Tafluprost DE/H/3869/001/DC Applicant

Decentralised Procedure

Public Assessment Report

Taptiqom

Timolol maleate/ Tafluprost

DE/H/3869/001/DC

Applicant: Santen Oy Niittyhaankatu 20

33720 Tampere

Finland

Reference Member State DE

DE/H/3869/001/DC Public AR Page 2/20

TABLE OF CONTENTS

I. INTRODUCTION.............................................................................................................. 4

II. EXECUTIVE SUMMARY ............................................................................................. 4

II.1 Problem statement ......................................................................................................... 4

II.2 General comments on the submitted dossier................................................................... 4

II.3 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.6

III. SCIENTIFIC OVERVIEW AND DISCUSSION ............................................................ 6

III.1 Quality aspects ............................................................................................................... 6

III.2 Non-clinical aspects ........................................................................................................ 8

III.3 Clinical aspects ............................................................................................................. 10

IV. BENEFIT RISK ASSESSMENT .................................................................................. 19


ADMINISTRATIVE INFORMATION

Proposed name of the medicinal

product in the RMS

Taptiqom 15 Mikrogramm/ml + 5 mg/ml Augentropfen im Einzeldosisbehältnis

Name of the drug substance (INN

name):

Tafluprost /Timolol (as maleate)

15 Micrograms/ml + 5 mg/ml

Pharmaco-therapeutic group

(ATC Code):

S01ED51

Pharmaceutical form(s) and

strength(s):

Eye drop solution in single dose containers

15 micrograms/ml + 5 mg/ml

Reference Number(s) for the

Decentralised Procedure

DE/H/3869/001/DC

Reference Member State: DE

Concerned Member States: AT, BE, BG, CY, CZ, DK, EE, EL, ES, FI, FR, HR, HU, IE, IS, IT, LT, LU, LV, MT, NL, NO, PL, PT, RO, SE, SI, SK, UK

Applicant (name and address) Santen Oy

Niittyhaankatu 20

33720 Tampere

Finland


I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Taptiqom 15 Mikrogramm/ml + 5 mg/ml Augentropfen im Einzeldosisbehältnis, in the “Reduction of intraocular pressure (IOP) in adult patients with open angle glaucoma or ocular hypertension who are insufficiently responsive to topical monotherapy with beta-blockers or prostaglandin analogues and require a combination therapy, and who would benefit from preservative free eye drops” is approved.

II. EXECUTIVE SUMMARY II.1 Problem statement Taptiqom is a preservative free sterile solution of eye drops packaged in a single-dose container. Taptiqom contains tafluprost 15 micrograms/ml and timolol (as maleate) 5 mg/ml. The fixed dose combinationTaptiqom is a new combination and is not registered in any country. As of april 2010, tafluprost is regristed in 29 countries around the world including 19 countries in the EU. The combination use of prostaglandins and beta-blockers is well-documented and there are several fixed combination products already approved and marketed in the European Union, including, Xalacom (timolol/latanoprost), Duotrav (timolol/travoprost), and Ganfort (timolol/bimatoprost). In all PG-timolol fixed combinations, the concentration of timolol is 0.5 %. However, most currently approved PG-timolol fixed-dose combinations in the European Union contain the preservative benzalkoniumchloride (BAK). The formulation of Taptiqom is very similar compared to the approved tafluprost preservative-free unit dose product. The 0.0015% tafluprost – 0.5% timolol fixed dose combination product is one of the first completely preservative-free combination products containing a prostaglandin and beta-adrenergic antagonist for glaucoma treatment.

Mode of action: Taptiqom is a fixed combination of two active ingredients tafluprost and timolol. These two components lower intraocular pressure (IOP) by complementary mechanisms of action and the combined effect results in additional IOP reduction compared to either compound alone. Tafluprost acid, the biologically active metabolite of tafluprost, is a highly potent and selective agonist of the human prostanoid FP receptor. Pharmacodynamic studies in monkeys indicate that tafluprost reduces intraocular pressure by increasing the uveoscleral outflow of aqueous humour. The precise mechanism of action of timolol maleate in lowering intraocular pressure is not clearly established at this time, although a fluorescein study and tonography studies indicate that the predominant action may be related to reduced aqueous formation. However, in some studies a slight increase in outflow facility was also observed.

Pharmacological classification: Tafluprost is a fluorinated analogue of prostaglandin F2α. The pharmacotherapeutic group is antiglaucoma preparations and miotics, beta blocking agents, ATC code: S01ED51. Timolol maleate is a nonselective beta-adrenergic receptor blocking agent. Taptiqom should be used for the reduction of intraocular pressure (IOP) in adult patients with open angle glaucoma or ocular hypertension who are insufficiently responsive to topical monotherapy with beta-blockers or prostaglandin analogues and who would benefit from preservative free eye drops. The recommended therapy is one eye drop in the conjunctival sac of the affected eye(s) once daily. No dosage alteration in elderly patients is necessary. Taptiqom should be used with caution in patients with renal/hepatic impairment as the tafluprost and timolol combination eye drops have not been studied in such patients. To reduce systemic absorption the nasolacrimal occlusion or closing the eyelids for 2 minutes is recommended.

II.2 General comments on the submitted dossier The submitted dossier has been considered as adequate. Study designs, analytical methodology and statistical evaluation of the provided studies are in accordance with current requirements.


The applicant submitted an application Dossier for a Decentralised Procedure of Taptiqom. The legal Basis of the Application is article 10b combination product and this is appropriate. Taptiqom is a new fixed combination of two well-known active ingredients tafluprost and timolol. The clinical development programme is in line with the proposed posology: Two phase-III clinical trials have been performed to demonstrate the efficacy of the tafluprost and timolol fixed dose combination (TT-FDC) product. In study 201051, non-inferiority was demonstrated to concomitant treatment with 0.0015% tafluprost q.d. and 0.5% timolol b.i.d., and in study 201050 superiority was demonstrated to monotherapy with 0.0015% tafluprost, and to monotherapy with 0.5% timolol. Thus, TT-FDC was shown to be equally effective as the two components used together as separate drugs, and more effective than either of the two components when used alone. In addition supporting data have been obtained. During the course of the clinical development scientific advice was sought from German competent authority (BfArM, March 2010), and EMA (May 2010). The sponsor has designed and conducted the clinical trial program to comply with the regulatory advice and requirements, in particular with respect to the design of the phase-III clinical trials such as stratifying the patient population based on previous treatments and timing of the administration of the study drugs. The applicant followed the given scientific advice in most points. The safety and efficacy of Taptiqom in children and adolescents below the age of 18 years have not been established. Therefore, Taptiqom is not recommended for use in children and adolescents below the age of 18 years. Further investigations are not required.

Wording of the Indication The clinical programme followed the guideline on fixed combination medicinal products (CPMP/EWP/240/95 Rev. 1) and prospective scientific advice recommendations by BfArM and EMA, with a clear target of having a second line indication for this product to be used after insufficient response to prostaglandin or timolol monotherapy as described in the guideline (“in second line therapy, when monotherapy with either component has not demonstrated a satisfactory benefit/risk ratio”, page 5 of CPMP/EWP/240/95 Rev. 1). The clinical programme showed that the tafluprost/timolol FDC is superior as compared to the corresponding monotherapies in the IOP lowering efficacy. In addition, it was shown that the IOP lowering effect of the FDC given once daily was non-inferior to the effect provided by the components given concomitantly (tafluprost once daily + timolol twice daily). None of the pivotal studies conducted by Santen was planned to investigate the use of Taptiqom only after the use of other FDC products. In contrast, the studies were designed to demonstrate safety and efficacy of the FDC of tafluprost/timolol in case that patients were not sufficiently responsive to treatment with monotherapies. The applicant claimed that it was not considered possible to compare tafluprost/timolol FDC with commercially available latanoprost/timolol or travoprost/timolol FDCs, as neither of these products had a preservative free formulation. The overall clinical programme of the applicant’s tafluprost/timolol combination utilized preservative–free medications also for the comparative arms. The applicant considers it relevant to draw attention to the fact that also for Ganfort (bimatoprost/timolol FDC) the pivotal study programme did not include any comparative studies against other fixed dose combinations but only studies against individual components in the same way (ref: Ganfort EPAR). According to the European Glaucoma Society (EGS) guidelines (2008), when a monotherapy is well tolerated and lowers IOP but the target IOP is not reached, a second drug is added to the glaucoma treatment. Thus, in clinical praxis, a patient using tafluprost, would usually be treated with the corresponding line-extension (in this case tafluprost/timolol FDC or tafluprost and timolol concomitantly), rather than switching to a FDC or combination therapy with a different prostaglandin. Therefore from a clinical perspective, there is no first-line combination therapy for fixed dose glaucoma treatments and experience from patients’ prior history of medications should be considered when determining suitable combination or adjunctive therapy.


Safety and tolerability aspects, and specifically a possibility to use a preservative-free medication when of benefit, may play an important role in a selected patient population. The applicant has therefore adapted the SmPC to that of Taflotan monotherapy. The applicant has agreed also with the recommendation from MHRA (UK) in their question that Taptiqom indication should be clarified to highlight the use particularly in those patients who would benefit from preservative-free eye drops. This is consistent with European Glaucoma Society guidelines (2008) and an EMA Public Statement (EMEA/622721/2009) that recommend use of preservative-free formulation eye drops in patients with susceptibilities such as dry eye condition. Thus the sentence “who would benefit from preservative free eye drops” should be added to the indication to define the patient population for this medicine more clearly. Therefore, the applicant has proposed the following indication which we consider to be clearly a second line indication, in line with the Taflotan monotherapy indication. “Reduction of intraocular pressure (IOP) in adult patients with open angle glaucoma or ocular hypertension who are insufficiently responsive to topical monotherapy with beta-blockers or prostaglandin analogues and require a combination therapy, and who would benefit from preservative free eye drops.” In the light of the actual guidelines this is acceptable.

II.3 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 substances timolol maleate and tafluprost. All non-clinical safety studies with tafluprost, the repeated-dose toxicity study in monkeys with a preserved tafluprost-timolol FDC product as well as the ocular pharmacokinetic studies with the preservative-free tafluprost-timolol-FDC product have been performed according to GLP regulations. All the clinical trials were planned and conducted by the Clinical Department of Santen Oy, Helsinki, Finland. Monitoring and certain administrative work were subcontracted to well reputed contract research organizations. The data management tasks were done (or supervised) and statistical analyses carried out by a well reputed contract research organization. All the clinical trials have been conducted in accordance with applicable Good Clinical Practices (GCP) consolidated guideline CPMP/ICH/13595. For each study the appropriate permission from the Independent Ethics Committee/Institutional Review Board and the Health Authority has been obtained.

III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance Tafluprost Tafluprost is a fluorinated analogue of prostaglandin F2α. The active substance is described as a single enantiomer drug with four chiral centres in the chemical structure. The active substance is a colourless to light yellow viscous liquid. An ASMF has been submitted. Due to the re-definition of the former starting material and due to the introduction of a new alternative manufacturing site for the manufacturing steps from the last intermediate onwards, several manufacturing sites are involved in the manufacture of tafluprost, now. The choice of the new starting material is regarded as justified, and the restricted part of the ASMF has been updated accordingly.


Tafluprost was approved as a new active substance of a drug product in 2008 for the first time, based on an older version of the ASMF. Tafluprost is not covered by any pharmacopoeial monograph. The chemical structure of tafluprost was characterized by elemental analysis, infrared spectroscopy, ultraviolet spectroscopy, mass spectroscopy, and nuclear magnetic resonance spectroscopy. The specification of tafluprost includes relevant parameters, including control limits of the enantiomeric purity. The acceptance criteria are considered justified. The analytical procedures are sufficiently described and validated. The batch results show compliance with the specification of the active substance. The active substance is filled in type I glass vials and sealed with a stopper and an aluminium cap under nitrogen atmosphere. The vials are packed in an aluminium laminated polyethylene bag for protection from light. Specifications and certificates of analysis of the packaging materials are provided. The packaging material was shown to be suitable for the packaging of tafluprost. The long-term stability data (up to 38 months at 5°C) as well the accelerated stability data (6 months at 25°C/60% RH) of nine batches are presented. All results complied with the current specification of the active substance. The retest period of 36 months at 5°C is adequately supported by the stability data.

Drug substance Timolol maleate The drug substance is covered by a Ph. Eur. monograph. A valid certificate of suitability from the EDQM is presented. The specification of the drug product manufacturer for the active substance is in line with the Ph. Eur. monograph and the certificate of suitability. Additionally, the specification contains a limit for the microbial purity. The batch results comply with the specification of the active substance. The active substance is packed in double polyethylene bags in a cardboard drum. The proposed retest period of 5 years without storage conditions is adequately supported by the compliant long-term stability data (60 months at 25°C/60% RH, four batches) and the compliant accelerated stability data (6 months at 40°C/75% RH, two batches).

Drug Product The drug product is an aqueous isotonic eye drops solution, containing the new combination of the active substances timolol maleate and tafluprost. One millilitre contains 6.84 mg timolol maleate (corresponding to 5.0 mg timolol) and 0.015 mg tafluprost. The formulation is non-preserved and is packaged in single-dose containers. Glycerol is used as tonicity agent for obtaining isotonicity. Disodium edetate is included as chelating agent to improve the stability of the drug product. Polysorbate 80 is added for solubilisation of tafluprost and minimisation of adsorption losses of tafluprost. The pH of the drug product is adjusted with sodium hydroxide and/or hydrochloric acid to pH 6.0-6.7. Disodium phosphate dodecahydrate is added as buffer. The choice and function of the excipients has been adequately explained. The final formulation of the current drug product was used as test product in the GLP-studies 77601 and 77602, in the Phase I PK clinical trial 201150 and the Phase III clinical trials 201050 and 201051. Compliant batch analytical data of the phase III clinical trial batch are presented. The sterilization method (sterile filtration and aseptic filling) as well as the manufacturing overage have been justified. The LDPE material of the single-dose containers complies with Ph. Eur. 3.1.4. The label is not directly in contact with the ampoule containing the drug product. Leachable studies were conducted. Drop size studies were performed with the single-dose containers from both drug product manufacturers, giving similar drop sizes. The integrity of the single-dose containers against microbial ingress was shown.


