Summary of Product Characteristics Updated 21-Apr-2016 | Kent Pharmaceuticals Ltd
Adults:250mg once dailyThe duration of treatment varies according to the indication and the severity of the infection. Renal impairmentThe use of Terbinafine tablets has not been adequately studied in patients with renal impairment and is therefore not recommended in this population (see section 4.4 Special warnings and precautions for use and section 5.2 Pharmacokinetic properties). Skin infectionsThe likely durations of treatment are as follows
|Tinea pedis (interdigital, plantar/moccasin-type): Tinea corporis Tinea cruris||2 to 6 weeks4 weeks2 4 weeks.|
OnychomycosisIn most patients the duration of successful treatment is 6-12 weeks.Fingernail onychomycosis: In most cases 6 weeks' treatment is sufficient in fingernail onychomycosis. Treatment periods of less than 3 months can be anticipated in patients with fingernail infection, toenail infection other than of the big toe, or patients of younger age.Toenail onychomycosis: In most cases 12 weeks' treatment is sufficient in toenail onychomycosis although a few patients may require treatment up to 6 months. Poor nail outgrowth during the first weeks of treatment may enable identification of those patients in whom longer therapy is required. Complete resolution of the signs and symptoms of infection may not occur until several weeks after mycological cure and is only seen several months after stopping treatment, which is the time for growth of a healthy nail.
Liver impairmentTerbinafine tablets are not recommended for patients with chronic or active liver disease (see section 4.4 Special warnings and precautions for use).
Children:A review of safety experience with oral terbinafine in children, which includes 314 patients involved in the UK LAMISIL® Post Marketing Surveillance study, has shown that the adverse event profile in children is similar to that seen in adults. No evidence of any new, unusual or more severe reactions to those seen in the adult population has been noted. However, as data is still limited its use is not recommended.
ElderlyThere is no evidence to suggest that elderly patients (aged 65 years or above) require different dosages or experience side-effects different to those of younger patients. The possibility of impairment of liver or kidney function should be considered in this age group (see section 4.4).Method of administration: Oral useThey should preferably be taken at the same time each day and can be taken on an empty stomach or after a meal.The duration of treatment is dependent on the indication and the degree of severity of the infection.
Liver FunctionTerbinafine tablets are not recommended for patients with chronic or active liver disease. Before prescribing Terbinafine tablets, a liver function test should be performed and any pre-existing liver disease should be assessed.Hepatotoxicity may occur in patients with and without pre-existing liver disease therefore periodic monitoring (after 4-6 weeks of treatment) of liver function test is recommended. Terbinafine tablets should be immediately discontinued in case of elevation of liver function test.Very rare cases of serious liver failure (some with a fatal outcome, or requiring liver transplant) have been reported in patients treated with Terbinafine tablets. In the majority of liver failure cases the patients had serious underlying systemic conditions and a causal association with the intake of Terbinafine tablets was uncertain (see section 4.8 Undesirable effects).Patients prescribed Terbinafine tablets should be instructed to report immediately any signs or symptoms suggestive of liver dysfunction such as pruritus, unexplained persistent nausea, decreased appetite, anorexia, or jaundice, vomiting, fatigue, right upper abdominal pain or dark urine, or pale stools. Patients with these symptoms should discontinue taking oral terbinafine and the patient's liver function should be immediately evaluated. (See 4.8 Undesirable effects).Single dose pharmacokinetic studies in patients with pre-existing liver disease have shown that the clearance of terbinafine can be reduced by 50% (see section 5.2). Therapeutic use of terbinafine in patients with chronic or active liver disease has not been studied in prospective clinical trials, and therefore cannot be recommended.
Haematological effectsPatients on terbinafine who develop a high fever or sore throat should be examined concerning possible haematological reactions (neutropenia, agranulocytosis, thrombocytopenia, and pancytopenia). Very rare cases of blood dyscrasias have been reported in patients treated with Terbinafine tablets. Aetiology of any blood dyscrasia that occurs in patients taking terbinafine should be carefully assessed and consideration should be given for a possible change in medication regimen, including stopping terbinafine.
Renal functionIn patients with renal impairment (creatinine clearance less than 50 mL/min or serum creatinine more than 300 µmol/L) the use of terbinafine has not been adequately studied, and therefore is not recommended. (See section 5.2 Pharmacokinetic properties).
