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 as indicated earlier during national scientific advice on 15th May 2017.

Ophthalmic use of the new FDC is only intended in adults, because its efficacy and safety has not been established in children and adolescents below 18 years of the age. The Applicant received a product- specific waiver by the PDCO for the fixed dose combination in all paediatric patients below 18 years of age on 12th September 2018 (P/0277/2018; EMA/PDCO/292401/2018).

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.

GMP active substance Regarding the statement on GMP for the active substance a statement/declaration is provided from the manufacturer responsible for manufacture of the finished product and batch release situated in the EU.

GLP Except for an initial dose-range finding experiment, the pivotal non-clinical ocular toxicity study including toxicokinetic determinations in various matrices and local tolerability studies with the dexamethasone/levofloxacin FDC were conducted in compliance with GLP regulations and prevailing OECD guidelines.

GCP and agreed ethical principles The Applicant confirms that the trial only has been conducted in Europe is in accordance with International Conference on Harmonisation Good Clinical Practice (ICH GCP) and all applicable laws

Dexamethasone/Levofloxacin,DE/H/6215-6217/001/DC Public AR 5/20 and Regulations. The Applicant also confirms that the trials have been conducted in Europe and Russia is in accordance with International Conference on Harmonisation Good Clinical Practice ICH Topic E6 (R1) Guideline and all applicable laws and regulations, including the archiving of essential documents.

III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug Substance Levofloxacin Hemihydrate For the drug substance Levofloxacin Hemihydrate the ASMF procedure is used.

The ASMF holder has submitted a letter of access to the BfArM who is RMS in the current DCP DE/H/6215-6217/001/DC.

Assessment of the Active Substance Master File is provided in a separate ASMF Assessment Report with a confidential annex on the Restricted Part.

The manufacturing process includes three manufacturing steps and resulting intermediated from all steps were isolated and analysed. A detailed discussion on residual solvents, catalysts and carry-over impurities has been provided. Assessment of genotoxic impurities has been presented.

Relevant impurities of Levofloxacin Hemihydrate are described in the Ph. Eur. transparency list and are supplemented by two USP related substances. Analytical methods have been described and validated.

Batch results on numerous batches of lower scale and three regular scale batches are satisfactory. The retest period of 48 months has been verified by stability study results. The updated ASMF AP (Applicant’s Part) and RP (Restricted Part) for Levofloxacin Hemihydrate comply with present regulatory requirements. (Updates dated 4th quarter 2019).

Drug Substance Dexamethasone sodium phosphate Dexamethasone sodium phosphate is a well-known active substance and described in the Ph.Eur. A valid Certificate of Suitability to the Monograph of the European Pharmacopoeia (CEP) has been granted to the active substance manufacturer by the EDQM: A retest period of 60 months has been certified by the EDQM when stored at a temperature between 2°C and 8°C in an air tight container protected from light. Module 3.2.S on Dexamethasone sodium phosphate complies with present regulatory requirements.

Drug product The drug product Dexamethasone/Levofloxacin 1 mg/ml + 5 mg/ml eye drops, preserved comprises a clear, greenish-yellow solution. It is a new fixed combination of two known active substances, an antibiotic and a steroid. The drug product is provided in 5 ml LDPE multi-dose containers.

Development of the drug product was described and the choice of active substances and excipients is considered justified. Novel excipients are not used.

The manufacturing process includes sterile filtration and aseptic filling. Validation of the manufacturing process has been successfully finalized with three recent full scale production batches of 250 liter and one pre-validation/bio-batch of 150 liter.

The drug product specifications are considered appropriate. Analytical methods have been described and validated. Batch analysis results of three recent full production batches demonstrate acceptable quality of the applied drug product.

ICH stability study results at ICH long term - conditions covering 18 months and at accelerated conditions covering 6 months for three recent production batches and one pre-validation/bio-batch are available and are on-going. Sterility of the drug product was verified after 22 months at long-term conditions for three production scale batches and at each time point for one pre-validation batch.

Dexamethasone/Levofloxacin,DE/H/6215-6217/001/DC Public AR 6/20

Based on available stability study results a shelf-life of 24 months is claimed. Bottles are stored at upright and at inverted orientation. A stability commitment to complete on-going stability studies is available.

An in-use stability of four weeks after first opening of the container is justified on the basis of one fresh batch and one batch after 18 months storage at ICH long term conditions. A commitment to perform in-use stability studies with an aged batch at the end of shelf-life is available as well.

Based on available data, a shelf-life of 24 months with no special storage condition is considered justified.

The results of a risk evaluation on nitrosamine presence were provided and are considered acceptable.

Conclusion on Quality: The documentation in module 3, quality, for the applied drug product dexamethasone and levofloxacin 1 mg/ml + 5 mg/ml eye drops, solution, comply with present regulatory requirements. From the quality point of view the Dexamethasone/Levofloxacin 1 mg/ml + 5 mg/ml eye drops, solution is approvable.

III.2 Non clinical aspects Pharmacology The synthetic glucocorticoid dexamethasone exerts potent anti-inflammatory and anti-allergic activities, whereas the fluoroquinolone levofloxacin is a broad spectrum antibiotic against various bacterial pathogens. Both active substances proved to be efficacious in various non-clinical animal models in vivo at comparable dosages as contained in the new FDC. Moreover, the clinical efficacy of these agents has also long been established during human ocular therapy. Considering the non- overlapping mode of action of both active substances and prevailing European recommendations of the pertinent non-clinical guideline (EMEA/CHMP/SWP/258498/2005), the Applicant solely referred to publicly available literature to substantiate their pharmacological activity. This is acceptable and no further primary, secondary or safety pharmacological investigations are deemed necessary.

