Terbisil

INSTRUCTION

for medical use for specialists

1.

NAME OF THE MEDICINAL PRODUCT

Trade name: Terbisil

®

INN : TerbinafinePharmaceutical form : tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Active ingredient: 250 mg terbinafine (in the form of 281.25 mg terbinafine hydrochloride) in each

tablet .For the full list of excipients, see section 6.1 .

3.

DESCRIPTION OF PHARMACEUTICAL FORM

White or almost white, round, biconvex tablets with a score line on one side and “ 250 ” engraved on theother, diameter 11 mm. The tablet can be divided into equal doses .

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Onychomycosis caused by dermatophyte fungi ( fungal infection of the nails ) .Tinea capitis .Tinea ( tinea corporis, tinea cruris, tinea pedis ) and yeast infection of the skin caused primarily

by the Candida genus (Candida albicans) if systhemic therapy is needed due to the localisation,

severity and extent of the infection .

Remark: Contrary to local Terbisil treatment, Terbisil tablets are not effective in the treatment of

pityriasis versicolor (known also as tinea versicolor), caused by Pityrosporum orbiculare (known also

as Malessezia furfur).

4.2

Posology and method of administration

Posology

Adults:

One 250 mg tablet daily is recommended for the treatment of adults .Duration of the treatmentThe duration of treatment depends on the indication and severity of infection .

Onychomycosis:

In most patients the duration of successful treatment is 6-12 weeks .In case of fingernail infection a treatment period of 6 weeks is usually sufficient .In case of toenail infection, especially of the big toenail, a treatment period of 12 weeks is required .In some cases, especially if nail outgrowth is poor, longer therapy might be necessary .The optimal clinical effect can be seen some months after mycological cure. This can be related to theperiod required for the outgrowth of healthy nail .

Skin infections:

In case of tinea pedis ( interdigital, plantar, moccasin type ) the duration of oral treatment is 2 to 6weeks .In case of tinea corporis, cruris the duration of oral treatment is 2 to 4 weeks .In case of cutaneous candidiasis the duration of treatment is 2 to 4 weeks .Complete disappearance of the clinical symptoms of the infection may not occur until several weeksafter mycological cure .

Scalp infections

For the treatment of scalp infections ( tinea capitis ) the likely duration of treatment is 4 weeks .Tinea capitis generally occurs in children .Additional information on special population

Liver impairment

Terbinafine tablets are contraindicated for patients with chronic or acute hepatic disease ( see sections4.3 and 4.4 ) .

Renal impairment

Use of terbinafine tablets has not been adequately studied in patients with renal impairment and istherefore not recommended in this population ( see sections 4.4 and 5.2 ) .

Elderly patients

There is no evidence to suggest that elderly patients ( aged 65 years or above ) require different dosagesor experience side effects different to those of younger patients. When prescribing terbinafine tabletsfor patients in this age group, the possibility of pre-existing impairment of hepatic or kidney functionshould be considered ( see section 4.4. ) .

Children

In children above 2 years of age, terbinafine tablets have been found to be well tolerated .There is no clinical experience in children under 2 years of age ( or below 12 kg body toàn thân weight ) .Children < 20 kg : As data on use in this population are limited, the product should be used only inabsence of an alternative treatment and if benefits exceed possible risk .Between 20 and 40 kg of body toàn thân weight : ½ tablet Terbisil ( 125 mg terbinafine ) once daily .Above 40 kg of body toàn thân weight or adolescents : 1 tablet Terbisil ( 250 mg terbinafine ) once dailyMethod of administrationThe tablets are taken orally without chewing with a small amount of water. They should preferably betaken at the same time each day. The tablets can be taken on an empty stomach or after a meal .

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 .Chronic or acute liver disease .

