Terbinafine 250mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
Terbinafine 250mg Tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 250 mg terbinafine, as terbinafine hydrochloride.
For excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Tablet
White, round, flat 11 mm tablets, scored on both sides with side scores, marked “T” above and “1” below the score on one side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Fungal infections of the skin and nails caused by Trichophyton (eg. T. rubrum, T.mentagrophytes, T. verrucosum, T. violaceum), Microsporum canis and Epidermophyton floccosum.
1. Treatment of Terbinafine sensitive fungal infections such as Tinea corporis, Tinea cruris and Tinea pedis (caused by Dematophytes see Section 5.1) is considered appropriate due to the site, severity or extent of the infection.
2. The treatment of onychomycosis (terbinafine-sensitive fungal infection of the nails) caused by dermatophytes.
N.B. Orally administered terbinafine tablets are not effective against Pityriasis versicolor.
The official local guidelines should be borne in mind, for example, national recommendations relating to the correct use and prescription of antimicrobial drugs”.
4.2 Posology and method of administration
Route of administration:
Oral use
The duration of treatment is dependent on the indication and the degree of severity of the infection. Adults:
250mg once daily.
Patients with impaired renal function (creatinine clearance less than 50ml/minute or serum creatinine of more than 300 micromol/l) should receive half the normal dose.
Skin infections
The likely durations of treatment
Tinea pedis (interdigital, plantar/moccasin 2 to 6 weeks type):
Tinea corporis: 4 weeks
Tinea cruris: 2 to 4 weeks
Complete disappearance of the symptoms of the infection may not occur until several weeks after mycological cure.
Onychomycosis
In most patients the duration of successful treatment is 6-12 weeks.
Fingernail onychomycosis: In most cases 6 weeks' treatment is sufficient in fingernail onychomycosis.
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 impairment
Terbinafine 250mg 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.
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. The possibility of impairment of liver or kidney function should be considered in this age group (see Precautions).
4.3 Contraindications
Hypersensitivity to Terbinafine or to any of the excipients Severe renal impairment Severe hepatic impairment
4.4 Special warnings and precautions for use
Liver Function
Terbinafine 250mg tablets are not recommended for patients with chronic or active liver disease.
Before prescribing Terbinafine 250mg tablets, 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 250mg tablets. In the majority of liver failure cases the patients had serious underlying systemic conditions and a causal association with the intake of Terbinafine 250mg tablets was uncertain (see section 4.8 Undesirable effects).
Patients prescribed Terbinafine 250mg tablets should be instructed to report immediately any signs or symptoms suggestive of liver dysfunction such as pruritis, unexplained persistent nausea, decreased appetite, anorexia or tiredness, jaundice, vomiting, fatigue, right upper abdominal pain, 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 section 4.8 Undesirable effects).
Dermatological effects
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 Terbinafine 250mg tablets. If progressive skin rash occurs, Terbinafine 250mg tablets treatment should be discontinued.
Terbinafine 250mg should be used with caution in patients with psoriasis, as very rare cases of exacerbation of psoriasis have been reported.
Haematological effects
Very rare cases of blood dyscrasias (neutropenia, agranulocytosis, thrombocytopenia, pancytopenia) have been reported in patients treated with Terbinafine 250mg tablets. Aetiology of any blood dyscrasias that occur in patients treated with Terbinafine 250mg tablets should be evaluated and consideration should be given for a possible change in medication regimen, including discontinuation of treatment with Terbinafine 250mg tablets.
Renal function
In patients with renal impairment (creatinine clearance less than 50 mL/min or serum creatinine of more than 300 micro mol/L) the use of Terbinafine 250mg tablets has not been adequately studied, and therefore, is not recommended (see section 5.2 Pharmacokinetic properties).
Other
Terbinafine 250mg Tablets should be used with caution in patients with lupus erythematosus as very rare cases of lupus erythematosus have been reported.
4.5 Interaction with other medicinal products and other forms of interaction
Effect of other medicinal products on Terbinafine
The plasma clearance of terbinafine may be accelerated by drugs which induce metabolism (such as rifampicin) and may be inhibited by drugs which inhibit cytochrome P450 (such as cimetidine). Where co-administration of such drugs is required, it may be necessary to adjust the dose of Terbinafine accordingly.
