LAMISIL ONCE 1 % CUTANEOUS SOLUTION PL …

1 MHRA PAR LAMISIL Once 1 % CUTANEOUS SOLUTION PL 00030/0213 1 LAMISIL ONCE 1 % CUTANEOUS SOLUTION PL 00030/0213 UKPAR TABLE OF CONTENTS Lay summary Page 2 Scientific discussion Page 3 Steps taken for assessment Page 32 Summary of product characteristics Page 33 Product information leaflet Page 39 Labelling Page 41 LAMISIL ONCE 1 % CUTANEOUS SOLUTION and PL 00030/0213 LAY SUMMARY The MHRA today granted Novartis Consumer Health Ltd Marketing Authorisations (licences) for the medicinal products LAMISIL Once 1 % CUTANEOUS SOLUTION and LAMISIL NCH 1 % CUTANEOUS SOLUTION (PL 00030/0213-4).

2 This medicine may be sold to the general public without prescription for the treatment of athlete s foot. Athlete s foot is a common, persistent infection of the foot, usually caused by a fungus called a dermatophyte. The fungus lives on dead skin, hair and toenails and thrives in warm, moist environments. A variety of treatments for this condition already exist. LAMISIL contains the active ingredient Terbinafine, which kills fungus. The clinical data presented to the MHRA, pre licensing, demonstrated that LAMISIL Once 1 % CUTANEOUS SOLUTION and LAMISIL NCH 1 % CUTANEOUS SOLUTION eradicate the fungal infection and relieve the symptoms of Athlete s foot. There were no clinically significant safety concerns and it was therefore judged that the benefits of using these products outweigh the risks; hence Marketing Authorisations have been granted.

3 MHRA PAR LAMISIL Once 1 % CUTANEOUS SOLUTION PL 00030/0213 2 LAMISIL ONCE 1 % CUTANEOUS SOLUTION PL 00030/0213 SCIENTIFIC DISCUSSION TABLE OF CONTENTS Introduction Page 4 Pharmaceutical assessment Page 5 Preclinical assessment Page 10 Clinical assessment (including statistical assessment) Page 16 Overall conclusions and risk benefit assessment Page 31 MHRA PAR LAMISIL Once 1 % CUTANEOUS SOLUTION PL 00030/0213 3 INTRODUCTION Based on the review of the data on quality, safety and efficacy the UK granted marketing authorisations for the medicinal products LAMISIL Once 1 % CUTANEOUS SOLUTION and LAMISIL NCH 1 % CUTANEOUS SOLUTION (PL 00030/0213-4) to Novartis Consumer Health Ltd on 4 November 2005.

4 The products can be obtained without prescription. These are duplicate, stand-alone, national applications for LAMISIL Once 1 % CUTANEOUS SOLUTION and LAMISIL NCH 1 % CUTANEOUS SOLUTION , containing terbinafine hydrochloride, submitted under Article (i) (known active substance) of Directive 2001/83/EC. They are line extensions to the marketing authorisations for LAMISIL 125 mg and 250 mg Tablets held by Novartis Pharmaceuticals (UK) Ltd (PL 00101/0303-0304). The applicant states that a subsequent Mutual Recognition Procedure is considered for PL 00030/0214, but not for PL 00030/0213. LAMISIL Once 1 % CUTANEOUS SOLUTION and LAMISIL NCH 1 % CUTANEOUS SOLUTION contain the active ingredient Terbinafine and are indicated for the treatment of Athlete s foot.