4.4

Special warnings

Liver functionTreatment with Terbisil is contraindicated for patients with chronic or acute hepatic disease. Beforeprescribing oral terbinafine treatment, liver function test should be performed. Hepatotoxicity mayoccur in patients with and without pre-existing hepatic disease therefore periodic monitoring ( after 4-6weeks of treatment ) of liver function test is recommended. Therapy with Terbisil should beimmediately discontinued in case of elevation of liver function test. Very rare cases of serious hepaticfailure ( some with a fatal outcome, or requiring hepatic transplant ) have been reported in patientstreated with terbinafine tablets. In the majority of hepatic failure cases the patients had seriousunderlying systemic conditions ( see sections 4.3 and 4.8 ) .Patients prescribed oral terbinafine treatment should be warned to report immediately any signs andsymptoms of unexplained persistent nausea, decreased appetite, fatigue, vomiting, right upperabdominal pain, or jaundice, dark urine or pale faeces. Patients with these symptoms shoulddiscontinue taking oral Terbisil therapy and the patient’s hepatic function should be immediatelyevaluated .Dermatological effectsSerious skin reactions ( e. g. Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash witheosinophilia and systemic symptoms [ DRESS ] ) have been very rarely reported in patients takingterbinafine tablets. If progressive skin rash occurs, Terbisil tablets treatment should be immediatelydiscontinued .Terbinafine should be used with caution in patients with pre-existing psoriasis or lupus erythematosusas very rare cases of manifestation and aggravation of psoriasis and cutaneous or systemic lupuserythematosus have been reported post marketing .Haematological effectsVery rare cases of blood disorders ( neutropenia, agranulocytosis, thrombocytopenia, pancytopenia )have been reported in patients treated with terbinafine containing tablets. Aetiology of any blooddisorders that occur in patients treated with Terbisil tablets should be evaluated and considerationshould be given for a possible change in medication regimen, including discontinuation of treatmentwith Terbisil tablets .Renal functionIn patients with renal impairment ( creatinine clearance less than 50 mL / min or serum creatinine ofmore than 300 micromol / L ) the use of terbinafine tablets has not been adequately studied, andtherefore, is not recommended ( see section 5.2 ) .Interaction with other medical products

According to studies performed in vitro and in vivo, terbinafine inhibits CYP 2D6-mediated

metabolism. Therefore, caution is needed during the co-administration of drugs that are mainlymetabolized via isoenzyme CYP2D6 [ e. g. tricyclic antidepressants ( TCA ) ,- blockers, selectiveserotonin reuptake inhibitors ( SSRI ), antiarrhythmics ( including class 1A, 1B and 1C antiarrhythmicsand MAO-B inhibitors ) ], especially if they have narrow therapeutic interval ( see section 4.5 ) .ChildrenThe use of this medicine below 2 years of age is not recommended due to the lack of experience .SodiumThis medicine contains less than 1 mmol sodium ( 23 mg ) per tablets, that is to say essentially‘ sodium-free ’ .

4.5

Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on terbinafineThe plasma clearance of terbinafine may be accelerated by drugs which induce metabolism and maybe inhibited by drugs which inhibit cytochrome P450. Where co-administration of such agents isnecessary, the dosage of Terbisil may need to be adjusted accordingly .

The following medicinal products may increase the effect or plasma concentration of terbinafine

Cimetidine decreased the clearance of terbinafine by 33 % .Fluconazole – due to its inhibiting effect of CYP 2C9 and CYP 3A4 enzymes – increased the CAUC of terbinafine by 52 % and 69 % respectively. Similar increase in exposure may occur when otherdrugs which inhibit both CYP2C9 and CYP3A4 such as ketoconazole and amiodarone areconcomitantly administered with terbinafine .

The following medicinal products may decrease the effect or plasma concentration of terbinafine

Rifampicin increased the clearance of terbinafine by 100 % .Effect of terbinafine on other medicinal products

Terbinafine may increase the effect or plasma concentration of the following medicinal products:

Compounds predominantly metabolised by CYP2D6

In vitro and in vivo studies have shown that terbinafine inhibits the CYP2D6-mediated metabolism.

This finding may be of clinical relevance for compounds predominantly metabolised by CYP2D6, e. g .certain members of the following drug classes, tricyclic antidepressants ( TCAs ), beta-blockers ,selective serotonine reuptake inhibitors ( SSRIs ), antiarrhythmics ( including class 1A, 1B and 1C ) andmonoamine oxidase inhibitors ( MAO-Is ) Type B ( see section 4.4. ) .Terbinafine decreased the clearance of desipramine by 82 % ( see section 4.4 ) .In studies in healthy subjects characterized as extensive metabolisers of dextromethorphan ( antitussivedrug and CYP2D6 probe substrate ), terbinafine increased the dextromethorphan / dextrorphanmetabolic ratio in urine by 16 – to 97 – fold on average. Thus, terbinafine may convert extensiveCYP2D6 metabolisers ( genotype ) to poor metaboliser fenotype .

