Guidance Document

Bundesinstitut für Arzneimittel und Medizinprodukte Decentralised Procedure Public Assessment Report Dexafluid Eye drops Dexamethasone sodium phosphate DE/H/2715/001/DC Applicant: mibe GmbH Arzneimittel Muenchener Str. 15 06796 Brehna Germany Reference member state: DE The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health. 1/13 Public AR 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 4 II.4 GENERAL COMMENTS ON COMPLIANCE WITH GMP, GLP, GCP AND AGREED ETHICAL PRINCIPLES. 5 III SCIENTIFIC OVERVIEW AND DISCUSSION 5 III.1 QUALITY ASPECTS 5 III.2 NONCLINICAL ASPECTS 5 III.3 CLINICAL ASPECTS 5 IV BENEFIT RISK ASSESSMENT 13 2/13 Public AR ADMINISTRATIVE INFORMATION Proposed name of the medicinal Dexafluid eye drops product in the RMS INN (or common name) of the active Dexamethasone sodium phosphate substance(s): Pharmaco-therapeutic group S01BA01 (ATC Code): Pharmaceutical form(s) and Eye drops strength(s): Reference Number for the DE/H/2715/001/DC Decentralised Procedure Reference Member State: DE Member States concerned: AT; CZ; SK Applicant (name and address) mibe GmbH Arzneimittel Muenchener Strasse 15 06796 Brehna Germany 3/13 Public AR I INTRODUCTION Based on the review of the data on quality, safety, and efficacy, the application for Dexafluid eye drops, in the steroid treatment of non-infectious inflammatory diseases affecting the conjunctiva, cornea, and anterior part of the eye, is approved. II EXECUTIVE SUMMARY II.1 Problem statement These applications for marketing authorisations via the decentralised procedure concern generic version of Dexamethasone sodium phosphate containing eye drops. The applications have been submitted in MS in accordance with Article 10(3) of Directive 2001/83/EC as amended. The originator is Dexa-sine eye drops solution is registered in most of the European countries under the brand name of Dexa-sine ® eye drops by Alcon Pharma GmbH, marketing authorisation number 12339.00.00 [Fachinformation 2008]. Dexa-sine eye drops ® has been authorized in the European community for more than ten years. The Marketing Authorization for Dexa-sine ® eye drops was first granted for the DE market on July 21, 1993. With Germany as Reference Member State (RMS) in this Decentralised Procedure, mibe GmbH Arzneimiel is applying for the Marketing Authorisations for “Dexafluid eye drops” in four countries: AT; CZ; DE; SK The applied product has the same qualitative and quantitative composition in the active substances and excipients and the same pharmaceutical form as the reference medicinal product. The medical product is therefore considered to have a similar therapeutic efficacy and safety as the reference medicinal product Dexa-sine ® eye drops. II.2 About the product Dexamethasone sodium phosphate is ane adrenocortical steroids. Dexamethasone sodium phosphate, the derivative of dexamethasone, is a synthetic glucocorticoid used as anti-inflammatory or immunosuppressive agents. Dexamethasone has little to no mineralocorticoid activity and is therefore not used by itself in the management of adrenal insufficiency. Dexamethasone sodium phosphate is a water soluble, inorganic ester of dexamethasone. Dexamethasone Sodium Phosphate Ophthalmic Solution, is a sterile, topical steroid solution. It is approximately three thousand times more soluble at 25°C than hydrocortisone. The use of corticosteroids, including dexamethasone and its derivatives, in ophthalmology is well established, e.g . in steroid responsive inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe, such as allergic conjunctivitis, acne rosacea, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, selected infective conjunctivitis when the inherent hazard of steroid use is accepted to obtain an advisable diminution in edema and inflammation; corneal injury from chemical or thermal burns, or penetration of foreign bodies. II.3 General comments on the submitted dossier This application for marketing authorisation for the generic drug product Dexafluid eye drops, solution is made under Article 10(3) hybrid of Directive 2001/83/EC as amended. Dexafluid eye drops, solution were developed by mibe GmbH Arzneimittel, Germany, as generic equivalents to the European brands of Dexa-sine ® eye drops by Alcon Pharma GmbH, marketing authorisation number 12339.00.00. The legal basis of the application is acceptable. The clinical overview on the clinical pharmacology, efficacy and safety, as provided by the applicant, are considered to be adequate. The indication claimed is in line with the SmPC of the approved innovator product Dexa-sine ® eye drops and this is appropriate and acceptable. The document in Module 1.5.1 summarizing the grounds and evidence used for demonstrating that the active substanze of the medicinal products have a well-established use with an acceptable level of safety and efficacy and the whole formulation of the product is essentially similar to the originator Dexa-sine ® eye drops. 