Mutual Recognition Procedure

Public Assessment Report

Taflotan sine 15 Mikrogramm/ml Augentropfen

Tafluprost

DE/H/5250/001/MR

Applicant: Santen Oy

Date: 17.07.2018

This module reflects the scientific discussion for the approval of Taflotan sine 15 Mikrogramm/ml Augentropfen. The procedure was finalised on 21.02.2018 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 ...... 5 III.1 Quality aspects ...... 5 III.2 Non-clinical aspects ...... 6 III.3 Clinical aspects...... 9 IV. BENEFIT RISK ASSESSMENT ...... 15

Taflotan sine 15 Mikrogramm/ml Augentropfen, DE/H/5250/001/MR Public AR 2/15 ADMINISTRATIVE INFORMATION

Proposed name of the medicinal Taflotan sine 15 Mikrogramm/ml Augentropfen product in the RMS: Name of the drug substance (INN name): Pharmaco-therapeutic group S01EE05 (ATC Code): Pharmaceutical form(s) and Eye drops, solution; 15 micrograms/ml strength(s): Reference Number(s) for the DE/H/5250/001/MR Decentralised Procedure: Reference Member State: DE Concerned Member States: AT, BE, BG, HR, CY, CZ, DK, EE, FI, EL, HU, IS, IT, LV, LT, LU, NL, NO, PL, PT, RO, SK, SI, ES, SE

Applicant (name and address): Santen Oy Niittyhaankatu 20 33720 TAMPERE Finland Names and addresses of all proposed Santen Oy manufacturer(s) responsible for Niittyhaankatu 20 batch release in the EEA: 33720 TAMPERE Finland

TUBILUX Pharma S.p.A. Via Costarica, 20/22 00071 POMEZIA (ROM) Italy

Taflotan sine 15 Mikrogramm/ml Augentropfen, DE/H/5250/001/MR Public AR 3/15 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for “Taflotan sine 15 Mikrogramm/ml Augentropfen”, indicated in adults ≥18 years as monotherapy for the reduction of elevated intraocular pressure (IOP) in open angle and ocular hypertension in patients,  who would benefit from preservative free eye drops  insufficiently responsive to first line therapy  are intolerant or contra-indicated to first line therapy or as adjunctive therapy to beta-blockers is approved.

II. EXECUTIVE SUMMARY II.1 Problem statement This mutual recognition application concerns “Taflotan sine 15 Mikrogramm/ml Augentropfen”, a preservative free ophthalmic solution containing the tafluprost pro-drug in a multi-dose container. “Taflotan” was originally authorised in two formulations in accordance with Art. 8(3) of Dir. 2001/83/EC in procedure DE/H/991/001 002/DC on 7th May 2008 including AT, CZ, DK, ES, FI, IT, NO, PL, SE and UK as CMS. One of the formulations contained the preservative benzalkonium chloride (BAK) and was packed in multi-dose containers (German MA no. 67940.00.00), while the other formulation was preservative-free and packed in single-dose containers (German MA no. 67942.00.00). For economic reasons, the BAK-preserved formulation was not licensed in all of the aforementioned CMS and is currently only authorised in DE, FI and IT. In contrast, the MA of the preservative-free formulation named “Taflotan sine 15µg/ml, eye drops” was subsequently extended to BG, EE, IS, LT, LV, NL, PT, RO, SK (DE/H/991/002/E/001) and BE, CY, FR, EL, HU, IE, LU, MT, SI (DE/H/991/002/E/002). In parallel, the MAH Santen Oy, Tampere, Finland, had received a German duplicate license of the preservative formulation based on the dossier of the former procedure DE/H/991/002/DC on 11th December 2008 (German MA no. 67941.00.00). Recently, the multi-dose container of this preservatived product has been changed to a multi-dose container with the perservative-free product, which was approved by national variation in Germany on 22nd February 2017. With Germany as RMS in this MRP, Santen Oy intends to extend this national license to the CMS AT, BE, BG, HR, CY, CZ, DK, EE, FI, EL, HU, IS, IT, LV, LT, LU, NL, NO, PL, PT, RO, SK, SI, ES, SE.

