Terbinafine 250mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Terbinafine 250mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains terbinafine hydrochloride, equivalent to 250mg terbinafine.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Tablet
Terbinafine 250mg Tablets are white to off-white tablets with a T on one side and score line on the reverse. The tablet can be divided into equal halves.
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. Oral terbinafine is indicated in the treatment of ringworm (tinea corporis, tinea cruris and tinea pedis) where oral therapy is considered appropriate due to the site, severity or extent of the infection.
2. Oral terbinafine is indicated in the treatment of onychomycosis.
Consideration should be given to official guidance on the appropriate use of antifungal agents.
4.2. Posology and method of administration
Adults
250mg once daily.
The duration of treatment varies according to the indication and the severity of the infection.
Skin infections
Likely durations of treatment are as follows:
Tinea pedis (interdigital, plantar/moccasin type): two to six weeks Tinea corporis: four weeks Tinea cruris: two to four weeks Onychomycosis
The duration of treatment for most patients is between six weeks and three months. Treatment periods of less than three months can be anticipated in patients with fingernail infection, toenail infection other than of the big toe, or patients of younger age. In the treatment of toenail infections, three months is usually sufficient although a few patients may require treatment of six months or longer. 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.
Children
Data are limited so 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 Section 4.4 Special warnings and precautions for use).
Liver impairment
Terbinafine tablets are not recommended for patients with chronic or active hepatic disease (see section 4.4 Special warnings and precautions for use).
Renal impairment
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).
Method of administration
Via the oral route.
4.3 Contraindications
Known hypersensitivity to terbinafine or to any of the excipients.
4.4. Special warnings and precautions for use
Liver function
Terbinafine tablets are not recommended for patients with chronic or active hepatic disease Before prescribing terbinafine tablets, liver function test should be performed. Hepatotoxicity may occur in patients with and without pre-existing hepatic disease therefore periodic monitoring (after 4-6 weeks of treatment) of liver function test is recommended. Terbinafine should be immediately discontinued in case of elevation of liver function test. Very rare cases of serious hepatic failure (some with a fatal outcome, or requiring hepatic transplant) have been reported in patients treated with terbinafine tablets. In the majority of hepatic 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 warned to report immediately any signs- or symptoms suggestive of liver dysfunction such as pruritus, of unexplained persistent nausea, decreased appetite, fatigue, vomiting, right upper abdominal pain, or jaundice, dark urine or pale faeces to their doctor. Patients with these symptoms should discontinue taking oral terbinafine and the patient's hepatic function should be immediately evaluated.
Single dose pharmacokinetic studies in patients with pre-existing liver disease have shown that the clearance of terbinafine may be reduced by about 50%.
Dermatological effects
Serious skin reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis) have been very rarely reported in patients taking terbinafine tablets. If progressive skin rash occurs, terbinafine tablets treatment should be discontinued.
Terbinafine should be used with caution in patients with pre-existing psoriasis, as very rare cases of exacerbation of psoriasis have been reported; or lupus erythematosus as very rare cases of lupus erythematosus have been reported.
Haematological effects
Very rare cases of blood disorders (neutropenia, agranulocytosis, thrombocytopenia, pancytopenia) have been reported in patients treated with terbinafine tablets. Aetiology of any blood disorders that occur in patients treated with terbinafine tablets should be evaluated and consideration should be given for a possible change in medication regimen, including discontinuation of treatment with terbinafine tablets.
Patients on terbinafine who develop a high fever or sore throat should be examined concerning possible haematological reaction.
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 tablets has not been adequately studied, and therefore, is not recommended (see section 5.2 Pharmacokinetic properties).
Other
Terbinafine 125 mg tablets contain lactose (21 mg/tablet). Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not take terbinafine 125 mg tablets.
4.5. Interactions 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 and may be inhibited by drugs, which inhibit cytochrome P450. Where co-administration of such agents is necessary, the dosage of terbinafine tablets 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 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:
According to the results from studies undertaken in vitro and in healthy volunteers, terbinafine shows negligible potential for inhibiting or enhancing the clearance of most drugs that are metabolised via the cytochrome P450 system (e.g. terfenadine, triazolam, tolbutamide or 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 cotromixazole (trimethoprim
and sulfamethoxazole), zidovudine or theophylline.
