UKPAR for Terbinafine Hydrochloride cream Terbinafine Hydrochloride 1% Cream PL 21300/0001-11 10 Tinea corporis, cruris: 1 to 2 weeks Tinea pedis: 1 week Cutaneous candidiasis: 2 weeks

UKPAR Terbinafine Hydrochloride 1% Cream PL 21300/0001-11

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TERBINAFINE HYDROCHLORIDE 1% CREAM

PL 21300/0001-11

UKPAR

TABLE OF CONTENTS Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

Page 17

Steps taken after authorisation – summary

Page 18

Summary of Product Characteristics Product Information Leaflet Labelling


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PL 21300/0001-11

UKPAR

LAY SUMMARY

The MHRA granted MPX International Limited Marketing Authorisations (licences) for the medicinal products Terbinafine Hydrochloride 1% Cream (PL 21300/0001, 3, 4, 9, and 10) which are prescription only medicines (POM) and (PL 21300/0002, 5, 6, 7, 8, and 11) are available on general sale list (GSL). These products are used for the local treatment of fungal infections of the skin. Terbinafine is an anti-fungal preparation. It kills fungi, which cause skin infections. No new or unexpected safety concerns arose from these applications and it was therefore judged that the benefits of taking Terbinafine Hydrochloride 1% Cream outweigh the risks, hence Marketing Authorisations have been granted.


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PL 21300/0001-11

UKPAR

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS Introduction

Page 4

Pharmaceutical assessment

Page 5

Preclinical assessment

Page 8

Clinical assessment (including statistical assessment)

Page 9

Overall conclusions and risk benefit assessment Page 16


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INTRODUCTION Based on the review of the data on quality, safety and efficacy the UK granted marketing authorisations for the medicinal products Terbinafine Hydrochloride 1% Cream on 29th March 2007. Terbinafine Hydrochloride 1% Cream (PL 21300/0001, 3, 4, 9, and 10) are prescription only medicines (POM) and (PL 21300/0002, 5, 6, 7, 8, and 11) are available on general sale list (GSL). The proposed products are submitted under article 10.3 last paragraph, as ‘hybrid’ applications. These products are cross referring to Lamisil Cream 1%, PL 00101/0305, granted 3 October 1990, and marketed by Novartis Pharmaceuticals UK Ltd.

Terbinafine Hydrochloride 1% Cream (PL 21300/0001, 3, 4, 9, and 10) are used to treat fungal infections of the skin caused by Trichophyton (e.g. T. rubrum, T.mentagrophytes, T. verrucosum, T. violaceum), Microsporum canis and Epidermophyton floccosum. Yeast infections of the skin, principally those caused by the genus Candida (eg. C. albicans). Pityriasis (tinea) versicolor due to Pityrosporum orbiculare (also known as Malassezia furfur). Terbinafine Hydrochloride 1% Cream (PL 21300/0002, 5, 6, 7, 8, and 11) are used for the treatment of tinea pedis (Athlete’s foot) and tine cruris (jock itch) caused by Trichophyton (e.g. T. rubrum, T. mentagrophytes) and Epidermophyton floccosum. Terbinafine is an antimycotic with a broad-spectrum of anti-fungal activity belonging to the allylamine group. This product interferes with fungal sterol biosynthesis by the inhibition of squalene epoxidase in the fungal cell membrane, which leads to an intracellular accumulation of squalene, resulting in fungal cell death.


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PHARMACEUTICAL ASSESSMENT DRUG SUBSTANCE Nomenclature INN: Terbinafine hydrochloride Chemical name: (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthalene methylamine hydrochloride CAS number: 78628-80-5 Structure

Molecular formula: C21H25N.HCl Molecular Weight: 327.9 General properties An almost white to pale creamy coloured crystalline powder. Soluble in absolute ethanol, in ethanol 96%, methanol and chloroform; slightly soluble in water, acetone, isopropyl alcohol; insoluble in toluene and ethyl acetate. There are no chiral C atoms in the structure. Melting range: 198-207°C The active substance used in the manufacture of the final product is in compliance with GMP and letter of access to the Drug Master File has been provided. An appropriate specification has been provided for the active substance terbinafine hydrochloride. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. Batch analysis data have been provided and comply with the proposed specification. Satisfactory certificates of analysis have been provided for working standards used by the active substance manufacturer and finished product manufacturer during validation studies. Active terbinafine hydrochloride is stored in appropriate packaging. The specifications and typical analytical test reports are provided and are satisfactory.