II.2 About the product Tafluprost is a fluorinated PGF2α analogue potent with high affinity and selectivity for the FP and negligible activity on non-prostanoid receptors/ transporters or other prostanoid receptors, except some activity on the EP3 receptor. After topical application to the eye, the tafluprost isopropyl ester pro-drug is rapidly hydrolysed to tafluprost acid, which is thought to reduce IOP by enhanced uveoscleral outflow of aqueous humour.

“Taflotan sine 15 Mikrogramm/ml Augentropfen” is indicated for reduction of intraocular pressure (IOP) in adults with open-angle glaucoma and ocular hypertension (ATC code: S01EE05). The preservative-free solution contains tafluprost at a concentration of 0.0015 % and the dosage is once daily.

Very few analogue-containing products are available as preservative-free eye drops leading to an unmet medical need in patients tolerating preservatives poorly e.g. with dry or sensitive eyes. In order to improve patient choice, a multidose container is now being introduced as an alternative presentation of the preservative-free formulation. It is recommended that the preservative- free formulation of Tafluprost 0.0015 % eye drops, solution in multi-dose bottles is also indicated as monotherapy in patients “who would benefit from preservative-free eye drops”, as is currently the case for the preservative-free formulation in single-dose containers.

Taflotan sine 15 Mikrogramm/ml Augentropfen, DE/H/5250/001/MR Public AR 4/15 II.3 General comments on the submitted dossier The submitted dossier has been considered as adequate. Study design, analytical methodology and statistical evaluation of the provided study are in accordance with current requirements. Prior to the start of the MRP and parallel to the preparation of the Assessment Report the MAH has submitted a national variation with a safety update in order to harmonize SmPC/PL with the product information of the MAH’s other “Taflotan” licenses. The harmonization is acceptable.

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, assembly, control and batch release of this product. For all manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations and GMP certificates issued by the inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. There are no manufacturing sites of the drug product outside the Community. Valid declarations of the Qualified Persons of all manufacturers responsible for manufacture and batch release in the EEA are presented for the active substance tafluprost. All non-clinical safety and toxicity studies with tafluprost as well as the ocular pharmacokinetic studies w have been performed according to GLP regulations. All the clinical trials have been conducted in accordance with GCP requirements. Permission from an Independent Ethics Committee/Institutional Review Board and the Health Authority has been obtained for each study.

III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance The ASMF procedure is used for tafluprost drug substance as it is not included in the Ph. Eur. One of the two drug substance manufacturers is ASMF holder and has submitted a letter of access to the BfArM, who is RMS in the current MRP DE/H/5250/MR. Assessment of the Active Substance Master File is provided in a separate ASMF Assessment Report with a confidential annex on the Restricted Part. Both manufacturers of tafluprost are applying the same method of manufacture and the same specifications. A detailed discussion on residual solvents, reagents and carry-over impurities has been provided. Due to the very low dose of tafluprost of 0.9 µg/day assessment of genotoxic impurities is considered acceptable. Analytical methods have been described and validated. Batch analysis results of three recent batches manufactured in 2011 at manufacturer A and in 2013 at manufacturer B are similar and demonstrate compliance with specifications. A retest period when stored at 5°C ± 3°C (long term conditions), protected from light, has been verified by stability study results with three production scale batches from both manufacturers and three former batches, when stored in amber glass bottles with stopper and aluminium cap. Stability studies with three batches from manufacturer B cover 6 months until now and are ongoing. A stability commitment was provided. An assessment of the restricted part of the ASMF is provided in a separate document

