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, and 90. Overall, the majority of dexamethasone plasma concentration measurements were below the lower limit of quantitation (LLOQ = 50 pg/ml). Ten of the 73 samples in the patients receiving the 0.7 mg dose and 2 of the 42 samples in the patients receiving the 0.35 mg dose were above the LLOQ (range, 52-94 pg/ml). The highest plasma concentration (94 pg/ml) was observed in one patient who had received the 0.7 mg dose. Age, body weight, and gender did not affect the plasma dexamethasone concentrations [Clinical Pharmacology 2009]. Systemic dexamethasone is quickly distributed into the kidneys, intestines, skin, liver, and muscle [Clinical Pharmacology 2009]. The volume of distribution is about 1l/kg [Anonymous 2009]. Its biological half-life in plasma is about 190 minutes. Binding of dexamethasone to plasma proteins is about 67 - 77%, which is less than for most other corticosteroids [Sweetman, S. C. 2009, Anonymous 2009]. According to other sources, the plasma elimination half-life of dexamethasone is approximately 1.8-3.5 hours (or 2- 5 h [Anonymous 2009]) whereas the biological half-life is 36-54 hours [Clinical Pharmacology 2009]. Twenty phakic patients scheduled for a first vitrectomy were included in a study to measure the dexamethasone concentration in aqueous humour, vitreous, and serum after repeated topical application of dexamethasone disodium phosphate (1 drop of dexamethasone disodium phosphate (0.1%) every 1 hours until the time of vitrectomy: total, 10 or 11 drops) [Weijtens, O. 2002]. At night, ointment containing dexamethasone (0.3 mg/g) and gentamicin (5 mg/g) was administered once. From 7 AM on, the drop application schedule was resumed. The mean dexamethasone concentrations in the aqueous humour, vitreous, and serum were 30.5 ng/ml (range, 7.1-57.7; standard deviation [SD] 15.0), 1.1 ng/ml (range, 0.0- 1.6; SD 0.4), and 0.7 ng/ml (range, 0.0-1.2; SD 0.4), respectively. The penetration of dexamethasone into the vitreous after repeated drop application is negligible. Despite the frequent dosing schedule, the dexamethasone concentration in the aqueous humour is far lower than after a subconjunctival injection with dexamethasone disodium phosphate. Systemic uptake is low [Weijtens, O. 2002].

Pharmacodynamics Following topical application to the conjunctiva of the eye, corticosteroids inhibit the inflammatory response to mechanical, chemical, or immunologic agents [AHFS DI 2009b] Corticosteroids inhibit oedema, fibrin deposition, capillary dilatation, and migration of leukocytes and phagocytes in the acute inflammatory response. The drugs also reduce capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation [AHFS DI 2009b] Based on these properties, corticosteroids and dexamethasone eye drops in particular are widely used in ophthalmology. Corticosteroids are applied topically to the conjunctiva for the symptomatic relief of corticosteroid- responsive allergic and inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe such as allergic or vernal conjunctivitis, acne rosacea keratitis, superficial punctate keratitis, herpes zoster keratitis, uveitis, iritis, and cyclitis. The drugs also are used topically as anti-inflammatory agents in corneal, conjunctival, and scleral injuries from chemical, radiation, or thermal burns or penetration of foreign bodies and, during the acute phase, may help prevent fibrosis and scarring and resultant visual impairment. Topical ophthalmic corticosteroids also are used prophylactically after ocular surgery (e.g., cataract extraction, glaucoma surgery, corneal transplant) to prevent inflammation, pain, and scarring, but the drugs may possibly delay wound healing. The drugs should not be used for minor abrasions or wounds [AHFS DI 2009b]. Application of corticosteroids to the eye may reduce the facility of aqueous outflow, thereby increasing intraocular pressure (IOP) and inducing or aggravating open-angle simple) glaucoma [AHFS DI 2009b] Results of various studies indicate that, on a weight basis, the anti-inflammatory activity of ophthalmic corticosteroids in decreasing order is: fluorometholone, dexamethasone, prednisolone, loteprednol etabonate, rimexolone, medrysone, and hydrocortisone [AHFS DI 2009b].

6/13 Public AR

Clinical efficacy Controlled clinical studies for analysis of efficacy and safety No clinical or safety studies are conducted by the applicant. The applicant has selected studies from literature. The analysis comprises 2 placebo-controlled studies and 13 active controlled studies in male and female adult patients (n = 3893 patients).

