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Public Assessment Report Scientific discussion

Tapin cream Lidocaine 25 mg/g + prilocaine 25 mg/g

DK/H/1520/001/MR

This module reflects the scientific discussion for the approval of Tapin. The procedure was finalised on 22 October 2009. For information on changes after this date please refer to the module `Update'.

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I.

INTRODUCTION

Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Tapin cream lidocaine 25 mg/g + prilocaine 25 mg/g, from Copyfarm A/S. The date of authorisation was on 20 February 2007 in Denmark. The product is indicated for: Surface anaesthesia on skin prior to needle insertion e.g. in association with insertion of intravenous catheter and taking of blood samples. Superficial surgical intervention of the skin and in genital mucosa prior to removal of condylomas. Surface anaesthesia prior to surgical cleaning of wounds of the lower leg (ulcus cruris). This mutual recognition procedure concerns a generic application claiming essential similarity with the reference product Emla cream 25 mg/g + prilocaine 25 mg/g which has been registered in Europe by AstraZeneca A/S since 1985. The marketing authorisation is granted based on article 10.1 of Directive 2001/83/EC.

II.

II.1

QUALITY ASPECTS

Introduction

Tapin cream contains as active substances lidocaine 25 mg/g and prilocaine 25 mg/g. Tapin cream is an oil-in-water emulsion, in which the oil phase consists of a eutectic mixture of lidocaine base and prilocaine base in a 1:1 ratio. The cream is white and soft. Tapin cream is packed in Aluminium tubes in pack sizes of: 5 g tube with 2 covering plasters; 5 g tube with 3 covering plasters; 5 x 5 g tube; 5 x 5 g tube with 12 covering plasters and 30 g tube. However, not all pack sizes may be marketed. The excipients are: Castor oil, polyoxylated, hydrogenated (Arlatone G); carbomer (Carbopol 980 NF); sodium hydroxide and purified water. The cream does not contain any preservatives. Compliance wih 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 lidocaine (base) and prilocaine (base) as active substances. Both exist in crystalline powder form and are practically insoluble in water. The CEP procedure is used for both active substances and certificates of pharmaceutical suitability are provided. For lidocaine, no special testing in addition to Ph.Eur. monograph tests is indicated. The CEP does not indicate a retest period but stability data have been provided to support a retest period of 5 years with no special storage precautions. The CEP for prilocaine indicates that residual solvent hexane must additionally be tested by GC to a limit of NMT 290ppm. The CEP indicates a retest period 5 years with no special storage precautions.

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The drug substance specifications comply with the requirements in Q3A (R), Q3C and Q6A EU/ICH guidelines and with the requirements of prilocaine and lidocaine Ph.Eur. Reference materials are adequately characterised. Packaging materials are suitable and provided adequate API protection.

II.3

Medicinal Product

The finished product is a cream containing lidocaine 25 mg/g + prilocaine 25 mg/g as a water in oil emulsion system in which the oil phase consists of a eutectic mixture of the base forms of lidocaine and prilocaine in the ratio 1:1. The development of the product has been satisfactorily performed and explained. The packaging materials have shown suitable by acceptable stability studies. The antimicrobial effect in the finished product has been tested and shown to comply with Ph.Eur. type A criteria after storage for the full shelf-life period of 3 years. The manufacturing process has been satisfactorily described. In-process controls are provided and are satisfactory. No critical steps have been identified. Satisfactory process evaluation data are provided. The company confirms that the validation protocol used for the commercial scale batches will be followed for the first three full scale batches. The finished product specification is considered compliant with the general requirements of EU/ICH Q6A Guideline on Specifications and Ph.Eur. requirements for semi-solid preparations for cutaneous use (0132). Limits for related substances have been adequately explained and justified. Batch analysis results are provided for 6 commercial scale batches. The batch results comply with the proposed specification and confirm consistency of product manufacture. The product is packed into Aluminium tubes of 5 g and 30 g with a baked-on epoxy-phenolic lacquer coating. The container type is standard and well established. The quality of the container components is satisfactory. Stability data are provided on batches of product stored in the market container in pack sizes of 5 g and 30 g. A shelf-life of 3 years when stored below 25°C is accepted. An in-use shelf-life of 6 months when stored below 25°C is also accepted.

III.

NON-CLINICAL ASPECTS

This product is a generic formulation of Emla cream, which is available on the European market. No new preclinical data have been submitted, and therefore the application has not undergone preclinical assessment. This is acceptable for this type of application

IV.

