Public Assessment Report. Scientific discussion. Dorzo Tim. Dorzolamide hydrochloride/timolol maleate DK/H/1516/001/DC

Transcription

1 Public Assessment Report Scientific discussion Dorzo Tim Dorzolamide hydrochloride/timolol maleate DK/H/1516/001/DC This module reflects the scientific discussion for the approval of Dorzo Tim. The procedure was finalised on 20 May For information on changes after this date please refer to the module Update. 1/6

2 I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Dorzo Tim 20 mg/ml + 5 mg/ml eye drops, solution, from Sandoz A/S. The date of authorisation in Denmark was 25 June The product is indicated in the treatment of elevated intra-ocular pressure (IOP) in patients with open-angle glaucoma or pseudo-exfoliative glaucoma when topical beta-blocker monotherapy is not sufficient. This decentralised procedure concerns a generic application claiming essential similarity with the reference product Cosopt, which has been registered in Denmark by Merck Sharp & Dohme B.V. since 31 March, The marketing authorisation is granted based on article 10.1 (generic application) of Directive 2001/83/EC in all CMS and article 10.3 (hybrid application) of Directive 2001/83/EC in the RMS. Dorzolamide hydrochloride/timolol maleate eye drops is a fixed combination of a topical carbonic anhydrase II inhibitor and a non-selective beta-adreno-receptor antagonist. Both active substances are well-established as ocular hypotensive drugs known to possess additive intraocular pressure-lowering effect when administered together. There has been well-established clinical use of the originator product Cosopt eye drops for many years. II. II.1 QUALITY ASPECTS Introduction Dorzo Tim 20 mg/ml + 5 mg/ml eye drops, solution contains as active substance 20 mg of dorzolamide (as hydrochloride) and 5 mg of timolol (as maleate) per ml solution. The product is a colourless to slightly yellowish, viscous solution. Dorzo Tim 20 mg/ml + 5 mg/ml eye drops, solution is packed in LDPE bottles with LDPE dropper and HDPE cap in pack sizes of 1 x 5 ml, 3 x 5 ml and 6 x 5 ml. However, not all pack sizes may be marketed. The excipients are benzalkonium chloride; hydroxyethylcellulose; mannitol (E421); sodium citrate dihydrate; sodium hydroxide (for ph-adjustment); hydrochloric acid (for ph-adjustment) and water for injection. 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 active substances dorzolamide hydrochloride and timolol maleate are established active substances described in the European Pharmacopoeia (Ph.Eur.). The manufacturer of timolol maleate has obtained a Certificate of Suitability, a copy of which is presented in the dossier. The drug substance is suitably controlled by the current Ph.Eur. monograph with a supplementary test concerning related substances by HPLC. The drug product manufacturer has included additional tests 2/6

3 regarding residual solvents and microbiological purity in the specification. A re-test period of 5 years, if stored in low density polyethylene bag kept in aluminium laminated bag is accepted according to the CEP. The documentation on the active substance dorzolamide hydrochloride is presented as a Drug Master File submitted by the Active Substance Manufacturer. Relevant quality characteristics of the drug substance are specified. The drug substance is specified according to the recently implemented monograph in the Ph.Eur. The batch results show compliance with the specifications. Stability studies have been performed with the drug substance and no significant changes of the parameters were observed. The stability data supports a re-test period of 4 years (12 months are extrapolated), if stored in double polyethylene film bags placed into high density polyethylene drums. II.3 Medicinal Product The drug product applied for is eye drops, solution, to be marketed in multi-dose containers (5 ml) made from low density polyethylene. The cap is made from HDPE. The eye drops contain dorzolamide 20 mg/ml and timolol 5 mg/ml. The development of the drug product is described in detail, including choice of sterilisation process and selection of container closure system, and the choice of active substances and excipients is justified. The manufacturing process has been satisfactorily described and the validation of the manufacturing process has been performed with four consecutive production scale batches. The drug product specifications cover appropriate parameters for this dosage form. The analytical procedures are validated. The batch analysis shows that the finished product manufactured meets the specification. The stability data support the proposed shelf-life of 24 months when the product is stored at not above 30 C. A shelf-life of 4 weeks after first opening of the container is justified. Photostability data demonstrate that the drug product must be protected from light and kept in the folding carton III. NON-CLINICAL ASPECTS Pharmacodynamic, pharmacokinetic and toxicological properties of dorzolamide/timolol are well known. As dorzolamide/timolol eye drops are widely used, containing well-known active substances, the applicant has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate. The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate. IV. IV.1 CLINICAL ASPECTS Introduction Dorzolamide/timolol are well-known active substances with established efficacy and tolerability. The bibliographic clinical overview on the pharmacology, efficacy and safety submitted by the applicant is adequate. To support the application, the Applicant has submitted a pharmacodynamic study in order to assess the pharmacodynamic equivalence (lowering of intra-ocular pressure) of a test preparation of eye drops containing 20 mg dorzolamide and 5 mg timolol in 1 ml eye drops (Dorzo Tim eye drops) 3/6