The following medicinal products may increase the effect or plasma concentration of terbinafine: Cimetidine decreased the clearance of terbinafine by 30%.
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.
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
Terbinaine 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. This finding may be of clinical relevance for patients receiving compounds predominantly metabolised by CYP2D6, e.g. certain members of the following drug classes, tricyclic antidepressants (TCA's), P-blockers, selective serotonin reuptake inhibitors (SSRIs), antiarrhythmics (including class 1A, 1B and 1C) and monoamine oxidase inhibitors (MAO-Is) Type B, especially if they also have a narrow therapeutic window.
Terbinafine decreased 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
Studies undertaken in vitro and in healthy volunteers suggest that terbinafine shows negligible potential to inhibit or induce the clearance of most drugs that are metabolized via other cytochrome P450 enzymes (e.g. tolbutamine, terfenadine, triazolam, oral contraceptives) with exception of those metabolised through CYP2D6 (see below).
Terbinafine does not interfere with the 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.
Some cases of menstrual disturbance (breakthrough bleeding and irregular cycle) have been reported in patients taking Terbinafine 250mg Tablets concomitantly with oral contraceptives.
Terbinafine may decrease the effect or plasma concentration of the following medicinal products: Terbinafine increased the clearance of ciclosporin by 15%.
Rare cases of changes in INR and/or prothrombin time have been reported in patients receiving terbinafine concomitantly with warfarin.
4.6 Fertility, pregnancy and lactation
Pregnancy
Foetal toxicity and fertility studies in animals suggest no undesirable effects. There is no adequate data from the use of terbinafine in pregnant women, therefore, terbinafine should not be administered during pregnancy unless the clinical condition of the woman requires treatment with oral terbinafine and the potential benefits for the mother outweigh any potential risks for the foetus.
Breast-feeding
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.
No studies on the effects of Terbinafine 250mg tablets treatment on the ability to drive and use machines have been performed. Patients who experience dizziness as an undesirable effect should avoid driving vehicles or using machines.
4.8 Undesirable effects
Side effects are generally mild to moderate, and transient. The following adverse reactions have been observed in the clinical trials or during post-marketing experience.
Adverse reactions are ranked under headings of frequency, using the following convention: Very common (1/10); Common (1/100, < 1/10); Uncommon ( 1/1,000, <1/100); Rare (1/10,000, < 1/1,000); Very rare (< 1/10,000), Not known (frequency cannot be estimated from available data) including isolated reports.
Gastrointestinal disorders
Very common: Gastrointestinal symptoms (Dyspepsia, feeling of fullness, abdominal distension, nausea, abdominal pain, diarrhoea).
Not known: Pancreatitis
Skin-and subcutaneous tissue disorders
Very common: Non serious forms of skin reactions (rash, urticaria).
Very rare: Serious skin reactions (such as Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Photosensitivity (e.g. photodermatosis, photosensitivity allergic reaction, and polymorphic light eruption), alopecia, if progressive skin rash occurs, 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)).
Nervous system disorders
Common: Headache.
Uncommon: Taste disturbances, including taste loss, which usually recover slowly after discontinuation of the drug. Isolated cases of prolonged taste disturbance have been reported, sometimes leading to a decrease of food intake and significant weight loss.
Rare: Paraesthesia, hypoaesthesia, dizziness.
Not known: Anosmia including permanent anosmia, hyposmia
Musculoskeletal and connective tissue disorders
Very common: Arthralgia and myalgia. These may occur as part of a hypersensitivity reaction in association with allergic skin reactions.
Not known: Rhabdomyolysis
Hepatobiliary disorders
Rare: Serious hepatic dysfunction, including hepatic failure, hepatic enzymes increased, including jaundice, cholestasis liver decompensation and hepatitis. If hepatic dysfunction develops, treatment with Terbinafine tablets should be discontinued (see also section 4.4. “Special warnings and precautions for use”). 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.
Blood and lymphatic system disorders
Very rare: Haematological disorders such as neutropenia, thrombocytopenia and agranulocytosis.
Not known: Anaemia,Pancytopenia Psychiatric disorders
Not known: Anxiety and depressive syptoms secondary to taste disturbances.
Immune system disorders
Very rare: Anaphylactoid reactions including angioedema manifestation or aggravation of cutaneous or systemic lupus erythematosus
Not known: Anaphylactic reaction, serum sickness-like reaction.