5 Terbinafine inhibits fungal sterol biosynthesis by inhibiting squalene oxidase, causing an increase in intracellular squalene concentrations and subsequent cytotoxicity. Selectivity for fungal cells over mammalian cells is attributed to the presence of ergosterol in fungal cytoplasmic cell membranes, which becomes deficient with squalene oxidase inhibition. It is recommended that LAMISIL be applied once on both feet, even if lesions are visible on one foot only. This application is the first for a single-dose, CUTANEOUS SOLUTION of terbinafine hydrochloride seen in the PAR LAMISIL Once 1 % CUTANEOUS SOLUTION PL 00030/0213 4 PHARMACEUTICAL ASSESSMENT GMP Statement Batch release is performed under the control of a qualified person at eight batch release sites for PL 00030/0214 ( LAMISIL NCH 1 % CUTANEOUS SOLUTION ) and one for PL 00030/0213 ( LAMISIL Once 1 % CUTANEOUS SOLUTION ).

6 Copies of the relevant manufacturing authorisations have been provided and are satisfactory. The sites for batch release are stated below. Only the first site (1) is proposed for PL 00030/0213. (1) Novartis Consumer Health, West Sussex, UK (2) Novartis Consumer Health Gebro GmbH, Fieberbrunn, Austria (3) Novartis Healthcare A/S, K benhavn , Denmark (4) Novartis Finland Oy, Espoo, Finland (5) Novartis Consumer Health GmbH, M nchen, Germany (6) Novartis (Hellas) , Athens, Greece (7) Novartis Norge AS, Oslo, Norway (8) Novartis Sverige AB, T BY, Sweden Introduction These are duplicate, stand-alone, national applications for LAMISIL Once 1 % CUTANEOUS SOLUTION and LAMISIL NCH 1 % CUTANEOUS SOLUTION , containing terbinafine hydrochloride, submitted under Article (i) (known active substance) of Directive 2001/83/EC.

7 These are applications for line extensions to the marketing authorisations for LAMISIL 125 mg and 250 mg Tablets held by Novartis Pharmaceuticals (UK) Ltd (PL 00101/0303-0304). The CTD dossiers provided are dated May 2004. This application is the first single-dose, CUTANEOUS SOLUTION of terbinafine hydrochloride seen in the UK. Terbinafine is an allylamine antifungal agent which, when used topically, is indicated for the treatment of fungal skin infections such as tinea pedis, tinea cruris and tinea corporis. A cream, gel or spray of terbinafine may be sold to the general public from pharmacies in formulations of 1 % maximum concentration, and the cream and spray may be sold elsewhere as they are on the General Sales List.

8 The largest pack size currently available as a P medicine contains 300 mg terbinafine hydrochloride. ACTIVE SUBSTANCE The active substance has been assessed in relation to other approved products on the UK market. INN: Terbinafine Molecular formula: MHRA PAR LAMISIL Once 1 % CUTANEOUS SOLUTION PL 00030/0213 5Mr: Terbinafine hydrochloride is a white to off-white finely crystalline powder, which is freely soluble in methanol, soluble in ethanol, sparingly soluble in acetonitrile and slightly soluble in water. The manufacturing process and controls have been adequately described and appropriate in-process controls and specifications are applied.

9 Appropriate proof of structure has been supplied for the active substance. There is no monograph for terbinafine hydrochloride in the British Pharmacopoeia, European Pharmacopoeia or United States Pharmacopoeia, but an appropriate specification for terbinafine hydrochloride has been proposed. Known impurities have been identified and characterised and the proposed limits for these are acceptable. Individual unknown and total impurities are controlled to acceptable levels. The analytical procedures used by the active substance manufacturer were assessed in relation to other approved products with the exception of one method for the determination of an impurity for which satisfactory analytical methodology and validation data are provided.

10 Reference standards are adequately described. The routine tests performed by the finished product manufacturer on receipt of each batch of terbinafine hydrochloride are provided and are described satisfactorily. Batch analyses have been supplied for six batches of the active substance. All batches demonstrated compliance to the proposed drug substance specification. Stability trials were performed in the packaging proposed for marketing and stability data support a retest period of 5 years in the proposed packaging, protected from light. DRUG PRODUCT Description and composition of the drug product The product is presented as a clear to slightly opaque, colourless to slightly yellow viscous SOLUTION , having an odour of ethanol.