Caffeine

Terbinafine decreased the clearance of caffeine administered intravenously by 19 % .

Information on other drugs concomitantly used with terbinafine resulting in no or negligible

interactions

According to the results from studies undertaken in vitro and in healthy volunteers, terbinafine showsnegligible potential for inhibiting or enhancing the clearance of most drugs that are metabolised viathe cytochrome P450 system ( e. g. terfenadine, triazolam, tolbutamide or oral contraceptives ) withexception of those metabolised through CYP2D6 ( see above ) .Terbinafine does not interfere with the clearance of antipyrine ( phenazone ) or digoxin .There was no effect of terbinafine on the pharmacokinetics of fluconazole. Further there was noclinically relevant interaction between terbinafine and the potential comedications cotrimoxazole( trimethoprim and sulfamethoxazole ), zidovudine or theophylline .Some cases of menstrual irregularities have been reported in patients taking terbinafine-containingtablet concomitantly with oral contraceptives, although the incidence of these disorders remains withinthe background incidence of patients taking oral contraceptives alone .

Terbinafine may decrease the effect or plasma concentration of the following medicinal products:

Terbinafine increased the clearance of ciclosporin by 15 % .Effects of meals on this medicineMeals have a moderate effect on the bioavailability of terbinafine ( increases the AUC by less than20 % ) but due to this dose alteration is not necessary .

4.6

Fertility, pregnancy and lactation

Women of child-bearing potentialSome cases of menstrual irregularities have been reported in patients taking terbinafine-containingtablets concomitantly with oral contraceptives, although the incidence of these disorders remainswithin the background incidence of patients taking oral contraceptives alone .There are no data to tư vấn special recommendations for women of child-bearing potential .PregnancyFoetal toxicity and fertility studies in animals suggest no adverse effects of terbinafine. Since there isno well documented clinical experience in pregnant women, terbinafine tablets should not be usedduring pregnancy unless clinical condition of the woman requires treatment with Terbisil and thepotential benefits for the mother outweigh any potential risks for the foetus .Breast-feedingTerbinafine is excreted in breast milk and therefore mothers taking terbinafine should not breast-feed .FertilityThere is no relevant information from human experience. Fertility studies in rats indicated no adversefindings in fertility or reproductive performance .

4.7

Effects on ability to drive and use machines

No studies on the effects of terbinafine tablets treatment on the ability to drive and use machines havebeen performed. Patients who experience dizziness as an undesirable effect should avoid drivingvehicles or using machines .

4.8

Undesirable effects

Adverse drug reactions from clinical trials or post-marketing experience ( Table 1 ) are listed byMedDRA system organ class. Within each system organ class, the adverse drug reactions are rankedby frequency, with the most frequent reactions first. Within each frequency grouping, adverse drugreactions are presented in order of decreasing seriousness .Table 1. Adverse reactions observed in the clinical trials and during post marketing experienceFrequency →System OrganClass( MedDRA )Verycommon( ≥ 1/10 )Common( ≥ 1/100 to< 1/10 )Uncommon( ≥ 1/1, 000to < 1/100 )Rare( ≥ 1/10, 000< 1/1, 000 )Very rare( < 1/10, 000 )Not known( cannot beestimatedfrom theavailabledata )Blood andlymphaticsystemdisordersAnaemiaNeutropeniAgranulocytosisThrombocytopeniaPancytopenImmunesystemdisordersAnaphylactreactions( includingangioedemaCutaneousAnaphylactic reactionsSerumsickness -likereactionsystemiclupuserythematoMetabolismand nutritiondisordersDecreasedappetitePsychiatricdisordersDepressionAnxietyNervoussystemdisordersHeadacheHypogeusiaDysgeusiaincludingageusia * *DizzinessParaesthesiHypoaestheAnosmiaincludingpermanentanosmiaHyposmiaEye disordersVisualimpairmentBlurredvisionVisualacuityreducedEar andlabyrinthdisordersTinnitusHypoacusis( hearingimpaired )VasculardisordersVasculitisGastrointestinaldisordersGastrointestinaldisorders( Abdominaldistension ,decreasedappetite ,dyspepsia ,