.HCl

N


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Based upon the results obtained, a preliminary retest period of 3 years has been proposed. This is acceptable. Storage conditions for the drug substance are given as: ‘Store at 15-30°C, in commercial packaging, protected from light.’ DRUG PRODUCT Other ingredients Other ingredients consist of pharmaceutical excipients, namely Sodium Hydroxide, Benzyl Alcohol, Sorbitan Stearate, Cetyl Palmitate, Cetyl Alcohol, Cetostearyl Alcohol, Polysorbate 60, Isopropyl Myristate, and Water purified. All excipients comply with satisfactory European Pharmacopoeial monograph. None of the excipients used contain material of animal or human origin. Pharmaceutical development The objective of the pharmaceutical development programme was to produce products containing 1% Terbinafine Hydrochloride cream that are tolerable and which could be considered as generic products to the originator products Lamisil Cream. The rationale for the type of pharmaceutical form developed and formulation variables evaluated during development have been stated and are satisfactory. Manufacture A description and flow-chart of the manufacturing method have been provided and are satisfactory. In-process controls are satisfactory based on process validation data and controls on the finished product. Satisfactory controls for temperature, appearance and pH of the manufacturing process and filling of the assembly process are described. Finished product specification The finished product specification is satisfactory. Test methods have been described and have been adequately validated as appropriate. Batch data have been provided and comply with the release specification. Certificates of analysis have been provided for any working standards used. Container Closure System The product is packed in to an aluminium tube, inside double lacquered with epoxy resin and closed by polyethylene caps. Specifications and certificates of analysis for all packaging materials have been provided. These are satisfactory. The applicant has confirmed that all packaging that comes into direct contact with the drug product complies with European Directive 90/128/EEC with respect to their contact with food. Stability Finished product stability studies have been conducted in accordance with current guidelines. Based on the results, a shelf-life of 4 years with storage condition ‘Store in the original container’ has been set, and this is satisfactory.


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SPC, PIL, Labels The SPCs, PILs, and Labels are pharmaceutically acceptable. The PIL is in compliance with current guidelines. The marketing authorisation holder has provided a commitment to update the marketing authorisation with a package leaflet in compliance with Article 59 of Council Directive 2001/83/EC and that the leaflet shall reflect the results of consultation with target patient groups, no later than 1st July 2008. Conclusion It is recommended that Marketing Authorisations are granted for these applications.


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PRECLINICAL ASSESSMENT

No new preclinical data have been supplied with these applications and none are required for applications of this type.


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CLINICAL ASSESSMENT 1 INTRODUCTION These are national abridged, standard applications, for Terbinafine 1% Cream containing 1% Terbinafine hydrochloride, submitted on the basis of generic medicinal product of Lamisil Cream, PL 00101/0305, granted on 3rd Oct, 1990 to Novartis Pharmaceuticals Ltd. The applicant has provided a hybrid application with literature references and a therapeutic equivalence study in tinea pedis in lieu of a bioequivalence study. 1.1 GCP aspects The applicant claims that all studies have followed GCP guidance and are complaint with the guideline. 1.2 Therapeutic Class Terbinafine is an antifungal drug for topical use; ATC code is D01A E15. 1.3 Background Terbinafine is a well established antifungal agent used both orally and as a topical application for cutaneous mycoses, depending upon the severity and specific nature of the mycoses. The current applications are for treatment of skin infections caused by trichophyton verrucosum, Microsporum canis, Candida albicans and pityrosporum orbiculare (tinea), applied locally for 1-2 weeks. 1.4 Regulatory Status The MPX international application for Terbinafine Cream have not been authorised in any other EU member state or elsewhere. There have been no refusals. 1.5 Indications, Dose and Dose Regimen The applicant submits the following; Indications: The Prescription only medicines are used for fungal infections of the skin caused by Trichophyton (e.g. T. rubrum, T.mentagrophytes, T. verrucosum, T. violaceum), Microsporum canis and Epidermophyton floccosum. Yeast infections of the skin, principally those caused by the genus Candida (eg. C. albicans). Pityriasis (tinea) versicolor due to Pityrosporum orbiculare (also known as Malassezia furfur). Posology Terbinafine cream can be applied once or twice daily. Cleanse and dry the affected areas thoroughly before application of Terbinafine cream. Apply the cream to the affected skin and surrounding area in a thin layer and rub in lightly. In the case of intertriginous infections (submammary, interdigital, intergluteal, inguinal) the application may be covered with a gauze strip, especially at night. The likely durations of treatment are as follows:


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Tinea corporis, cruris: 1 to 2 weeks Tinea pedis: 1 week Cutaneous candidiasis: 2 weeks Pityriasis versicolor: 2 weeks Relief of clinical symptoms usually occurs within a few days. Irregular use or premature discontinuation of treatment carries the risk of recurrence. If there are no signs of improvement after two weeks, the diagnosis should be verified. Children The experience with topical terbinafine in children is still limited and its use cannot therefore be recommended. Use in the elderly There is no evidence to suggest that elderly patients require different dosages or experience side-effects different to those of younger patients. Method of administration Via the topical route. And The General sale list are used for treatment of tinea pedis (Athlete’s foot) and tinea cruris (jock itch) caused by Trichophyton (e.g. T. rubrum, T. mentagrophytes) and Epidermophyton floccosum. Posology Terbinafine cream can be applied once or twice daily. Cleanse and dry the affected areas thoroughly before application of Terbinafine cream. Apply the cream to the affected skin and surrounding area in a thin layer and rub in lightly. The likely durations of treatment are as follows: Tinea cruris: 1 to 2 weeks Tinea pedis: 1 week Relief of clinical symptoms usually occurs within a few days. Irregular use or premature discontinuation of treatment carries the risk of recurrence. If there are no signs of improvement after two weeks, the diagnosis should be verified. Children The experience with topical Terbisil in children aged 16 and under is still limited and its use cannot therefore be recommended. Use in the elderly There is no evidence to suggest that elderly patients require different dosages or experience side-effects different to those of younger patients. Method of administration

Via the topical route.


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1.6 Consideration for Paediatric use There is no experience with terbinafine in children and hence its use is not recommended. 2 CLINICAL PHARMACOLOGY 2.1 Pharmacokinetics This is a locally acting locally applied preparation with minimal systemic absorption (<5%). Hence systemic pharmacokinetics is not relevant. 2.2 Pharmacodynamics The pharmacodynamic effects of Terbinafine have been well established both as a topical agent and for systemic administration in the indications sought. The applicant has provided sufficient published literature to support the claims. These are considered acceptable. 2.3 Bioavailability & Bioequivalence Bioavailability and bioequivalence are not deemed appropriate nor are considered feasible for locally applied, locally acting preparations (see the relevant guideline CPMP/EWP/239/96). 3 CLINICAL EFFICACY 3.1 Introduction The applicant has provided a review of clinical efficacy for terbinafine (Lamisil) in the indications sought and a therapeutic equivalence study in tinea pedis that is detailed and discussed below. Therapeutic Equivalence study: This was a randomised, prospective, comparative, double-blind, active controlled, parallel group, multi-centre study. Patients with a clinical diagnosis of interdigital tinea pedis were included. There were 3 clinic visits with centralised evaluation of all cultures. The sample sizes were as follows; Terbinafine Lamisil (Novartis) Randomised 733 366 356 Efficacy Population 718 362 356(visit -2) Clinical PP population 538 270 268 Mycology Full Population 447 214 233 Complete per-protocol 296 144 152 The complete Per protocol population formed the population for primary efficacy criterion. Study Flow Chart:

VIST-1 (Entry)

Treatment Period 1week

Visit-2 Follow-Up Period 1week

Visit-3- Test of Cure


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End points; Primary Efficacy Variable

• Mycological cure at Visit -3 Secondary efficacy variables:

• Mycological cure at Visit-2 • Clinical Cure (visit -2 & 3) • Complete Cure ( Visit 2 and 3) • Score of Clinical signs & symptoms The applicant employed the following scale; 0: None Complete absence of any signs 2: mild Obvious but minimal involvement 3: moderate Something that is easily noted 4: Severe Quite marked. • Sum of scores of Clinical signs and Symptoms

The sum of scores was calculated from scores of signs- fissuring, erythema, maceration, vesiculation, exudation, desquamation and from the symptoms; pruritus, burning/stinging.