Drug product Tafluprost 15 µg/ml PFMD eye drops, solution, containing tafluprost as drug substance comprises a sterile, preservative-free solution contained in a 10 ml multi-dose container fitted with an OSD (ophthalmic squeeze dispenser). The fill volume is 3 ml. As the applicant intends to provide a preservative-free multi-dose container the original drug product tafluprost 15 µg/ml MD, preserved which has been approved in 2008 has been transferred into the present preservative-free Tafluprost 15 µg/ml PFMD eye drops, solution in multi-dose container via national type II variation. The Tafluprost 15 µg/ml PFMD was approved in Germany in 02.2017. The formulation is identical to the initially approved preservative-free Tafluprost 15 µg/ml SDU which is available in single dose (unit dose) vials. The OSD allows a preservative-free formulation to be delivered in a multidose bottle while maintaining the required microbial quality/sterility. During pharmaceutical development of Tafluprost 15 µg/ml PFMD with OSD intensive studies on functionality, growth promotion properties and further microbiological challenge tests have been performed. As a result of these studies it is concluded that the PFMD – OSD system is able to maintain sterility of the drug product solution during storage/transportation and during use because of

Taflotan sine 15 Mikrogramm/ml Augentropfen, DE/H/5250/001/MR Public AR 5/15 three main features: 1. A complex venting system of the OSD, 2. some shelf-preserving properties of the drug product solution 3. A detailed user instruction. Point 3. is considered to be the limitation of the applied drug product because an elderly patient group (50 - >80 years) should be able to correctly use the device according to the users instruction as provided in the SPC/PIL. The manufacturing process includes sterile filtration and aseptic processing. Validation of the manufacturing process has been performed with three full scale production batches by each manufacturer respectively. The drug product specifications are considered appropriate for the quality control of the present dosage form. Analytical methods have been described and validated. Batch analysis results of three recent full production batches demonstrate compliance with the specification. ICH stability study results are available for three batches from both manufacturers, respectively. Stability studies cover 30 months for one manufacturer’s batches and 12-18 months for the other manufacturer’s batches and are ongoing until the claimed shelf-life of 36 months is covered. A shelf life of 36 months together with the storage precautions “store in a refrigerator, store in the original container, do not freeze” has been justified by stability study results. The claimed in-use stability of 28 days after opening will be confirmed with an aged batch near end of shelf-life as soon as available. The respective stability commitments on ICH long term studies and on in-use stability studies were provided see section VI below.

Conclusion on drug product stability

Drug product: Tafluprost 15 µg/ml eye drops PFMD, provided in 10 ml PFMD-OSD containers, fill volume: 3 ml

STABILITY Unopened container: Shelf-life: 36 months based on 36, 24 and 6 month real time data Storage: 5°C ±3°C stability commitment available Protected from light, Protect from freezing

After first opening: In-use stability 28 days to be confirmed with an aged batch Storage: 5°C ±3°C respective stability commitment available Protected from light, Protect from freezing

III.2 Non-clinical aspects Tafluprost acid (the pharmacologically active hydrolysed form of tafluprost) is a potent and highly specific FP prostanoid receptor agonist with a mean IC50 value of 0.5 nM based on competitive binding experiments with radiolabelled PGF2α. In the same test, acid and unoprostone acid showed a 12- and 1700-times lower affinity with IC50 values of 6.3 and 900 nM. Except for the EP3 receptor (IC50 = 67 nM), the affinity on other prostanoid or non-prostanoid receptors was negligible (IC50 > 1000 nM). In normotensive and hypertensive monkeys, consecutive once daily ocular instillations of tafluprost only slightly improved aqueous humour formation. However, uveoscleral outflow was significantly increased, which is therefore considered the primary mechanism of IOP reduction as established for other prostaglandin analogues used for glaucoma treatment. The IOP lowering effect was maximal 6 h after single dosing and became more pronounced after repeated administration of tafluprost. Apart from the active substance tafluprost acid, none of its metabolites, the 1,2-dinor- and 1,2,3,4- tetranor-tafluprost acid as well as the lactone of 1,2,3,4-tetranor-tafluprost acid, effectively reduced IOP. In a full battery of safety pharmacology investigations, tafluprost did not affect locomotor activity in an Irwin test in mice. The prolongation of the QTc interval observed in dogs at a i.v. dose of 1 µg/kg, was not confirmed in a second study with i.v. doses up to 10 µg/kg. Tafluprost also did not interfere with HERG channel tail currents or action potential parameters in dog Purkinje fibres at concentrations up to 100 ng/ml. With regard to the maximum plasma concentration after ocular instillation of approximately 0.025 ng/ml, no arrhythmogenic effects of tafluprost are anticipated.