nausea,

mildabdominalpain ,diarrhoea )PancreatitisHepatobiliarydisordersHepaticfailureHepatitisJaundiceCholestasisHepaticenzymesincreased( see section4.4 )Frequency →System OrganClass( MedDRA )Verycommon( ≥ 1/10 )Common( ≥ 1/100to < 1/10 )Uncommon( ≥ 1/1, 000 to< 1/100 )Rare( ≥ 1/10, 000 to< 1/1, 000 )Very rare( < 1/10, 000 )Not known( cannot beestimated fromthe availabledata )Skin andRashPhotosensitivityStevens -Drug rashsubcutaneoustissue disordersUrticariareaction( Photodermatosis ,Photosensitivityallergic reactionand Polymorphiclight exanthema )JohnsonsyndromeToxicepidermalnecrolysisAcutegeneralizedexanthematouspustulosis ( Ifprogressiveskin rashoccurs ,Terbisiltreatmentshould bediscontinued )ErythemamultiformeToxic skinrashDermatitisexfoliativeDermatitisbullosaPsoriasiformeruptionsExacerbationof psoriasisAlopeciaincludingeosinophilia andsystemicsymptomsMusculoskeletaland connectivetissue disordersSymptomsaffectingmuscularsystem( ArthralgiaMyalgia )RhabdomyolysisGeneraldisorders andadministrationsite conditionsFatigueFeverFlu-likesymptomsInvestigationsWeightdecreased * * *Blood creatininephosphokinaseincreased* Anxiety and depressive symptoms secondary to dysgeusia .* * Hypogeusia, including ageusia, which usually recover within several weeks after discontinuation ofthe drug. Isolated cases of prolonged hypogeusia have been reported .* * * Weight decreased secondary to hypogeusia .Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit / risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting system .

4.9

Overdose

Symptoms of overdoseA few cases of overdose ( up to 5 g ) have been reported. It caused headache, nausea, epigastric painand dizziness .TreatmentThe recommended treatment of overdose : eliminating the drug, primarily by the administration ofactivated charcoal, and giving symptomatic therapy, if needed .

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group : Antifungals for dermatological use, antifungals for systemic use, ATCcode : D01BA02Mechanism of actionTerbinafine is an allylamine which has a broad spectrum of antifungal activity which is effective intreatment of dermatophyton infections of the skin, hair and nails. The following fungi are sensitive to

the treatment: Trichophyton (e.g. T. rubrum, T.mentagrophytes, T. verrucosum, T. tonsurans,

T. violaceum), Microsporum (e.g. M. canis), Epidermophyton floccosum, Candida (e.g Candida

albicans) and Malassezia from the group of yeasts.

At low concentrations terbinafine is fungicidal against dermatophytes, moulds and certain dimorphicfungi. The activity against yeasts, e. g. Candida species is fungicidal or fungistatic depending on thespecies .Terbinafine interferes with fungal sterol biosynthesis which leads to a deficiency in ergosterol and toan intracellular accumulation of squalene, resulting in fungal cell death .Terbinafine inhibits the squalene epoxidase in the fungal cell membrane. The squalene epoxidase isnot connected to the cytochrome P450 system .Pharmacodynamic effectsWhen given orally, terbinafine concentrates in skin, nails and hair at levels associated with fungicidalactivity .Clinical efficacy and safety