General criteria for selection of studies comprise the following points in particular were: • Controlled studies • Conformity with the indication applied for (non-infectious inflammatory conditions/ illnesses of the conjunctiva, the cornea, and the anterior eye segment) • Conformity regarding the originator medicinal product and the route of administration: topical to the eye (dexamethasone 1 mg/ml) • Adult patients • Outcome for efficacy evaluation: - Clinical resolution of all inflammatory signs and symptoms (Eye redness and irritation, Blurred vision, Eye pain, Increased sensitivity to light, floating spots at the eyes, swelling, heat, tearing, photophobia) - Tyndall effect (Aqueous flare and cells)

OVERVIEW OF EFFICACY Criteria on efficacy Dynamics of symptoms of eye inflammations, i.e. their disappearance or prevention of their appearance, were considered as primary criteria for efficacy. In addition, in a second group of clinical studies, the Tyndall effect was used as surrogate parameter to assess the severity of acute inflammation in the anterior ocular segment.

Quality of studies and compliance with GCP Controlled, randomized clinical Phase III or Phase IV studies were included in the analysis. The studies were conducted in renowned facilities in Western and Eastern countries. Although not regularly stated, accordance with the current requirements of the GCP and the Declaration of Helsinki is therefore expected.

Efficacy results Anti-infective effects assessed by course of clinical symptoms: Controlled clinical studies demonstrated that Dexamethasone 0.1% Eye Drops have clearly superior anti-inflammatory activity in comparison to placebo. Active controlled studies showed that the medicinal product under investigation prides higher or similar anti-infective effects compared with topical diclofenac and indomethacin. Anti-infective effects assesses by using the Tyndall effect: In active controlled studies where the Tyndall effect was used for assessment of outcome was shown that dexamethasone is at least comparable with alternative topical anti-inflammatory therapies. A number of additional active-controlled clinical studies with topical dexamethasone, primarily used after different ocular surgical procedures support the already established beneficial anti-inflammatory effects of the medicinal product under discussion.

Individual study results Controlled clinical studies included in analysis of efficacy and safety Placebo-controlled studies There are 2 placebo-controlled studies conducted in the USA [Sanders, D. R. 1984], and Sweden [Laurell, C. G. 2002]. In both studies, patients suffered from post-operative One of the studies compared dexametasone in combination antibiotics as fixed combinations vs. consecutive treatment with consecutive application of the same substances [Moustafa, B. 2007]. Patients receiving the fixed combination will have advantages compared to those patients receiving the active ingredients as single agent therapy. A major advantage of a combined medicinal product is the lack of a wash-out effect with the combination therapy. A consecutive, random, prospective study was conducted to compare the effect of topical dexamethasone and flurbiprofen drops on postoperative inflammation in patients undergoing extracapsular cataract extraction with lens implantation. Objective, quantitative measurements were made postoperatively, using the Kowa FC-1000 Flare Cell Meter. The two treatments were equally effective [Drews, R. C. 1990].

7/13 Public AR

Controlled clinical studies not included in the safety analysis (topical dexamethasone) Prophylaxis of complications after ocular surgery There are numerous clinical studies where dexamethasone eye drops (or similar formulations) were used immediately after the end of different ocular operations. This use is clearly for prophylaxis of complications due to immunological and/or inflammatory reactions. In the majority of cases dexamethasone is co-administered with other drugs, e.g. anti-infective drugs [Notivol, R. 2004b]. Examples will be given only.