4 compared to an EU-approved market standard (Cosopt) and secondary to evaluate the relative decrease in intra-ocular pressure. The study was performed a monocentric, observer-blinded, randomized, single-dose, two-period crossover study in healthy volunteers, with 1 drop (single dose) applied in the conjunctival sac of the right eye per period. The periods were separated by a wash-out of 7 days. A total of 38 individuals were enrolled and randomized and 37 completed. The absolute decrease in intraocular pressure (IOP) 2 hours after application was used as primary endpoint and the relative decrease in IOP (% from baseline) 2 hours after application was used as a secondary endpoint. The results are shown in table 1 below. The confidence intervals were determined by means of a parametric (ANOVA) statistical method. Pharmacodynamic equivalence could be concluded if the two-sided 95% confidence interval of the difference of the primary endpoint was completely contained in the pre-specified equivalence limits of -1.5 mmhg to +1.5 mmhg. Table 1: Primary and secondary endpoints: absolute decrease in intraocular pressure 2 hours post dose and relative (as % of baseline) decrease in intraocular pressure 2 hours post dose Both products produced an almost identical decrease in IOP: 4.72 ± 0.92 mmhg after the test product and 4.61 ± 1.24 mmhg after the reference product. The 95% confidence interval for the difference of the primary endpoint was within the predefined equivalence range. Similarly no statistically difference was found in the relative decreased in IOP from baseline to 2 hours post dose (secondary endpoint). Both the test product and the reference product were well tolerated and no differences were detected in the safety profile of the two products. Based on the results of the comparative pharmacodynamic study essential similarity between the test product Dorzo Tim eye drops and the innovator product Cosopt (Merck Sharp & Dohme B.V.) eye drops has been demonstrated. Benefit-risk is considered positive for the use of Dorzo Tim eye drops for treatment of elevated intra-ocular pressure in patients with open-angle glaucoma or pseudoexfoliative glaucoma when topical beta blocker monotherapy is not sufficient. 4/6

5 The RMS has been assured that the therapeutic equivalence study has been conducted in accordance with acceptable standards of Good Clinical Practice (GCP, see Directive 2005/28/EC) and Good Laboratory Practice (GLP, see Directives 2004/9/EC and 2004/10/EC). 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 for the reference medicinal product. The MAH has a pharmacovigilance system at their disposal, which is based on the current European legislation. The Pharmacovigilance system described fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the identification and notification of any a potential risks occurring either in the Community or in a third country. V. PRODUCT INFORMATION SmPC and Package leaflet The content of the SmPC and package leaflet approved during the decentralised procedure is in accordance with that accepted for the reference product Cosopt marketed by Merck Sharp & Dohme B.V. Readability test The package leaflet has been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The test consisted of a pilot test with 3 participants, followed by two rounds with 10 participants each. During the interviews the respondents were asked 15 questions and asked to answer in their own words. The readability test has been sufficiently performed. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Based on the results of the comparative pharmacodynamic study essential similarity between the test product Dorzo Tim eye drops and the innovator product Cosopt (Merck Sharp & Dohme B.V.) eye drops has been demonstrated. Benefit-risk is considered positive for the use of Dorzo Tim eye drops for treatment of elevated intraocular pressure in patients with open-angle glaucoma or pseudoexfoliative glaucoma when topical beta blocker monotherapy is not sufficient. Dorzo Tim 20 mg/ml + 5 mg/ml eye drops, solution has a proven chemical-pharmaceutical quality and is a generic form of Cosopt eye drops. Cosopt eye drops is a well-known medicinal product with an established favourable efficacy and safety profile. 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 other dorzolamide/timolol containing products. 5/6

6 A European harmonised birth date has been allocated ( ) and subsequently the first data lock point for dorzolamide/timolol is , after which the PSUR submission cycle is 3 years. The date for the first renewal will be: 22 November The following post-approval commitments have been made during the procedure: The enclosed stability studies will be continued. The results should be available upon request and the Authorities must be informed immediately should any stability problems arise during the studies. 6/6