Public Assessment Report. Scientific discussion. Cosopt Preservative-Free. 20 mg/5 mg/ml, eye drops, solution. Dorzolamide/Timolol DK/H/0134/002/E001

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1 Public Assessment Report Scientific discussion Cosopt Preservative-Free 20 mg/5 mg/ml, eye drops, solution Dorzolamide/Timolol DK/H/0134/002/E001 This module reflects the scientific discussion for the approval of Cosopt Preservative-Free. The procedure was finalised on 22 December For information on changes after this date please refer to the module Update. 1/8

2 I. INTRODUCTION Cosopt Preservative-Free 20 mg/5 mg/ml dorzolamide/timolol, eye drops, solution from Merck Sharp & Dohme was first authorised in Denmark on 11 August 2005 following a national procedure. Following the national approval, the MAH sought recognition of the marketing authorisation by other member states via a mutual recognition procedure with Denmark as reference member state. The mutual recognition procedure ended on 30 May Following the mutual recognition procedure, a repeat use procedure was initiated to include even more member states. This report concerns the 1st wave repeat use procedure. Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Cosopt Preservative-Free 20 mg/5 mg/ml dorzolamide/timolol, eye drops, solution from Merck Sharp & Dohme. The repeat use procedure was finalised on 22 December The product is indicated in the treatment of elevated intraocular pressure (IOP) in patients with openangle glaucoma or pseudoexfoliative glaucoma when topical beta-blocker monotherapy is not sufficient. Cosopt Preservative-Free is comprised of two components: dorzolamide hydrochloride and timolol maleate. Each of these two components decreases elevated intraocular pressure by reducing aqueous humor secretion, but does so by a different mechanism of action. Dorzolamide hydrochloride is a potent inhibitor of human carbonic anhydrase II. Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. Timolol maleate is a nonselective beta-adrenergic receptor blocking agent. 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. The combined effect of these two agents results in additional intraocular pressure reduction (IOP) compared to either component administered alone. The application for Cosopt Preservative-Free is an application according to article 8.3 of Directive 2001/83/EC. The application is an extension to Cosopt eye drops, solution (DK/H/0134/001/MR) which was approved in MRP on 7 July Following the mutual recognition procedure a number of variations were approved and the changes incorporated into the dossier. II. II.1 QUALITY ASPECTS Introduction Each ml contains mg of dorzolamide hydrochloride corresponding to 20 mg dorzolamide and 6.83 mg of timolol maleate corresponding to 5 mg timolol. The product is a clear, colourless to nearly colourless, slightly viscous solution. Cosopt Preservative-Free is available in low density polyethylene single dose containers in an aluminum sachet containing 15 single-dose containers. The following pack-sizes have been authorised: 30 x 0.2 ml (2 sachets with 15 single dose containers); 60 x 0.2 ml (4 sachets with 15 single dose containers) and 120 x 0.2 ml (8 sachets with 15 single dose containers). However, not all pack sizes may be marketed. 2/8

3 The solution contains: Hydroxyethyl cellulose; Mannitol (E421); Sodium citrate (E331); Sodium hydroxide (E524) for ph adjustment and Water for injections. Compliance with Good Manufacturing Practice The RMS has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place for this product type at all sites responsible for the manufacturing of the active substance as well as for the manufacturing and assembly of this product prior to granting its national authorisation. II.2 Drug Substance The product contains 2 active ingredients, dorzolamide hydrochloride and timolol maleate for which full information is provided directly by the applicant. In addition to this product, both active substances are also used in a number of other approved ophthalmic products marketed by the Applicant such as Cosopt, Timosopt, Trusopt and Timoptic (all of which are preserved). Structural formula: Dorzolamide hydrochloride, which is described in the European Pharmacopoeia (2359), exists as a white to off-white, crystalline powder and is soluble in water and methanol. The synthesis is satisfactorily described and controlled and the choice of starting materials is appropriate. The specification is Ph.Eur. compliant with additional testing for assay by titration, assay by silver nitrate, heavy metals, water by KF, chiral purity, ID by HPLC and microbial purity. It is also in line with requirements of the USP monograph for dorzolamide hydrochloride. Test methods are well described and validated. The packaging materials are suitable and provide adequate protection to the API. Stability data are provided to support the proposed retest period. Timolol maleate INN: Compendial names: Chemical name: Dorzolamide hydrochloride INN: Dorzolamide hydrochloride Compendial names: Dorzolamide hydrochloride Chemical name: (4S-trans)-4-ethylamino-5,6-dihydro-6-methyl-4H-thieno(2,3-b)thiopyran-2- sulfonamide,7,7-dioxide monohydrochloride. Molecular formula: C 10 H 16 N 2 O 4 S 3 HCl Molecular mass: Timolol maleate Timolol maleate (S)-1-[(1,1-dimethylethyl)amino]-3-[[4-(4-morpholinyl)-1,2,5-thiadiazol-3- yl]oxy]-2-propanol,(z)-2-butenedioate (1:1) salt Molecular formula: C 13 H 24 N 4 O 3 S C 4 H 4 O 4 Molecular mass: /8

4 Structural formula: Timolol maleate, which is described in the European Pharmacopoeia (0572), exists as a white or practically white powder and is soluble in water, ethanol and methanol. The synthesis is satisfactorily described and controlled and the choice of starting materials is appropriate. The specification is Ph.Eur. compliant with additional testing for chromatographic purity (HPLC), ID by UV (294nm), heavy metals, specific rotation (USP test), appearance, Impurities by HPLC and microbial purity. It is also in line with requirements of the USP monograph for timolol maleate. Test methods are well described and validated. The packaging materials are suitable and provide adequate protection to the API. Stability data are provided to support the proposed retest period. II.3 Medicinal Product The medicinal product is a sterile, isotonic, buffered, slightly viscous, preservative-free aqueous solution intended to be marketed in single-dose LDPE containers within a protective aluminium pouch. The product contains 20 mg/ml dorzolamide (as hydrochloride) and 5mg/ml timolol (as maleate). Each single dose container contains a minimum of 0.2 ml eye-drop solution. The development of the product has been satisfactorily performed and explained, and compatibility between API, the excipients and container is demonstrated. The packaging materials have shown suitable by acceptable stability studies. A batch formula representing manufacture of batches of the proposed batch size is presented. Manufacture is by aseptic means and the final solution is made by a combination of 2 sterile solutions of hydroxyethylcellulose with active solution. Full production details and in-process controls are provided. Satisfactory validation data are provided showing that the process steps are well controlled and consistent. A finished product specification is provided and is in line with general Ph.Eur. requirements for sterile eye drop solutions and with general IC requirements. Test methods are presented in adequate detail and validation data provide for relevant methods. Batch analysis results are provided for 3 commercial scale batches showing compliance with the proposed specification. Stability data are provided for batches stored under long-term, intermediate, accelerated, freeze-thaw, high temperature, refrigerated and photostability testing conditions to support a shelf-life of 24 months when stored below 30ºC, protected from light and freezing. The unused pipettes must be stored in their protective aluminium pouches. After first opening the aluminium pouch, the shelf-life is 15 days. 4/8

5 III. NON-CLINICAL ASPECTS Findings indicate that the preservative-free pharmaceutical formulation of 2% dorzolamide and 0.5% timolol possesses significant ocular hypotensive activity in rabbits and monkeys, and is equivalent to that displayed by the preservative-containing formulation. In cynomolgus monkeys with unilateral ocular hypertension induced by laser-induced photocoagulation of the trabecular meshwork, the acute topical administration of pharmaceutical formulations containing 2% dorzolamide and 0.5% timolol, with and without % benzalkonium chloride as preservative, elicit similar peak percentage reductions in intraocular pressure (IOP). In addition, these peak percentage reductions in IOP are similar to that elicited following the coadministration of 2% dorzolamide and 0.5% timolol dissolved in 0.5% hydroxyethylcellulose. In ocular normotensive albino rabbits, the acute topical administration of pharmaceutical formulations containing 2% dorzolamide and 0.5% timolol, with and without % benzalkonium chloride as preservative, resulted in ocular hypotensive effects which are comparable in terms of effect on IOP and duration of action. Similarly, in albino rabbits with unilateral ocular hypertension produced by the intraocular injection of alpha-chymotrypsin, IOP reductions are equivalent at all time points from thirty minutes up to and including five hours following the acute topical instillation of pharmaceutical formulations containing 2% dorzolamide and 0.5% timolol, with and without % benzalkonium chloride as preservative. IV. CLINICAL ASPECTS IV.1 Introduction Based on the submitted data the reference member state considers the benefit/risk profile of Cosopt Preservative-Free eye drops solution in single-dose container favourable. The clinical efficacy in terms of IOP decreasing action is demonstrated to be equivalent to what is obtained with the approved combination, and the safety pattern is consistent as well, in a well-conducted clinical study in patients with open angle glaucoma or ocular hypertension. As moreover a preservative-free formulation per se is desirable at least for some patients, there are no arguments against the approval. The MAH has conducted a single clinical study: A multiple-dose, double-masked, parallel, active treatment controlled study of preservative-free 2 % dorzolamide/0.5 % timolol combination with preservative in patients with elevated IOP in which the efficacy and safety of the approved dorzolamide hydrochloride/timolol maleate eye drops solution, Cosopt, was compared with the preservative-free eye drops solution (PF) (which is the subject for the present application.) in patients with ocular hypertension or open angle glaucoma. The study was an equivalence trial. EFFICACY A Multiple Dose, double-masked, parallel, active treatment Controlled Study of Preservative-Free 2.0 % Dorzolamide/0.5% Timolol Combination (PF) and 2% Dorzolamide/0.5% Timolol Combination With Preservative in Patients with Elevated IOP. Study design: This was a randomised double-blind comparison of the two agents administered twice daily for 12 weeks, following a 3-weeks wash-out phase. In this run-in period the patients discontinued their usual antiglaucoma medication and received only timolol 0.5% twice daily. At baseline (= Day 1), patient fulfilling the criteria of inclusion were randomised to one of the two treatment groups. Patients were evaluated at Day 1, after Weeks 2, 6 and 12, and, in addition, a telephone inquiry was made in order to capture any possible serious adverse experience after discontinuation of the study drug. The Criteria of inclusion encompassed: Open angle glaucoma or ocular hypertension in one or both eyes; treatment with open label 0.5% timolol ophthalmic solution bid for at least 3 weeks prior to baseline; IOP 22 5/8