• Investigator’s Rating The investigator’s rating based on 75%, 50% or less improvement. These however appear to have been arbitrary assessment.

• Patient’s assessment of efficacy. Statistical methods; The confidence interval approach to assess therapeutic equivalence of efficacy was used. Equivalence was concluded if the centre-weighted two-sided 95% CI for the difference between the two treatments lay entirely within the equivalence range (10% ±). Results; Efficacy evaluation; Mycological cure was achieved in patients in the mycological PP population; cure rates of 77.8 % and 78.3% respectively. Calculated CI was -9.9%; 8.9% which was entirely within the equivalence range (-10%; +10%), therapeutic equivalence was concluded. Analysis of the full mycological population appear to confirm the above results; Cure rates of 70.6% and 71.2 % for trebisil ( Generic terbinafine) and lamisil respectively, a difference of 0.7% (CI -9.1 to +7.7%). Secondary efficacy parameters;

• Mycological cure at visit 2 showed wider confidence intervals with the cure rates being lower than at visit -3 and difference between cure rates (for terbinafine and lamisil) being higher.

• Clinical cure rates at visit 2 and 3; Clinical cure (no residual sign /symptoms) were as follows;

Trebisil Lamisil V-2 10% 10% V-3 33.7% 28.7%

• Cure rates in clinical population were similar in the clinical full population.


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• Complete Cure at Visit 2 & 3

The following table summarises the efficacy data: Endpoint and analysis population Terbisil Lamisil Difference and 95% CIMycological cure Visit 3 – PP 77.8 78.3 -0.5 (-9.9, 8.9) Mycological cure Visit 3 – FAS 70.6 71.2 -0.7 (-9.1, 7.7) Mycological cure Visit 2 - PP 75.7 68.4 7.3 (-2.9, 17.5) Mycological cure Visit 2 – FAS 64.5 69.5 -5.0 (-13.8, 3.7) Clinical cure Visit 3 – PP 33.7 28.7 5.0 (-2.8, 12.8) Clinical cure Visit 3 – FAS 27.3 25.8 1.5 (-5.0, 8.0) Clinical cure Visit 2 - PP 10.0 10.1 -0.1 (-5.2, 5.0) Clinical cure Visit 2 – FAS 9.1 8.1 1.0 (-3.1, 5.1) Complete cure Visit 3 – PP 29.9 23.7 6.2 (-3.9, 16.3) Complete cure Visit 3 – FAS 26.6 21.5 5.2 (-2.8, 13.1) Complete cure Visit 2 - PP 11.1 5.9 5.2 (-1.2, 11.5) Complete cure Visit 2 – FAS 8.9 5.2 3.7 (-1.0, 8.5) The rates were higher in the trebisil group but not statistically significant. The other secondary efficacy parameters were not statistically significant between treatment groups as per clinical study report. 4 CLINICAL SAFETY 4.1 Introduction The expert claims that safety of terbinafine has been well established (as Lamisil) that has been in clinical use since 1990. This is applicable to the topical formulation and simultaneously, the orally administered form is also available. Whilst submitting a therapeutic equivalence study, the applicant claims this to be a substitute for the bioequivalence study and claims essential similarity to the topical Lamisil cream. Safety aspects arising out of the “therapeutic equivalence study” are discussed by the expert and summarised here.

Adverse event Terbinafine Lamisil N= % N= % Burning at application site 5 6 % 8 9.6% Erythema 1 1.2% 0 0 Pain 1 1.2% 0 0 Pruritus (site) 2 2.4% 1 1.2% Warmth 0 0 2 2.4% Total 9 10.85 11 13.2%

As no differences were demonstrated in this reasonably sized study, the expert concludes that there are no safety concerns related to this generic formulation and claims this is supported by the published literature relating to Lamisil.


