Public Assessment Report Scientific discussion. Ovixan (mometasone furoate) SE/H/1088/01/DC

Transcription

1 Public Assessment Report Scientific discussion Ovixan (mometasone furoate) SE/H/1088/01/DC This module reflects the scientific discussion for the approval of Ovixan. The procedure was finalised at For information on changes after this date please refer to the module Update. Postadress/Postal address: P.O. Box 26, SE Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Phone: +46 (0) Fax: +46 (0) Internet: Template version:

2 I. INTRODUCTION Galenica AB has applied for a marketing authorisation for Ovixan 0.1% cream claiming essential similarity to Elocon 0,1% cream marketed in Sweden by SP Europe. The product contains mometasone furoate as active substance. For approved indications see the Summary of Product Characteristics. II. II.1 QUALITY ASPECTS Introduction Ovixan is presented in the form off-white smooth cream containing 0.1% of mometasone furoate. The excipients are coconut oil, cetostearyl alcohol, stearic acid 50, macrogol stearate, glycerol monostearate, propylene glycol, sodium citrate, citric acid and purified water. The cream is filled into white aluminium laminated plastic tubes closed with a white screw cap of polypropylene. II.2 Drug Substance The drug substance, mometasone furoate has a monograph in the Ph Eur. Mometasone furoate is a white to almost white crystalline powder, practically insoluble in water, soluble in acetone and in methylene chloride, and slightly soluble in ethanol (96%). Approximately 1mg/ml mometasone furoate is soluble in propylene glycol. Mometasone furoate degrades at an alkaline ph. The structure of mometasone furoate has been adequately proven and its physico-chemical properties sufficiently described. Relevant information on polymorphism is presented. The route of synthesis has been adequately described and satisfactory specifications have been provided for starting materials, reagents and solvents. The active substance specification includes relevant tests and the limits for impurities/degradation products have been justified. The analytical methods applied are suitably described and validated. Stability studies under ICH conditions have been conducted and the data provided are sufficient to confirm the retest period. II.3 Medicinal Product Ovixan 0.1% cream is formulated using excipients described in the current Ph Eur. All raw materials used in the product are of vegetable origin/has demonstrated compliance with Commission Directive 2003/63/EC and the NfG on Minimising the risk of transmitting Animal Spongiform Encephalopathy Agents via human and veterinary medicinal products (EMEA/410/01). The product development has taken into consideration the physico-chemical characteristics of the active substance. 2/7

3 The manufacturing process has been sufficiently described and critical steps identified. Results from the process validation studies confirm that the process is under control and ensure both batch to batch reproducibility and compliance with the product specification. The tests and limits in the specification are considered appropriate to control the quality of the finished product in relation to its intended purpose. Stability studies under ICH conditions have been performed and data presented support the shelf life claimed in the SPC, with no special storage precautions. III. NON-CLINICAL ASPECTS III.1 Discussion on the non-clinical aspects Since this product has been shown to be essentially similar and refers to a product approved based on a full application with regard to preclinical data, no further such data have been submitted or are considered necessary. IV. CLINICAL ASPECTS IV.1 Pharmacokinetics No specific pharmacokinetic studies have been conducted with Ovixan and no assessments of plasma concentrations of mometasone were performed in the clinical studies. The extent of systemic absorption is known to be very low from Elocon cream (less than 1%). Hence, the lack of pharmacokinetic data for this product can be accepted. IV.2 Pharmacodynamics Mometasone furoate is a synthetic 16α-methyl analogue of beclomethasone. The action of corticosteroids is wide-ranging, including anti-inflammatory and immunosuppressive effects, which at least partly attribute to the inhibition of the release of various cytokines. Depending on the potency corticosteroids are classified into four different classes; class I (mild strength), II (moderate strength), III (high strength) and IV (extra high strength). Mometasone furoate is classified as a class III steroid. The clinical experience of the compound as topical agent in the treatment of psoriasis is considered extensive. Since bioequivalence cannot be demonstrated through pharmacokinetic studies, the applicant has used a vasoconstrictor assay (VCA) approach. Vasoconstrictor assay (VCA) studies are commonly used to assess bioavailability of topical corticosteroid formulations for dermatological use. In this assay, the vasoconstrictive properties of corticosteroids on the skin microvasculature are used as a marker of potency and penetration of different corticosteroid products. The submitted pharmacodynamic study GAL-Moa-01 did, however, not have an optimal design and therefore formal bioequivalence vs. the reference product Elocon cream could not be concluded. IV.3 Discussion on the clinical aspects Clinical efficacy 3/7