IV.1

CLINICAL ASPECTS

Introduction

Lidocaine and prilocaine are well-known active substances with established efficacy and tolerability.

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The application is for a local anaesthetic cream containing a mixture of lidocaine 25 g/g and prilocaine 25 mg/g with an essentially identical composition to the brand-leader Emla cream. The MAH has conducted an in-vitro study on human skin evaluating the percutaneous absorption of Tapin ream vs. Emla cream using skin biopsy specimen from healthy volunteers (Franz static diffusion cells). The amount of active drug (prilocaine and lidocaine) found in the stratum corneum, epidermis and dermis 6 hours after a single application are basically similar (see table below).

In another percutaneous in-vitro study with the same setup as used above ortho-toluidine, the principal metabolite of prilocaine, was added to the Tapin cream in concentrations of 0.025% and 0.05%. No accumulation of the degradation product of prilocaine in the skin was observed during a 6-hours contact period. Pivotal Clinical Study The MAH has conducted a pivotal comparative clinical study evaluating the efficacy and safety of single application of Tapin cream against the brand-leader Emla cream (Astra Zeneca A/S) in 60 children undergoing venipuncture as part of a clinical examination. A total number of 72 children were included. However, 3 children did not apply the cream and 4 other children in other ways violated the protocol, leaving 69 children in the "Intent To Treat" (ITT) population and 65 children in the "All Patient Treated" (APT) population. The demographic characteristics of the 65 children randomized to either Tapin cream (n=31) or Emla cream (n=34) did not differ in age, gender, height, weight or concomitant diseases at inclusion. There were no difference in time between application and venipuncture or used quantity of the products between the two groups of children when evaluated in both the ITT and the APT population. Efficacy The primary efficacy end-point was a composite "main criterion" evaluating the acceptability of the two products using four questions. There was in both treatment groups a high degree of satisfaction with the use of the creams. No difference was detected in any of the questions using the Fisher's or the Wilcoxon's test. As secondary efficacy variable the MAH used a specific "Faces pain scale-revised (FPS-R)" with a semi-quantitative scale: score=0: no pain, score=2: mild pain, score=3: moderate pain, score=6: severe pain and score 8 or 10: very severe pain (VAS score scale 0-10). The median pain-scores in the two groups showed no clinically or statistically significant differences. Safety No systemic or severe adverse events were reported. The local safety was assessed using an overall evaluation (good, mean or bad) together with a specific evaluation of the following signs and symptoms (yes/no): itching, redness, paleness, burning sensation, and oedema.

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Conclusion An in-vitro pharmacokinetic study has demonstrated that lidocaine and prilocaine are absorbed into the skin (epidermis and dermis) to the same degree after single application of the Tapin cream and the Emla cream on healthy human skin. No cutaneous accumulation of the impurity ortho-toluidine was found during a percutaneous absorption assay in-vitro eliminating the risk of systemic exposure of this metabolite. Tapin cream has been shown to possess a local anaesthetic effect comparable to the marketed Emla cream. The local safety profile of the Tapin cream was comparable to that of the brand-leader Emla cream in children undergoing venipuncture. No specific safety issues were identified. Bases on the above, the benefit-risk is considered favourable. The RMS has been assured that the studies have 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

The lidocaine and prilocaine combination was first approved in 1985, and there is now more than 10 years post-authorisation experience with the active substances. The safety profile of lidocaine and prilocaine 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 mutual recognition procedure is in accordance with that accepted for the reference product Emla cream marketed by AstraZeneca A/S. 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 2 participants, followed by two rounds with 10 participants each. The readability test has been sufficiently performed.

VI.

OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION

Tapin cream has a proven chemical-pharmaceutical quality and has been shown to possess a local anaesthetic effect comparable to the marketed Emla cream (AstraZeneca A/S) in a controlled clinical 5/6

trial in children. As the local safety profile of the two products is basically similar the benefit-risk ration is considered positive. Bioequivalence has been shown to be in compliance with the requirements of European guidance documents. 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 accepted for the reference product Emla cream marketed by AstraZeneca A/S. A European harmonised birth date has been allocated (1985-04-01) and subsequently the first data lock point for lidocaine+prilocaine is March 2009 after which the PSUR submission cycle is 3 years. The date for the first renewal will be: 20 February 2012. The following post-approval commitments have been made during the procedure: · The validation protocol used for the commercial scale batches will be followed for the first three full scale batches.

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Microsoft Word - Final Module 5 Scientific discussion DKH1520 Tapin.doc