Onychomycosis

The efficacy of terbinafine containing tablets in the treatment of onychomycosis is illustrated by theresponse of patients with toenail and / or fingernail infections who participated in three US / Canadianplacebo controlled clinical trials ( SFD301, SF5 and SF1508 ) .Results of the first toenail study, as assessed at week 48 ( 12 weeks of treatment with 36 weeks follow -up after completion of therapy ), demonstrated mycological cure, defined as simultaneous occurrenceof negative KOH plus negative culture, in 70 % of patients. Fifty-nine percent ( 59 % ) of patientsexperienced effective treatment ( mycological cure plus 0 % nail involvement or > 5 mm of newunaffected nail growth ) ; 38 % of patients demonstrated mycological cure plus clinical cure ( 0 % nailinvolvement ) .In a second toenail study of dermatophytic onychomycosis, in which non-dermatophytes were alsocultured, similar efficacy against the dermatophytes was demonstrated. The pathogenic role of thenon-dermatophytes cultured in the presence of dermatophytic onychomycosis has not beenestablished. The clinical significance of this association is unknown .Results of the fingernail study, as assessed at week 24 ( 6 weeks of treatment with 18 weeks follow-upafter completion of therapy ), demonstrated mycological cure in 79 % of patients, effective treatment in75 % of the patients, and mycological cure plus clinical cure in 59 % of the patients .The mean time to treatment success for onychomycosis was approximately 10 months for the firsttoenail study and 4 months for the fingernail study. In the first toenail study, for patients evaluated atleast six months after achieving clinical cure and at least one year after completing terbinafine therapy ,the clinical relapse rate was approximately 15 % .

Tinea capitis

Three comparative efficacy studies were performed on per os terbinafine (62.5-250 mg daily dose),

SF 8001, SFE 304 and SF 8002, enrolling a total of 117 evaluable patients, more than 97 % of whichwere children. A single dose was administered after the evening meal for 4 weeks ( terbinafine ), or for8 weeks ( griseofulvin ). Efficacy was justified by negative mycological examination and decrease ofsymptoms on the 8 th week of therapy and in the control treatments ( on the 12 th week in the SF 8001and SFE 304 study, and on the 24 th week in the SF 8002 study ). Negative mycological results wasseen in the terbinafine group in 85 %, 88 % and 72 % of the patients in the three studies – while in thegriseofulvin group the results were 73 %, 89 % and 69 %, respectively. The derived variable ‘ effectivetreatment ’ ( negative mycological results plus no, or mild symptoms ) was seen in 82 %, 78 % and 69 %of patients treated with terbinafine ; compared to 66 %, 74 % and 59 % of patients treated withgriseofulvin, respectively. In the SF 8001 study a statistical difference was seen, favouring terbinafine .Two II phase studies determining the duration of treatment were performed, finished by a total of 342patients with T. capitis ( mainly children ) .A 12 – week randomised, double blind, parallel group study was performed in the United States and inCanada in children suffering in Tinea capitis caused by Trichophyton spp. ( SFO327CT201 ). The aimof the study was to determine the optimal duration ( 1,2 or 4 weeks ) and the safety of treatment ofterbinafine ( tablets ) once daily, in a dose corrected for body toàn thân weight .Another, 16 – week, randomised, active controlled, parallel group, multicenter study was performed in

Europe in children (>4 years) with Tinea capitis caused by Microsporum spp. The duration of

terbinafine treatment arms ( 6, 8, 10, and 12 weeks ) were arranged in a double blind manner, while thecomparator griseofulvin arm was open label ( SFO327CT202 ). The aim of the study was to determine

the safe and optimal duration of therapy in patients with Tinea capitis caused by Microsporum spp.

The dose of terbinafine was determined by the bodyweight in both studies, according to the followingrule : < 20 kg : 62.5 mg, 20-40 kg : 125 mg, > 40 kg : 250 mg once daily. Terbinafine was very welltolerated in both studies. The analysis of efficacy data showed that both 2 – week and 4 – week longtreatment was effective in Tinea capitis caused by Trichophyton species. There was no significantdifference in the Microsporum study in cure rates between different durations of treatment, and the 6 -week treatment showed a high cure rate ( 62 % ), with good tolerability and compliance. Thes e results

show that terbinafine decreases the treatment of T. capitis caused by Trichophyton spp. to 2-4 weeks

compared with the standard therapy with griseofulvin for 6-8 weeks .During the phase II clinical studies in Tinea capitis the adverse reactions were mild, and relatively rarein the 588 enrolled children, and their connection with the treatment was often uncertain. 11 cases ofSGPT-level increase, and 1 taste loss was reported. Other events included mild gastrointestinal -, orskin reactions, or laboratory results referring to intercurrent infections .

