Decentralised Procedure Public Assessment Report Levendex 1 mg/ml + 5 mg/ml Augentropfen, Lösung Ducressa 1 mg/ml + 5 mg/ml Augentropfen, Lösung Sevendoc 1 mg/ml + 5 mg/ml Augentropfen, Lösung Dexamethasone/Levofloxacin DE/H/6215-6217/001/DC Applicants: NTC S.r.l., Santen Oy, Doc Generici S.r.l. Date: 20th January 2021 This module reflects the scientific discussion for the approval of the above-mentioned products. The procedure was finalised on 28th May 2020. 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 .......................................................................... 5 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles .. 5 III SCIENTIFIC OVERVIEW AND DISCUSSION .................................................................... 6 III.1 Quality aspects ......................................................................................................................... 6 III.2 Non clinical aspects .................................................................................................................. 7 III.3 Clinical aspects ....................................................................................................................... 11 IV BENEFIT RISK ASSESSMENT ............................................................................................. 20 Dexamethasone/Levofloxacin,DE/H/6215-6217/001/DC Public AR 2/20 ADMINISTRATIVE INFORMATION Proposed name of the medicinal Levendex 1 mg/ml + 5 mg/ml Augentropfen, Lösung product in the RMS Ducressa 1 mg/ml + 5 mg/ml Augentropfen, Lösung Sevendoc 1 mg/ml + 5 mg/ml Augentropfen, Lösung Name of the drug substances (INN): Dexamethasone sodium phosphate Levofloxacin hemihydrate Pharmaco-therapeutic group S01CA01 (ATC Code): Pharmaceutical form(s) and Eye drops, solution; 1 mg/ml + 5 mg/ml strength(s): Reference Number(s) for the DE/H/6215-6217/001/DC Decentralised Procedure Reference Member State: DE Concerned Member States: DE 6215: ES, IT DE 6216: AT, BE, BG, CZ, DK, EE, EL, ES, FI, FR, HR, HU, IE, IS, IT, LI, LT, LV, NL, NO, PL, PT, RO, SE, SI, SK, UK DE 6217: IT Legal basis of application: Art. 10b of Dir. 2001/83/EC (“fixed combination”) Applicant (name and address) DE 6215: NTC S.r.l. Via Luigi Razza 3, 20124 Milan, Italy DE 6216: Santen Oy Niittyhaankatu 20, 33720 Tampere, Finland DE 6217: Doc Generici S.r.l. Via Filippo Turati 40, 20121 Milan, Italy Names and addresses of all proposed DE 6215+6217: manufacturer(s) responsible for Tubilux Pharma S.p.A. batch release in the EEA Via Costarica 20/22, 00071 Pomezia, Italy DE 6216: Santen Oy Kelloportinkatu 1 33100 Tampere, Finland Dexamethasone/Levofloxacin,DE/H/6215-6217/001/DC Public AR 3/20 I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for “Levendex 1 mg/ml + 5 mg/ml Augentropfen, Lösung“, „Ducressa 1 mg/ml + 5 mg/ml Augentropfen, Lösung“ and „Sevendoc 1 mg/ml + 5 mg/ml Augentropfen, Lösung”, indicated for prevention and treatment of inflammation, and prevention of infection associated with cataract surgery in adults, is approved. Notwithstanding that the Applicant has withdrawn the UK from DE/H/6216/001/DC, the concerns from the UK have been assessed in the course of this procedure. II EXECUTIVE SUMMARY II.1 Problem statement These decentralized marketing authorization applications according to Art. 10b of Dir. 2001/83/EC as amended concern the first fixed dose combination (FDC) of the known active substances dexamethasone and levofloxacin under the trade names “Levendex 1 mg/ml + 5 mg/ml Augentropfen, Lösung“, „Ducressa 1 mg/ml + 5 mg/ml Augentropfen, Lösung“ and „Sevendoc 1 mg/ml + 5 mg/ml Augentropfen, Lösung” for “Prevention and treatment of inflammation, and prevention of infection associated with cataract surgery in adults”. The same concentrations of both active substances, 1 mg/ml of the corticosteroid dexamethasone and 5 mg/ml of the fluoroquinolone antibiotic levofloxacin, have been licensed as eye drops under different brand names since more than a decade across Europe (e.g. “Dexa-sine SE” or “Dexa-EDO”, German MA nos. 6249998.00.00 and 6863959.00.00, “Oftaquix 5 mg/ml, eye drops solution”, German MA no. 53538.00.00). With respect to the non-clinical and clinical studies conducted on behalf of the Applicants, 10 years of data protection are claimed. With Germany as the Reference Member State in these Decentralized Procedures, the respective Applicants are applying for Marketing Authorizations in Italy and Spain (DE/H/6215/001/DC), Austria, Belgium, Bulgaria, Czech Republic, Croatia, Denmark, Estonia, Finland, France, Greece, Hungary, Iceland, Ireland, Italy, Liechtenstein, Lithuania, Latvia, the Netherlands, Norway, Poland, Portugal, Romania, Spain, Slovak Republic, Slovenia, and Sweden (DE/H/6216/001/DC) and Italy (DE/H/6217/001/DC), respectively. The Applicant received national scientific advice regarding non-clinical, clinical and regulatory aspects by the German Federal Agency for Drugs and Medical Devices (BfArM) on 15th May 2017. Follow- up scientific advice on clinical matters was granted by the BfArM on 27th October 2017. II.2 About the product The FDC product constitutes the first combination of 1.32 mg/ml dexamethasone-21-phosphate (equivalent to 1 mg/ml dexamethasone) with 5.12 mg/ml of levofloxacin hemihydrate (corresponding to 5 mg/ml levofloxacin) as aqueous solution for ocular instillation in a multidose low density polyethylene (LDPE) container containing the preservative benzalkonium chloride. The aqueous solution ensures homogeneity of the formulation and does not require shaking before ocular instillation. The synthetic glucocorticoid dexamethasone (9-fluoro-11β, 17-dihydroxy-16α-methyl-3, 20-dioxopregna-1,4 dien-21-yl disodium phosphate), inhibits inflammatory and allergic reactions by suppression of cyclooxygenases, expression of pro-inflammatory cytokines and vascular endothelial cell adhesion molecules. As a consequence, the adhesion of circulating leukocytes to the vascular endothelium and their infiltration of inflamed tissue is reduced. The anti-inflammatory activity of dexamethasone is 25-30 times stronger than that of endogenous cortisol, whereas systemic side effects such as sodium and water retention, loss of potassium and disturbed glucose metabolism are minimal in comparison to cortisol. Topical use of steroids in the eye has proven to be effective in the treatment of inflammatory and allergic diseases affecting the anterior part of the eye, cornea and conjunctiva. Dexamethasone and other steroids are used for post-surgery prophylaxis and management of inflammations. However, for treating diseases of the posterior part of the eye, systemic administration of a steroid is required. Dexamethasone/Levofloxacin,DE/H/6215-6217/001/DC Public AR 4/20 Levofloxacin, a broad-spectrum third-generation fluoroquinolone antibiotic, is the active L-isomer of ofloxacin that inhibits bacterial type II topoisomerases—DNA gyrase and topoisomerase IV. Accordingly, levofloxacin targets both Gram positive bacteria (e.g. Streptococcus aureus methicillin- susceptible strain, S. pyogenes, S. pneumonia and S. viridans strains) and Gram negative bacteria (e.g. Escherichia coli, Haemophilus influenzae, Pseudomonas aeruginosa common isolates, Moraxella catarrhalis and Chlamydia trachomatis). The efficacy of the two individual agents, levofloxacin eye drops for the treatment of local infection and dexamethasone for prevention and treatment of inflammation, and prevention of infection associated with cataract surgery in adults, is considered well established. Nevertheless, the non- inferiority of the fixed dose combination product for the prevention and treatment of inflammation and prevention of infection associated with cataract surgery in adults has been clinically studied for 7 days followed by 7 days of dexamethasone vs. standard combinatorial treatment with 3 mg/ml tobramycin/1 mg/ml dexamethasone (“Tobradex”) for 14 days (see below). The FDC is proposed to be instilled as one drop into the conjunctival sac after cataract surgery every 6 h for 7 days. The therapy should not be discontinued prematurely, but needs to be continued with the next dose as planned, even if one dose has been missed. No dose adjustment in elderly patients is required. At the end of the administration of the fixed combination, if the continuation of the treatment with dexamethasone is necessary, it can be administered as monotherapy, without tapering of the antibiotic. II.3 General comments on the submitted dossier The submitted dossier contains a mixture of proprietary non-clinical and clinical studies conducted with the FDC on behalf of the Applicants and bibliographic data on dexamethasone and levofloxacin from publicly available literature sources. Considering the well-established clinical use of the individual active substances and the legal basis of these MAAs (Art. 10b of Dir. 2001/83/EC as amended), this is deemed acceptable by the RMS