Taflotan sine 15 Mikrogramm/ml Augentropfen, DE/H/5250/001/MR Public AR 6/15 Tafluprost acid increased the maximum tension, resting tension, and frequency of spontaneous contractions of isolated uteruses of non-pregnant female rats and rabbits at concentrations of 1 ng/ml and higher, respectively. Based on the very low systemic concentrations of tafluprost acid following ocular administration, the ophthalmic use of tafluprost does not need to be contraindicated during pregnancy, but a strict wording as currently reflected in section 4.6 of the SmPC is warranted.

Pharmacokinetics The pharmacokinetic properties of tafluprost were analysed in rats and monkeys after ocular instillation or intravenous administration. Additional toxicokinetic data were gained in mice and dogs in toxicity studies. Maximum plasma concentrations of radioactivity were determined within 5 min after ocular instillation of 3H-labelled tafluprost in monkeys, whereas the maximum concentration in the aqueous humour was detected at 2 h post-dose and further declined to 1/100 at 24 h post-dose. Only trace amounts of radioactivity were detected in the posterior segment in phakic eyes and the crystalline lens. The ocular absorption study in rabbits demonstrated comparable levels of tafluprost acid after a single ocular instillation of 0.0015 % tafluprost ophthalmic solution either with or without benzalkonium chloride. Tafluprost rapidly passes the corneal barrier and distributes to ocular tissues and fluids. Ophthalmologically administered tafluprost also reaches systemic tissues via the nasolacrimal duct. No significant passage across the blood-brain barrier was noted. Following repeated ocular dosing, the substance was not completely eliminated within 24 h. Placental and milk transfer of tafluprost was demonstrated each after ocular installation in pregnant and lactating rats. The foetal exposure was about 2/3 of that of the plasma exposure, whereas pups receive about 0.1 % of the maternal dose via milk. After ocular instillation, tafluprost was rapidly hydrolysed to tafluprost acid probably via corneal esterases. Tafluprost acid undergoes beta-oxidation to the 1,2 dinor and 1,2,3,4 tetranor metabolites that both may be glucuronidated. The tetranor metabolite exists in equilibrium with the corresponding lactone. Hydroxylation of the phenyl ring with subsequent sulphate conjugation of the dinor and tetranor metabolites of tafluprost acid may also account for minor pathways in the metabolism. The amount of unchanged tafluprost in ocular tissues of rats and monkeys was negligible. The metabolic rate was generally higher in hepatocytes of rats (62 %) and monkeys (72 %) than in humans (50 %), and there were marked differences in the metabolism of tafluprost between both animal species. A significant metabolic contribution of CYP450 was excluded. Less than 1 % of the administered ocular tafluprost dose was found as unchanged pro-drug or tafluprost acid in urine and faeces of rats and monkeys, indicating almost complete biotransformation. In male rats, biliary into faeces was higher than excretion into the urine, whereas no major differences between the urinary and faecal excretion were identified in females. In monkeys, no major differences between genders were seen in the urinary and fecal excretion rates following the ocular instillation, and urinary excretion was predominant over fecal excretion following i.v. administration. With respect to the well-established profile of other PGF2 analogues, no pharmacokinetic drug interaction studies were performed.

Toxicology Single and repeated-dose toxicity A low acute toxicity of tafluprost was observed in rats, dogs and monkeys following various routes of single administration. Repeat-dose toxicity studies were performed with i.v. administration in rats and dogs, as well as with ocular administration in monkeys. In rats, no tafluprost-related toxicities were seen in a 4 weeks study. Accordingly, the 100 µg/kg/day i.v. high dose was established as NOAEL. In contrast, animals of all dose groups (10, 30 and 100 µg/kg/day) died or had to be euthanized in the 6 months chronic toxicity study, but no treatment- related macroscopical or microscopical clinical findings could be identified. Haematological changes in RBC and parameters, increased haematopoiesis as well as hyperostosis and myelofibrosis in the bone marrow were detected and no NOAEL was defined.