Pharmacokinetics The pharmacokinetic characteristics of dexamethasone and levofloxacin are generally well-known and have been summarized by the Applicant based on the submitted bibliography. These references were complemented by toxicokinetic determinations of both agents in the pivotal 28 days ocular repeated- dose toxicity study with the new FDC in rabbits using appropriately validated LC-MS/MS methodology (see below) as earlier recommended by the RMS during national scientific advice on 15th May 2017.

Toxicology In line with the national scientific advice of the BfArM granted on 15th May 2017, the Applicant investigated the new FDC in a pivotal 28 days repeated-dose ocular toxicity study in rabbits including toxicokinetic determinations of dexamethasone-21-phosphate, dexamethasone and levofloxacin in plasma, aqueous humour, cornea and conjunctiva using dosages established in an initial 7 days DRF study. In both studies, FDC concentrations of up to 2.64/10.24 mg/ml dexamethasone-21- phosphate/levofloxacin hemihydrate (corresponding to 2 mg dexamethasone/ 10 mg levofloxacin) did not elicit any ocular intolerabilities, changes of intraocular pressure or histopathological alterations in the eyes. Similarly, the FDC did not impact on corneal opacity or permeability in the Bovine corneal opacity and permeability assay in vitro. In addition, the FDC did not cause irritation, oedema or erythema/eschar formation in an acute dermal irritation study in rabbits or reveal any sensitisation potential in the Guinea pig maximisation test. Hence, these investigations demonstrate a favourable ocular tolerability of the FDC.

Toxicokinetic determinations confirmed the rapid hydrolysis of dexamethasone-21-phosphate to dexamethasone as indicated by low levels of the phosphate in all analysed matrices. The ocular exposure of dexamethasone and levofloxacin in aqueous humour, cornea and conjunctiva dose- dependently increased after ocular instillation of the FDC and reached clearly higher levels than in plasma. The systemic exposure of both agents also increased in a dose-related manner without any

Dexamethasone/Levofloxacin,DE/H/6215-6217/001/DC Public AR 7/20 differences between genders and low systemic accumulation was noted in the course of the 28 days toxicity study.

However, systemic toxicities involving glomerulopathy and focal tubular cell necrosis in the kidneys, hepatic hypertrophy with intracellular hyaline inclusions and single cell necrosis, minor atrophy of the adrenal gland cortex and lymphocyte decreases due to atrophy in the splenic white pulp, thymus and lymph nodes were evident in the 28 days repeated-dose ocular toxicity study in rabbits. These changes coincide with earlier reports after dexamethasone administration in animals including ocular instillation in rabbits, while deviating from the established toxicity profile of levofloxacin. Hence, these findings are attributable to exaggerated pharmacological effects of dexamethasone. In view of the short-term clinical administration of the FDC over 7 days and the lack of comparable findings in the clinical development of the FDC or during individual ocular use of dexamethasone- or levofloxacin- containing eye drops in patients, the minor 3-fold safety margin obtained by allometric scaling at the NOAEL in the 28 days repeated-dose ocular toxicity study in rabbits is regarded acceptable.

All other toxicity aspects have been sufficiently documented based on publicly available literature. Both dexamethasone and levofloxacin do not exert a clinically relevant genotoxic and carcinogenic potential. Likewise, no reproductive and developmental toxicity studies are deemed necessary, because the impact of dexamethasone on male and female fertility, postnatal development and its teratogenic potential is well established, whereas levofloxacin does not appear to affect fertility or embryo-foetal development. The essential conclusions from these investigations are adequately reflected in section 5.3 of the SmPC and the section “Pregnancy and breast-feeding” of the PL. Thus, marketing authorisation is recommended from a non-clinical point of view.

Environmental Risk Assessment (ERA) The environmental risk assessment (ERA) provided for levofloxacin is considered complete and acceptable. The predicted environmental concentration (PEC) is 0.0006 µg/L which did not exceed the trigger value of 0.01 µg/L detailed by pertinent European recommendations (EMEA/CHMP/SWP/4447/00 corr. 2; EMEA/CHMP/SWP/4447/00 Rev. 1). A bioaccumulation potential is not indicated based on the logKOW <3. A PBT assessment was not required. Based on the information submitted the ERA for levofloxacin does not indicate a potential risk to the environment.

We consider that a final conclusion on the potential risk of dexamethasone to the environment based on the available data cannot be drawn right now. The predicted environmental concentration (PEC) is 0.000048 µg/L, which did not exceed the trigger value of 0.01 µg/L. A bioaccumulation potential is not indicated based on the logKOW <3 and also a PBT assessment was not required. A study on Aerobic Degradation of Dexamethasone acetate in Two Water/Sediment Systems (OECD 308) was submitted as type II variation for the procedure DK/H/C/2649, (API: dexamethasone sodium phosphate) and the study is also accepted for Ducressa, Levendex and Sevedoc (API: dexamethasone sodium phosphate). These results support that dexamethasone and its transformation products M4, M8 and M9 displays a low persistence with DT50 values in the water/sediment system ≤ 30 days and can be classified as not persistent. Nevertheless, most likely M-10 will degrade over time, but at the same time the DT50 will be most likely above the vP threshold of 180 days in sediment (M-10 displays a sediment shift), therefore M-10 is by definition “very persistent” (calculated DT50, 20°C: >180 d). Moreover, in line with the recommendations in the ERA guideline EMEA/CHMP/SWP/4447/00 corr. 2, the results trigger an extended effects analysis on a sediment dwelling organism.

Considering the endocrine mode of action of dexamethasone, the Applicant is presenting the ERA conclusions by using the reference LaLone et al., 2012. In this paper NOEC of 0.1 µg/L was determined in a 21-day reproduction and a 29-day embryo larvae assay performed in the fish P. promelas. Considering that the reference value is a LOAEC value an assessment factor of 1000 is applied, which results in a PNEC of 0.0001 µg/L. The worst-case risk quotient (RQ) can be calculated as follows:

Dexamethasone/Levofloxacin,DE/H/6215-6217/001/DC Public AR 8/20

RQ = PEC/PNEC = 0.000048 µg/L / 0.01 µg/L = 0.48 The RQ calculation is below 1, which indicates that dexamethasone does not present a risk for the aquatic environment when used according to the proposed SmPC.

The Applicant states that the discussion on the sediment dwelling organism test in accordance with OECD 218 is currently ongoing in the procedure for the Applicant’s closely related procedure DK/H/2649/001/DC. A commitment has been made to provide the results probably by Q4/2021 in support of the current application. The Applicant is therefore asked to provide the final study report on toxicity to sediment dwelling organisms by Q4/2021. If there is a delay in timeline, the RMS should be informed immediately.

Summary of main study results Substance (INN/Invented Names): Dexamethasone CAS-number (if available): PBT screening Result Conclusion Bioaccumulation OECD107 1.79 Potential PBT (N) potential- log Kow PBT-assessment Parameter Result relevant for Conclusion conclusion Bioaccumulation log Kow 1.79 not B BCF B/not B Persistence M-10, DT50 whole vP system = 634 d Toxicity NOEC or CMR T/not T PBT-statement : The compound is not considered as PBT nor vPvB Phase I Calculation Value Unit Conclusion PECsurface water , refined = 0.000048 g/L > 0.01 threshold (N) (prevalence) (for both eyes) Other concerns Dexamethasone Endocrine active (Y) (e.g. chemical class) substances (EAS) Phase II Physical-chemical properties and fate Aerobic and Anaerobic OECD 308 DT50, water = 0.33 d The parent compound Transformation in The test has been DT50, sediment = n/a quickly hydrolyses to Aquatic Sediment systems performed with DT50, whole system = 0.26 d yield dexamethasone. dexamethasone shifting to sediment = % Several identified TPs acetate are formed afterwards. Dexamethasone and its transformation products M4, M8 and M9 displays a low persistence (DT50≤30 days). M-10 will degrade over time, therefore M-10 is by definition “very persistent” (calculated DT50, 20°C: >180 d)

Dexamethasone/Levofloxacin,DE/H/6215-6217/001/DC Public AR 9/20

M-3: Dexamethasone DT50, water = 7.3 d DT50, sediment = 8.3 d DT50, whole system = 7.2 d shifting to sediment = 29 % M-4 O OH HO OH H

F H HO DT50, whole system = 3.8 d M-8 O HO H

F H O DT50, whole system = 30 d O M-9 O

HO OH H

F H O OH DT50, whole system = 11 d M-10 O HO OH H vP

F H O OH DT50, whole system = 634 d

Phase IIa Effect studies Study type Test Endpoint value Unit Remarks protocol Fish, 21-d fish 21-d fish NOAEC 0,1 µg/L Fathead minnow reproduction test, reproduction (LaLone et al., 2012)

Substance (INN/Invented Names): Levofloxacin

CAS-number (if available): PBT screening Result Conclusion Bioaccumulation OECD107 0.26 Potential PBT (N) potential- log Kow PBT-assessment Parameter Result relevant for Conclusion conclusion Bioaccumulation log Kow 0.26 not B BCF B/not B Persistence DT50 or ready P/not P biodegradability Toxicity NOEC or CMR T/not T PBT-statement : The compound is not considered as PBT nor vPvB

Dexamethasone/Levofloxacin,DE/H/6215-6217/001/DC Public AR 10/20

Phase I Calculation Value Unit Conclusion PEC surfacewater , 0.00024 g/L > 0.01 threshold (N) refined (prevalence) Other concerns (N) (e.g. chemical class)

ENVIRONMENTAL RISK ASSESSMENT COMMITMENT The Applicant commits to provide the missing final study report on toxicity to sediment dwelling organisms by Q4/2021. If there is a delay in timeline, the RMS should be informed immediately.

III.3 Clinical aspects Pharmacodynamic properties No pharmacodynamic studies on the new product were conducted. Pharmacotherapeutic group: Anti- inflammatory agents and anti-infectives in combination, corticosteroids and anti-infectives in combination (ATC code: S01C A01).

The product (here called Levodesa) is a fixed dose combination of two active substances: levofloxacin and dexamethasone. These two active substances have a completely different mechanism of actions being a topically combination of an antibiotic and a corticosteroid. In fact, dexamethasone is the most commonly used steroid in ophthalmic therapy in Europe while levofloxacin is a modern antibiotic of the quinolone class that is characterized by a broad spectrum of action, with confirmed activity on, both Gram-positive and Gram-negative bacteria. Levodesa is used for ocular inflammation, after surgery when an antibiotic and a corticosteroid are indicated.

Levofloxacin: Mechanism of action: As a fluoroquinolone antibacterial agent, levofloxacin, that is the active L-isomer of Ofloxacin, inhibits bacterial type II topoisomerases—DNA gyrase and topoisomerase IV. Levofloxacin preferentially targets DNA gyrase in Gram negative bacteria and topoisomerase IV in Gram positive bacteria. The spectrum of activity against ocular pathogens includes aerobic Gram-positive microorganisms (e.g. S. aureus MSSA, S. pyogenes, S. pneumoniae, viridans group streptococci), aerobic Gram-negative bacteria (e.g. E. coli, H. influenzae, M. catarrhalis, P. aeruginosa community isolates), other organisms (e.g. Chlamydia trachomatis).