Ear and labyrinth disorders
Very rare: Vertigo
Not known: Hypoacusis, impaired hearing, tinnitus
General disorders
Rare : Malaise
Not known: Fatigue, influenza-like illness, pyrexia
Metabolism and nutrition disorders
Very common: Decreased appetite
Vascular disorders
Not known: Vasculitis
Investigations
Not known: Blood creatine phosphokinase increased
Reporting of suspected adverse reactions
Reporting 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
Few cases of overdose (up to 5g) have been reported, giving rise to headache, nausea, epigastric pain and dizziness. Recommended treatment for overdose consists of eliminating the active substance, primarily by the administration of activated charcoal, and giving symptomatic supportive therapy if required.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Dermatologicals; antifungals for systemic use ATC code: D01B A 02
Terbinafine is an allylamine which has a broad spectrum of antifungal activity. At low concentrations terbinafine is fungicidal against dermatophytes, moulds and certain dimorphic fungi. The activity versus yeasts is fungicidal or fungistatic depending on the species.
Terbinafine interferes selectively with fungal sterol biosynthesis at an early stage through inhibition of the enzyme squalene epoxidase. This leads to a deficiency in ergosterol and to an intracellular accumulation of squalene in the fungal cell membrane. Both the deficiency in ergosterol and the accumulation of squalene are responsible for fungal cell death.
When given orally, the active substance concentrates in skin, hair and nails at levels associated with fungicidal activity. Measurable concentrations of the active substance are still evident 15 - 20 days after cessation of treatment.
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 rang (pg/ml) |
|
Trichophyton rubrun |
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 |
Terbinafine exhibits poor efficacy against many yeasts of the Candida species.
Terbinafine tablets in contrast to locally administered terbinafine treatment, has no effect in the treatment of Pityriasis (Tinea) versicolor.
5.2 Pharmacokinetic properties
A single oral dose of 250mg terbinafine results in mean peak plasma concentrations of 0.97 mcg/ml within 2 hours after administration. The absorption half-life is 0.8 hours and the distribution half-life is 4.6 hours. Terbinafine binds strongly to plasma proteins (99%).
Terbinafine rapidly diffuses through the skin and concentrates in the lipophilic stratum corneum. Terbinafine is also secreted in sebum, thus achieving high concentrations in hair follicles, hair and parts of the skin rich in sebaceous glands. There is also evidence that terbinafine is distributed into the nail plate within a few weeks after commencing therapy.
Terbinafine is rapidly metabolised by the CYP-isoenzymes, mainly by CYP2C9, CYP1A2, CYP3A4, CYP2C8 and CYP2C19. Biotransformation results in metabolites with no antifungal activity, which are excreted predominantly in the urine. The elimination half-life is 17 hours. There is no evidence of accumulation in the plasma.
No age-dependent changes in pharmacokinetics have been observed but the elimination rate may be reduced in patients with renal or hepatic impairment, resulting in higher blood levels of terbinafine.
In patients with pre-existing mild to severe hepatic impairment, single dose pharmacokinetic studies have shown that the clearance of Terbinafine can be reduced by 50%.”
The bioavailability of terbinafine is only slightly affected by food, and therefore a dose adjustment is not necessary.
5.3 Preclinical safety data
The 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.
6. PHARMACEUTICAL PARTICULARS
6.1. List of excipients
Magnesium stearate Silica, colloidal anhydrous Croscarmellose sodium Hypromellose Microcrystalline cellulose
6.2. Incompatibilities
Not applicable
6.3. Shelf life
36 months
6.4. Special precautions for storage
Blister Alu/PVC: Keep the blister in the outer carton HDPE containers: store in the original package.
6.5. Nature and contents of container
Al/PVC-PVdC blister and HDPE tablet container with LDPE cap Pack Sizes: 14, 28 tablets.
Not all container types or pack sizes may be marketed.
6.6. Instructions for use and handling
No special requirements
7. MARKETING AUTHORISATION HOLDER
Relonchem Limited Cheshire House, Gorsey Lane,
Widnes, Cheshire,
WA8 0RP United Kingdom
8. MARKETING AUTHORISATION NUMBER
PL 20395/0045
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
18/03/2011