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4.2 Assessor’s overall conclusions on clinical safety There are no new safety concerns arising out of the “therapeutic equivalence study” submitted by the applicant. The assessor concurs with the expert that based on the published data relating to Lamisil, no major safety issues exist. 5 CLINICAL EXPERT REPORT The clinical expert report has been written by a pharmaceutical physician. It is an adequate summary of the clinical data provided in the dossier. 6 PRODUCT LITERATURE 6.1 SPC: Summary of Product Characteristics The SPC is consistent with the reference product. 6.2 PIL; Patient Information Leaflet The Patient information leaflet is consistent with the reference product. 6.3 Labels The packagings are consistent with the reference product. 7 DISCUSSIONS 7.1 Pharmacodynamics & Pharmacokinetics The kinetics of terbinafine has been well established previously and the expert discusses these issues sufficiently in the expert report. There are no major dynamic interactions of terbinafine when used as cutaneous cream and hence this issue is not of major concern. 7.2 Bioequivalence The applicant has not submitted any bioequivalence data for this cutaneous cream. This is considered appropriate as the systemic absorption of such a cutaneous formulation is considered minimal and bioequivalence is not expected. Therapeutic equivalence with the established product is has been provided. 7.3 Efficacy & Safety The applicant has not provided new safety or efficacy data. This is acceptable for an application of this type. 7.4 Risk – benefit The risk benefit for terbinafine cream is favourable and therefore acceptable 8 CLINICAL AND PRE-CLINICAL ASSESSORS' CONCLUSIONS There are no pre-clinical issues with the use of Terbinafine as this product has been in clinical use for a number of years both as local application and as an oral formulation (terbinafine tablets). From a clinical stand point, the applicant has provided a therapeutic equivalence study comparing the generic product with the brand leader, lamisil. This is satisfactory.


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OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT QUALITY The important quality characteristics of Terbinafine Hydrochloride 1% Cream are well defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. PRECLINICAL No new preclinical data were submitted and none are required for application of this type. EFFICACY The efficacy of Terbinafine Hydrochloride 1% Cream has been well documented in the past. No new or unexpected safety concerns arise from these applications. The SPC, PIL and labelling are satisfactory. RISK BENEFIT ASSESSMENT The quality of the product is acceptable. Extensive clinical experience with Terbinafine Hydrochloride 1% Cream is considered to have demonstrated the therapeutic value of the compound. The risk benefit is, therefore, considered to be positive.


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PL 21300/0001-11

STEPS TAKEN FOR ASSESSMENT

1 The MHRA received the marketing authorisation applications on 2nd June 2004

2 Following standard checks and communication with the applicant the MHRA

considered the applications valid on 2nd July 2004

3 Following assessment of the applications the MHRA requested information relating to the quality dossiers on 1st March 2005, 2nd February 2006, 19th July 2006, and 24th October 2006

4 The applicant responded to the MHRA’s requests, providing further information on 20th January 2006, 14th July 2006, 12th October 2006, and 7th January 2007,

5 The applications were determined on 29th March 2007


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PL 21300/0001-11

STEPS TAKEN AFTER AUTHORISATION - SUMMARY

Date submitted

Application type

Scope Outcome

12/06/2007 Type IB To add own label supplier Approved 19/10/2007

22/06/2007 Type II To update SPC and consequentially the PIL and Labelling only for the GSL

Approved 12/07/2007


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SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Terbinafine Hydrochloride 1 % cream

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

10 mg terbinafine hydrochloride (equivalent to 8.89 mg terbinafine) in 1 g cream.

Excipient: 80 mg cetyl alcohol and cetostearyl alcohol in 1 g cream.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Cream

White or almost white cream, with slight almond odour.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications Fungal infections of the skin caused by Trichophyton (e.g. T. rubrum, T.mentagrophytes, T. verrucosum, T. violaceum), Microsporum canis and Epidermophyton floccosum.

Yeast infections of the skin, principally those caused by the genus Candida (eg. C. albicans).

Pityriasis (tinea) versicolor due to Pityrosporum orbiculare (also known as Malassezia furfur).

4.2 Posology and method of administration

Terbinafine cream can be applied once or twice daily. Cleanse and dry the affected areas thoroughly before application of Terbinafine cream. Apply the cream to the affected skin and surrounding area in a thin layer and rub in lightly. In the case of intertriginous infections (submammary, interdigital, intergluteal, inguinal) the application may be covered with a gauze strip, especially at night.

The likely durations of treatment are as follows:

Tinea corporis, cruris: 1 to 2 weeks

Tinea pedis: 1 week

Cutaneous candidiasis: 2 weeks

Pityriasis versicolor: 2 weeks

Relief of clinical symptoms usually occurs within a few days. Irregular use or premature discontinuation of treatment carries the risk of recurrence. If there are no signs of improvement after two weeks, the diagnosis should be verified.

Children

The experience with topical terbinafine in children is still limited and its use cannot therefore be recommended.


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Use in the elderly

There is no evidence to suggest that elderly patients require different dosages or experience side-effects different to those of younger patients.

Method of administration


4.3 Contraindications

Known hypersensitivity to the active substance or any of the excipients.

4.4 Special warnings and precautions for use Terbinafine cream is for external use only. Contact with the eyes should be avoided. If it gets into the eyes accidentally, the eyes should be washed with plenty of water and the patient should turn to an ophthalmologist if necessary.

The cream contains cetyl alcohol and cetostearyl alcohol which may cause local reactions (i.e. contact dermatitis).

4.5 Interaction with other medicinal products and other forms of interaction

There are no known drug interactions with Terbinafine cream.

4.6 Pregnancy and lactation

Foetal toxicity and fertility studies in animals suggest no adverse effects.

There is no clinical experience with Terbinafine cream in pregnant women, therefore, unless the potential benefits outweigh any potential risks, Terbinafine cream should not be administered during pregnancy.

Terbinafine is excreted in breast milk and therefore mothers should not receive Terbinafine cream whilst breast-feeding.

4.7 Effects on ability to drive and use machines

There are no data available that terbinafine would affect driving ability or any other activity requiring concentration.

4.8 Undesirable effects

In the Therapeutic equivalence study with Terbisil 1% cream and Lamisil 1% cream (EQUATE) a total of 733 patients were exposed to either Terbisil (n=366) or Lamisil (n=367) during the 1 week of the treatment period, where 10.1% of the patients (74 patients) experienced at least one adverse event. A total number of adverse events related to the study medications were 20 events during the study.

Frequency � Primary System Organ Class MedDRA V. 8.0

Common >1/100, >1/10

Frequency

Application site irritation 15.6 %

Application site pruritus

3.6 %

General disorders and administration site conditions

Application site warmth 2.4 %


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Application site pain 1.2 %

Application site erythema

1.2 %

Pain*

Application site hypersensitivity*

* These adverse reactions did not occur during the study “Equate”.

Erythema, pruritus, warmth, pain or irritation (stinging, burning sensation) occasionally occur at the site of application. Treatment generally does not have to be discontinued for this reason. These symptoms must be distinguished from application site hypersensitivity reactions, which are rare but require discontinuation of therapy.

4.9 Overdose

Terbinafine cream is for external use only. If accidental ingestion of the cream occurs, appropriate method of gastric lavage can be used.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties Antifungals for topical use

ATC code: D01A E15

Terbinafine is an antimycotic with a broad-spectrum of anti-fungal activity belonging to the allylamine group. At low concentrations terbinafine is fungicidal against dermatophytes, moulds and certain dimorphic fungi. The activity against yeasts, e.g. Candida species is fungicidal or fungistatic depending on the species.

Terbinafine interferes with fungal sterol biosynthesis by the inhibition of squalene epoxidase in the fungal cell membrane, which leads to an intracellular accumulation of squalene, resulting in fungal cell death.

