. The re-test period is according to the CEP. II.3 Medicinal Product The development of the product has been described, the choice of excipients is justified and theire functions explained. A shelf-life of 5 years when protected from light is acceptable. The drug product is stable and the active substance is easily dissolved in water. The drug product specification is adequately set for a tablet. All excipients comply with their respective Ph. Eur. monograph. A HPLC method is used to determine assay of thiamazole and a GC method is used to determine related substances of thiamazole in the drug product. The methods are adequately validated. PAR Scientific discussion 3/6 III. NON-CLINICAL ASPECTS III.1 Introduction The non-clinical overview report refers 66 publications up to year 2015. The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate. Pharmacodynamic, pharmacokinetic and toxicological properties of thiamazole are well known. As thiamazole is a widely used well-known active substance, the applicant has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate. III.2 Ecotoxicity/environmental risk assessment (ERA) Since Thiamazole Uni-Pharma 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. IV. CLINICAL ASPECTS IV.1 Introduction Thiamazole is a well-known active substance with established efficacy and tolerability. As Thiamazole is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate. The clinical report refers 154 publications up to 2014. The clinical overview on the clinical pharmacology, efficacy and safety is adequate. IV.2 Pharmacokinetics Biowaiver It has been adequately justified that thiamazole can be classified as a BCS class I substance. Reference has been made to solubility data of the drug substance obtained by the applicant and literature for permeability of the drug substance. The requirements for a BCS based biowaiver are fulfilled. Additionally the active substance is not classified as a narrow therapeutic index (NTI) drug. In conclusion it is considered that possible differences with respect to bioavailability of the Uni- Pharma product and the ERP/Danish market leader product are negligible and not expected to result in therapeutic bioinequivalence. The justification for BCS (Biopharmaceutics Classification System) - based biowaiver can be accepted. IV.3 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 Thiamazole Uni-Pharma. PAR Scientific discussion 4/6 The agreed summary list of safety concerns with no additional pharmacovigilance or risk minimisation measures is as follows: Summary of safety concerns Important identified risks Myelotoxic adverse reactions Goitre growth Use during pregnancy Use during breastfeeding Use in patients with history of mild hypersensitivity reactions Use in patients with metabolic disorders Important potential risks Overdose Hypothyroidism Use in patients with hepatic impairment Hepatic disorders Increased body weight Missing information Use in patients with renal impairment Use in children up to 2 years old. V. USER CONSULTATION The package leaflet has been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose of user testing the PIL was English. A pilot study including 4 subjects was carried out. After this the PL was tested in 2 test rounds, each including 10 subjects. A total of 12 males and 12 females, aged from 18 to 62 and with varying educational background, participated. The results show that the package leaflet meets the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Thiamazole Uni-Pharma, Tablet 5mg has a proven chemical-pharmaceutical quality and is a generic form of Thiamazol 5 mg HEXAL. Thiamazol 5 mg HEXAL is a well-known medicinal product with an established favourable efficacy and safety profile. The application contains an adequate review of published clinical data and documentation to support the BCS based biowaiver. The requirements for a BCS based biowaiver are fulfilled. In conclusion it is considered that possible differences with respect to bioavailability of the Uni-Pharma product and the ERP/Danish market leader product are negligible and not expected to result in therapeutic bioinequivalence. Approval is recommended from the clinical point of view. The chemical-pharmaceutical documentation and Quality Overall Summary in relation to the Thiamazole Uni-Pharma, 5 mg, tablets are considered sufficient in view of the present European regulatory requirements. The MAH presented a risk management plan summarising the safety concerns. There are no additional pharmacovigilance or risk minimisation measures. PAR Scientific discussion 5/6 Agreement between Member States was reached during a written procedure. There was no discussion in the CMD(h). The Concerned Member States, on the basis of the data submitted, considered that essential similarity has been demonstrated for Thiamazole Uni-Pharma with the reference product, and have therefore granted a marketing authorisation. The decentralised procedure was finalised on 08-03- 2017. Thiamazole Uni-Pharma was authorised in DK on 26-04-2017. According to the List of Union reference dates and frequency of submission of periodic safety update reports (PSURs), no routine PSURs are required for this product. The date for the first renewal will be: 08-03-2022. There were no post-approval commitments made during the procedure. PAR Scientific discussion 6/6 .
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