It was demonstrated that the secondary packaging of the single-dose containers (laminate pouches) is suitable for protecting the drug product from water loss and from light. Two alternative manufacturing sites are approved for finished product manufacturing. The batch formulas are in line with the composition of the drug product and the manufacturing overage of tafluprost. A description of the manufacturing process, a flow chart and process validation/evaluation data are provided. All excipients are specified according to the respective Ph. Eur. monographs. Additionally, the microbial purity is specified. The release and shelf-life specification of the drug product are justified. Compliant batch results of three production scale batches from both manufacturing sites are presented. Analytical procedures are described and are validated. Long-term stability data at 5°C (36 months data of two batches, 30 months of third batch and 24 months data of fourth batch) and accelerated stability data at 25°C/40% RH (6 months, all four batches) are presented. All long-term and accelerated stability data met the current shelf-life specification. A shelf-life of 36 months at 2-8°C (in a refrigerator) is sufficiently supported by these stability data. A shelf-life of 28 days after first opening of the foil pouch at not more than 25°C is considered justified, based on the stability data of the single-dose containers after first opening of the pouch. Opened single-dose containers have to be discarded with any remaining solution immediately after use.

III.2 Non-clinical aspects Pharmacology The two active substances of the present fixed combination are the prostanoid FP receptor agonist tafluprost and the non-selective beta-adrenergic antagonist timolol. The individual compounds are well known and their pharmacological properties have been fully characterised. Both drugs act complementary in the treatment or prevention of glaucoma, i.e. the PGF2α analogue tafluprost enhances the uveoscleral outflow of aqueous humour, whereas timolol reduces the formation of aqueous humour. The applicant did not perform new pharmacodynamic studies with the fixed combination but provided an acceptable review based on literature as well as the studies originally submitted for license application of the individual tafluprost product Taflotan® (0.0015 % tafluprost). Previously performed studies in monkeys have revealed an additive ocular hypotensive effect after the concomitant use of tafluprost and timolol. Thus the development of the new fixed combination is supported by the reviewed non-clinical data.

Pharmacokinetics The two active substances of the present fixed combination 0.0015% tafluprost and 0.5% timolol are well known and their pharmacokinetic properties have been fully characterised. Tafluprost is well absorbed into the eye both from the preserved and unpreserved ophthalmic solution. During the absorption tafluprost is hydrolysed to the free acid (pharmacologically active form). The primary inactivation is by beta-oxidation. The complete metabolism is complex. The half-life of tafluprost acid in plasma is short. In primates the predominant excretion of metabolites is urinary. The penetration of tafluprost and timolol from the fixed combination 0.0015% tafluprost and 0.5% timolol into the eye has been investigated in two separate ocular PK studies in rabbits. In the D106 Response, the applicant provided confirmatory data showing that the test product used in the two performed nonclinical PK studies 77601 and 77602 complies with the to be marketed product. This study revealed that corneal penetration for tafluprost appears to be similar from the preservative-free TT-FDC and the preservative-free tafluprost monopreparation eye drops. Contrary, timolol was somewhat less absorbed from the preservative-free TT-FDC compared to the corresponding preservative-free timolol control preparation. The tafluprost/timolol combination product will be administered once daily, i.e. the dose regimen is comparable to the tafluprost monotherapy, but differs with respect to timolol, which is usually used twice daily.


Toxicology The two active substances of the present fixed combination 0.0015% tafluprost and 0.5% timolol are well known and their toxicological properties have been fully characterised. The toxicological profile of tafluprost is briefly summarized in the non-clinical assessment report. As stated, tafluprost did not show genotoxicity or carcinogenicity potential. It did not induce skin sensitization. In reproductive and development toxicity studies in rabbits, an increase of post-implantation loss, abortion and fetal malformation were observed. Furthermore, transition of tafluprost and/or metabolites to fetuses and milk was observed in rats. Taptiqom should therefore not be used during pregnancy and lactation unless clearly necessary. No data for timolol are summarized, due to the extensive clinical experience with this compound for IOP reduction. The current toxicology package in support of the new fixed combination is limited to one 13-week ocular toxicity study in monkeys, in order to evaluate the potential local or systemic toxicity. The study and the duration of the study is considered adequate in view of the recommended non-clinical program for fixed combinations of already authorised compounds (CHMP/SWP/258498/2005 Guideline on the non-clinical development of fixed combinations of medicinal products), however, the submitted 0.0015% tafluprost/0.5% timolol fixed drug combination is formulated without preservative. Based on clinical and histophathological examinations, no additional or increased toxic potential of the combination of tafluprost and timolol was seen. Overall, a preserved 0.001% benzalkonium chloride containing fixed dose combination of 0.0045% tafluprost and 1.5% timolol, i.e. 3 times higher active drug concentrations compared to the therapeutic formulation, was well tolerated. The toxicokinetic data from the 13-week ocular toxicity study in monkeys confirmed systemic exposure following ocular application of test products. Plasma concentrations from products containing either individual tafluprost and timolol or a fixed combination of both do not differ significantly. Therefore, based on the performed preclinical studies and current experience with individual drug products on the market, it is reasonable to assume, that local tolerance as well as systemic side effects of the combination is likely similar or better compared to individual drug therapy.

Environmental Risk Assessment (ERA)

Summary of main study results

Substance (INN/Invented Name): Timolol

CAS-number (if available):

PBT screening Result Conclusion

Bioaccumulation potential-

log Kow

according

OECD107

log Kow = 1.48 Potential PBT

(N)

Substance (INN/Invented Name): Tafluprost

CAS-number (if available):

PBT screening Result Conclusion

Bioaccumulation potential-

log Kow

OECD107 log Kow = 4.5 – 4.6 (pH

3-11)

Potential PBT

(Y)

Conclusions on studies: The PECsurface water values for timolol and tafluprost are clearly below the action limit of 0.01

µg/l and thus no further Phase II environmental risk assessment is required. Nevertheless, a final conclusion on potential environmental risk cannot be drawn since the data provided for

PBT screening of tafluprost are not sufficient and cannot be used for further PBT assessment. The applicant provided a commitment, informing that a PBT assessment for the active

ingredient tafluprost (including the full study reports) will be performed. The data including full study reports will be provided as post authorisation measure.