Fungal infections of the skin (tinea corporis, tinea cruris, tinea pedis) and yeast infections of the skin

caused by the genus Candida (e.g. Candida albicans) where oral therapy is generally considered

appropriate owing to the site, severity or extent of the infection

Three controlled, double blind, randomised, multicenter studies 5OR ( 4 week study ), 6-7 OR ( 4 weekstudy ) and 11-21 OR ( 6 week study ), evaluated efficacy and safety of terbinafine tablets in thetreatment of Tinea corporis and cruris. Two double blind, placebo controlled studies ( 85OR, 7OR )evaluated the efficacy of terbinafine 125 mg b. i. d. in patients diagnosed with Tinea corporis / cruris .The studies included a total of 43 patients randomised to terbinafine and 45 on placebo. There was nosignificant difference in terms of demographic and anamnestic data within groups. Efficacy ,demonstrated by negative mycology tests and a reduction in clinical symptomatology, was evaluatedat 4 weeks and at the follow-up examination. In both studies, minimal efficacy was demonstrated inpatients treated with placebo compared to the efficacy of orally administered terbinafine at the end oftherapy and at follow up .The third study ( 11-21 OR ), a 6 weeks, double blind, randomised, multicenter study compared efficacyand safety of terbinafine 125 mg b. i. d. to griseofulvin 250 mg b. i. d. One hundred twenty six ( 126 )patients in each group were included in the efficacy analysis. This study showed high rate ofmycological cure, reduction in signs and symptoms in the terbinafine treated study arm andsignificantly better ( 93-94 % ) overall efficacy at the end of therapy and at follow up of terbinafine125 mg b. i. d. compared to 86-87 % overall efficacy of comparator .In summary, terbinafine 125 mg b. i. d. administered for the period of 4-6 weeks demonstratedstatistically superior efficacy compared to placebo and marketed drug griseofulvin in the treatment ofTinea corporis / cruris in the above major efficacy studies .In a double blind, placebo controlled 4 weeks study SF 00438, terbinafine 125 mg b. i. d was comparedto placebo in patients with cutaneous candidiasis. Twenty one patients were randomised to eachtreatment arm, of which 19 were evaluated respectively. Of those, 29 % of patients in the treatmentarm and 17 % of patients on placebo demonstrated mycological cure at the end of treatment and 67 %of terbinafine treated patients had negative mycological results at the end of follow up. Given theabove response rates, 2 weeks therapy of terbinafine should be the minimum duration of treatmentperiod and approximately half of the patients would require 3-4 weeks of treatment to achieve cure .Two double blind, controlled studies compared terbinafine 125 mg b. i. d. to placebo ( 39-40 OR ) and togriseofulvin 250 mg b. i. d. ( 20OR ) in the treatment of Tinea pedis. Both studies recruited patients withchronic, recurrent disease. In the study 39-40 OR, 65 % of patients on terbinafine reported mycologicalcure at follow up whereas none of the placebo treated patients responded. In the study 20OR ,terbinafine was shown to be highly effective with 88 % of cure at follow up after 6 weeks therapycompared to 45 % of patients on griseofulvin. Thes e patients when observed after 10 months reported94 % cure rate, compared to 30 % efficacy of griseofulvin in the same patient population .Table 2. Major efficacy studies – Tinea corporis / cruris, Tinea pedis, Candida infectionsStudyTypeDrugNo. ofevaluablepatientsDropoutMycological results% negativeClinical resultsEnd RXF / upEnd RXF / up4 weeksdoubleblind / placeboterbinafine125 mg twicedailyPlacebo6-7 OR4 weeksdoubleblind / placeboterbinafine125 mg twicedailyPlacebo11-21 OR6 weeks ,double blind125 mgb. i. d. / Griseofulvinterbinafine125 mg twicedailyGriseofulvin250 mg twicedailySF 004382 weeksdoubleblind / placeboterbinafine125 mg twicedailyPlacebo39-40 OR6 weeksdouble blind ,125 mgb. i. d. / placebo

terbinafine

125 mg twicedailyPlacebo

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