Taflotan sine 15 Mikrogramm/ml Augentropfen, DE/H/5250/001/MR Public AR 7/15 In dogs, two studies of one-month and 9-months duration were performed with tafluprost dosages of 0.1, 1 and 10μg/ kg/day. Apart from transient pharmacological effects (e.g. salivation, emesis, loose feces, increased respiration, heart rate, and blood pressure) the NOAEL was set to be 0.1 µg/kg/day in the one-month study and 1 µg/kg/day in the 9 months study based on moderate to severe effects, like transient prolonged OTc, increase in salivary gland weights and minor hypertrophy of the submandibular gland acini as well as increased ALT (GPT) level and increased urinary volume in animals receiving the highest dose. One dog of the 10 µg/kg dose group had to be killed due to hepatic failure. Three repeated-dose ocular toxicity studies of 1, 3 and 12 months duration in monkeys consistently revealed increased pigmentation of the iris (irreversible) and sunken eye lids (reversible), which are known from other PGF2 agonists. The change in iris colour usually developed from week 2 onwards and was related to an increased melanin content of stroma melanocytes of the iris, with no evidence of melanocyte proliferation. Accordingly, the NOAEL was set to the 0.05% high dose. Safety margins based on NOAEL values in repeated-dose toxicity studies ranged from 100- (dog) to 10,000-fold (rat) with regard to the clinical (topical) dose. A calculation based on AUC-values is generally hampered by the rapid metabolism of tafluprost acid and the very low plasma levels of this pharmacologically active agent after application of one drop of 0.0015 % ophthalmic solution to each eye

Genotoxic and carcinogenic potential Tafluprost did not exert any genotoxic potential in a standard battery of in vitro (Ames test, CHL cells) and in vivo investigations (mouse bone marrow micronucleus test). In two long-term carcinogenicity studies with s.c. administration of tafluprost for 18 months in mice and 24 months in rats, no carcinogenic potential was evident. Reproductive and developmental toxicity In the fertility and early embryonic development study, i.v. administered tafluprost did not impact on reproductive performance or fertility of male and female rats. The NOAEL for male and female fertility was established at the 100 µg/kg/day high dose. In the embryo-foetal development study in the rat, no maternal toxicity was observed, but developmental toxicities (post-implantation loss, decreased foetal weight and ossification) were noted at the 10 and 30 µg/kg/day intermediate and high dose levels. The NOAEL for maternal toxicity was 30 µg/kg/day and for developmental effects 3 µg/kg/day. In an initial embryo-foetal development study in rabbits, dose-dependently reduced foetal viability and malformations were also observed at the 0.03 µg/kg/day i.v. tafluprost low dose or above. In a subsequent study with lower i.v. dosages in rabbits, a NOAEL for developmental toxicity could also not be established, because skeletal malformations were still apparent at ≥0.001 µg/kg/day. The NOAEL for maternal toxicity was the 0.01 µg/kg/day high dose. In a pre-/postnatal development study in rats, no maternal toxicity, but poor nursing behaviour was noted at 1 µg/kg/day i.v. tafluprost or above. Increased mortality, decreased body weight gain and delayed pinna unfolding were additionally observed in the offspring of the high dose group. The NOAEL for reproductive functions of the dams and toxicity in the F1 generation was 0.3 µg/kg/day.

The potential of tafluprost for reproduction toxicity is adequately reflected in pertinent sections of the product information.

Local tolerance A slight ocular irritation potential of the vehicle was observed in rabbits, but tafluprost ophthalmic solution was considered non-irritant in the primate eye at relevant concentration range.

Other toxicity studies Tafluprost ophthalmic solutions (0.005% and 0.05%) were negative in the guinea pig skin sensitization test. Further toxicity studies are not warranted.