III.3 Clinical aspects

Overview of clinical pharmacology

When assessing the clinical pharmacology of TT-FDC, one should consider that the product consists of two well-characterized compounds for glaucoma treatment; tafluprost and timolol. Furthermore both components of the combination product are used at the same concentration as each drug is used during monotherapy. Therefore, the clinical pharmacology studies have focused on the pharmacokinetics of the combination product, whether an interaction between tafluprost and timolol occurs that could affect the systemic pharmacokinetic profile. The nonclinical pharmacokinetic studies with TT-FDC have been reviewed in the Non-clinical Overview Document, and will only briefly be referred to in this section. Summary of clinical pharmacology studies with TT-FDC: The clinical pharmacology program with TT-FDC comprises study 201150 to investigate the systemic pharmacokinetics of tafluprost acid and timolol and to compare it to the respective monotherapies. It is emphasized, that the efficacy and safety of the TT-FDC was evidenced by the two pivotal phase III studies (201050 and 201051), and thus there was no formal intention of showing bioequivalence. Nor was there any objective of bridging efficacy and safety between the monotherapies and TT-FDC based on the systemic exposures of these topically administered eye drops (bearing in mind also the different dosing of timolol in TT-FDC and monotherapy). Specifically, for topical ocular medications like TT-FDC, the systemic plasma concentrations do not predict efficacy but in contrast are of interest from the systemic safety point of view. Of note, in study 201150 IOP was also measured which can be regarded as a pharmacodynamic part of the study.

Pharmacokinetics

Ocular bioavailability

No ocular bioavailability/pharmacokinetic study has been performed with the TT-FDC product in man as both components, tafluprost and timolol are known to penetrate readily into the eye from formulations similar to that of the TT-FDC product. In non-clinical studies performed in rabbits comparable penetration of tafluprost acid and timolol into the aqueous humour was demonstrated upon topical application of the TT-FDC product and monotherapies (studies 77601 and 77602).

Systemic bioavailability The systemic bioavailability of tafluprost acid and timolol from the TT-FDC product has been investigated in a special phase-I clinical pharmacokinetic study and compared to tafluprost and timolol monotherapies. The study drugs were administered for a total of 8 days. The study included only healthy volunteers under age of 45 in order to exclude possible interfering conditions (differences between different age groups/subject populations were not examined). TT-FDC was administered once daily in the morning, and so was 0.0015% tafluprost whereas 0.5% timolol was administered twice daily. The treatment periods were separated with a washout period of at least four weeks to abolish the carry over effect (later confirmed in the study as the elimination half-life of tafluprost acid was very short, not detectable after 30 minutes in humans, and the elimination half-life of timolol was 2.5 to 5 hours). The pharmacokinetic parameters in the plasma were investigated on Day 1 and Day 8 after administration of the study drugs in the morning, and the systemic absorption and elimination of the tafluprost acid and timolol from the TT-FDC product were compared to the monotherapies, respectively. The following pharmacokinetic parameters were determined from the plasma samples for tafluprost acid and timolol after the TT-FDC and the

corresponding monotherapy: AUC0-last, Cmax and tmax; t1/2 and AUC0-∞ could be calculated for timolol only. The accumulation index (RA) was calculated from the AUC data (Day 8/Day1). The absorption and elimination of tafluprost acid were rapid both after single (Day 1) and repeated dosing (Day 8) of the TT-FDC and 0.0015% tafluprost eye drops, and the plasma concentrations were low for both products on both days. The accumulation of tafluprost acid from Day 1 to Day 8 was negligible. Pharmacokinetic data on Day 8 after one week’s repeated instillation of the products are presented; all data are presented in the summary of clinical pharmacology studies and 201150 study report.


The systemic exposure to tafluprost acid following once daily administration was low and essentially the same after the single (Day 1) and repeated (Day 8) dosing of tafluprost monotherapy and TT-FDC. On Day 1, timolol was absorbed into plasma a little slower from the TT-FDC product compared to the timolol eye drops. However, the difference in the key pharmacokinetic parameters AUC0-last and Cmax remained markedly below 10%, thus indicating similarity of the products. The Day 8 pre-dose concentrations of timolol in plasma were on average 235 pg/ml in the subjects dosed b.i.d. with 0.5% timolol eye drops (around 12 hours after the preceding dose) compared to only 37 pg/ml with the TT-FDC q.d. treatment (24 hours after the preceding dose). A concentration of 235 pg/mL corresponds to around 0.5 nanomoles/L, i.e. close to the KD value for timolol (0.6 nanomoles/L) on beta adrenergic receptors (Sears, 1984). Hence 0.5% timolol eye drops b.i.d. may exert significant beta-adrenergic blockade in the systemic circulation around the clock with recognizable clinical side effects in susceptible individuals (Hayreh et al., 1999). In this respect it can be anticipated that the TT-FDC product may cause less systemic side effects that are related to beta-adrenergic blockade. Otherwise, there was no outstanding difference between the TT-FDC and timolol monotherapy on Day 8 (beyond the one already seen before dosing). Thus, the pharmacokinetic parameters on Day 8 were comparable between the products and no evidence of drug-drug interaction existed. There was only slight and comparable accumulation of timolol from Day 1 to Day 8 with both products. Pharmacokinetic data of timolol on Day 8 are presented; all data are presented in the summary of clinical pharmacology studies and 201150 study report. Furthermore, in a supportive Japanese study (clinical trial 01111002) performed with 0.0015% tafluprost – 0.5% timolol fixed dose combination ophthalmic solution preserved with 0.001% benzalkonium chloride (DE-111), no pharmacokinetic changes in the plasma concentrations of tafluprost acid and timolol due to repeated instillation were found in the treatment groups by the in vivo pharmacokinetic examination. In addition, since no differences in the plasma concentrations of tafluprost acid and timolol were found by instillation of the DE-111 compared to those in the tafluprost group, the timolol group and the concomitant administration group, it was considered that there were no pharmacokinetic interactions caused by the combination formulation of DE-111.

Pharmacodynamics No clinical pharmacodynamic study has been performed with the TT-FDC product as both components of the combination product have well known pharmacodynamic properties. However, in phase-I clinical trial 201150 IOP was measured twice on Day 1 and Day 8. The IOP values demonstrate that even in healthy volunteers with low IOP the pressure reduction was excellent and at all times better than that of the reference drugs (0.0015% tafluprost and 0.5% timolol).

Clinical efficacy Two phase-III clinical trials have been performed to demonstrate the efficacy of the TT-FDC product. In study 201051, non-inferiority was demonstrated to concomitant treatment with 0.0015% tafluprost q.d. and 0.5% timolol b.i.d., and in study 201050 superiority was demonstrated to monotherapy with 0.0015% tafluprost, and to monotherapy with 0.5% timolol. Thus, TT-FDC was shown to be equally effective as the two components used together as separate drugs, and more effective than either of the two components when used alone. In addition supporting data with DE-111 from Japan have been obtained. DE-111 is a similar fixed dose combination product based on 0.0015% tafluprost and 0.5% timolol, but the product is preserved with 0.001% BAC in contrast to TT-FDC which is preservative-free. The phase-III clinical trials with TT-FDC are presented. Detailed descriptions of IOP-lowering efficacy are provided.