Terbinafine is used for the treatment of fungal infections of the skin and nails, which is caused by Trichophyton (e.g. T. rubrum, T.mentagrophytes, T. verrucosum, T. violaceum), Microsporum canis and Epidermophyton floccosum. The following table outlines the range of minimum inhibitory concentrations (MIC) against the dermatophytes.

Organism MIC range (µg/ml)

Trichophyton rubrum 0.001 – 0.15

Trichophyton mentagrophytes 0.0001 – 0.05

Trichophyton verrucosum 0.001 – 0.006

Trichophyton violaceum 0.001 – 0.1

Microsporum canis 0.0001 – 0.1

Edidermorphyton fluccosum 0.001 – 0.05


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5.2 Pharmacokinetic properties Less than 5% of the dose is absorbed after topical application; systemic exposure is therefore very slight.

5.3 Preclinical safety data

Not applicable

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients Sodium hydroxide,

Benzyl alcohol,

Sorbitan stearate,

Cetyl palmitate,

Cetyl alcohol,

Cetostearyl alcohol,

Polysorbate 60,

Isopropyl myristate,

Water purified.

6.2 Incompatibilities

None known.

6.3 Shelf life

4 years

Shelf life after opening: 1 month

6.4 Special precautions for storage No special precautions for storage.

Store in original container.

6.5 Nature and contents of container

Aluminium tube closed by polyethylene cap. The tubes are containing 7.5 g, 15 g or 30 g cream.

6.6 Special precautions for disposal

No special instructions.

7 MARKETING AUTHORISATION HOLDER

MPX International Ltd.

127 Shirland Road, London W9 2EP, United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 21300/0001

PL 21300/0003

PL 21300/0004

PL 21300/0009


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PL 21300/0010

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

29/03/2007 10 DATE OF REVISION OF THE TEXT

29/03/2007 s


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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT Terbinafine Hydrochloride 1% cream

2 QUALITATIVE AND QUANTITATIVE COMPOSITION 10 mg terbinafine hydrochloride (equivalent to 8.89 mg terbinafine) in 1 g cream.

Excipient: 80 mg cetyl alcohol and cetostearyl alcohol in 1 g cream.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Cream

White or almost white cream, with slight almond odour.

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

The treatment of tinea pedis (Athlete’s foot) and tinea cruris (jock itch) caused by Trichophyton (e.g. T. rubrum, T. mentagrophytes) and Epidermophyton floccosum.

4.2 Posology and method of administration

Terbinafine cream can be applied once or twice daily. Cleanse and dry the affected areas thoroughly before application of Terbinafine cream. Apply the cream to the affected skin and surrounding area in a thin layer and rub in lightly.

The likely durations of treatment are as follows:

Tinea cruris: 1 to 2 weeks

Tinea pedis: 1 week

Relief of clinical symptoms usually occurs within a few days. Irregular use or premature discontinuation of treatment carries the risk of recurrence. If there are no signs of improvement after two weeks, the diagnosis should be verified.

Children

The experience with topical Terbisil in children aged 16 and under is still limited and its use cannot therefore be recommended.

Use in the elderly

There is no evidence to suggest that elderly patients require different dosages or experience side-effects different to those of younger patients.

Method of administration



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4.3 Contraindications Known hypersensitivity to the active substance or any of the excipients.

4.4 Special warnings and precautions for use

Terbinafine cream is for external use only. Contact with the eyes should be avoided. If it gets into the eyes accidentally, the eyes should be washed with plenty of water and the patient should turn to an ophthalmologist if necessary.

The cream contains cetyl alcohol and cetostearyl alcohol which may cause local reactions (i.e. contact dermatitis).

4.5 Interaction with other medicinal products and other forms of interaction

There are no known drug interactions with Terbinafine cream.

4.6 Pregnancy and lactation

Foetal toxicity and fertility studies in animals suggest no adverse effects.

There is no clinical experience with Terbinafine cream in pregnant women, therefore, unless the potential benefits outweigh any potential risks, Terbinafine cream should not be administered during pregnancy.

Terbinafine is excreted in breast milk and therefore mothers should not receive Terbinafine cream whilst breast-feeding.

4.7 Effects on ability to drive and use machines

There are no data available that terbinafine would affect driving ability or any other activity requiring concentration.