Cataract surgery Moxifloxacin/dexamethasone formulation for topical prophylaxis and reduction of inflammation in phacoemulsification: a comparative, double masked clinical trial [Freitas, L. L. 2007]. One of these studies was conducted to compare the efficacy and safety of a combined 0.5% moxifloxacin and 0.1% dexamethasone formulation (Vigadexa) versus conventional dosing with 0.5% concomitant moxifloxacin (Vigamox) and 0.1% dexamethasone (Maxidex) for the prevention of infection and control of inflammation after cataract surgery by phacoemulsification (four times a day for 15 days). Baseline and postoperative assessments were made on surgery days -2, 1, 3, 8, and 15. There was no sign of intraocular infection at any time and only minimal inflammation beyond day 3. Physicians rated bacterial infection to be absent in both groups on days 1, 3, 8 and 15. Ninety-seven percent of patients in each group had ≤ 5 cells by day 15. Objective and subjective parameters were essentially the same in both treatment groups (P > 0.05). One patient in the conventional therapy group developed viral conjunctivitis unrelated to the surgery [Freitas, L. L. 2007]. The authors concluded that treatment with the combined moxifloxacin/dexamethasone eye drops was as effective as conventional treatment in preventing infection and con and cells but showed a slightly higher incidence of punctate keratitis and eye discomfort [Herbort, C. P. 2000]. Dexamethasone 0.1% vs. rimexolone 1% in the postoperative treatment after cataract extraction [Vico-Ruiz, E. 2009]. This recent study compared the efficiency and secondary effects of using 1% rimexolone or 0.1% dexamethasone as postoperative treatment for cataract surgery. After surgery, 19 of the patients were randomly assigned to receive topical 0.1% dexamethasone (DEX group) as inflammatory treatment and the remaining 18 subjects were treated with 1% rimexolone (RIMEX group) following the same regime. Twenty four hours and one month after surgery, visual acuity, conjunctival hyperaemia, anterior chamber cells, anterior chamber flare, intraocular pressure, corneal thickness, and macular oedema were determined in each patient. The repeated measures test performed on 24 hours and 1 month data revealed a significant difference between the two treatments in terms of Tyndall (P = 0.001) and flare (P = 0.034) values; these variables being lower in the dexamethasone group. No differences were observed in the remaining variables examined. The authors concluded that rimexolone is as efficient and safe as dexamethasone for the treatment of patients undergoing cataract extraction [Vico-Ruiz, E. 2009].

Keratectomy Topical corticosteroids were used following keratotmy and keratectomy. Following keratotomy in patients with myopia under 8.00 D, the use of dexamethasone 0.1% twice daily for 3 months postoperatively did not improve the refractive outcome [Haverbeke, L. 1993]. This results is in accordance with the experience of other authors [Gartry, D. S. 1992, Machat, J. J. 1993].

Cyclocryotherapy-induced inflammation A comparison of the effect of flurbiprofen, dexamethasone, and placebo on cyclocryotherapy-induced inflammation [Hurvitz, L. M. 1984] A double-blind study was performed to compare the effects of a placebo, a topical corticosteroid, and a topical non-steroidal prostaglandin inhibitor on the inflammation and the course of intraocular pressure that follows cyclocryotherapy. Flurbiprofen 0.03%, dexamethasone phosphate 0.1%, and a sterile vehicle placebo were used both pre and postoperatively. No significant difference among eyes treated with flurbiprofen, dexamethasone, or placebo was noted except for greater erythema with flurbiprofen, and a possibly spurious decrease in flare four weeks after treatment with flurbiprofen [Hurvitz, L. M. 1984].

8/13 Public AR

Clinical safety Adverse reactions in clinical trials The published clinical studies were analysed for reported adverse event. Since adverse events were not always reported in the publications, the number of clinical studies analysed for efficacy and those analysed for safety may differ. A summary of adverse effects based on 5 clinical studies where 338 patients were presented below:

Incidence of Dexamethasone eye drops-associated adverse events in individual studies - Summary of 6 treatment arms in 5 clinical studies with 338 patients.

Common (≥1%-<10%) Eye disorders

Uncommon (≥0.1%-<1%) Nervous system disorders

Eye disorders

General disorders and administration site conditions Face oedema Based on this small pool of patients, eye pain and hyhaema (appearance of blood in the front (anterior) chamber of the eye) are common adverse events. Headache, eye inflammation, conjunctivitis, corneal oedema, ulcerative keratitis, and face oedema are uncommon adverse events. It appears that none of these effects were classified as serious. Moreover, regarding the prior operative measures in the majority of clinical studies, dexamethasone cannot be considered as the cause of the reported adverse effects. This conclusion is supported by a comparison of adverse events reported with placebo- and reference-medication treated patients (please refer to Table 2.7.4.3 in section 2.7.4.7). Eye inflammation and hyphaema are the most frequent adverse events in the placebo group. The most frequently Dexamethasone Sodium Phosphate 1 mg/ml, eye drops reported adverse event in patients treated with reference therapy was eye inflammation, eye pain, and hyphaema.