Dermatological effectsTerbinafine should be used with caution in patients with pre-existing psoriasis, as very rare cases of exacerbation of psoriasis have been reported.Serious skin reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms) have been very rarely reported in patients taking oral terbinafine. If progressive skin rash occurs treatment with terbinafine should be discontinued.
OtherPatients with autoimmune conditions are at increased risk of adverse reactions. Terbinafine should be used with caution in patients with lupus erythematosus as very rare cases of lupus erythematosus have been reported.
Effect of other medicinal products on terbinafine:The plasma clearance of terbinafine may be accelerated by drugs, which induce metabolism (such as rifampicin - Rifampicin increased the clearance of terbinafine by100%.) and may be inhibited by drugs, which inhibit cytochrome P450 (such as cimetidine - Cimetidine decreased the clearance of terbinafine by 30%.). Where co- administration of such drugs is required, it may be necessary to adjust the dose of terbinafine accordingly.Fluconazole increased the Cmax and AUC of terbinafine by 52% and 69% respectively, due to inhibition of both CYP2C9 and CYP3A4 enzymes. Similar increase in exposure may occur when other drugs which inhibit both CYP2C9 and CYP3A4 such as ketoconazole and amiodarone are concomitantly administered with terbinafine.
Effect of terbinafine on other medicinal products:Terbinafine may increase the effect or plasma concentration of the following medicinal products:Caffeine Terbinafine decreased the clearance of caffeine administered intravenously by 21%.Compounds predominantly metabolised by CYP2D6 In vitro and in vivo studies have shown that terbinafine inhibits the CYP2D6-mediated metabolism. For this reason, it is important to monitor patients who are treated simultaneously with drugs that are mainly metabolised by this enzyme, e.g. certain members of the following drug classes,tricyclic antidepressants (TCA's), β-blockers, selective serotonin re-uptake inhibitors (SSRIs),, antiarrhythmics (including class 1A, 1B and 1C) and monoamine oxidase inhibitors (MAO-Is) type B, especially if they have a narrow therapeutic window (see section 4.4)In particular terbinafine decreases the clearance of desipramine by 82%.In studies in healthy subjects characterized as extensive metabolisers of dextromethorphan (antitussive drug and CYP2D6 probe substrate), terbinafine increased the dextromethorphan/dextrorphan metabolic ratio in urine by 16- to 97-fold on average. Thus, terbinafine may convert extensive CYP2D6 metabolisers (genotype) to poor metaboliser status (phenotype).Information on other drug concomitantly used with Terbinafine resulting in no or negligible interactions. Other in vitro and clinical studies (including studies undertaken in healthy volunteers)suggest that terbinafine shows negligible potential to inhibit or induce the clearance of most drugs that are metabolised via other cytochrome P450 enzymes (e.g. tolbutamine, terfenadine, triazolam, oral contraceptives). There have been some cases reported of menstrual disturbances such as breakthrough bleeding and irregular cycle in patients taking terbinafine concomitantly with oral contraceptives (with both combined oestrogen and progestogen and progestogen only), although the incidence of these disorders remains within the background incidence of patients taking oral contraceptives alone.Terbinafine does not interfere with clearance of antipyrine or digoxin.There was no effect of terbinafine on the pharmacokinetics of fluconazole. Further there was no clinically relevant interaction between terbinafine and the potential comedications cotrimoxazole (trimethoprim and sulfamethoxazole), zidovudine or theophylline.Terbinafine may decrease the effect or plasma concentration of the following medicinal products:Terbinafine increases the clearance of ciclosporin by 15%.There are rare reports of changes in INR and/or prothrombin time when terbinafine is given with warfarin.
Pregnancy:Foetal toxicity and fertility studies in animals suggest no adverse effects. Since clinical experience in pregnant women is very limited terbinafine should not be administered during pregnancy unless the clinical condition of the mother requires treatment with oral terbinafine and the potential benefits outweigh any potential risks for the foetus.
Lactation:Terbinafine is excreted in breast milk and therefore mothers should not receive terbinafine treatment whilst breast-feeding.
Fertility:Foetal toxicity and fertility studies in animals suggest no adverse effects.