Non-inferiority and superiority trials One non-inferiority phase-III clinical trial (201051) has been performed, in which TT-FDC was compared to concomitant treatment with 0.0015% tafluprost and 0.5% timolol. The other phase-III clinical trial (201050) was a stratified superiority study in which TT-FDC was compared to monotherapy with 0.0015% tafluprost and monotherapy with 0.5% timolol in patients previously uncontrolled on tafluprost and timolol therapy, respectively.


A robust statistical analytical plan was included in each of the trial protocols encompassing testing with repeated measurements analysis of covariance (RM ANCOVA) with baseline as covariate as well as repeated measurements analysis of variance (RM ANOVA) without baseline as covariate on both the intention-to-treat (ITT) and per protocol (PP) datasets.

Clinical trial 201051 Clinical trial 201051 is a non-inferiority study that compared TT-FDC once-daily to the concomitant treatment with tafluprost once-daily and timolol twice-daily administered adjunctively for 6-months. Results showed the TT-FDC once-daily met its pre-specified endpoint and was non-inferior to the concomitant administration of tafluprost once-daily and timolol twice-daily given concomitantly with a similar safety profile. The study, performed during 2011-2012, was a multinational, multicenter clinical trial conducted at 35 centers in 7 European countries. The study was randomized, double-masked active-controlled, with parallel-groups of patients diagnosed with OH or OAG (including POAG, PEG or PiG). The objective of the study was to compare the efficacy and safety of the preservative-free fixed-dose combination of tafluprost 0.0015% and timolol 0.5% eye drops (TT-FDC) to the concomitant administration of preservative-free tafluprost 0.0015% and preservative-free timolol 0.5% eye drops (CCA). The primary aim of the study was to demonstrate that after a 6-month treatment period TT-FDC q.d. was non-inferior to the concomitant administration of tafluprost 0.0015% eye drops q.d. and timolol 0.5% eye drops b.i.d. in patients with open-angle glaucoma (OAG) or ocular hypertension (OH). Diurnal IOP measurements were performed at 8:00, 10:00 and 16:00 at Baseline and Weeks 2 and 6, and Months 3 and 6. The three time points were chosen, because they represented (office hours closest to) the expected peak and trough effects of TT-FDC, timolol and tafluprost. The primary evaluation of IOP was based on the worse eye (i.e. the eye with a higher IOP at the baseline 8:00 measurement). Patients with OH or OAG with an untreated IOP of ≥23 mmHg at the baseline 8:00 measurement were randomized and treated: 201 patients received TT-FDC and 199 patients CCA. Primary efficacy variable was the change from baseline in average diurnal IOP at 6 months. A prospectively defined non-inferiority limit of 1.5 mmHg was applied for the variable. The same limit has commonly been used in glaucoma studies (e.g. EPAR DuoTrav, 2007). Secondary efficacy variables comprised the proportion of responders at 6 months (e.g. change from baseline in IOP of 20% or more by steps of 5%); change from baseline in the average diurnal IOP at 2 and 6 weeks, and 3 months as well as change from baseline in time-wise IOPs. Statistical methods: A repeated measurements analysis of covariance (RM ANCOVA) model was used to analyze the primary efficacy variable. A two-sided 95% confidence interval (CI) for the average difference estimated from the model was used in the evaluation of the noninferiority hypothesis: non-inferiority was established if the upper limit of the confidence interval for the treatment difference (TT-FDC - CCA) was less than or equal to the prespecified margin of 1.5 mmHg. Both the per protocol (PP) and the intention-to-treat (ITT) datasets were used in the evaluation of the primary hypothesis; however, in order to avoid increase in the type II error rate the PP dataset was regarded as the primary one (CPMP/ICH/363/96). The last observation carried forward (LOCF) imputation method was applied for the ITT dataset. All continuous secondary efficacy variables were analysed according to the same principles as the primary efficacy variable. Sensitivity analyses were carried out using a model without baseline IOPs as covariate (RM ANOVA). The proportion of responders was analyzed using a Cochran-Mantel-Haenszel (CMH) test. The most prevalent AEs and selected ocular safety and tolerability variables were analyzed with the CMH test as well. Changes in blood pressure and heart rate were evaluated using an analysis of variance (ANOVA) model. Results: A substantial and comparable reduction of IOP (>30% from baseline) was seen with TT-FDC and CCA throughout the study. At 6 months, the estimated overall treatment difference (TT-FDC - CCA) for the PP dataset (primary analysis) was 0.308 mmHg with a 95% CI from -0.194 to 0.810 mmHg thus providing firm evidence of non-inferiority between TT FDC and CCA. The analysis using the ITT (LOCF) dataset (secondary analysis) confirmed these results. The analysis without the baseline IOP as a covariate (sensitivity analysis for PP dataset only) gave similar results.


These three analyses provided unequivocal proof that TT-FDC is non-inferior to CCA. Furthermore, there were no significant differences in the proportion of responders, and all other secondary efficacy variables unanimously supported non-inferiority. The treatment effect was also consistent across the prospectively defined subgroups.

Clinical trial 201050 Clinical trial 201050 is a 6-month stratified superiority study of TT-FDC once-daily against monotherapy with tafluprost once-daily and monotherapy with timolol twice-daily. Results showed the TT-FDC met its prespecified endpoint and achieved statistically significant differences compared to each monotherapy while maintaining an acceptable safety profile. The study, a stratified, randomized, double-masked, active-controlled, parallel-group, multinational and multicenter phase-III trial in patients with OAG or OH, was performed during 2011-2012, at 60 centers in 10 European countries and Israel. The objective of the study was to compare the efficacy and safety of the preservative-free fixed-dose combination of tafluprost 0.0015% and timolol 0.5% eye drops (TT-FDC) to the corresponding individual monotherapies. The primary aim of the study was to demonstrate that after a 3-month treatment period TT-FDC administered once daily is superior to both tafluprost 0.0015% eye drops (TAF) administered once daily and timolol 0.5% eye drops (TIM) administered twice daily in patients with OAG or OH who were insufficiently controlled by prostaglandin alone (PG stratum) or timolol alone (TM stratum) prior to the study. A total of 189 patients with inadequately controlled IOP during prior timolol monotherapy were randomized and treated in the TM stratum (95 patients with TT-FDC and 94 with TIM) and 375 patients with inadequately controlled IOP during prior prostaglandin monotherapy were randomized and treated in the PG stratum (188 patients with TT-FDC and 187 with TAF). Diurnal IOP measurements were performed at 8:00, 10:00, 16:00 and 20:00 at Baseline and Weeks 2 and 6, and Months 3 and 6. The four time points were chosen, because they represented the expected peak and trough effects of TT-FDC, TIM and TAF. The primary evaluation of IOP was based on the worse eye. For IOP to be uncontrolled, the patient had to have a clinical need for additional IOP lowering medication as judged by the investigator, and at the Screening visit IOP in either treated eye had to be at least 22 mmHg at any time of the day (TM stratum), or IOP had to be at least 20 mmHg at any time of the day (PG stratum). Furthermore, at the End-of-run-in visit, after 2-week treatment with preservative-free timolol 0.5% (TM stratum), or preservative-free tafluprost 0.0015% (PG stratum), the patient had to have in either treated eye at the 8:00 measurement IOP of at least 22 mmHg (TM stratum) or 20 mmHg (PG stratum). Finally, at the Baseline visit, after a washout period of at least 4 weeks, the patients had to have in either eye an increase of at least 2 mmHg in the average diurnal IOP (measured at 8:00, 10:00, 16:00 and 20:00) as compared to the average diurnal IOP at the End-of-run-in visit. Primary efficacy variable was the change from baseline in mean diurnal IOP at 3 months (since the IOP was not optimally controlled for the patients receiving monotherapies and a steady IOP lowering effect is reached well before 3 months). Secondary efficacy variables comprised proportion of responders at 3 months, change from baseline in the average diurnal IOP at 2 and 6 weeks, and 6 months, as well as change from baseline in the time-wise IOPs. Statistical methods: A repeated measurements analysis of covariance (RM ANCOVA) model was used to analyze the primary efficacy variable within both strata. A two-sided 95% confidence interval (CI) for the average difference estimated from the model was used in the evaluation of the superiority hypothesis: superiority was established if the upper limit of the CI (TT-FDC – TIM) in the TM stratum and (TT-FDC – TAF) in the PG stratum was less than 0 mmHg (or, equivalently the corresponding p-value was less than 0.05). The intention-to-treat (ITT) dataset was used in the analysis of efficacy, but the evaluation of the primary hypothesis was also done using the PP dataset. Last observation carried forward (LOCF) was the primary method of handling missing data for the ITT datasets at 3 months. All continuous secondary efficacy variables were analyzed according to the same principles as the primary efficacy variable. Sensitivity analyses were carried out using a model without baseline diurnal IOP as a covariate (RM ANOVA). The proportion of responders was analyzed using the Cochran-Mantel-Haenszel (CMH) test.