Taflotan sine 15 Mikrogramm/ml Augentropfen, DE/H/5250/001/MR Public AR 8/15 Environmental Risk Assessment (ERA) The applicant provided a calculation of the predicted environmental concentration in surfacewater (PECsw) according to the guideline on the environmental risk assessment of medicinal products for human use (EMEA/CHMP/SWP/4447/00). Based on the recalculated PECsurface water of PECSW = 0.0045 ng/L by the assessor for two eyes no Phase II risk assessment for tafluprost is required. However, a final conclusion cannot be drawn since no data on log Kow for the PBT screening are provided. Therefore the applicant was kindly asked to submit an experimentally determined log Kow for the active ingredient tafluprost (including the study reports). To our knowledge a log Kow and a PBT assessment of tafluprost has been provided in the procedure DE/H/3869/II/05 by the applicant, which should be considered. The applicant agreed to submit the requested data and provided a commitment (signed 28.08.2017) to submit a variation with the results of the experimental PBT assessment including a revised ERA report within 3 months after the MR procedure DE/H/5250/001/MR has been completed. The variation procedure DE/H/3869/001/II/005 has been approved on August 1st, 2017.

III.3 Clinical aspects Tafluprost belongs to a group of well characterized for glaucoma treatment, the common denominator being that all members of the group are selective and potent FP prostanoid receptor agonists. Consequently, the purpose of the clinical pharmacology studies with tafluprost has been to demonstrate the most essential properties of the drug. The clinical pharmacology studies with tafluprost comprise pharmacokinetic studies as well as phase-I and phase-II dose response studies.

Pharmacokinetics Tafluprost belongs to a group of well characterized prostaglandins for glaucoma treatment, the common denominator being that all members of the group are selective and potent FP prostanoid receptor agonists. Consequently, the purpose of the clinical pharmacology studies with tafluprost has been to demonstrate the most essential properties of the drug. The clinical pharmacology studies with tafluprost comprise pharmacokinetic studies as well as phase-I and phase-II dose response studies.

Pharmacodynamics The clinical pharmacodynamic studies with tafluprost are limited to dose-response studies. The early dose-response and short-term treatment studies were performed in both non-Japanese (Caucasian) and Japanese subjects. Dose-response studies performed with tafluprost in monkeys (concentration range 0.00002% - 0.005%) demonstrated that the 0.005% concentration resulted in the best IOP reduction (studies 2001MP241; 204GU141). Hence it was logical to include the 0.005% concentration as the highest dose in the phase-I dose-response studies. In the two first dose-response studies 0.0001%, 0.0005%, 0.0025% and 0.005% concentrations were tested in healthy human subjects (studies WW-74450-EU and WW-74451-EU). Three applications were administered during 2 days, the other eye in each subject serving as control (treated with vehicle only). In both studies a dose-response relationship was established. In Caucasians the best effect was achieved with the 0.0025% concentration (study WW-74450-EU) and in Japanese the best effect was elicited by the 0.005% concentration (study WW74451) as illustrated in Fig. 2.5.3.3.2-1.

Taflotan sine 15 Mikrogramm/ml Augentropfen, DE/H/5250/001/MR Public AR 9/15

Clinical efficacy A total of 7 clinical trials (Table 2.5.4.1-1) which are relevant for assessing the efficacy of tafluprost have been performed and are included in the dossier. Two studies are pivotal long-term phase-III clinical trials with latanoprost or as comparator, and one study is a phase III clinical trial in which the additive effect of tafluprost to timolol was investigated. In addition, a phase-III clinical trial has been performed to compare the IOP reducing effect of the unpreserved tafluprost ophthalmic formulation with that of the preserved formulation. Supporting data obtained in clinical trials which have been performed in Japan are also summarized. One of the phase-III clinical trials (study 74458)

Taflotan sine 15 Mikrogramm/ml Augentropfen, DE/H/5250/001/MR Public AR 10/15 is still in progress, with a total time of treatment per patient extending to 24 months. The phase-II and –III clinical program with tafluprost in Europe and USA is presented in Table 2.5.4.1-1.