Dexamethasone: Mechanism of action: The efficacy of corticosteroids for the treatment of inflammatory conditions of the eye is well established. Corticosteroids achieve their anti-inflammatory effects through suppression of vascular endothelial cell adhesion molecules, cyclooxygenase I or II, and cytokine expression. This action culminates in a reduced expression of proinflammatory mediators and the suppression of adhesion of circulating leukocytes to the vascular endothelium, thereby preventing their migration into inflamed ocular tissue. Dexamethasone has marked anti-inflammatory activity with reduced mineralocorticoid activity compared with some other steroids and is one of the most potent anti-inflammatory agents.

Pediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Levodesa in all subsets of the paediatric population for the prevention and treatment of inflammation and prevention of infection associated with cataract surgery (see section 4.2 for information on pediatric use).

Pharmacokinetic properties The ocular instillation of Levodesa results in absorption of both active ingredients to the ocular tissues and, at a much lower extent, to the systemic circulation. After instillation to rabbit eyes, the plasma concentrations of levofloxacin increase with the dose after both single and repeated administration. Low levels of dexamethasone sodium phosphate are measured in plasma. In fact, dexamethasone sodium phosphate is rapidly metabolised in vivo to dexamethasone,

Dexamethasone/Levofloxacin,DE/H/6215-6217/001/DC Public AR 11/20 which is the active metabolite. Dexamethasone exposure increases with the dose and after repeated doses a minor accumulation of both levofloxacin and dexamethasone is evident. Both levofloxacin and dexamethasone levels in ocular tissues (aqueous humour, cornea and conjunctiva) result to be higher than the maximum plasma levels after single and repeated doses. In particular, after 28-day treatment levofloxacin and dexamethasone levels in ocular tissues are 50 to 100-fold and 3 to 4-fold higher than the Cmax in plasma, respectively. In the adsorption-distribution study (EudraCT code: 2018-001149-15) one-hundred-twenty-five patients undergoing cataract surgery have been randomized to 3 groups: levofloxacin, dexamethasone and Levodesa. One drop of each drug was administered 60 and 90 minutes before limbal paracentesis. The mean of the observed values for the concentration of levofloxacin was equal to 711.899 ng/mL (95% CI: 595.538; 828.260) in the Levodesa group compared to 777.307 ng/mL (95% CI: 617.220; 937.394) when levofloxacin was administered alone. The concentrations of levofloxacin in the aqueous humour are well above the minimum inhibitory concentrations for the ocular pathogens in levofloxacin’s spectrum of activity. When Levodesa was administered dexamethasone reached an aqueous humour concentration of 11.774 ng/mL (95% CI: 9.812; 13.736) compared to 16.483 ng/mL (95% CI: 13.736; 18.838) when dexamethasone was administered alone. Both levofloxacin and dexamethasone are eliminated via urine.

Clinical efficacy: The efficacy of Eye Drop Combi for the proposed indication has been demonstrated in only one pivotal study conducted by the Applicant in 788 patients. The study design was multicentre, randomised, investigator-masked, reference-controlled, evaluating the efficacy and safety of Eye Drop Combi in the prevention and treatment of inflammation and prevention of infection associated with cataract surgery. The indication was the same as the one applied for by the Applicant. The reference chosen (Tobradex® eye drops suspension, containing tobramycin 3mg/ml and dexamethasone 1mg/ml in FDC) is considered the gold standard for the intended indication for ocular instillation. Route, single and daily dose, as well as treatment duration of the reference in the study report are the same as those reported in the approved labelling for the study indication. The blinded- Assessor design was necessary because test and reference were available in different formulations (solution versus suspension) as well as different treatment duration, and a double-dummy design was not feasible. In fact, while the reference product is a suspension, due to the presence of dexamethasone which is insoluble in water, its vehicle is a solution. Thus, in a double dummy design, the group “test” would have been treated with two solutions, while the group “reference” would have been given a suspension and a solution, which renders the double dummy not feasible. The study endpoints were those reported in the international literature of similar products in the same indication. The relevant points of the protocol were agreed on with the BfArM during a Scientific Advice (SA) and a Follow Up Scientific Advice (FUSA). Reference is made to BfArM Written Advices on 15th May 2017 and on 27th October 2017. Under recommendation of the BfArM, the duration of the antibiotic treatment was limited to 7 days for the test product Eye Drop Combi. This was rendered possible by the special design foreseeing a 7-day treatment with the FDC (levofloxacin and dexamethasone sodium phosphate) followed by a second 7-day treatment with dexamethasone alone, while the reference product (tobramycin and dexamethasone FDC) was given for 14 days as per labelling. A bibliographic search has been conducted in the database of the National Center for Biotechnology Information PubMed (http://www.ncbi.nlm.nih.gov/pubmed/), as well as in the Chemical Abstracts database (https://www.cas.org/products/scifinder/), confirming that there is no further efficacy documentation on the FDC product besides that provided by the Applicant. The pivotal study referred to in this section is fully GCP compliant.