Spectrum of adverse effects in reviews The safety profile of dexamethasone, and dexamethasone eye drops in particular, was evaluated repeatedly in commercial scientific databases, e.g. [HSDB 2009, AHFS DI 2009b, Clinical Pharmacology 2009, DRUGDEX Evaluations 2009] The most comprehensive compilations available in the Hazardous Data Base [HSDB 2009], and the ‘Gold Standard Monographs’[Clinical Pharmacology 2009] will be quoted. The most frequent adverse reactions to ophthalmic dexamethasone are visual impairment (i.e., visual acuity and field defects), secondary ocular infection (including viral and fungal infections) exacerbation, and perforation of the globe [Clinical Pharmacology 2009]. Rarely, ocular irritation consisting of burning and stinging may occur with ophthalmic administration. Temporary or permanent visual impairment, including blindness, has been reported with corticosteroid administration by several routes of administration including intranasal and ophthalmic administration. Ophthalmic preparations of dexamethasone can cause an increased intraocular pressure, the magnitude of which dependson the frequency and duration of dosing. Ocular hypertension can occur after 1-6 weeks of topical ophthalmic therapy, and it usually is reversible upon discontinuance of the drug. Prolonged use of ophthalmic dexamethasone therapy can result in ocular hypertension, optic nerve damage, and visual defects. Although systemic corticosteroids are used to treat Graves' ophthalmopathy, ocular effects, such as exophthalmos, posterior subcapsular cataracts, retinopathy, or ocular hypertension, can result from prolonged use of corticosteroids and could result in glaucoma, or ocular nerve damage including optic neuritis [Clinical Pharmacology 2009].

9/13 Public AR

Because some systemic absorption may occur following topical application or intravitreal implantation of corticosteroids to the eye, the possibility of adverse systemic effects exists. Headache, hypotension, rhinitis, pharyngitis, and taste perversion have been reported in patients following topical instillation of ophthalmic corticosteroids. Other adverse systemic effects associated with systemic corticosteroids are uncommon with topical ophthalmic corticosteroids, even with extended use, but the risk may be increased with frequent topical ophthalmic administration of potent steroids [HSDB2009]. Rare instances of anaphylactoid reactions, such as anaphylactic shock and angioedema have occurred in patients during corticosteroid therapy [Clinical Pharmacology 2009].

Spontaneous reports on adverse effects Corneal melting with intraocular lenses A single publication reported on corneal melting with intraocular lenses in patients with collagen vascular diseases and keratoconjunctivitis sicca after cataract surgery and implantation of intraocular lenses in 5 patients [Yang, H. K. 1982]. The authors suggested that postoperative development of corneal melting may have been potentiated by the use of topical 0.1% dexamethasone sodium phosphate alcohol and neomycin.

Lacrimal canalicular obstruction Among others, one case of lacrimal canalicular obstruction associated with topical dexamethasone was reported in the literature [McNab, A. A. 1998].

Discussion of special risk factors Effects of dexamethasone eye drops on blood glucose profile Topical dexamethasone or diclofenac for one month administered to patients who underwent cataract surgery revealed a significant increase in blood glucose levels only in the diabetic dexamethasone group, from 170±55.5 mg/dl before surgery to 229±76.8 mg/dl one month later (P=0.05). This level was significantly higher than the one-month level in the diabetic patients treated with diclofenac [Bahar, I. 2007]. The authors concluded that postoperative dexamethasone eye drops have a greater effect on the blood glucose profile of diabetic patients than on non-diabetic patients. Clinicians should be alerted to this risk and may initiate appropriate follow-up in this patient subgroup. A similar effect was reported in another publication. Intensive application of topical corticosteroids (drops) for a short period of time (7 days) seems to raise statistically significantly the blood glucose levels in patients with controlled diabetes mellitus, which, however, return to pre-treatment levels after discontinuation of eyedrops without any side effects [Kymionis, G. D. 2007]. Ophthalmic dexamethasone therapy should be undertaken with caution in patients with diabetes mellitus because these patients have an increased risk of developing ocular hypertension during therapy. Topical corticosteroids should be used with caution in patients with diabetes mellitus. Exacerbation of diabetes may occur with systemic absorption of the topical corticosteroid. Use of topical corticosteroids may further delay healing of skin ulcers in diabetic patients [Clinical Pharmacology 2009]. Intensive use of dexamethasone eyedrops may temporarily raise the blood glucose level, in patients with diabetes mellitus in particular.