4.8 Undesirable effects

In the Therapeutic equivalence study with Terbisil 1% cream and Lamisil 1% cream (EQUATE) a total of 733 patients were exposed to either Terbisil (n=366) or Lamisil (n=367) during the 1 week of the treatment period, where 10.1% of the patients (74 patients) experienced at least one adverse event. A total number of adverse events related to the study medications were 20 events during the study.

Frequency � Primary System Organ Class MedDRA V. 8.0

Common >1/100, >1/10

Frequency

Application site irritation 15.6 %

Application site pruritus

3.6 %

Application site warmth

2.4 %

Application site pain 1.2 %

Application site erythema

1.2 %

Pain*

General disorders and administration site conditions

Application site hypersensitivity*

* These adverse reactions did not occur during the study “Equate”.


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Erythema, pruritus, warmth, pain or irritation (stinging, burning sensation) occasionally occur at the site of application. Treatment generally does not have to be discontinued for this reason. These symptoms must be distinguished from application site hypersensitivity reactions, which are rare but require discontinuation of therapy.

4.9 Overdose

Terbinafine cream is for external use only. If accidental ingestion of the cream occurs, appropriate method of gastric lavage can be used.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Antifungals for topical use

ATC code: D01A E15

Terbinafine is an antimycotic with a broad-spectrum of anti-fungal activity belonging to the allylamine group. At low concentrations terbinafine is fungicidal against dermatophytes, moulds and certain dimorphic fungi. The activity against yeasts, e.g. Candida species is fungicidal or fungistatic depending on the species.

Terbinafine interferes with fungal sterol biosynthesis by the inhibition of squalene epoxidase in the fungal cell membrane, which leads to an intracellular accumulation of squalene, resulting in fungal cell death.

Terbinafine is used for the treatment of fungal infections of the skin and nails, which is caused by Trichophyton (e.g. T. rubrum, T.mentagrophytes) and Epidermophyton floccosum. The following table outlines the range of minimum inhibitory concentrations (MIC) against the dermatophytes.

Organism MIC range (µg/ml)

Trichophyton rubrum 0.001 – 0.15

Trichophyton mentagrophytes 0.0001 – 0.05

Edidermorphyton fluccosum 0.001 – 0.05

5.2 Pharmacokinetic properties

Less than 5% of the dose is absorbed after topical application; systemic exposure is therefore very slight.

5.3 Preclinical safety data

Not applicable

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients Sodium hydroxide,

Benzyl alcohol,

Sorbitan stearate,

Cetyl palmitate,


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Cetyl alcohol,

Cetostearyl alcohol,

Polysorbate 60,

Isopropyl myristate,

Water purified.

6.2 Incompatibilities

None known.

6.3 Shelf life

4 years

Shelf life after opening: 1 month

6.4 Special precautions for storage

No special precautions for storage.

Store in original container.

6.5 Nature and contents of container Aluminium tube closed by polyethylene cap. The tubes are containing 7.5 g and 15 g cream.

6.6 Special precautions for disposal

No special instructions.

7 MARKETING AUTHORISATION HOLDER

MPX International Ltd, 127 Shirland Road, London W9 2EP, United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 21300/0002

PL 21300/0005

PL 21300/0006

PL 21300/0007

PL 21300/0008

PL 21300/0011

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

29/03/2007 10 DATE OF REVISION OF THE TEXT

29/03/2007


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PATIENT INFORMATION LEAFLET

PL 21300/0001, 3, 4, 9, AND 10


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PL 21300/0002, 5, 6, 7, 8, AND 11


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LABELLING

PL 21300/0001


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PL 21300/0002


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PL 21300/0003


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PL 21300/0004


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PL 21300/0005


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PL 21300/0006


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PL 21300/0007


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PL 21300/0008


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PL 21300/0009


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PL 21300/0010


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PL 21300/0011


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Documents

UKPAR for Terbinafine Hydrochloride cream Terbinafine Hydrochloride 1% Cream PL 21300/0001-11 10 Tinea corporis, cruris: 1 to 2 weeks Tinea pedis: 1 week Cutaneous candidiasis: 2 weeks