6 mmhg in one or both eyes at 8.30 a.m. on Day 1 (i.e. after the timolol run-in period). The main criteria of exclusion were: Previous exposure to treatment with 2% dorzolamide/0.5% timolol combination, intraocular surgery or ocular trauma within the previous 6 months, acute or recent ocular inflammation and/or infection within the previous 3 months, significant ocular symptoms or signs (photophobia, flashes or streaks of light, metamorphopsia. diplopia or transient loss of vision), acute or chronic angle closure. Measurements of the IOP were to be taken at 8.30 a.m. and 11 a.m. (+/- half an hour). Efficacy parameters: The primary hypothesis evaluated the change in mean IOP from baseline at through (i.e. just prior to the morning dose) at week 12. Assuming that the between-patient standard deviation for changes in IOP of 3 mmhg a sample size of 240 patients would give 97% probability of concluding equivalence if the two treatments were equal. Confidence must be 95% or better that the true difference between the 2 treatments in mean IOP changes from baseline to Week 12 falled within the interval 1.5, 1.5 mmhg. Secondary endpoints: The relative ocular hypotensive effect at peak (approximately 2 hours after the morning dose). The comparison of safety and tolerability for the two formulations over a 12- weeks period. The primary analysis was an All-Patients-Treated, Last-Observation-Carried Forward (APT-LOCF) analysis, but a Per-Protocol, Observed Cases (PP-OC) analysis was performed as well. Results: A total of 261 (131 PF and 130 combination group, respectively) patients entered the treatment phase, of whom 254 (127 patients in either treatment group) completed the study period. A total of 7 (2.7%), 4 and 3 in the two groups, respectively discontinued, all because of adverse experiences. Thus, the APT-LOCF population consists of 258 patients, with 130 and 128 subjects in the preservative-free and in the approved combination formulation, respectively. The PP-OC population encompassed 254 patients with 127 and 127 patients in each treatment group. The mean age was 55.4 years (range 22-90). The Male: Female distribution in the population was 48.9 %: 51.1%. Except for the percentage of males and females randomised to the preserved combination (with 33 % and 67 %, respectively; a difference which is unlikely to have any clinical implications) the two treatment groups were well balanced demographically. The proportion of patients with ocular hypertension was 95.4 % as opposed to the proportion with open angle glaucoma that was 11.5 %. At baseline the mean h0 (through) IOP was 23.7 mm Hg (range 22-30) in both groups. The mean baseline h2 (peak) IOP was 21.2 mmhg (range 14-27) and 21.4 mmhg (15-28) in the preservative-free group and the combination group, respectively. The mean IOP values were equivalent at all time points in the two treatment groups. The mean baseline IOP was 23.7 mmhg in both treatment groups at through. The mean through IOP at week 12 was 20.8 mmhg and 21.1 mmhg in the two treatment groups, corresponding to a mean change of -2.9 mm Hg and 2.6 mmhg (-12% and - 11%) from baseline, in the PF and the combination group, respectively. The results of the PP-OC analysis were consistent with the results from the APT-LOCF analysis. Efficacy conclusion: The absence of a difference in therapeutic effect between the sought preservative-free formulation and the approved formulation of 2% dorzolamide/0.5% timolol ophthalmic solution has been demonstrated. The recorded percentual IOP-lowering effect from baseline to the end of treatment is somewhat lower than what has earlier been observed. This may be a consequence of the lower IOP value at baseline in this study population. SAFETY All 261 patients who were included in the study contributed safety data. In patients receiving the preservative-free formulation and the conventional formulation, respectively, the percentage of patients with any adverse experience was 26.7% and 33.8 %, respectively. As for drug related adverse experiences the corresponding figures were 20.6 % and 26.9 %, respectively. The proportion of patients who discontinued because of drug related adverse events was 3.1 % and 1.5 %, in the two groups. None of these differences were statistically significant. Two patients, both in the preservative- 6/8