Effects of topical steroids on corneal epithelial healing The effects of topical dexamethasone sodium phosphate 0.1% on corneal epithelial healing after epithelial debridement in vitreoretinal surgery were evaluated in 85 patients. Topical dexamethasone administered five times/day did not significantly retard corneal epithelial healing in subjects undergoing vitreoretinal surgery with postoperative topical steroid treatment, compared with subjects who did not receive steroid treatment [Yulek, F. 2006]. A similar study examined the effect of topical treatment given immediately after photorefractive keratectomy in 60 patients. Topical dexamethasone significantly retarded epithelial healing and presented a higher number of central islands than placebo, 3 days after surgery. It is concluded that topical dexamethasone used during the first three days following photorefractive keratectomy may affect the epithelial healing and early visual rehabilitation [Tomas-Barberan, S. 1999]. Thus, contrary evidence is available. It appears that dexamethasone topical eye drops may prolong healing processes. The clinical significance of this observation is not yet clear.

10/13 Public AR

Effects on opacification of lens and the cornea Cataract formation: Topical use of dexamethasone may be associated with the cataract formation. Steroid induced cataract have been reported in the early phase of development of dexamethasone eye drops [Yablonski, M. E. 1978, Mohan, R. 1989]. These effects were obtained after prolonged systemic or topical use and preferentially in association with increase of intraocular pressure (‘steroid-induced’ glaucoma). Diabetic patients appear to be at special risk for cataract formation. The condition is reversible without permanent damage when the duration of steroid therapy is short and vice versa. More recent studies on posterior capsule opacification after phacoemulsification in patients with postoperative steroidal and non-steroidal treatment did not support these study results. The authors concluded that topical instillation of diclofenac, dexamethasone, or a placebo in the immediate period after phacoemulsification and intraocular lens implantation did not seem to influence the formation of posterior capsule opacification 2 years after cataract surgery [Zaczek, A. 2004]. Corneal calcification: A recent study suggested that the use of preservative-free medication might be a contributory factor in a series of deep corneal calcification associated with preservative free eyedrops and persistent epithelial defects. All 6 reported single cases of calcareous degeneration of the cornea had persistent epithelial effects, treated with preservative-free medications (timolol, dexamethasone, and prednisolone), in the presence of active inflammation on the ocular surface [Lake, D. 2008]. Formation of cataract and corneal calcification are the consequence of a destroyed local metabolism. It cannot be excluded that dexamethasone may contribute to these conditions.

Steroid allergy / hypersensitivity Steroid allergy, against dexamethasone in particular, has been reported in seldom cases after topical and systemic administration of steroid medications [Peng, Y. S. 2001, Alexiou, C. 1999]. Although true corticosteroid hypersensitivity is rare, patients who have demonstrated a prior hypersensitivity reaction to dexamethasone should not receive any form of dexamethasone. It is possible, though also rare, that such patients will display crosshypersensitivity to other corticosteroids. It is advisable that patients who have a hypersensitivity reaction to any corticosteroid undergo skin testing, which, although not a conclusive predictor, may help to determine if hypersensitivity to another corticosteroid exists. Such patients should be carefully monitored during and following the administration of any corticosteroid [Clinical Pharmacology 2009]. Allergic reactions against dexamethasone cannot be excluded in single cases.

Effects on intraocular pressure Ocular or systemic administration of glucocorticoids leads to an increase in intraocular pressure in susceptible individuals, largely, through reduced aqueous outflow [Stokes, J. 2003]. (Please refer also to section 2.5.3.2.3.1 Intraocular pressure, page 12.) Ocular hypertensive response to topical steroids have been reported in the literature repeatedly, in children in particular, e.g. [Lam, D. S. 1997, Lee, Y. J. 2006, Biedner, B. Z. 1980, Lam, D. S. 2005, Ng, J. S. 2000, Kwok, A. K. 1997, Ohji, M. 1991, Snir, M. 2000]. The intraocular pressure effect of fluorometholone 0.1% was compared with that of dexamethasone 0.1% by performing corticosteroid provocative tests on 24 matched pairs of eyes. Fifteen of the 24 dexamethasone treated eyes, 62.5%, showed a change in intraocular pressure greater than 5 mmHg, while only 2 of the 24 fluorometholone treated eyes, 8.3%, showed a change in pressure greater than 5 mmHg. Based on the statistical significant difference, the authors recommend fluorometholone as the topical steroid of choice for patients with glaucoma and other known steroid responders when topical steroid treatment is indicated [Akingbehin, A. O. 1983]. Ophthalmic dexamethasone is more likely than other ophthalmic agents to cause increased intraocular pressure, so intraocular pressure should be measured every 2—4 weeks for the first 2 months of therapy, and every 1—2 months thereafter [Clinical Pharmacology 2009]. Ophthalmic dexamethasone therapy should be undertaken with caution in patients with a history of open-angle glaucoma, myopia, or Krukenberg's spindle because these patients have an increased risk of developing ocular hypertension during therapy [Clinical Pharmacology 2009].