Dexamethasone/Levofloxacin,DE/H/6215-6217/001/DC Public AR 12/20

The overview of efficacy of the product consisted of one study, which is summarised in the table below: Study design Daily dose, Reference Study No. Indication and Endpoints No. of patients route and Efficacy results drug objective(s) duration Levodesa_ Prevention Multicentre, Primary endpoint Screened: Eye Drop Combi Tobradex At screening all patients had no 04-2017 and treatment randomised, The proportion of patients without 863 4x 30 µl drops (tobramycin + signs of anterior chamber of investigator- signs of anterior chamber Randomized: daily x 7 days dexamethasone) inflammation. No significant inflammation masked, inflammation (sum of cells and 808 followed by 4 x 30 µl drops differences after 3 and 7 days of and reference- flare score = 0) after 14 days. Safety population: Maxidex daily x14 days treatment: no signs of prevention of controlled, 788 (dexamethasone) inflammation in 73.16% vs. infection Rating of Secondary endpoints FAS*: 788 4x 30 µl drops 76.84% and 85.57% vs. 86.77% associated efficacy and Efficacy: Eye Drop Combi: daily x 7 days in Eye Drop Combi group vs. with cataract safety of Eye • Incidence of endophthalmitis 395 tobramycin + dexamethasone surgery Drop Combi in • Proportion of patients without M: 166 respectively. the treatment signs of anterior ocular chamber F: 229 At 14 days patients with no signs and prevention inflammation (sum of cells and PP**: 762 of inflammation in Eye Drop of flare score = Combi was 95.19% vs. 94.91% inflammation 0) after 3 and 7 days of treatment tobramycin + dexamethasone. and prevention • Proportion of patients with The difference was 0.0028 (95% of infection conjunctival hyperemia score equal CI: [-0.0275; 0.0331]), which associated with to 0 after 3, 7 and 14 days of demonstrated the non- inferiority cataract surgery treatment of Levofloxacin + • Proportion of patients with Total dexamethasone since the 95% CI Ocular Symptoms Score (TOSS) did not cross the predefined non- equal to 0 after 3, 7 and 14 days of inferiority margin Δ = -0.10 and treatment lay entirely to the right of the • Proportion of patients with ocular margin. pain/discomfort score equal to 0 after 3, 7 and 14 days of treatment • Proportion of patients using rescue therapy during treatment Safety: • Number of patients with a significant increase (> 6 mmHg) in intraocular pressure (IOP) after 3, 7 and 14 days of treatment • Number of patients with a decrease in visual acuity after 14 days of treatment • Incidence of adverse events • Global evaluation, burning, stinging, blurred vision as assessed *Full Analysis Set at each visit via 4- point scales **Per Protocol

Dexamethasone/Levofloxacin,DE/H/6215-6217/001/DC draft Public AR 13/20

The study drugs for the two treatment arms were as follows: Test arm • Eye Drop Combi (levofloxacin 5 mg/ml + dexamethasone sodium phopshate 1.32 mg/ml) eye drops solution • Maxidex® (dexamethasone 1 mg/ml eye drops suspension)

Eye Drop Combi (levofloxacin + dexamethasone sodium phosphate eye drops) for 7 days, 1 drop - 4 times a day (hours 8.00, 13.00, 18.00 and 23.00 ± 30 minutes), followed by dexamethasone eye drops alone (Maxidex®) for an additional 7 days, 1 drop - 4 times a day (hours 8.00, 13.00, 18.00 and 23.00 ± 30 minutes).

Control arm tobramycin 3 mg/ml + dexamethasone 1 mg/ml eye drops suspension (Tobradex®)

• tobramycin + dexamethasone eye drops (Tobradex®) for 14 days, 1 drop - 4 times a day (hours 8.00, 13.00, 18.00 and 23.00 ± 30 minutes).

Results of the primary endpoint: The proportion of patients without signs of anterior chamber inflammation (sum of cells and flare score = 0) after 14 days. The proportion of patients with presence/absence of signs of anterior chamber inflammation (primary endpoint) was summarized at each visit in the FAS population by treatment group. Patients without signs of anterior chamber inflammation had no cells in the anterior chamber and no aqueous flare. Missing data were handled as follows: the Last Observation Carried Forward (LOCF) method was used to impute missing values if at least one post-baseline value was available, while drop-out patients with only the baseline value were considered as “failures” (i.e. worst-case scenario). At screening visit, all patients had no signs of anterior chamber inflammation. No significant differences were observed between the two treatment groups for the proportion of patients with no signs of anterior chamber inflammation after 3 and 7 days of treatment: 73.16% vs. 76.84% and 85.57% vs. 86.77% in the Eye Drop Combi (levofloxacin + dexamethasone sodium phosphate) group vs. tobramycin + dexamethasone group, respectively. After 14 days of treatment, the proportion of patients with no signs of inflammation (primary endpoint of the study) in the Eye Drop Combi group compared to the tobramycin + dexamethasone group was 95.19% vs. 94.91%. The difference between the two proportions was 0.0028 (95% CI: [-0.0275; 0.0331]), which demonstrated the non-inferiority of Eye Drop Combi since the 95% CI did not cross the predefined non-inferiority margin Δ = -0.10 and lay entirely to the right of the margin. The Applicant performed a sensitivity analysis considering all dropout patients as failures, independently of the time of dropout. This analysis confirmed the results obtained by applying the LOCF approach. After 14 days of treatment, the proportions of patients without signs of inflammation were 94.94% and 94.66% in the Eye Drop Combi and tobramycin + dexamethasone group, respectively. The difference between the two proportions was 0.0028 (95% CI: [-0.0282; 0.0338]). Similar results were observed in the PP population by applying the LOCF approach. The study met its primary endpoint, and the result was strengthened by the consistency between the primary analysis, the sensitivity analysis and the PP analysis.

Dexamethasone/Levofloxacin,DE/H/6215-6217/001/DC Public AR 14/20

Table. Overview on presence/absence of signs of anterior chamber inflammation: Levofloxacin + tobramycin + dexamethasone dexamethasone (N=395) (N=393) n % n % Presence/absence Visit 1 - Screening Signs absent 395 100.00 393 100.00 of signs of Visit 3 – Day 4 Signs absent 289 73.16 302 76.84 anterior chamber Signs present 106 26.84 91 23.16 inflammation Visit 4 – Day 8 Signs absent 338 85.57 341 86.77 Signs present 57 14.43 52 13.23 Visit 5 – Day 15 Signs absent 376 95.19 373 94.91 Signs present 19 4.81 20 5.09

Results of secondary Efficacy Endpoints Results 1. Incidence of endophthalmitis: No occurrence of endophthalmitis was reported during the study.

2. Patients without signs of anterior ocular chamber inflammation after 3 and 7 days of treatment: The differences between the proportions of patients without signs of anterior chamber inflammation in the Eye Drop Combi arm compared to the tobramycin + dexamethasone arm were -0.0368 (95% CI: - 0.0972; 0.0236]) and -0.0120 (95% CI: -0.0602; 0.0362]) after 3 and 7 days of treatment, respectively. Proportion of patients with presence/absence of signs of anterior chamber inflammation after 3 and 7 days of treatment were similar but not equal on Visit 3-Day 4 with a slight but significant advantage to the reference product and on Visit 4 Day 8 with a slight but not-significant advantage to the reference product.

3. Patients with conjunctival hyperemia score equal to 0 after 3, 7 and 14 days of treatment: The proportions of patients without conjunctival hyperemia were similar in both groups throughout the study, no significant differences were observed.

4. Patients with Total Ocular Symptoms Score (TOSS) score equal to 0 after 3, 7 and 14 days of treatment: The total ocular symptom score is calculated as the sum of the patient-reported evaluation of 3 ocular symptoms: itching/burning, redness, and tearing (eyes watering). The proportions of patients with a TOSS score equal to 0 (zero) after 3, 7 and 14 days of treatment were not significantly different.

5. Ocular pain and discomfort: Only marginal differences were seen in the proportions of patients complaining of ocular pain and discomfort at each visit.

Conclusion of study results The efficacy of Eye Drop Combi has been demonstrated for the intended indication in the population that closely corresponds to the one expected to receive the drug on the market. The population evaluated were those subjects enrolled in the clinical study conducted by the Applicant. In total, there were 788 subjects, with 395 patients receiving the product in the final to be marketed formulation (eye drop solution). The overall analysis of adverse events has been done considering all clinical studies sponsored by the Applicant. There are no published data on the FDC levofloxacin/dexamethasone identified in the literature with the last report dated from February 2019. A total of 438 patients included in the clinical trials were available for the evaluation of safety. Overall, adverse events were usually mild. In the absorption study, single doses of Eye Drop Combi were considered well tolerated and no adverse events were reported. In the pivotal study, reported adverse reactions were mainly in the Eye disorders SOC, and the frequency was similar to that of the reference Tobradex®. At least one TEAE was reported for 107 of

Dexamethasone/Levofloxacin,DE/H/6215-6217/001/DC Public AR 15/20 the 788 patients (13.58%) making up the Safety Set, 14.18% in the Eye Drop Combi + Maxidex® group and 12.98% in the Tobradex® group. One death occurred due to myocardial infarction in Eye Drop Combi + Maxidex® group (unrelated). Other serious TEAEs occurred in 3 patients of the Eye Drop Combi + Maxidex® arm and 2 patients of the Tobradex® arm. Three patients had falls (and consequent fractures) (2 in the Eye Drop Combi + Maxidex® group and 1 in the Tobradex® group), one in the Tobradex® group had a myocardial infarction and one (Eye Drop Combi + Maxidex® group) a retinal detachment. None of the SAEs were suspected of being related to study treatments. Otherwise, only slight differences between groups were observed in terms of the number of patients reporting serious TEAEs, drug-related TEAEs and TEAEs leading to treatment discontinuation. Ocular TEAEs of the operated eye were reported for 8.86% of the Eye Drop Combi + Maxidex® arm and 10.43% of the Tobradex® arm. No substantial difference in the distribution of ocular events was present. Corneal oedema was the most common TEAE and was reported in 3.29% of the Eye Drop Combi arm and 4.83% of the Tobradex® arm. The study protocol did not list those adverse events that were expected as a consequence of the cataract surgery: all TEAEs were reported as per standard procedure without reference to those probably due to surgery. On the other hand, it is opinion of the Reviewer that many ocular AEs (including corneal oedema) in both groups were likely due to phacoemulsification.

Clinical laboratory evaluations Other clinical laboratory evaluations were not done and this is acceptable for this topical product. The approach of the Applicant is justified by the fact that the product is for ocular instillation only, and that the therapy is short term. The dosages used in clinical studies by ocular instillation are much smaller than those approved by systemic routes of administration. As a consequence, the plasma levels of both ingredients are negligible in respect of their ability to cause systemic effects. A significant increase from baseline in intraocular pressure was defined as one greater than 6 mmHg. The proportions of patients with a significant increase after 3, 7 and 14 days of treatment were 1.27% vs. 1.27%, 0.51% vs. 1.78%, and 1.03 % vs. 0.51% in the Eye Drop Combi + Maxidex and in Tobradex groups, respectively (differences not significant). The tolerability of all study treatments was high: the percentage of patients reporting no intolerability was > 90% in both groups and for each tolerability parameter. No noteworthy differences between the two treatment groups were present at each visit for all parameters.

Conclusion on efficacy From a clinical point of view the product is non-inferior in the primary and most secondary endpoints to the reference product. Of particular importance is the fact that prevention of infection was similarly effective in both treatment groups and in patients treated with Eye Drop Combi for only 7 days compared to the control arm, in which the antibiotic treatment was administered for 14 days. Considering that the duration of antibiotic administration is one of the main factors facilitating the appearance of bacterial resistance, the results of this study, which support the efficacy and safety of short antibiotic prophylaxis, can contribute significantly to containment of the occurrence of antibiotic resistance.

Antibiotic prophylaxis after cataract surgery Cataract surgery remains the most commonly performed ocular procedure worldwide. The advances in technology and improvement in surgical techniques have resulted in better visual outcomes, thereby increasing patients’ expectation of optimal results. Although the incidence of endophthalmitis remains low following routine cataract extraction, the risk still exists as a potentially blinding, albeit preventable, complication. Surgeons are mindful of the importance of careful standardized antiseptic techniques, including the use of topical povidone-iodine using the 5% solution and povidone-iodine scrub of the ophthalmic area with 10% solution. Common standard practices also include administration of preoperative and postoperative topical antibiotics. Antibiotic prophylaxis combined with dexamethasone eye drops for the prevention and treatment of inflammation, and prevention of infection associated with cataract surgery has been found to be the golden standard for several decades. Therefore, fixed combination eye drops with antibiotics and dexamethasone are admitted in Germany. There are few data on this topic, although this is an area of legitimate interest in view of the fact that postoperative administration of antibiotic eye drops can be defined the best option, especially in case

Dexamethasone/Levofloxacin,DE/H/6215-6217/001/DC Public AR 16/20 of surgical complications, with bad wound healing or if for the patient's risk of postoperative nosocomial infection justifies an antibiotic cover in the early postoperative period. A survey conducted in 2007 by the members of the American Society of Cataract and Refractive Surgery (ASCRS) suggested a strong preference for perioperative topical antibiotic prophylaxis. Most respondents favored the newer generation fluoroquinolones. Therefore, the choice of the antibiotic agents seems to be supported.

Recent data suggest that perioperatively given topical antibiotic eye drops have no added benefit effect to avoid postoperative endophthalmitis, if intracameral injection of cefuroxime are applied (standard of care): The report of the Swedish Cataract Register 3 from 2013 shows that there is no statistical benefit from additional topical antibiotics, neither pre- or neither postsurgery, if in both cases postoperatively, intracameral antibiotics were used. As noted by the Authors themselves in the conclusions of the study, no information is provided regarding the effectiveness of postoperative prophylaxis for one or more weeks with the combination between antibiotic and corticosteroid because such prophylaxis is not performed in Sweden. (1). Other report also show no increase in observed endophthalmitis rates after omitting the postoperative eye drops, but the sample size, as declared by the Authors themselves in the conclusions of the study, was completely insufficient to assess the possible non-inferiority of absence versus presence of topical antibiotic prophylaxis [Raen 2013(4)]. In the ESCRS study (3) it is demonstrated that although a slight trend was evident, there is no statistical benefit from additional perioperatively topical antibiotics, neither pre-nor still in both cases postoperatively, though intracameral antibiotics (standard of care) were used (2). However, in the ESCRS study, all patients underwent postoperative topical antibiotic treatment with levofloxacin four time a day for 6 days. For the multinational characteristics of the Phase III pivotal study, the experimental design did not include the requirement of prophylaxis with intracameral administration, the execution of which was left free. In the pivotal study, the percentage of patients without intracameral antibiotic prophylaxis was similar in the two treatment groups (20%). For this reason, the potential risk of endophthalmitis in the enrolled patients is to be considered higher (about 0.2%) than that of a population in which intracameral prophylaxis is always performed, but similar in the two treatment groups. The fact that in the group of patients treated with Eye Drop Combi there were no cases of endophthalmitis despite a higher potential risk confirms that the short postoperative topical prophylaxis (7 days) with levofloxacin is not associated with an increase in the frequency of endophthalmitis compared to that expected.

Currently, fluoroquinolone drops are becoming preferred because of their relatively wide spectrum of action, their ability to a certain extent into the corneal epithelium and their availability in trade. The resistance rate to these drugs however, is steadily increasing. Therefore, the “Deutschsprachigen Gesellschaft für Intraokularlinsen-Implantation und refraktive Chirurgie” (DGII (5)) recommends that antibiotic eye drops containing – especially newer one like vancomycin– should be reserved. With regard to the high MICs reached in the eye and to the short duration of treatment, it seems unlikely that the product will contribute to the development of resistance. It is considered that the duration of antibiotic administration is one of the main factors facilitating the appearance of bacterial resistance along with inappropriate tapering. However, from the submitted study results it can be concluded that prevention of infection was similarly effective in both treatment groups and in patients treated with Eye Drop Combi for only 7 days compared to the control arm, in which the antibiotic treatment was administered for 14 days. The results of the provided study support the efficacy and safety of short antibiotic prophylaxis.

In Conclusion the proposed indication by MAH for Eye Drop Combi , “for prevention and treatment of inflammation, and prevention of infection associated with cataract surgery in adults” without restriction can be agreed.

Clinical safety No safety studies on the new product were conducted. The safety profile assessment of the present dossier is based on the Applicant’s clinical studies on Eye Drop Combi, and on the safety profile already known for the single active ingredients as per their most recently approved labelling. During the clinical pharmacology development of Eye Drop Combi, its safety profile was assessed in

Dexamethasone/Levofloxacin,DE/H/6215-6217/001/DC Public AR 17/20

43 patients included in the safety population of study Levodesa_05-2017. During the efficacy and safety pivotal study, 395 patients were included in the safety population of the study Levodesa_04-2017. Data from clinical trials corroborate nonclinical toxicological findings, revealing a favourable safety profile, with infrequent reports of mild adverse events, mostly related to the SOC “Eye disorders”, likely related to surgery rather than to the drug treatment. No related serious adverse events (SAEs) were recorded.

Overall extent of exposure and demographic characteristics The clinical trials discussed in Section 2.7.4 support the clinical use of Eye Drop Combi and its good safety profile, and include a total sample of 438 patients effectively given Eye Drop Combi. All of them belong to the target population of the intended indication. In regard to the demographic characteristics, the study populations consisted of male and female adult and elderly patients, with a moderate prevalence of females (58%) and over 80% of patients being ≥65 years old. The clinical trials were conducted using the intended route of administration (ocular instillation), with the final to-be-marketed formulation. The doses tested were single dose (2 drops 30 min apart) before surgery in 43 patients of study Eye Drop Combi 05 2017, and 1 drop 4 times daily for 7 days, followed by a 7-day course with dexamethasone alone (Maxidex® eye drops) in 395 patients of study Levodesa_04-2017. In the latter study, the treatment started soon after surgery, and safety data of that clinical trial refer to the whole 14-day time course of the study.