Some cases of menstrual irregularities have been reported in patients taking Terbinafine concomitantly with oral contraceptives, although the incidence of these disorders remains within the background incidence of patients taking oral contraceptives alone.
Terbinafine may increase the effect or plasma concentration of the following medicinal products:
Caffeine: Terbinafine decreased the clearance of caffeine administered intravenously by 19%.
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 this enzyme, e.g. certain members of the following drug classes, such as tricyclic antidepressants (TCAs), P-blockers, selective serotonin reuptake inhibitors (SSRIs), antiarrhythmics (including class 1A, 1B and 1C) and monoamine oxidase inhibitors (MAOIs) Type B, and 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 CYP2D6probe substrate), terbinafine increased the dextromethorphan/dextrorphan metabolic ratio in urine by 16- to 97-fold on average. Thus, terbinafine may convert extensive CYP2D6 metabolisers to poor metaboliser status.’
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 International Normalised Ratio (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 adverse effects.
There is no reported clinical experience with terbinafine in pregnant women, therefore, unless the potential benefits outweigh any potential risks, terbinafine should not be administered during pregnancy.
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.
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 have been performed. Patients who experience dizziness as an undesirable effect should avoid driving vehicles or using machines.
4.8. Undesirable effects
In general Terbinafine tablets are well tolerated. Side effects are usually 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 (Z 1/10); common (Z 1/100, < 1/10); uncommon (Z 1/1,000, < 1/100); rare (Z 1/10,000, < 1/1,000;); very rare (< 1/10,000), including isolated reports.
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Blood and the lymphatic system disorders | |
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Very rare |
Haematological disorders such as neutropenia, agranulocytosis, pancytopenia, thrombocytopenia have been reported very rarely. |
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Not known |
Anaemia |
|
Immune system disorders | |
|
Very rare |
Anaphylactoid reactions (angioedema, precipitation and exacerbation of cutaneous and systemic lupus erythematosus). |
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Not known |
Anaphylactic reactions, serum sickness-like reaction |
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Metabolism and nutrition disorders | |
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Very common |
Decreased appetite |
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Psychiatric disorders | |
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Not known |
Anxiety, depression* |
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Nervous system | |
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Common |
Headache |
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Uncommon |
Hypogeusia**, ageusia**Taste disturbances, |
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Very rare |
including taste loss, which usually recover within several weeks after discontinuation of the drug. Isolated cases of prolonged taste disturbances have been reported, sometimes leading to a decrease of food intake leading to significant weight loss. Dizziness, paraesthesia, and hypoaesthesia Anosmia including permanent anosmia, hyposmia |
|
Not known | |
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Ear and labyrinth disorders | |
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Very rare |
Vertigo |
|
Not known |
Hypoacusis, hearing impaired, tinnitus |
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Vascular disorders | |
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Not known |
Vasculitis |
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Gastrointestinal disorders | |
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Very common |
Gastrointestinal symptoms (feeling of fullness, abdominal distension, dyspepsia, nausea, abdominal pain, and diarrhoea). This may be severe enough to lead to anorexia and weight loss. |
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Not known |
Pancreatitis |
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Hepato-biliary disorders | |
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Rare |
Hepatobiliary dysfunction (primarily cholestatic in nature), including increase in hepatic enzymes and cases of serious liver failure (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. |
|
Not known |
Hepatitis, jaundice, cholestasis |
|
Skin and subcutaneous tissue disorders |
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Very common |
Non-serious forms of skin reactions (rash, urticaria). |
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Very rare |
Rare cases of serious skin reactions (eg. Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis (AGEP), erythema multiforme) have been reported. If progressive skin rash occurs, terbinafine treatment should be discontinued. Psoriasiform eruptions or exacerbation of psoriasis. Alopecia (Hair loss), although a causal relationship has not been established. |
|
Not known |
Photosensitivity reaction, photodermatosis, photosensitivity allergic reaction and polymorphic light eruption, exfoliative dermatitis (erythroderma), pruritus. |
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Musculoskeletal, connective tissue and bone disorders | |
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Very common |
Musculoskeletal reactions (arthralgia, myalgia). |
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Not known |
Rhabdomyolysis |
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General disorders | |
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Rare: |
malaise |
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Very rare |
Fatigue |
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Not known: |
Influenza like illness, pyrexia |
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Investigations | |
|
Not known |
Blood creatinine phosphokinase increased, weight decreased*** |
* Anxiety and depressive symptoms secondary to dysgeusia (perversion of taste).