Results in prior timolol users (TM stratum): a substantial reduction of IOP from baseline was seen with TT-FDC and TIM throughout the study. For both treatments, a steady IOP lowering effect was reached already at 2 weeks and the effect sustained up to 6 months. From 6 weeks onwards the decrease was on average 32.0% for TTFDC and 28.5% for TIM. At 3 months, the estimated overall treatment difference (TT-FDC - TIM) for the ITT LOCF dataset (primary analysis) was -0.885 mmHg with a 95% CI from -1.745 to -0.024 mmHg (p=0.044), thus providing evidence of superiority of TT-FDC to TIM. The analysis using the PP dataset (secondary analysis) confirmed these results (p=0.009). The analysis without baseline IOP as covariate (sensitivity analysis for the ITT LOCF dataset) gave similar results. Taken together, these analyses provided solid proof that TT-FDC is superior to TIM. Furthermore, there was a clear numerical advantage for the benefit of TT-FDC in the proportion of responders at 3 months, and of the remaining secondary efficacy variables all provided clear numerical and most statistically significant evidence on the superiority of TT-FDC. The treatment effect (superiority) was also consistent across the prospectively defined subgroups. Results in prior prostaglandin users (PG stratum): a substantial reduction of IOP from baseline was seen with TT-FDC and TAF throughout the study. For both treatments, a steady IOP lowering effect was reached already at 2 weeks (31.8% for TT-FDC and 26.7% for TAF) and the effect sustained up to 6 months. From 6 weeks onwards the decrease was on average 32.8% for TT-FDC and 27.6% for TAF. At 3 months, the estimated overall treatment difference (TTFDC - TAF) for the ITT LOCF dataset (primary analysis) was -1.516 mmHg with a 95% CI from -2.044 to -0.988 mmHg (p<0.001), thus providing firm evidence of superiority of TTFDC to TAF. The analysis using the PP dataset (secondary analysis) confirmed these results (p<0.001). The analysis without baseline IOP as a covariate (sensitivity analysis for the ITT LOCF dataset) gave similar results. Taken together, these analyses provided unequivocal proof that TT-FDC is superior to TAF. Furthermore, there was a marked numerical and statistical advantage for TT-FDC in the proportion of responders at 3 months, and the remaining secondary efficacy variables supported unanimously the superiority of TT-FDC. The treatment effect (superiority) was consistent across the prospectively defined subgroups, and even somewhat more pronounced in patients with a higher baseline IOP.

Comparison of endpoint effects in phase -III clinical trials A comparison of the endpoint effects in diurnal IOP in the phase-III studies (3 and 6 months of treatment in studies 201050 and 201051, respectively), and the calculated mean effect at the endpoint in the whole material are presented.The IOP response to TT-FDC was overall quite similar in both studies, although the effect was slightly smaller (p=0.302) in study 201051 probably due to lower baseline IOP.

Demographic characteristics of phase-III clinical trials with TT-FDC The mean age in the studies was 63.5-67.4 years. Approximately 2/3 of the patients were females, except for the prior timolol users’ stratum (TM stratum) in study 201050 where 58% were females. Of the patients treated with TT-FDC 71% suffered from primary open-angle glaucoma. Only about 6% suffered from secondary glaucoma, the rest (23%) being ocular hypertensive patients. The study populations were rather similar with respect to distribution of gender, age, and disease. With a few exceptions the patients were all Caucasians. The study cohorts are not representative for the Asian or African-American black populations. Concomitant illnesses comprised primarily cardiovascular disorders, metabolism/ endocrine and nutrition disorders, musculoskeletal and connective tissue disorders, and disorders of the nervous system. The distribution of the concomitant illnesses between the treatment arms was fairly homogenous in the studies.

Dose regimen studies No dose-response or dose regimen studies have been deemed necessary to perform with the TT-FDC product as the components, tafluprost and timolol, in the combination product are well known glaucoma drugs that are often combined in clinical practice and a dose regimen of once daily in the morning is rational because timolol has less effect on IOP during the night (McCannel et al., 1992) and tafluprost, as all prostaglandin analogues, should be administered once daily for optimal effect.


JUSTIFICATION FOR THE FDC Justification for the FDC of tafluprost and timolol is therefore provided given a simplification of therapy from three daily drops to one daily drop, which may improve patient compliance (EMEA Guideline On Clinical Development Of Fixed Combination Medicinal Products). The simplification of therapy to one daily drop was accomplished while maintaining a similar safety profile and achieving efficacy that was non-inferior to the three daily drop regimen. Further justification for the FDC of tafluprost and timolol is provided by an improvement of the benefit/risk due to the demonstration by the FDC to produce statistically significant additional efficacy above that achieved by each of the single component substances while maintaining an acceptable safety profile. An overview of the clinical program with TT-FDC is presented.

The clinical programme of tafluprost/timolol fixed dose combination followed the guideline

for combination products (CPMP/EWP/240/95 Rev. 1) and prospective scientific advice recommendations by BfArM and EMA to support targeted 2nd line indication for patients after insufficient response to prostaglandin or timolol monotherapies as described in the

guideline (“in second line therapy, when monotherapy with either component has not demonstrated a satisfactory benefit/risk ratio”, page 5 of CPMP/EWP/240/95 Rev. 1).