7 free treatment group experienced serious adverse events (benign thyroid tumour, and degenerative osteoarthritis). Both events were regarded as not related to the study drug. The most frequently reported ocular adverse events were ocular burning/stinging in 16.0% and 21.5%, respectively, corneal erosions in 2.3 % for both treatment groups and blurred vision in 1.5% for both treatment groups. Taste perversion occurred in 3.1% and 5.4%, respectively. No statistically significant differences between the groups were detected between the rates of adverse events. As for emerging or worsening ocular signs the most frequently reported was punctate epithelial erosions or SPK, which occurred in 16.8 % in the PF treatment group and 23.8% in the combination treatment group. As for visual acuity, Investigator s assessment of clinical significant progression, cup/disc ratio no noteworthy findings in the two treatment groups were observed. Review of The Global Indices revealed in some cases small (statistically significant) differences between the two treatment groups, however, these differences are unlikely to be of clinical significance. Safety conclusion: Not surprisingly, the adverse event pattern for the preservative-free formulation is very similar to what is observed with the approved 2% dorzolamide/0.5 % timolol BAC preserved ophthalmic solution. The most frequently reported ocular adverse events were burning/stinging, corneal erosions and blurred vision with both preparations. Numerically, ocular adverse events were less frequent with the preservative-free formulation than with the preserved one. IV.2 Risk management plan & Pharmacovigilance system Dorzolamide/timolol was first approved in 1998, and there is now more than 10 years postauthorisation experience with the active substances. The safety profile of dorzolamide/timolol can be considered to be well established and no product specific pharmacovigilance issues were identified pre- or postauthorisation which are not adequately covered by the current SPC. Additional risk minimisation activities have not been identified. The MAH has a pharmacovigilance system at their disposal, which is based on the current European legislation. The Applicant has made a commitment to update the Detailed Description of the Pharmacovigilance System (DDPS) via a variation within 6 months after finalisation of the procedure. V. PRODUCT INFORMATION SmPC and Package leaflet The content of the SmPC and package leaflet approved during the mutual recognition procedure is in accordance with that accepted for the original procedure. Readability test Reference is made to the user consultation study performed on the package leaflet during the original procedure. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Based on the submitted data the reference member state considers the benefit/risk profile of Cosopt Preservative-Free 20 mg/5 mg/ml dorzolamide/timolol, eye drops, solution in single-dose container favourable. The clinical efficacy in terms of IOP decreasing action is demonstrated to be equivalent to 7/8

8 what is obtained with the approved combination, and the safety pattern is consistent as well, in a wellconducted clinical study in patients with open angle glaucoma or ocular hypertension. As moreover a preservative-free formulation per se is desirable at least for some patients, there are no arguments against the approval. The MAH has provided written confirmation that systems and services are in place to ensure compliance with their pharmacovigilance obligations. The SmPC, package leaflet and labelling are in the agreed templates and are in agreement with what is currently approved for the product. Agreement between Member States was reached during a written procedure. There was no discussion in the CMD(h). The Concerned Member States, on the basis of the data submitted, considered that a marketing authorisation for Cosopt Preservative-Free 20 mg/5 mg/ml dorzolamide/timolol, eye drops, solution, could be granted. The repeat use procedure was finalised on 22 December A European harmonised birth date has been allocated ( ) and subsequently the first data lock point for dorzolamide and timolol is The next PSUR should be submitted in accordance with this data lock point, after which the PSUR submission cycle is 3 years. As the product has been renewed for an unlimited period in the RMS and the CMS during the first mutual recognition procedure, there will be no further renewal. The following post-approval commitments have been made during the procedure: A variation application to include reference to ph and osmolarity in section 3 of the SPC will be submitted post repeat use procedure. The Applicant commits to submit a Type II variation within 6 months after finalisation of the procedure in order to update the Product Information accordingly. The Applicant commits to update the Detailed Description of the Pharmacovigilance System (DDPS) via a variation within 6 months after finalisation of the procedure. 8/8