Terbinafine 250mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Terbinafine 250 mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 281.25 mg terbinafine hydrochloride equivalent to 250 mg terbinafine.
For excipients, see 6.1.
3 PHARMACEUTICAL FORM
Tablets.
White, round tablet with the letter ‘T’ and breakline on opposite face.
4.1 Therapeutic indications
Fungal infections of the skin and nails caused by Trichophyton (e.g. T. rubrum, T. mentagrophytes, T. verrucosum, T. violaceum), Microsporum canis and Epidermophyton floccosum.
Treatment of ringworm (tinea corporis, tinea cruris and tinea pedis) where oral therapy is considered appropriate due to the site, severity or extent of infection. Treatment of onychomycosis.
Consideration should be given to official guidance on the appropriate use of antifungal agents.
4.2 Posology and method of administration
Tablets for oral administration.
Adults
250 mg once daily. The duration of treatment varies according to the indication and the severity of infection.
Skin Infections Likely durations of treatment are as follows:
Tinea pedis (interdigital, plantar/moccasin type): 2 to 6 weeks. Tinea corporis: 4 weeks Tinea cruris: 2 to 4 weeks Onychomycosis
The duration of treatment for most patients is between 6 weeks and 3 months. 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. In the treatment of toe nail infections, 3 months is usually sufficient although a few patients may require treatment of 6 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.
Liver impairment
Terbinafine tablets are not recommended for patients with chronic or active liver disease (see section 4.4 Special warnings and precautions for use).
Renal impairment
The 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 and section 5.2.
Children
A review of safety experience with oral Terbinafine in children, which includes 314 patients involved in the UK Terbinafine 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 have been noted. However, as data is still limited its use is not recommended.
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).
4.3 Contraindications
Terbinafine 250 mg Tablets should not be used in patients with known hypersensitivity to the drug or any other ingredients in the formulation.
Terbinafine should not be used in nail mycosis when the nail changes are a result of a primary bacterial infection.
4.4 Special warnings and precautions for use
Rarely cases of cholestasis and hepatitis have been reported, these usually occur within two months of starting treatment. Patients prescribed Terbinafine tablets should be instructed to report immediately any signs or symptoms suggestive of liver dysfunction such as pruritus, unexplained persistent nausea, anorexia or tiredness, jaundice, vomiting, fatigue, abdominal pain or dark urine, pale stools; hepatic origin should be verified and therapy should be discontinued.
Single dose pharmacokinetic studies in patients with pre-existing liver disease have shown that clearance of Terbinafine may be reduced by about 50%. The therapeutic use of Terbinafine in patients with chronic or acute liver disease has not been studied in clinical trials and therefore cannot be recommended.
Terbinafine should be used with caution in patients with psoriasis as very rare cases of exacerbation of psoriasis have been reported.
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.
Patients with impaired renal function (creatinine clearance less than 50 ml/min or serum creatinine of more than 300 pmol/l) should receive half the normal dose. Terbinafine can in very rare cases cause liver failure in patients with or without preexisting liver disease which can lead to liver transplantation or death (hepatotoxicity). It is recommended that serum transaminase levels should be determined before the beginning of therapy which can give indications of an acute or preexisting liver disease, periodic monitoring (after 4-6 weeks of treatment) of liver function test is recommended.
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 ).
Very rare cases of blood dyscrasias (neutropenia, agranulocytosis, thrombocytopenia, pancytopenia) have been reported in patients treated with Terbinafine tablets. Aetiology of any blood dyscrasias 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.
If a patient develops a fever, tonsillitis or any other infection, an extensive cutaneous reaction or one which touches the mucous membrane, therapy should be discontinued.
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).
Terbinafine 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 agents is necessary the dosage of Terbinafine 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 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
In vitro studies have shown that Terbinafine inhibits the CYP2D6 mediated metabolism. This in vitro finding may be of clinical relevance for patients receiving compounds predominantly metabolised by this enzyme such as tricyclic antidepressants (TCA’s), P-blockers, selective serotonin reuptake inhibitors (SSRI’s), antiarrhythmics (including class 1A, 1B and 1C and monoamine oxidase inhibitors (MAOI’s) Type B especially if they also have a narrow therapeutic window,. 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.
Terbinaine may increase the effect or plasma concentration of the following medicina products:
Caffeine - Terbinafine decreased the clearance of caffeine administered intravenously by 21%.
Other studies undertaken in vitro and in healthy volunteers suggest that Terbinafine shows negligible potential to inhibit or induce the clearance of drugs that are metabolised via other cytochrome P450 enzymes (e.g. tolbutamine, terfenadine, triazolam, oral contraceptives). However, some cases of menstrual disturbance (breakthrough bleeding and irregular cycles) have been reported in patients taking Terbinafine concomitantly with oral contraceptives.