4/13 Public AR 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. III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance The drug substance is Dexamethasone disodium phosphate. A CEP has been provided. The specification of the manufacturer and the drug product manufacturer has been provided. Analytical procedures are described. Batch results show compliance with the specification of the active substance. Drug Product For reference Dexa-sine from Alcon Pharma GmbH Germany, Marketing Authorisation Number 12339.00.00, a sterile isotonic solution for steroidal treatment of non-infectious inflammatory diseases of conjunctiva, cornea, and the anterior eye section is chosen. The proposed drug product is an aqueous solution of 1.00 mg/ml Dexamethasone sodium phosphate as active substance. The excipients are disodium phosphate dodecahydrate, povidone K25, sodium chloride, and water for injections. Benzalkonium chloride is added for preservative in combination with the synergist disodium edetate. The closure system consists of 5 ml plastic bottle multi-dose containers made of low-density polyethylene (LDPE) and an appropriate dropper plus cap. The batch formula is consistent with the drug product formula. Manufacturing process and in- process controls are described. Furthermore, the sterilization process had been validated from the microbial point of view and in regard to the irradiation process. The excipients are adequately specified. The release and shelf-life specification cover chemical, physical and microbial parameters relevant for this dosage form. The analytical procedures are described and validated. The reference standards are described sufficiently, as well as the analytical batch results of production-scale presented show compliance with the specification of the drug product. Potential degradation products in the drug product have been characterized. The drug product was shown to be stable under accelerated, intermediate, and at least at long- term conditions for 18 month. A shelf life period of 24 months, as well as an in-use stability of 28 days resp. 4 weeks at normal storage conditions declared is in line to Ph. Eur. recommendations are accepted. III.2 Nonclinical aspects The pharmacodynamics, pharmacokinetics and toxicology of dexamethasone sodium phosphate are well established and are adequately discussed in the non-clinical overview. No new non-clinical data has been submitted in support of this “hybrid application”, and none are required for an application that refers to Article 10(3) Directive 2001/83 EC. An acceptable justification for the lack of an environmental risk assessment has been provided. III.3 Clinical aspects Pharmacokinetics The pharmacokinetics of dexamethasone sodium phosphate is well known. No new data has been submitted and none is required. 5/13 Public AR Following topical instillation of corticosteroids into the conjunctival sac, the drugs are absorbed into the aqueous humour, and systemic absorption occurs. However, because topical ophthalmic corticosteroid dosage is less than when the drugs are given systemically, clinical evidence of systemic absorption usually does not occur [AHFS DI 2009b]. Topical preparations distribute throughout the area of application; ophthalmic preparations distribute into the local tissues [Clinical Pharmacology 2009]. Systemic bioavailability of dexamethasone after topical application depends on the state of the skin at the application site. In general, absorption of topical preparations is increased in areas of skin damage, inflammation, and occlusion, or where the stratum corneum is thin such as the eyelids, and face [Clinical Pharmacology 2009, Sweetman, S. C. 2009]. Serum concentrations for dexamethasone are available only if the drug was administered intravitreally: After the insertion of the dexamethasone intravitreal implant (0.35 mg or 0.7 mg) in 21 patients, plasma concentrations were obtained on days 7, 30, 60,

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