11/13 Public AR

Known precautions Topical ophthalmic corticosteroid therapy is not curative, and the cause of inflammation should be determined and eliminated if possible. Acute, self-limiting disorders respond more favourably than do chronic conditions. Topically applied ophthalmic corticosteroids appear to be as effective as systemic steroids for the treatment of most anterior ocular inflammations. Subconjunctival injections of repository forms of corticosteroids (e.g., methylprednisolone acetate suspension, triamcinolone acetonide suspension) may be required in severe anterior segment ocular inflammation, and systemic corticosteroid therapy is necessary when deeper ocular structures (e.g., posterior segment of globe, optic nerve, orbit) are involved [AHFS DI 2009b]. Corticosteroids may reduce resistance to and aid in the establishment of bacterial, viral, or fungal infections and mask the clinical signs of infection, preventing recognition of ineffectiveness of the antibiotic, or may suppress hypersensitivity reactions to substances in the product. Fungal infection should be suspected in patients with persistent corneal ulceration who have been or are receiving these drugs, and corticosteroid therapy should be discontinued if fungal infection occurs [AHFS DI 2009b].

Contraindications The following contraindications for use of topical dexamethasone eye drops should be regarded [DrugPoint Summary 2009, AHFS DI 2009b, Clinical Pharmacology 2009]: - Glaucoma, advanced - Hypersensitivity to dexamethasone or any other component of the product - Ocular or periocular infections, including viral diseases of cornea and conjunctiva, including active epithelial herpes simplex keratitis, vaccinia, varicella, mycobacterial diseases, and fungal diseases; active or suspected (ophthalmic solution).

User Testing The applicant have chosen the direct personal interview method according to the “Sless & Wiseman Method” (David Sless and Rob Wiseman, 2nd edition).for the readability tests. The cumulative fulfilled results of Round 1 and 2 in all three success criteria “answers / usability”, “traceability” and “comprehensibility” are 90 % or higher. With the results the applicant was able to attest, that the package leaflet of the medicinal product Dexamethason 1 mg/ml Augentropfen mibe is readable for the patients.

Pharmacovigilance system The applicant has provided documents that set out a detailed description of the system of pharmacovigilance (Version 3 dated 13 May 2009). A statement signed by the applicant and the qualified person for pharmacovigilance, indicating that the applicant has the services of a qualified person responsible for pharmacovigilance and the necessary means for the notification of any adverse reaction occurring either in the Community or in a third country has been provided. The Pharmacovigilance system as described by the applicant fulfils the requirements as described in Volume 9A of the Rules Governing Medicinal Products in the European Union and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country.

Risk Management Plan According to the pharmaceutical company there is no need for a specific RMP since no safety concerns have been identified for the product.

Safety It is known that ophthalmologic preparations containing phosphate buffer as an excipient or phosphate as a component of the active substance may induce corneal calcification in patients with predisposing factors (Lake et al. 2008, Bernauer et al. 2006, Kompa et al. 2006, Schrage et al. 2005, Prasad Rao et al. 1995, Taravella et al. 1994). Therefore a warning, that patients with corneal disorders should avoid this drug, is included in the product information. Additional the MAH should closely monitor all ADRs concerning corneal disorders and should assess these reactions explicitly in the PSURs. It is advised the applicant to apply an extension of the PSUR submission cycle together with the application. The first PSUR should be submitted after three years and in general a PSUR submission cycle of three years is adequate. 12/13 Public AR

IV BENEFIT RISK ASSESSMENT The application contains an adequate review of published clinical data. The applicant’s Summary of Product Characteristics (SmPC) an Patient information leaflet (PL) is overall compliant with the SmPC and PL for the existing brand, with no novel claims or dose recommendations. The application is approved. For intermediate amendments see current product information.

13/13 Public AR