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 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 INR and/or prothrombin time have been reported in patients receiving terbinafine concomitantly with warfarin.
4.6 Fertility, pregnancy and lactation
Foetal toxicity and fertility studies in animals suggest no adverse effects.
There is no clinical experience with Terbinafine in pregnant women. Therefore unless the potential benefits outweigh any potential risks, Terbinafine should not be administered during pregnancy.
Terbinafine is excreted in breast milk and therefore mothers should not take Terbinafine whilst breast feeding.
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
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._
|
Blood and lymphatic system disorders |
Very Rare |
Neutropenia, agranulocytosis, thrombocytopenia |
|
Not Known |
Anaemia Pancytopenia | |
|
Immune system disorders |
Very Rare |
Anaphylactoid reactions (including angioedema), cutaneous and systemic lupus erythematosus. |
|
Not Known |
Anaphylactic reaction, serum sickness-like reaction. | |
|
Metabolism and nutrition disorders |
Very Common |
Decreased appetite |
|
Psychiatric disorders |
Not known |
Anxiety and depressive symptoms secondary to taste disturbances |
|
Nervous system disorders |
Common |
Headache |
|
Uncommon |
Taste disturbances, including taste loss, which usually recover within several weeks 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 | |
|
Ear and labyrinth disorders |
Very Rare |
Vertigo |
|
Not Known |
Hypoacusis, impaired hearing, tinnitus | |
|
Vascular disorders |
Not Known |
Vasculitis |
|
Gastrointestinal disorders |
Very common |
Gastrointestinal symptoms (feeling of fullness abdominal distension, dyspepsia, nausea, abdominal pain, diarrhoea). |
|
Not known |
Pancreatitis | |
|
Hepatobiliary disorders |
Rare |
Cases of serious hepatic dysfunction, including hepatic failure, hepatic enzymes increased, jaundice, cholestasis and hepatitis. If hepatic dysfunction develops, treatment with Terbinafine 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 |
Very |
Non-serious forms of skin reactions (rash, |
|
tissue disorders |
common |
urticaria). |
|
Rare |
Alopecia | |
|
Very rare |
Serious skin reactions (e.g. Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis). angioneurotic oedema. Photosensitivity (e.g. photodermatosis, photosensitivity allergic reaction and polymorphic light eruption). If progressive skin rash occurs, Terbinafine treatment should be discontinued. | |
|
Not known |
Psoriasiform eruptions or exacerbation of psoriasis. Serious skin reactions (e.g. acute generalized exanthematous pustulosis (AGEP)). | |
|
Musculoskeletal and connective tissue disorders |
Very common |
Musculoskeletal reactions (arthralgia, myalgia). |
|
Not known |
Rhabdomyolysis | |
|
General disorders |
Rare |
Malaise, Fatigue |
|
Not known |
Influenza-like illness, pyrexia | |
|
Investigations |
Not known |
Blood creatine phosphokinase increased |
Musculo-skeletal disorders including arthralgia and myalgia have been reported.
These may occur as part of a hypersensitivity reaction in association with allergic skin reactions.
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Oral antifungal agent (ATC code D01B A02)
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 firstpass metabolism is approximately 50%. A single oral dose of 250mg terbinafine resulted in mean peak plasma concentrations of 1.30pg/ml within 1.5 hours after 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 ~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. The absorption half life is 0.8 hours and the distribution half life is 4.6 hours.
Terbinafine binds strongly to plasma proteins. 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. The elimination half life is 17 hours. There is no evidence of accumulation.
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.
5.3 Preclinical safety data
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 100 mg/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, increased incidences of liver tumours were observed in males at the highest dosage level of 69 mg/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 higher doses (non-toxic effect level 50 mg/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
Magnesium stearate Colloidal anhydrous silica Hypromellose Sodium starch glycollate Microcrystalline cellulose.
6.2 Incompatibilities
None known.
6.3 Shelf life
24 months.
6.4 Special precautions for storage
No special storage precautions.
6.5 Nature and contents of container
PVC/PVDC aluminium foil opaque blisters in a cardboard carton containing 14 and 28 tablets.
6.6 Special precautions for disposal
No special instructions.
7. Marketing Authorisation Holder
Medreich Plc Warwick House Plane Tree Crescent Feltham TW13 7HF
MARKETING AUTHORISATION NUMBER(S)
PL 21880/0099
9
10
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
4th April 2005
DATE OF REVISION OF THE TEXT
12/06/2013