Blood and lymphatic system disordersVery rare: Haematological disorders such as neutropenia, thrombocytopenia, agranulocytosisNot known: Pancytopenia, anaemia
Immune system disordersVery rare:Anaphylactoid reactions (including angioedema), cutaneous and systemic lupus erythematosusNot known: anaphylactic reaction, serum sickness-like reaction.
Psychiatric disordersVery rare: Anxiety and depression symptoms secondary to taste disturbance
Nervous system disordersCommon: Headache.Uncommon:Taste loss and taste disturbances have been reported in approximately 0.6% of patients treated with terbinafine. This usually resolves within several weeks on drug discontinuation, although isolated cases of prolonged taste disturbance leading to decreased food intake and weight loss has been reported.Rare:Paraesthesia, hypoaesthesia and dizzinessNot known:Anosmia including permanent anosmia, hyposmia
Ear and labyrinth disorders:Very rare: VertigoNot known:Hypoacusis, impaired hearing, tinnitus
Vascular disorders:Not known: vasculitis
Gastrointestinal disordersVery common:Gastrointestinal symptoms (Dyspepsia, feeling of fullness, loss of appetite, nausea, mild abdominal pain, diarrhea, abdominal distension,)Very rare: Parotid SwellingNot known: Pancreatitis
Metabolism and nutrition disorders:Very common: Decreasedappetite
Hepatobiliary disordersRare:Serious hepatic dysfunction, including hepatic failure, hepatic enzymes increased, jaundice, cholestasis, liver decompensation and hepatitis. If hepatic dysfunction develops, treatment with terbinafine tablets should be discontinued (see also section 4.4.).Very rare cases of serious liver failure have been reported (some with a fatal outcome, or requiring liver transplant). In the majority of liver failure cases the patients had serious underlying systemic conditions and a causal association with the intake of Terbinafine was uncertain.
Skin-and subcutaneous tissue disordersVery common:Non-serious forms of skin reactions (rash, urticaria)Very Rare:Serious skin reactions (e.g. Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis)Photosensitivity (e.g. Photodermatosis, photosensitivity allergic reaction and polymorphic light eruption)AlopeciaIf the skin rash is progressive then treatment with terbinafine should be discontinued. Not known:Psoriasiform eruptions or exacerbation of psoriasis, serious skin reactions e.g. acute generalised exanthematous pustulosis (AGEP).
Musculoskeletal and connective tissue disordersVery common:Arthralgia and myalgia. These may occur as part of a hypersensitivity reaction in association with allergic skin reactions.Not known: Rhabdomyolysis
General disordersRare: MalaiseNot known: fatigue, influenza-like illness, pyrexia
Investigations:Not known:Blood creatine phosphokinase increased
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the yellow card scheme at www.mhra.gov.uk/yellowcard.
|Organism||MIC rang (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|
|Epidermophyton floccosum||0.001 0.05|
5.3 Preclinical safety dataThe approximate LD50 value of terbinafine is over 4 g/kg in both mice and rats.In long-term studies (up to 1 year) in rats and dogs no marked toxic effects were seen in either species up to oral doses of about 100mg/kg a day. At high oral doses, the liver and possibly also the kidneys were identified as potential target organs.In a two-year oral carcinogenicity study in mice, no neoplastic or other abnormal findings attributable to treatment were made up to doses of 130 (males) and 156 (females) mg/kg a day. In a two-year oral carcinogenicity study in rats, an increased incidence of liver tumours was observed in males at the highest dosage level of 69 mg/kg, at which systemic exposure was similar to clinical exposure. The mechanism of tumour development has not been established. The clinical relevance is unknown. The changes which may be associated with peroxisome proliferation have been shown to be species- specific since they were not seen in the carcinogenicity study in mice, dogs or monkeys.During high-dose studies in monkeys, refractile irregularities were observed in the retina at the higher doses (non-toxic effect level 50mg/kg). These irregularities were associated with the presence of a terbinafine metabolite in ocular tissue and disappeared after discontinuation of the active substance.They were not associated with histological changes.A standard battery of in vitro and in vivo genotoxicity tests revealed no evidence of mutagenic or clastogenic potential.No undesirable effects on fertility or other reproduction parameters were observed in studies in rats or rabbits.
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