4 As stated above, formal bioequivalence vs. the reference product Elocon cream could not be concluded based on the pharmacodynamic study. The focus of the assessment will therefore be put on a phase III study included in the application. The submitted phase III clinical study (GAL-Moa-003) was designed to assess the effect of Ovixan Galenica 0.1% cream compared to Elocon 0.1% cream in patients with mild to moderate plaque psoriasis, defined as having a PASI score <10. The design was a multicentre, randomized, double-blind, non-inferiority, intra-individual study with efficacy as primary objective. Fifty eight white patients (45 men and 13 women) with a mean age of 58 years (range 32-79) were included in the study (ITT set). The number of men included in the study was considerably higher than the number of women. This might be a chance finding since psoriasis is equally frequent in men and women, and is not considered to have any impact on the results of the study. The mean PASI score was 5, and the mean TSS score was 7.7 for each lesion, at baseline. The inclusion and exclusion criteria used at the three hospitals in Sweden which recruited patients for the study are considered acceptable. Total severity sign (TSS) score was used to assess the primary objective (efficacy) of the clinical study performed in support of the application, whereas the Physician s Global Assessment (PGA1) of improvement, the Patient s Global Assessment of improvement (PGA2) and the Cosmetic questionnaire were used as supportive evidence. The design of the study and the methods used are considered adequate. The treatment schedule as presented is in large considered adequate for topical corticosteroids. Non-inferiority was demonstrated for Ovixan cream versus the comparator product Elocon cream in the ITT- as well as in the PP-analysis. In both analyses, assay sensitivity was established with significant differences between Elocon and Elocon vehicle. The results of the secondary variables, Physician s Global Assessment (PGA1) and Patient s Global Assessment (PGA2) support the conclusion from the analysis of the primary variable. The non-inferiority testing seems to suggest that Elocon is no worse than Ovixan cream even though no delta margin for the secondary variables were clearly stated in advance. The aim of developing the proposed product was to improve the cosmetics of Elocon cream and thereby also hopefully increase the patient s compliance. The results presented do not indicate any significant difference between the two active treatments, though. However, it is important that the patient has an option to choose between several products with the same active ingredient in different cream bases in order to increase treatment compliance. Clinical safety The safety data base consisted of 61 randomized patients, while the in the PP analysis, 50 patients were included. This is considered a large enough safety data base considering that mometasone furoate is a well known compound with long clinical experience at the proposed use of the product. Four patients withdrew from the study due to adverse events (chest pain in left side, itch, worsening of psoriasis and a cold). It is assessed that worsening of psoriasis and itch might be related to study treatment. In total 14 adverse events were reported, but no serious adverse event was reported during the conduct of the study. Of the 14 reported AEs, 7 were judged as moderate and 7 as mild. The 4/7

5 majority of the adverse events were in the categories Infections and infestations (4/14) and Skin and subcutaneous tissue disorders (3/14). No new adverse events were observed with Ovixan 0.1% cream that has not been seen found with other topical momentasone containing products. No differences in local tolerability were observed between the four treatments; two active and two vehicle preparations, which is somewhat surprising since the vehicles of the proposed product and the vehicle of Elocon cream are very different. However, both products contain propylene glycol which is known to have a local irritant effect. It is therefore possible that quite a large proportion of the local adverse events, such as pain and burning sensation, are directly caused by propylene glycol. Pharmacovigilance system The MPA considers that the Pharmacovigilance system as described by the applicant 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 notification of any adverse reaction suspected of occurring either in the Community or in a third country. Risk Management Plan A Risk management Plan has not been submitted, with the following justification by the applicant: This application concerns a new cream formulation containing mometasone furoate. Mometasone furoate for topical use has been on the market since The proposed Summary of Product Characteristics is based on the text for the reference product, Elocon 0.1% cream (Schering Plough) which has a well established risk-benefit profile. Routine risk minimisation activities are in place in connection with the pharmacovigilance system. It is therefore not considered necessary to have any additional risk minimisation plan. The applicant s justification for not submitting an RMP is acceptable. Periodic Safety Update Report (PSUR) The applicant has applied for a PSUR submission scheme of 3 years upon approval. Mometasone is found on the PSUR Work sharing list published by the Heads of Medicines Agencies with an EU Harmonised Birthday and related Data Lock Point (DLP). The next PSUR should have a DLP in May The suggestion is acceptable. V. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION In a phase 3 study, non-inferiority was demonstrated for Ovixan cream versus the comparator product Elocon cream in the ITT as well as in the PP analyses. In both analyses, assay sensitivity was established with significant differences between Elocon and Elocon vehicle. The results of the secondary variables supported the conclusion from the analysis of the primary variable. The aim of developing the proposed product was to improve the cosmetics of Elocon cream and thereby also hopefully increase the patient s compliance. The results presented do not indicate any significant difference between the products, though. However, it is important that 5/7

6 the patient has an option to choose between several products with the same active ingredient in different cream bases in order to increase treatment compliance. No new adverse events were observed with Ovixan 0.1% cream that has not been seen with other topical momentasone containing products. It is possible that quite a large proportion of the local adverse events, such as pain and burning sensation, are directly caused by the propylene glycol content of the product. User consultation 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 language used for the purpose of user testing the PIL was Swedish. The results show that the package leaflet meets the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use. The risk/benefit ratio is considered positive and Ovixan 1% cream is recommended for approval. VI. APPROVAL Decentralised procedure for Ovixan 1% cream was successfully finalised on /7

7 Public Assessment Report Update Scope Procedure number Product Information affected Date of start of the procedure Date of end of procedure Approval/ non approval Assessment report attached Y/N (version) Postadress/Postal address: P.O. Box 26, SE Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Phone: +46 (0) Fax: +46 (0) Internet: Template version: