Decentralised Procedure. Public Assessment Report. Diclofenac sodium / Diclofenac / Diclo sodium 140 mg medicated plaster Diclofenac sodium

Transcription

1 Decentralised Procedure Public Assessment Report Diclofenac sodium / Diclofenac / Diclo sodium 140 mg medicated plaster Diclofenac sodium DE/H/ /001/DC Applicant: Sophena GmbH Pharmavertrieb Reference Member State DE The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health Public AR Page 1/9

2 TABLE OF CONTENTS I. INTRODUCTION... 4 II. EXECUTIVE SUMMARY... 4 II.1 Problem statement... 4 II.2 About the product... 4 II.3 General comments on the submitted dossier... 4 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.. 5 III. SCIENTIFIC OVERVIEW AND DISCUSSION... 5 III.1 Quality aspects... 5 III.2 Non-clinical aspects... 6 III.3 Clinical aspects... 6 IV. BENEFIT RISK ASSESSMENT... 9 Diclofenac sodium 140 mg medicated plaster, DE/H/ /001/DC Public AR Page 2/9

3 ADMINISTRATIVE INFORMATION Proposed name of the medicinal product(s) in the RMS INN (or common name) of the active substance(s): Pharmaco-therapeutic group (ATC Code): Pharmaceutical form(s) and strength(s): Reference Number(s) for the Decentralised Procedure Reference Member State: Member States concerned: Applicant (name and address) Diclofenac-Natrium Sophena/ Diclofenac-Natrium Sophena / Diclofenac-Natrium Sophena 140 mg Wirkstoffhaltiges Pflaster Diclofenac sodium M02AA mg medicated plaster DE/H/ /001/DC DE DE2677: FR DE2678: PL DE2679: BE, CZ, DK, EE, EL, FI, HU, LT, LV, NO, PT, SE, SK, UK Withdrawn: ES Sophena GmbH Pharmavertrieb Fonyoder Strasse Leipheim, Germany Diclofenac sodium 140 mg medicated plaster, DE/H/ /001/DC Public AR Page 3/9

4 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Diclofenac Sodium 140 mg medicated plaster, in the treatment of local symptomatic and short term treatment of pain in acute strains, sprains or bruises of the extremities following blunt trauma, e.g. sports injuries in adolescents from 16 years of age and adults is approved. II. EXECUTIVE SUMMARY II.1 Problem statement This Decentralised Procedure concerns a full application of a topical diclofenac medicated plaster, under the trade name Diclofenac Sodium 140 mg medicated plaster. Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) and each medicated plaster contains 140 mg of diclofenac. The mode of action is generally attributed to the inhibition of cyclooxygenase (COX), which is the enzyme responsible for the biosynthesis of prostaglandins (PGs), which are mediators of pain, inflammation and platelet aggregation. The proposed product is a medicated plaster, containing diclofenac as the active ingredient. This is an application submitted according to Article 10(3) of Directive 2001/83/EC, as amended, this legal basis is the most appropriate for products for local use, as recommended by the Coordination Group for Mutual Recognition and Decentralised Procedures Human (CMDh). With DE acting as RMS, Sophena GmbH Pharmavertrieb is applying for the Marketing Authorisations for Diclofenac-Natrium Sophena/ Diclofenac-Natrium Sophena / Diclofenac-Natrium Sophena 140 mg Wirkstoffhaltiges Pflaster in FR (DE2677), PL (DE2678) and BE, CZ, DK, EE, EL, ES, FI, HU, LT, LV, NO, PT, SE, SK, UK (DE2679). The applicant has informed the RMS that registration procedure has been withdrawn in Spain during the clock-stop. II.2 About the product Topical administration of non-steroidal anti-inflammatory drugs (NSAIDs), such as diclofenac, offers the advantage of local, enhanced drug delivery to affected tissues with a reduced incidence of systemic adverse effects due to reduced serum concentrations. Moreover, topical application also lessens the risk of drug-drug interactions. The benefit of topical NSAID treatment has been proven in the past. Diclofenac Sodium 140 mg Medicated Plaster contains diclofenac sodium as active ingredient and is indicated for: Local symptomatic and short term treatment of pain in acute strains, sprains or bruises of the extremities following blunt trauma, e.g. sports injuries in adolescents from 16 years of age and adults. DICLOFENAC SODIUM PLASTER consists of a 10cm x 14cm self-adhesive, medicated plaster made of an acrylic matrix containing the active ingredient, applied on a 100% polyester unwoven fabric backing layer inert to the components of the matrix; the matrix is protected on either side by monosiliconized paper. Each medicated plaster contains 140 mg diclofenac sodium. The proposed posology for adults is one medicated plaster to be applied to the painful area twice daily, in the morning and in the evening. II.3 General comments on the submitted dossier This Decentralised Procedure concerns a hybrid application of a topical diclofenac sodium medicated plaster, under the trade names Diclofenac-Natrium / Diclofenac / Diclo sodium 140 mg Schmerzpflaster. The submitted dossier is considered adequate to support the application. Diclofenac sodium 140 mg medicated plaster, DE/H/ /001/DC Public AR Page 4/9

5 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product. For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. For manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports, close-out letters or exchange of information issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-community sites. A qualified person declaration that the active substance is manufactured in compliance with the detailed guidelines on good manufacturing practice for starting materials has been provided. Additionally, a GMP certificate of manufacturing facility issued by the competent authority, following an inspection is presented for the active substance Diclofenac Sodium. The specific non-clinical studies performed for characterization of local tolerance of the medicinal product were conducted according to GLP. The applicant declares that the clinical studies were conducted in accordance with the Declaration of Helsinki, as referenced in EU Directive 2001/20/EC. It complied with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) and applicable regulatory requirements. III. III.1 SCIENTIFIC OVERVIEW AND DISCUSSION Quality aspects Drug substance The chemical-pharmaceutical documentation and Expert Report in relation to Diclofenac sodium 140 mg medicated plaster are of sufficient quality in view of the current European regulatory requirements. Diclofenac sodium is a drug substance described in the European Pharmacopoeia. Details on characteristics, manufacturing process, impurity profile, specifications, analytical procedures and validations of drug substances are presented in an Active Substance Master File. In between, the drug substance manufacturer has updated the ASMF. The control tests and specifications for drug substance product are adequately drawn up. Stability studies have been performed with the drug substance. No significant changes in any parameters were observed. The proposed retest period of 5 years is justified. Drug Product The ingredients and the manufacturing process of the diclofenac sodium 140 mg medicated plaster are in general considered suitable to produce a pharmaceutical product of the proposed quality. As required in Directive 2001/83/EC, the documentation provides an adequate synopsis of the method of preparation, mentioning the various stages of production (preparation of coating solution, spreading, drying, cutting and packaging), the in-process controls and batch formula. Diclofenac sodium 140 mg medicated plaster, DE/H/ /001/DC Public AR Page 5/9

6 The excipients are appropriately controlled, using either Ph. Eur. Monographs or in-house testing. Satisfactory certificates of analysis have been supplied. On the basis of the presented stability results, A shelf-life of 36 months with the storage precaution Do not store above 30 C is accepted. III.2 Non-clinical aspects As adequately documented in the submitted non-clinical overview, the general pharmacodynamic, pharmacokinetic and toxicological properties of diclofenac are well known. In addition, specific studies conducted on acute skin irritation, acute ocular irritation, skin sensitization, skin tolerance after repeated applications and phototoxic/photoallergic potential showed that the new medicinal product is locally well tolerated and does not possess any unusual properties compared to other, already marketed, similar products. In conclusion, there are no objections to approval of Diclofenac Sodium 140 mg Medicated Plaster` from a non-clinical point of view. III.3 Clinical aspects Pharmacokinetics One Bioavailability study Q <Study 01> was conducted. It is referred to section clinical safety, systemic safety. Pharmacodynamics Diclofenac is a known substance with a well assessed pharmacodynamic profile. The according publications are discussed in the clinical overview. Dose finding No clinical dose-finding study was performed to support this application. It is agreed that such a study may not be indispensable necessary in view of the broad experience with topically applied diclofenac gels, spray, solutions and also diclofenac containing plasters which have been EU wide licensed within the last years. The dosing recommendation for Diclofenac sodium 140 mg medicated plaster is the same as that approved for the reference medicinal product. It is acceptable that the dose and concentration of the diclofenac patch can be extrapolated from the data of the already licensed plasters. Insofar a daily dose of 2x140mg diclofenac is comprehensible. Overall, with respect to the clinical database of topical and the systemic application forms and the clinical study (Study Q ) the argumentation/rationale of the applicant can be followed. Clinical efficacy One double blind randomized phase III efficacy study was carried out to evaluate efficacy: Study Q <Study 02> Randomized, double-blind, placebo-controlled. parallel-groups, multi-centre, clinical trial (Phase III) with Diclofenac Sodium 140 mg medicated plaster in patients with fresh impact injuries of the limbs. The primary objective of this trial was to show superior efficacy of Diclofenac Sodium 140 mg medicated plaster over Placebo plaster as assessed by absolute change of pain on movement from baseline Visit 1 (Day 1) to Visit 3 (Day 3) in the indication fresh impact injuries of the limbs. The plaster was applied two times a day, approximately every 12 hours, in the morning and in the evening, continued for in total 7 days. Diclofenac sodium 140 mg medicated plaster, DE/H/ /001/DC Public AR Page 6/9

7 A total of 168 patients with fresh impact injuries of the limbs was randomly assigned to the doubleblind treatment of the study (Diclofenac Sodium 140 mg: n=84; placebo: n=84) and assessed for efficacy in the FAS population. After exclusion of eight patients due to major protocol violations, a total of 160 patients (Diclofenac Sodium 140 mg: n=83; placebo: n=77) were evaluated additionally as Per-Protocol population. The population characteristics in the two arms are similar. Efficacy results The reduction in pain-on-movement VAS values from baseline to V3 was markedly greater in the Diclofenac Sodium 140 mg treatment group than in the placebo group. On average, the treatment effect was mm in favour of Diclofenac Sodium 140 mg compared to placebo and was statistically significant (ANOVA: p<0.0001). This reduction reached % in the verum group compared to a corresponding average reduction of % in the placebo group. Similar to the mean reduction of the POM values, the secondary endpoint mean pain-at-rest values (PAR) - assessed also by using VAS decreased more markedly in the actively treated group compared to placebo from baseline to Visit 3, 4, and 5. The treatment effect on all visit changes was statistically significant (ANOVA: p<0.0001). On average, the treatment effects were mm at V3, mm at V4, and 10.0 mm at V5 in favour of Diclofenac Sodium 140 mg, respectively. The treatment effect on all visit changes was statistically significant (ANOVA: p<0.0001). There was also a significant difference in time to onset of efficacy between the treatment groups (p logrank <0.0001). There was a quantitative centre-x-treatment interaction regarding the primary variable, i.e. the magnitude of the mean treatment effect between the two study drugs differed between the centres. However, on average and for all sites, this reduction was greater in the Diclofenac Sodium 140 mg treatment group than in the placebo group, the existence of the quantitative interaction between treatment and centres does not invalidate the analysis in pooling across centres. There were no relevant differences between the study drugs regarding the paracetamol intake. Clinical safety In the efficacy study <Q > 12 patients (Diclofenac Sodium 140 mg: n=5, Placebo: n=7) had at least one TEAE during the course of the clinical trial. There were twice as much as TEAEs in the placebo group (n=10) compared to the Diclofenac Sodium 140 mg group (n=5). All TEAEs in this clinical trial were non-serious. Diclofenac sodium 140 mg medicated plaster, DE/H/ /001/DC Public AR Page 7/9

8 Local tolerability All enrolled and randomised patients (n=168) were analysed for Safety (SAF). Application site disorders were the most common side effects (application site dryness, erythema (one with diclofenac Sodium 140 mg), pain, pruritus). All but one of the reported cutaneous side effects (n=9/10) occurred in the placebo group. This might indicate that the plaster itself has a local irritant potency which is diminished by the anti-inflammatory effect of diclofenac. Systemic AEs In the efficacy study <Q > two patients experienced headache in the Diclofenac Sodium 140 mg group. All TEAEs of the Diclofenac Sodium 140 mg treatment group were assessed as mild by the investigators. In the bioavailability study <Q >, the most frequent AE was headache reported by 5 subjects during treatment with the Test compound and by 7 subjects during treatment with the Reference one. Other AE reported with lower frequency were nausea, vomiting, upper respiratory tract inflammation, pain due to menstruation, pain/erythema/hematoma due to venipuncture, hypotension, epigastric pain, lumbar hernia and sciatic pain. Systemic absorption/safety With regard to systemic safety study Q <Study 01>, Comparative bioavailability and local tolerability of two topical diclofenac patches applied twice a day in repeated dose regimen to healthy volunteers, shows that systemic exposure was numerically less with the test product in comparison to the reference. Both showed a low systemic absorption. Insofar systemic safety is considered justified. Parameter Sample size Test Diclofenac Sodium Adj.Geom.Mean Ref. Flector Adj.Geom.Mean Ratio 90% C.I. AUC(0-8) (ng*h/ml) (0.519, 0.779) AUC(0-20) (ng*h/ml) (0.571, 0.834) Cmax (ng/ml) (0.561, 0.848) Patch adhesion: The adhesion of Test and Reference proved to be not dissimilar even if the adhesiveness events were more frequent with the reference Flector both overall and considering the most severe events. Scores of 3-4 (>50% detached all detached) was encountered in 51 times for Test and 74 times for Reference. Assessment of User Testing Overall, the test methodology follows the guidelines of the European Commission (Guideline on the readability of the label and package leaflet of medicinal products for human use, Revision January 2009; Update of Directive 2001/83/EC as amended by Directive 2004/27/EC / Guidance concerning consultations with target patient groups for the packet leaflet, May 2006). Both the first and the second test round met the success criteria of 90% of the subjects being able to locate the requested information, and of those, 90% being able to give the correct answer, to indicate that they understood the information presented. The general impression of the PL (Content, language and layout) was mostly positive. In conclusion, the user test is considered acceptable. Diclofenac sodium 140 mg medicated plaster, DE/H/ /001/DC Public AR Page 8/9

9 Pharmacovigilance system The applicant has provided documents that set out a detailed description of the Kappler system of pharmacovigilance (Version 6 dated 25 July 2011). A statement signed by the applicant and the qualified person for pharmacovigilance, indicating that the applicant has the services of a qualified person responsible for pharmacovigilance and the necessary means for the notification of any adverse reaction occurring either in the Community or in a third country has been provided. The Pharmacovigilance system as described by the applicant fulfils the requirements as described in Volume 9A of the Rules Governing Medicinal Products in the European Union 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. The Applicant/Proposed Future MAH Pierre Fabre (FR, DE/H/2677) has submitted a signed Summary of the Applicant's/Proposed Future MAH's Pharmacovigilance System and asked the RMS to replace the previously submitted DDPS with the new Summary of 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 accepts this substitution. IV. BENEFIT RISK ASSESSMENT Diclofenac Sodium 140 mg plaster showed clinically relevant and statistically significant superiority versus placebo in pain on movement (day1- day3, primary endpoint) in patients with fresh impact injuries of the limbs. The assessed patient population is appropriate to support the claimed indication: Local symptomatic and short term treatment of pain in acute strains, sprains or bruises of the extremities following blunt trauma, e.g. sports injuries in adolescents from 16 years of age and adults. All secondary endpoints support the shown improvement of the primary endpoint. Rescue medication was taken in approximately twice in the placebo group which is an additional indicator of the effectiveness of the test product. An imbalance was identified within the responses between the centres however the effects shown in all centres point into the same direction and reach clinically relevant extent versus placebo. Taking into account the two studies, a total of 110 were exposed to Diclofenac sodium 140 mg plaster. In essence, the safety evaluation of Diclofenac Sodium 140 mg plaster for the treatment of injuries of the limbs or other acute sports-related traumatic blunt soft tissue injuries did not reveal any additional risks and confirmed an acceptable safety profile which is in accordance with known AE frequency and severity of topically applied NSAIDs. Systemic absorption as an indicator for systemic safety is less and therefore considered better of the test product compared with the reference (Flector plaster). Adhesive properties of the test product are suggested better compared with the reference. In conclusion, benefit/risk balance of the product is favourable. The application is approved. Diclofenac sodium 140 mg medicated plaster, DE/H/ /001/DC Public AR Page 9/9