Public Assessment Report. Scientific discussion. Natriumfusidat LEO 30 mg/100 cm 2 impregnated dressing. (Sodium fusidate) DK/H/2431/001/DC

Transcription

1 Public Assessment Report Scientific discussion Natriumfusidat LEO 30 mg/100 cm 2 impregnated dressing (Sodium fusidate) DK/H/2431/001/DC 23 November 2015 This module reflects the scientific discussion for the approval of Natriumfusidat LEO. The procedure was finalised on 23 July 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 Natriumfusidat LEO impregnated dressing, from LEO Pharma A/S. The product is indicated for the treatment of skin infections caused by bacteria susceptible to sodium fusidate in children from 1 year of age and adults. A comprehensive description of the indications and posology is given in the SmPC. Natriumfusidat LEO impregnated dressing is a topical dressing containing the active substance sodium fusidate. It consists of a 10 cm x 10 cm cotton leno-weave fabric, impregnated with 1.5 g of 2% sodium fusidate in essentially the same lipid-rich base used for Fucidin ointment (LEO Pharma A/S) plus a small amount of all-rac-α-tocopherol antioxidant. This decentralised procedure concerns a hybrid application. For the purpose of establishing the expiry of the data protection period, reference is made to Fucidin 250 mg film-coated tablets which has been registered in Denmark by LEO Pharma A/S since The reference product in Denmark is Fucidin impregnated dressing which has been registered by LEO Pharma A/S since The marketing authorisation is granted based on article 10(3) of Directive 2001/83/EC. The antibiotic substance fusidic acid was discovered in 1960, developed for therapeutic use by LEO Pharma A/S and has been marketed in many countries worldwide since Fusidic acid, or as sodium fusidate, is available in intravenous, ocular, oral and topical products. Natriumfusidat LEO impregnated dressing contains sodium fusidate, the salt of fusidic acid as active substance. Sodium fusidate and fusidic acid have equal antibacterial and non-clinical and clinical properties as the active drug (fusidate) is the same for both substances. Fusidic acid is an antimicrobial agent, with a steroidal structure but without any steroidal activity, belonging to the unique group of fusidanes. Fusidanes act as inhibitors of bacterial protein synthesis by blocking the elongation factor G (EF-G), preventing it from binding with ribosomes and GTP (guanosine triphosphate) and thereby stopping the energy supply to the synthesis process. LEO Pharma A/S is the marketing authorisation holder of Fucidin impregnated dressing and the product has been marketed since June 1964 and is now approved in more than 30 countries. Fucidin impregnated dressing received its first Marketing Authorisation approval in Germany in More than 50 years of post-marketing exposure data on Fucidin impregnated dressing supports a favourable safety profile with well characterised benefits in the treatment of skin infections. II. QUALITY ASPECTS II.1 Introduction The impregnated dressing consists of a 10 cm x 10 cm piece of cotton gauze impregnated with ointment. The ointment is off-white to white in colour. Each impregnated dressing contains 30 mg/100 cm 2 sodium fusidate. Each impregnated dressing is placed between two pieces of parchment paper, which is placed in a single use aluminium laminate foil sachet. Pack sizes of 10 and 50 impregnated dressings are available. However, not all pack sizes may be marketed. 2/6

3 The excipients in the dressing are: Cetyl alcohol; wool fat; liquid paraffin; white soft paraffin; all-racα-tocopherol and butylhydroxytoluene (E321). 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. II.2 Drug Substance The active substance, sodium fusidate, is described in the European Pharmacopoeia (monograph 0848). It is a white or almost white, crystalline powder, slightly hygroscopic. It is freely soluble in water and in ethanol (96 per cent). Chemical structure: The documentation on the active substance, sodium fusidate, is presented in the form of a Certificate of Suitability. The control tests and specifications for drug substance product are adequately drawn up. The re-test period/storage condition is according to the CEP. II.3 Medicinal Product The development of the product has been described, the choice of excipients is justified and their functions explained. The manufacturing process has been satisfactory described and justified. The product specifications includes appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Batch analysis has been performed on a total of 6 batches. The batch analysis results show that the finished products meet the specifications proposed. The conditions used in the stability studies are according to the ICH stability guideline. The control tests and specifications for drug product are adequately drawn up. A shelf-life of 3 years with the storage condition: Do not store above 30 C has been accepted based on 6 months stability data stored at 40 C/75% RH and 12 months intermediate data. 3/6

4 III. NON-CLINICAL ASPECTS III.1 Introduction Pharmacodynamic, pharmacokinetic and toxicological properties of sodium fusidate are well known. As sodium fusidate is a widely used and well-known active substance, the MAH has not provided additional studies and none are required. An overview based on a literature review is therefore appropriate. The non-clinical overview report refers 100 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) An expert report regarding environmental risk assessment of fusidic acid has been provided. The log Kow for fusidic acid at ph 7.4 was stated to be 2.68 and no further studies are required. Considering the data, fusidic acid is not expected to pose a risk to the environment. IV. CLINICAL ASPECTS IV.1 Introduction Sodium fusidate is a well-known active substance with established efficacy and tolerability. As sodium fusidate 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. IV.2 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 Natriumfusidat LEO. The following summary list of safety concerns has been agreed with no additional pharmacovigilance or risk minimisation measures: Table 1. Summary table of safety concerns as approved in RMP 4/6

5 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 2 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 Natriumfusidat LEO impregnated dressing has a proven chemical-pharmaceutical quality and is similar to Fucidin impregnated dressing. Fucidin impregnated dressing is a well-known medicinal product with an established favourable efficacy and safety profile. The MAH has provided written confirmation that systems and services are in place to ensure compliance with their pharmacovigilance obligations. A Risk Management Plan has been presented summarising the safety concerns. 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 a marketing authorisation could be granted for Natriumfusidat LEO. The decentralised procedure was finalised on 23 July Natriumfusidat LEO was authorised in Denmark on 18 November 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: 23 July The following post-approval commitments have been made during the procedure: An additional analysis of the stability samples will be performed to confirm that the active substance is homogenously suspended in the drug product, without agglomeration and crystal growth throughout shelf life. The following additional studies will be conducted to confirm that the in-process control Average weight of applied ointment is predictive for Uniformity of dosage units of the finished product and that the finished product is compliant with Ph.Eur requirements, if tested: For 3 batches investigate (at the start, at the middle and at the end of production) the applied mass of ointment in the sandwich (at least 1.5 g, the target value is 1.75g) according to internal LEO method and to Mass Variation (Ph.Eur ). According to table , Application of Content Uniformity (CU) and Mass Variation (MV) test for dosage forms, MV is acceptable for both Solids in single-dose containers (single component) and for Solutions enclosed in single-dose containers and it is therefore also considered appropriate for this Semi-solid product in a single-dose container. For the same 3 batches all documentation concerning the ointment filling process will be included i.e. samples are drawn every 30 minutes and average weight of applied ointment is calculated (target weight 1.75 g) 5/6

6 By this test procedure it should be demonstrated that the loss of ointment takes place when removing the aluminium laminate foil from the sandwiches and that despite this removal procedure the drug product will comply with Ph.Eur The intended studies should be performed no later than The obtained results should be included in the dossier (3.2.P.5.6) to support omission of test for uniformity of dosage units (2.9.40) and omission of an in vitro release test from the drug product specification. 6/6