All but one of the phase-II and phase-III clinical trials to investigate efficacy and safety were performed according to standard protocols using randomization, double-masking, and placebo/active- control. In study 77550 (phase-III) unit dose packages were used for the unpreserved formulation whereas multidose dispensers were used for the preserved formulation. Hence the study was randomized, single-masked (investigator-masked). In the phase III studies, the number of patients has been based on appropriate statistical calculations, which take also into account that sufficient safety data will be available on tafluprost during chronic treatment. A surrogate endpoint, i.e. reduction of IOP, has been used to assess efficacy, which is customary in glaucoma drug research as the changes in the visual fields or excavation of the optic nerve head are too slow to be picked up in clinical trials of reasonable duration. In the phase III studies, the primary efficacy variable has been the change from baseline in the overall diurnal IOP at endpoint, which takes into account all IOP measurements at different timepoints during the study day. In the two pivotal studies (74458 and 15-003), the non-inferiority criterion set by the regulatory authorities has been adopted, i.e. the limit for non-inferiority has been 1.5 mmHg based on the upper limit of the 95% confidence interval (CI) for the difference in treatment effect between tafluprost and the comparator drug. Accordingly, an equivalence criterion of ±1.5 mmHg set by the regulatory authorities was adopted in the 77550 study (unpreserved vs. preserved formulation). The clinical

Taflotan sine 15 Mikrogramm/ml Augentropfen, DE/H/5250/001/MR Public AR 11/15 dose-response studies and main clinical studies have been considered as adequate in the main points: study design, number of patients, choice of comparator, stratification of gender and race. The therapeutical equivalence of Taflotan to Timolol 0,5% and the therapeutical equivalence of both formulation(preserved and unperserved) is shown in phase III study. Unfortunately, Tafluprost in comparison to Latanoprost did not quite reach the predetermined criterion for non-inferiority based on the primary statistical analysis (RM-ANCOVA), but the unadjusted sensitivity analysis (RM- ANOVA) showed non-inferiority.Taking the results of all studies into consideration, it can be concluded that 0.0015% tafluprost q.d. was as effective as or slightly less effective (around 1 mmHg or less) than 0.005% latanoprost q.d., and at least as effective as 0.5% timolol b.i.d. The effect of tafluprost furthermore was additive to that of timolol. Overall, tafluprost can be considered a very efficacious IOP-reducing drug. The unpreserved solution containing 0.0015% tafluprost was as effective as the preserved solution and can thus be used in patients that do not tolerate eye drops containing preservatives.

Clinical safety Safety data have been collected in all clinical trials performed with tafluprost (phase-I to phase-III). In addition, safety data from supporting studies performed in Japan have been obtained. Obviously the phase-II and phase-III clinical trials performed in a masked way are the most important studies for assessing safety. It should be emphasized that GCP regulations have been strictly implemented in the entire clinical program with tafluprost. Side-effects anticipated to occur, such as increased iridial pigmentation and eyelash changes, have been carefully investigated. Ocular safety has been assessed in all studies routinely e.g. with biomicroscopy and ophthalmoscopy. Also visual acuity has been thoroughly determined at each visit in every study, either using the ETDRS chart and LogMAR scores or Snellen chart (in phase-I studies). In addition to AEs, signs and symptoms not regarded as AEs have been registered.

Taflotan sine 15 Mikrogramm/ml Augentropfen, DE/H/5250/001/MR Public AR 12/15 In the phase-I and phase-II clinical trials the only relevant systemic AE that possibly could be related to the treatment was headache, which occurred in all trials, but generally was not more frequent than with latanoprost or timolol. As expected, only few systemic adverse events were reported in the clinical studies for tafluprost.The observations in the phase-II clinical trials suggest that the 0.005% concentration of tafluprost may be too high concerning local side effects in some individuals.The ocular AE profile of 0.0015% tafluprost was comparable to that of 0.005% latanoprost, except ocular/conjunctival hyperemia and eye pruritus. Tafluprost caused somewhat more ocular/conjunctival hyperemia and eye pruritus than latanoprost and timolol. Indeed, most of the other ocular AEs were rather uniformly distributed between the treatment groups. Thus, the unpreserved formulation of 0.0015% tafluprost can be considered equally well tolerated/safe as the preserved formulation.

