Public Assessment Report. Scientific discussion. Furosemid Orifarm 40 mg tablets. (Furosemide) DK/H/2430/001/DC. 1 December 2015

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1 Public Assessment Report Scientific discussion Furosemid Orifarm 40 mg tablets (Furosemide) DK/H/2430/001/DC 1 December 2015 This module reflects the scientific discussion for the approval of Furosemid Orifarm. The procedure was finalised on 11 May For information on changes after this date please refer to the module Update.

2 I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Furosemid Orifarm 40 mg tablets, from Orifarm Generics A/S. The product is indicated for: Treatment of oedema associated with - cardiac disease - liver disease - renal disease including nephrotic syndrome. In patients with nephrotic syndrome, therapy of the underlying disorder has first priority. Treatment of pulmonary oedema. Arterial hypertension. A comprehensive description of the indications and posology is given in the SmPC. Furosemide is sulphonamide-type loop diuretic which inhibits the re-absorption of electrolytes mainly in the ascending limb of the loop of Henle and also the distal renal tubules resulting in excretion of calcium, chloride, potassium and sodium enhancing water excretion. This decentralised procedure concerns a generic application claiming essential similarity with the reference product Lasix 40 mg tablets, which has been registered in Denmark by Sanofi-Aventis Denmark A/S since The marketing authorisation is granted based on article 10.1 of Directive 2001/83/EC. II. QUALITY ASPECTS II.1 Introduction Each tablet contains 40 mg furosemide. The tablets are white, circular tablets, plain on one side and marked with F 40 on the other side (F and 40 are separated by a break line) (size: approx. 8 mm. in diameter). The tablets can be divided into equal doses. The tablets are packed in PVDC/PVC/Aluminium blisters in pack-sizes of 50, 56, 98, 100, 250 and 300 tablets. However, not all pack sizes may be marketed. The tablets contain: Lactose monohydrate; magnesium stearate; maize starch; pregelatinized starch and sodium starch glycolate (Type A). 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 manufacturing of the active substance as well as for the manufacturing and assembly of this product prior to granting its national authorisation. 2/7

3 II.2 Drug Substance The active substance, furosemide, is described in the European Pharmacopoeia. It is practically insoluble in water, soluble in acetone, sparingly soluble in ethanol (96 per cent), and practically insoluble in methylene chloride. It shows polymorphism. Molecular structure: The documentation on the active substance is supplied in the form of a Certificate of Suitability (CEP). Information relating to the finished product manufacturer s control of active substance has been presented. The specification complies with the CEP/Ph. Eur. monograph and additional test for particle size. Certificates of analysis issued by the finished product manufacturer have been provided. The re-test period is according to the CEP. II.3 Medicinal Product The development of the product has been adequately described, the choice of excipients is justified and their functions explained. All excipient are of Ph. Eur. quality. The finished product is manufactured by wet granulation followed by compression. The manufacturing process has been described in sufficient details and satisfactory validation reports have been presented for the proposed batch sizes. The product specifications cover appropriate parameters for this dosage form and is acceptable. Details and satisfactory validations of all relevant analytical procedures are presented. Batch analysis has been performed on 6 batches. The batch analysis results show that the finished product meets the proposed specifications. Stability studies have been conducted in accordance with the ICH stability guidelines. Up to 48 months long-term data (25 C/60% RH) and 6 months accelerated data (40 C/75% RH) is presented. All the specifications are met, and the proposed shelf-life of 3 years is considered acceptable with the storage condition Keep the blister in the outer carton in order to protect from light. due to the product s sensitivity against light. III. NON-CLINICAL ASPECTS III.1 Introduction Pharmacodynamic, pharmacokinetic and toxicological properties of furosemide are well known. As furosemide is a widely used, well-known active substance, the MAH has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate. 3/7

4 The non-clinical overview report refers 40 publications up to year The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate. III.2 Ecotoxicity/environmental risk assessment (ERA) Since Furosemid Orifarm 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 Furosemide is a well-known active substance with established efficacy and tolerability. As furosemide is a widely used, well-known active substance, the MAH has not provided additional studies (apart from a supportive bioequivalence study referenced below) and further studies are not required. Overview based on literature review is, thus, appropriate. The clinical report refers 27 publications up to year The clinical overview on the clinical pharmacology, efficacy and safety is adequate. IV.2 Pharmacokinetics To support the application, the MAH has submitted results from one bioequivalence study. The study was an open-label, randomized, two-treatment, three-sequence, three-period, reference replicate crossover, single-dose bioavailability study conducted under fasting conditions with a wash out period of 7 days between each of the three periods. 40 mg was administered in each period. The duration of the treatment was 16 days. Furosemid Orifarm 40 mg tablets was compared to Lasix 40 mg tablets by Sanofi-Aventis, Portugal, from the PT market place. A total of 54 healthy male/female subjects were enrolled in the study. 49 subjects completed the study. 50 subjects were included in the statistical analysis. Primary variables for the evaluation of bioequivalence were AUC 0-t and C max. The 90% confidence intervals of the ratio of least square mean (test/reference) of C max and AUC 0-t should be within the acceptance range of % in order for bioequivalence to be concluded. Results Table 1. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax, median, range) for furosemide, n=50 The pharmacokinetic parameters for furosemide are reported as follows: 4/7

5 The 90% CI around the ratio of the ln-transformed C max and AUC 0-t for furosemide are reported as follows: For C max and AUC 0-t the 90% confidence interval for the ratio of the test and reference products were within the acceptance criteria of %. Pharmacokinetic conclusion Based on the submitted bioequivalence study Furosemid Orifarm 40 mg tablets is considered bioequivalent with Lasix 40 mg tablets. The RMS has been assured that the bioequivalence study has been conducted in accordance with acceptable standards of Good Clinical Practice (GCP, see Directive 2005/28/EC) and Good Laboratory Practice (GLP, see Directives 2004/9/EC and 2004/10/EC). 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 Furosemid Orifarm. The following summary list of safety concerns with no additional pharmacovigilance measures or risk minimisation measures has been agreed: 5/7

6 Table 2. Summary table of safety concerns as approved in RMP 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. 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. The test consisted of: a pilot test with 3 participants, followed by two rounds with 10 participants each. The questions covered the following areas sufficiently: traceability, comprehensibility and applicability. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Furosemid Orifarm 40 mg tablets has a proven chemical-pharmaceutical quality and is a generic form of Lasix. Lasix is a well-known medicinal product with an established favourable efficacy and safety profile. Bioequivalence has been shown to be in compliance with the requirements of European guidance documents. 6/7

7 The MAH has presented a risk management plan summarising the safety concerns. There are no additional pharmacovigilance or risk minimisation measures. 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 Furosemid Orifarm with the reference product, and have therefore granted a marketing authorisation. The decentralised procedure was finalised on 11 May Furosemid Orifarm was authorised in Denmark on 11 June 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: 11 May The following post-approval commitments have been made during the procedure: The HPLC method for related substances will be revalidated for impurity C regarding precision, linearity and accuracy reflecting the new limit. The re-validation will be performed before marketing of the product. The next commercial batch will be included in a holding time study to support the proposed holding time for the bulk products. A further investigation of the performance of the assay method will be performed. The report of the above investigations will be available within two months after end of procedure and can be shared with Agency upon request. If any changes to the method are required, a variation application will be submitted as soon as possible in order to update the method. 7/7