Consequently, the primary aim of the clinical development programme was to show that the FDC of tafluprost/timolol is superior in IOP lowering efficacy as compared to the corresponding monotherapies. In addition to this, Santen was able to show that IOP lowering

effect of the FDC given once daily was non-inferior to the effect provided by the components given concomitantly (tafluprost once daily + timolol twice daily).

None of the pivotal studies conducted by Santen was planned to investigate the use of Taptiqom only after the use of other FDC products. In contrast, the studies were designed to demonstrate safety and efficacy of the FDC of tafluprost/timolol in case that patients were

not sufficiently responsive to treatment with monotherapies. Direct head to head comparison study against commercially available prostaglandin/timolol

combination, such as latanoprost/timolol FDC or travoprost/ timolol FDC, was not required to be performed according to the Scientific Advice received. Likewise, another combination therapy Ganfort received marketing authorization without any FDC comparison studies to

e.g. Xalcom (ref: Ganfort EPAR). When looking at data of patients with corresponding IOP-level at baseline, the IOP-lowering

effect of the four combination products can be considered to be of similar magnitude (table below).

Critical

Attributes TAPTIQOM DUOTRAV GANFORT UD XALCOM

IOP lowering

effect 7-9 mmHg

(baseline IOP

24-26 mmHg)

7-9 mmHg and 8-9 mmHg

(baseline IOPs

between 26 and

27 mmHg)

9-12 mmHg

(baseline IOP

26 mmHg or above )

Source:

suggested SmPC

of Taptiqom

7-9 mmHg

(baseline IOP

23-26 mmHg)

8-10 mmHg (baseline

25-27 mmHg)

9-12 mmHg

(baseline

27-30 mmHg)

Source: SmPC

of Duotrav

8-9 mmHg (baseline IOP 24-

25 mmHg)

Source: Clin

Trials.gov

8 mmHg

Source: SmPC of

Xalacom


Also in a randomized, single blind study* comparing commercially available prostaglandin/timolol FDCs, the IOP-lowering effect of Duotrav, Ganfort and Xalcom was found to be 6.8 mmHg, 8.7 mmHg and 8.3 mmHg respectively at 6 months (baseline IOPs

26-28 mmHg). This is in line with the mean diurnal IOP-lowering effect of 8.3 mmHg with tafluprost/timolol at 6 months (pooled data from individual Taptiqom phase III studies).

Considering the comparable efficacy, good safety profile and benefits of preservative- free formulation, the applicant considers that the benefit/risk profile of Taptiqom can be considered positive also compared with other prostaglandin/timolol FDC:s.

* Rigollet, Ondategui, Pasto and Lop: Randomized trial comparing three fixed combinations of prostaglandins/prostamide with timolol maleate. Clinical Ophthalmology, Feb 2011. Conclusion on efficacy: Considering all the studies performed with TT-FDC it can be concluded that the product is non-inferior to concomitant treatment with 0.0015% tafluprost q.d. and 0.5% timolol b.i.d. and superior to monotherapy with 0.0015% tafluprost q.d. as well as monotherapy with 0.5% timolol b.i.d. The TT-FDC product is a very efficacious IOP-reducing medicine intended for the treatment in patients whose high IOP is insufficiently controlled by monotherapy with prostaglandin analogues or beta-adrenergic antagonists. The results obtained in the pivotal clinical studies fully support the indication for the TT-FDC product.

Clinical safety The TT-FDC product consists of two well-known pharmacologic compounds tafluprost and timolol. Both are abundantly used for glaucoma treatment. Tafluprost is an isopropyl ester prodrug of a bi-fluorinated PGF2α analogue. The hydrolysed product tafluprost acid is a selective FP prostanoid receptor agonist, that is highly potent and a full agonist. Timolol is an unselective beta-adrenergic receptor antagonist, a much used beta-blocker for glaucoma treatment. In addition timolol is used systemically for cardiovascular diseases. The major side-effects of prostaglandins are local, confined to the eye and comprise conjunctival hyperaemia, increased iridial pigmentation, eyelash changes, and occasionally eyelid pigmentation. In addition, it cannot be excluded that the prostaglandins of this group in aphakic or compromised pseudophakic eyes, may cause, or exacerbate, cystoid macular oedema and iritis, although definite proof is missing. The major side-effects of timolol, in contrast, are systemic and mostly confined to the lungs and the heart. Typically bronchoconstriction in susceptible persons may ensue, particularly in patients suffering from bronchial asthma or obstructive lung disease. In addition cardiac arrhythmias, e.g. bradycardia and even reduced blood pressure may occur, possibly leading to transient balance problems in the elderly. With exception of increased iridial pigmentation, all the side-effects mentioned above are reversible. Since the iridial melanocytes are “continent” and the turnover of melanin normally is very slow one can assume that any reversal of the increased pigmentation in the iris is extremely slow (Stjernschantz et al., 2002). In practical terms the side-effect can therefore be regarded as irreversible. However, no sinister effect associated with the increase of iridial pigmentation is known based on a large histopathological study with latanoprost (Albert et al.,2004). Both tafluprost and timolol have previously undergone thorough toxicological testing according to guidelines and were found to have acceptable safety profiles. DE-111 eye drops were tested for ocular toxicity in a 13-week study in monkeys at concentrations up to 3 times higher than the clinical concentration with acceptable results.

Summary of safety studies performed with TT-FDC Safety data have been collected in all clinical trials performed with TT-FDC (phase-I and phase-III), including also safety data from supporting studies performed in Japan. It should be emphasized that GCP regulations have been strictly implemented in the clinical program with TT-FDC. Well known adverse events anticipated to occur, such as increased iridial pigmentation and eyelash changes, have not been documented by photographs as in previous studies with tafluprost as these events are regarded pharmacological rather than toxicological.


Adverse events All adverse events (AEs) occurring, or worsening, during treatment (treatment emergent AEs) with the study drugs are included in the individual study reports. Additionally, all AEs and adverse drug reactions (ADR) observed in the TT-FDC and DE-111 studies are listed in the Appendix of Summary of Clinical Safety.

Common adverse events The adverse events are divided into ocular and non-ocular (systemic) adverse events. Tafluprost in the TT-FDC product can be anticipated to cause mostly ocular adverse events, typical for prostaglandins in general, whereas timolol in the TT-FDC product is likely to cause more systemic adverse events because usually timolol is very well tolerated in the eye.

Ocular adverse events In the phase-I pharmacokinetic study performed in healthy volunteers the main ocular adverse event with TT-FDC was ocular/conjunctival hyperemia, followed by photophobia, eye pain and eye pruritus. All were judged related (i.e. ADR) to TT-FDC and were mild except for 2 cases of hyperemia which were regarded as moderate. The most frequent ocular AEs that occurred in the two phase-III clinical trials are presented. All AEs listed, related and unrelated, have been aggregated to give a worst case scenario and to avoid excluding possibly incorrectly classified AEs. In particular, ocular/conjunctival hyperaemia, eye pain, eye pruritus, eye irritation, foreign body sensation, blurring of vision and changes in eyelashes occurred in patients who received TT-FDC but the difference overall to tafluprost and timolol was small except for hyperemia in study 201050 (TM stratum). Most of the other ocular AEs were rather uniformly distributed between the treatment groups. It has to be noted that punctate keratopathy occurred at unusually low rate, probably because all the eye drops were preservative-free. The incidence of ocular/conjunctival hyperemia as an ADR was 7% in the phase III studies.

Non-ocular (systemic) adverse events The most frequent non-ocular (systemic) adverse events that occurred in the phase-III clinical trials with TT-FDC are presented. It should be noted that related and unrelated AEs have been aggregated, thus the figures e.g. with respect to infections are not representative. Headache was the most common non-ocular AE. It occurred at about the same rate in all study groups. Headache was also the most common non-ocular AE in the phase-I clinical trial. Overall the incidence of systemic AEs was low with no clear-cut difference between TT-FDC, tafluprost and timolol. However, in the TM stratum of study 201050 somewhat more non-ocular AEs occurred with timolol in comparison to TT-FDC.

Serious adverse events and deaths All serious AEs that occurred during the entire clinical trial program with the TT-FDC product, and with the comparator drugs are presented. In the entire clinical program performed with TT-FDC in Europe there have been a total of 34 serious AEs out of which 19 occurred in association with TT-FDC. None of the serious AEs was classified as definitely or possibly related to the treatment with TT-FDC, and with respect to the age and concomitant diseases of the patients the serious AEs can be considered as co-incidental events. In the Japanese supporting studies a total of 7 serious AEs occurred (5 during treatment with DE-111 and two during the run-in period before the start of the study treatment). None was regarded as related to DE-111 treatment. No patient died during any of the clinical trials with TT-FDC or DE-111 (in Japan).

Drug-drug interactions No clear-cut interaction between tafluprost and timolol in the TT-FDC product with respect to pharmacokinetics or efficacy has been observed. Other drug-drug interactions have not been studied. Known potential timolol drug-drug interactions will be addressed in the TT-FDC product labelling.


Drug-disease interactions No special investigations on drug-disease interactions have been performed. Timolol is contraindicated in patients with pulmonary insufficiency, e.g. bronchial asthma and obstructive lung disease and certain cardiac diseases such as atrioventricular block, bradycardia, sick sinus syndrome, overt cardiac failure and cardiogenic shock. Neither timolol or tafluprost should be used in patients with hypersensitivity to the active substances. Tafluprost should only be used with great caution, in patients with previous episodes of iritis, or maculopathies e.g. cystoid macular edema, or in conjunction with intraocular surgery. The contraindications and special precautions of both of these two active components must be considered when prescribing TT-FDC.

Conclusion on safety The product has generally been safe and well tolerated in the clinical trials performed. The safety profile of Taptiqom was similar to that of 0.0015% tafluprost and 0.5% timolol.

User Testing The package leaflet is well designed and clearly worded. In this form, the user tested PLs for Taptiqom eye drops satisfy the EU directives and, according to the participants’ appraisal, are sufficiently legible and comprehensible.

Summary Pharmacovigilance system The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/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 Summary of safety concerns Important identified risks Hyperpigmentation, Reactive airway disease

including bronchial asthma / a history of bronchial asthma, Severe chronic obstructive pulmonary disease, Sinus bradycardia, Sick sinus syndrome (including sino-atrial block), Second or third degree atrioventricular block not controlled with pace-maker, Overt cardiac failure, Cardiogenic shock.

Important potential risks Vascular disorders, Masking of hypoglycemic symptoms in patients with diabetes mellitus, Masking of thyrotoxicosis, Surgical anesthesia, Choroidal detachment, Anaphylaxis.

Important missing information Children and adolescents have not been studied in clinical trials. Therefore, TT-FDC is not recommended for use in children or adolescents below age 18. Use in renal impairment. Use in hepatic impairment. Use in pregnancy and in lactating women.

Routine PhV activities are considered sufficient to cover the risk of safety concerns identified with this medicine. The safety concerns are well established for tafluprost (and other PGAs) and timolol. Routine pharmacovigilance activities are considered sufficient to prevent the risk in patients. All concerns are presented in product information (SmPC, PL). Therefore no risk minimization measures are proposed.


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

Periodic Safety Update Report (PSUR) The PSUR submission should follow the DLP in the EURD list. Currently the combination tafluprost/timolol is not included in the EURD list. After finalisation of the application procedure the RMS will inform the EMA and request the inclusion of the combination in the EURD list. The RMS will propose the following entry: first DLP 29.04.2015 (in line with the DLP of tafluprost), after the first DLP 3 yearly PSUR submission.

Common renewal date Include final proposal for a common renewal date (i.e. in general 5 years after the finalisation of the procedure.

IV. BENEFIT RISK ASSESSMENT The benefit/risk ratio is as follows: Benefit: 1. Taptiqom is one of the first completely preservative-free combination product containing a

prostaglandin and beta-adrenergic antagonist for glaucoma treatment All “risks and uncertainties” have been taken care of in the conditions for marketing authorisation, within the product information, as follow-up measures or in a risk management plan.

2. The provided application is in compliance with CHMP guidance documents/SA in the points. Optimal dose ranges and dosage regimens are chosen.

3. Conjunctival redness found in the PK-study was mild and attributed to tafluprost. It was more frequent with the tafluprost monopreparation than with Taptiqom and more frequent with the Taptiqom compared to the timolol mono product. Based on the two new ocular pharmacokinetic studies it can be concluded that corneal penetration for tafluprost appears to be similar from the Taptiqom product as from tafluprost monopreparation eye drops. All safety issues been addressed in the pharmacovigilance plan.

4. The choice of the reference product concerning the fixed–combination guideline is well selected. The applicant has sufficiently demonstrated that the risk/benefit profile of Taptiqom is comparable with appropriate recognised combination therapy, e.g. Duotrav and Xalacom.

Risks 1. No data on children or any paediatric development plans are provided. 2. No new pharmacodynamic studies in animals were performed with the combination of tafluprost

and timolol. 3. No drug interaction studies have been performed with tafluprost. 4. Based on clinical and histophathological examinations, no additional or increased toxic potential

of the combination of tafluprost and timolol was seen.


The benefits clearly overweigh the risks as evident from the clinical trials. Taptiqom is one of the first completely preservative-free combination product containing a prostaglandin and beta-adrenergic antagonist for glaucoma treatment. The unpreserved formulation containing tafluprost was 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/timolol eye drops for glaucoma patients with dry/sensitive eyes. Based on the performed clinical and preclinical studies and current experience with individual drug products on the market, it is reasonable to assume, that local tolerance as well as systemic side effects of the combination is likely similar or better compared to individual drug therapy and that the efficacy is not-inferior to the compared to individual drug therapy. The application is approved. For intermediate amendments see current product information.

Documents

Tafluprost DE/H/3869/001/DC Applicant