** Hypogeusia (reduced taste), including ageusia (loss of taste),
** *Weight decreased secondary to hypogeusia.
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 the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
4.9 Overdose
A few cases of overdose (up to 5g) have been reported, giving rise to headache, nausea, epigastric pain and dizziness. The recommended treatment of overdosage consists in eliminating the drug, primarily by the administration of activated charcoal, and giving symptomatic supportive therapy if needed.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
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 specifically with fungal sterol biosynthesis at an early step. This leads to a deficiency in ergosterol and to an intracellular accumulation of squalene, resulting in fungal cell death. Terbinafine acts by inhibition of squalene epoxidase in the fungal cell membrane.
The enzyme squalene epoxidase is not linked to the cytochrome P450 system. Terbinafine does not influence the metabolism of hormones or other drugs.
When given orally, the drug concentrates in skin at levels associated with fungicidal activity.
5.2. Pharmacokinetic properties
Following oral administration, terbinafine is well absorbed (>70%) and the absolute bioavailability of terbinafine from Terbinafine tablets as a result of first-pass metabolism is approximately 50 %. A single oral dose of 250mg terbinafine resulted in a mean peak plasma concentrations of 1.3 microgram/ml within 1.5 hours of administration. At steady-state, in comparison to a single dose, peak concentration of terbinafine was on average 25% higher and plasma AUC increased by a factor of 2.3. From the increase in plasma AUC an effective half-life of approximately 30 hours can be calculated. The bioavailability of terbinafine is moderately affected by food (increase in the AUC of less than 20%), but not sufficiently to require dose adjustments.
When given orally, the drug concentrates in skin and nails at levels associated with fungicidal activity. Terbinafine binds strongly to plasma proteins (99%). It rapidly diffuses through the dermis and concentrates in the lipophilic stratum corneum.
Terbinafine is also secreted in sebum, thus achieving high concentrations in hair follicles, hair and sebum rich skins. There is also evidence that terbinafine is distributed into the nail plate within the first few weeks of commencing therapy.
Terbinafine is metabolised rapidly and extensively by at least seven CYP isoenzymes with major contributions from CYP2C9, CYP1A2, CYP3A4, CYP2C8 and CYP2C19. Biotransformation results in metabolites with no antifungal activity, which are excreted predominantly in the urine.
No clinically relevant age-dependent changes in pharmacokinetics have been observed. Single dose pharmacokinetics studies in patients with renal impairment (creatinine clearance < 50 mL/min) or with pre-existing liver disease have shown that the clearance of Terbinafine may be reduced by about 50%.
5.3 Preclinical safety data
In long-term studies (up to one 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 69mg/kg a day. 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 drug discontinuation. 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 adverse effects on fertility or other reproduction parameters were observed in studies in rats or rabbits.
6.1. List of excipients
Microcrystalline cellulose Colloidal silica anhydrous Hypromellose
Sodium starch glycollate Type A Magnesium stearate
6.2. Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4. Special precautions for storage
Keep the blister in the outer carton
6.5 Nature and contents of container
PVC/PVDC/aluminium foil opaque blister packs containing 7, 14, 28, 30 or
100* tablets.
*
Not all pack sizes may be marketed
6.6 Special precautions for disposal
Not applicable
7 MARKETING AUTHORISATION HOLDER
Wockhardt UK Ltd Ash Road North Wrexham LL13 9UF UK
MARKETING AUTHORISATION NUMBER(S)
PL 29831/0197
9
10
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
20th May 2005
DATE OF REVISION OF THE TEXT
29/10/2015