Legal Status Subject to medical prescription

User Testing A Bridging report has been provided. The user test was assessed and accepted The Readability User Test (R.U.T.) of the patient information leaflet (PIL) for Taflotan Eye Drops took place in London (Pilot RUT) and Oxford (1st and 2nd cycles), United Kingdom from 2006-09-07 to 2006-12-06.

Target Patient Group Definition: Participants were chosen amongst people who use eye drops or used eye drops in the past. These were people with preferably lower educational levels and from both genders. The age group will be chosen to represent elderly people because the users of this product are mostly elderly. Additionally persons above 45 years of age who never used eye drops were chosen as these are potential glaucoma patients. A complete list of the inclusion and exclusion criteria can be found in the company’s part.

Questionnaire Development Orangeglobal prepared a specific questionnaire for the Readability User Test. In a first step all the relevant key safety messages were identified and the results of this analysis were entered into a quality assurance table (section 3.2.3). The quality assurance table ensured that the questionnaire addressed all relevant key safety messages of the PIL and all the topics named in the guidelines of Sless and Wiseman2. As the additional handling section of the single dose container PIL was tested, two additional questions were asked to examine the comprehensibility of this important information.

Taflotan sine 15 Mikrogramm/ml Augentropfen, DE/H/5250/001/MR Public AR 13/15 The questionnaire was used in the interview for the Readability User Test and was the basis for the subsequent evaluation.

Conclusion: The package leaflet is well designed and clearly worded. In this form, the user tested PILs for Taflotan Eye Drops both satisfy the EU directives and, according to the participants’ appraisal, are sufficiently legible and comprehensible. The user testing is accepted.

Pharmacovigilance system The Applicant has submitted a signed Summary of the Applicant's Pharmacovigilance System (renewal procedure). 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 following summary of safety concerns was proposed: Summary of safety concerns Important identified risks  None Important potential risks  Embryotoxicity  Lactation  Possible drug interactions  Combination of tafluprost and other PGAs  Hyperpigmentation Important missing information  Children and adolescent below age 18  Patients with aphakia patients, and in glaucoma. Such patients should therefore be treated with caution.  Patients with neovascular, angle-closure, narrow- angle, pigmentary pseudoexfoliative or congential glaucoma, or patients wearing contact lenses.  Patients with renal/hepatic impairment  Patients with asthma The MAH proposed routine pharmacovigilance activities and no additional risk minimisation activities.

Periodic Safety Update Report (PSUR) With regard to PSUR submission, the MAH 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. • For medicinal products that do not fall within the categories waived of the obligation to submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow the DLP according to the EURD list.

Taflotan sine 15 Mikrogramm/ml Augentropfen, DE/H/5250/001/MR Public AR 14/15 IV. BENEFIT RISK ASSESSMENT Tafluprost non-preserved is a very effective IOP reducing agent that is generally safe and well tolerated. With the exception of pregnant women, children and patients with compromised eyes, e.g. due to surgery or intraocular inflammation, the benefits clearly overweigh the risks as evident from clinical trials. The safety of tafluprost in asthmatics has not been studied, but can be assumed to be similar to that of the other prostaglandins on the market for glaucoma treatment. The unpreserved formulation containing tafluprost is the first prostaglandin eye drop without preservative. This is a significant clinical advantage as there is currently an unmet clinical need of preservative-free prostaglandin eye drops for glaucoma patients with dry/sensitive eyes. The benefit-risk-ratio is positive. The application is approved. For intermediate amendments see current product information.

Taflotan sine 15 Mikrogramm/ml Augentropfen, DE/H/5250/001/MR Public AR 15/15