Adverse events An overview of the studies contributing to the safety analysis of Eye Drop Combi is summarised in the following table 2.5-6.

Table 2.5-6: Safety studies with Eye Drop Combi

Number of subjects Study No. Treatment Safety Dose Reference (section) duration Total (age) Test drug evaluation drug Levodesa_ Eye Drop Combi Single dose 125 n=43 Tamesad Adverse events 05-2017 2x30 µl drops 30 min M:56 F:69 M: 17 n=40 apart Mean age: F:26 M: 19 Tamesad 2 x26 µl 74.14±8.03 yo F: 21 drops Oftaquix 30 min apart n=42 Oftaquix 2 x30 µl drops M: 20 30 min apart F: 22

Levodesa_0 Test: Eye Drop Combi 7 days for test n=788 n=395 Tobradex Adverse events 4-2017 4 x 30 µl drops daily x drug followed <65 yo: 141 M: 166 N=393 Ocular adverse 7 days by 7 days ≥65 yo: 647 F: 229 M: 154 events followed by 4 x 30 µl with F: 239 Intraocular drops daily x 7 days dexamethason pressure Maxidex e alone Visual acuity (dexamethasone) Local Reference: Tobradex 14 days for tolerability (tobramycin + reference drug dexamethasone) eye drops 4 x 30 µl drops daily x 14 days

F: female; M=male; yo= years old

Safety in special groups and situations Eye Drop Combi is a product indicated only for adult patients, mostly elderly, to be treated by ocular topical route and for short term. Any influence of intrinsic factors such as sex, race, ethnicity, height,

Dexamethasone/Levofloxacin,DE/H/6215-6217/001/DC Public AR 18/20 weight, lean body mass, genetic polymorphism, body composition, other illness and organ dysfunction has not been studied, because it is unlikely. Clinical trials with Eye Drop Combi were mostly conducted in Caucasian subjects.

Conclusion on safety It can be concluded that the product is safe. The adverse events reported with the use of Eye Drop Combi were mild and well tolerated. The most common adverse events were related to ocular discomfort, which could be due to the cataract surgery. Furthermore, no related serious adverse events or deaths were reported in clinical studies, confirming the good safety profile of Eye Drop Combi.

Legal Status The medicinal product is subject to medical prescription.

User Testing The readability test has shown that the information given is clear, understandable, easy to find and that this information can be used easily, safely and appropriately by the users of the drug. The information given in the leaflets of both drugs are available at the same location in the leaflet. The difference in font style should not have a negative impact on the readability as discussed previously. Consequently, leaflet is accessible to and understandable by those who receive it, so that they can use the medicine safely and appropriately.

Summary Pharmacovigilance system The Applicant has submitted a signed Summary of the Applicant's and/or 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 applicants have submitted risk management plans, 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 Levendex, Ducressa, and Sevendoc.

Safety specification The Applicants propose the following summary of safety concerns:

Important identified risks None Important potential risks None Missing information None

Pharmacovigilance Plan Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicants, which is endorsed.

Risk minimisation measures Routine risk minimisation is suggested and no additional risk minimisation activities are proposed by the applicants, which is endorsed.

Summary of the RMP The submitted Risk Management Plans (version 1.0) are considered acceptable.

The MAHs shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMPs presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMPs.

Dexamethasone/Levofloxacin,DE/H/6215-6217/001/DC Public AR 19/20

An updated RMP should be submitted: - At the request of the RMS; - Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures.

Periodic Safety Update Report (PSUR) With regard to PSUR submission, the MAHs should take the following into account: • PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR. • For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list. • In case the active substance will be removed in the future from the EURD list because the MAs have been withdrawn in all but one MS, the MAHs shall contact that MS and propose DLP and frequency for further PSUR submissions together with a justification.

IV BENEFIT RISK ASSESSMENT The product is a fixed dose combination of levofloxacin 5 mg/ml and dexamethasone sodium phosphate 1.32 mg/ml formulated in an eye drop solution, tested in well-designed clinical trials in adult and elderly patients undergoing cataract surgery for the prevention and treatment of inflammation, and prevention of infection associated with cataract surgery. Tested in a pivotal study aimed at investigating efficacy and safety in the intended indication, the FDC in the to-be-marketed formulation administered for one week, followed by the administration of dexamethasone alone for another week, proved to be non-inferior to a two-week treatment with a combination of tobramycin and dexamethasone in preventing or reducing inflammation and in preventing infection, i.e. the primary goals of combined therapy in ophthalmic surgery. The result was supported by the consistency of the sensitivity and PP analyses. Therefore, the study met its primary objective. Furthermore, efficacy and safety results were comparable between the two treatment groups for all endpoints. It is important to note that the complete resolution of inflammatory signs was achieved in a high percentage of patients (>85 %) already after the first 7 days of treatment in both groups of patients. With reference to the possible side effects of topical ocular treatment with corticosteroids, this finding may lead to a re-evaluation of the duration of corticosteroid treatment following cataract surgery, in order to further improve the risk / benefit ratio of the treatment. From a clinical point of view, of particular importance is the fact that prevention of infection was similarly effective in patients treated with the FDC for only 7 days compared to the control arm, in which the antibiotic treatment was administered for 14 days. Considering that the duration of antibiotic administration is one of the main factors facilitating the appearance of bacterial resistance, along with tapering of the antibiotic treatment which was not part of the design of this trial, the results of this study, which support the efficacy and safety of short antibiotic prophylaxis, can contribute significantly to the policy of containment of the use of antibiotics and further development of antibiotic resistance.

In Conclusion: From a non-clinical, clinical and quality point of view the benefit/risk ratio is considered positive. The application is approved. For intermediate amendments see current product information

Dexamethasone/Levofloxacin,DE/H/6215-6217/001/DC Public AR 20/20