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 the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet
Round white to off-white flat bevelled edge tablet with a score line and R250 on reverse.
Diameter approx. 11 mm
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
4 CLINICAL PARTICULARS
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.
1. Terbinafine 250 mg Tablets are 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. Terbinafine 250 mg Tablets are indicated in the treatment of onychomycosis.
4.2 Posology and method of administration
Posology
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 as follows:
2 to 6 weeks 4 weeks 2 to 4 weeks
Tinea pedis (interdigital, plantar/moccasin type) Tinea corporis Tinea cruris
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 the big toe or patients of younger age. In the treatment of toenail 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 where longer therapy is required.
Complete resolution of signs and symptoms of infection may not occur until several weeks after mycological cure.
Additional information on special population
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 Special warnings and precautions for use and section 5.2 Pharmacokinetic properties).
Children
A review of safety experience with oral terbinafine in children, which includes 314 patients involved in the 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 (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
The scored tablets are taken orally with water. They should preferably be taken at the same time each day and can be taken on any 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.
4.4 Special warnings and precautions for use
Liver Function
Terbinafine 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).
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, 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.
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 Tablets. If progressive skin rash occurs, Terbinafine Tablets treatment should be discontinued.
Terbinafine Tablets should be used with caution in patients with pre-existing 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 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.
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).
Other
Terbinafine 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 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 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
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. 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 (see section 4.4).
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 97fold on average. Thus, terbinafine may convert extensive CYP2D6 metabolisers (genotype) to poor metaboliser (phenotype) status.
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 metabolised 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 concomitantly with oral contraceptives, although the incidence of these disorders remains within the 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%.
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 adverse effects.
Since clinical experience in pregnant women is very limited, Terbinafine Tablets should not be used during pregnancy unless
clinical condition of the woman requires treatment with oral terbinafine and the potential benefits for the mother outweigh any potential risks for the foetus.
Lactation:
Terbinafine is excreted in breast milk and thereforemothers should not receive Terbinafine Tablets 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 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 to < 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 be estimated from available data).
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Blood and lymphatic system disorders | |
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Very rare Not known |
Neutropenia, agranulocytosis, thrombocytopenia Anaemia, Pancytopenia |
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Immune system disord |
ers |
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Very rare Not known |
Anaphylactoid reactions (including angioedema), cutaneous and systemic lupus erythematosus Anaphylactic reaction, 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 and depressive symptoms secondary to taste disturbance |
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Nervous system disort |
ers |
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Common Uncommon Rare Not known |
Headache Taste disturbances, 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 and significant weight loss. Paraesthesia, hypoaesthesia, dizziness Anosmia including permanent anosmia, hyposmia |
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Ear and labyrinth disorders | |
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Very rare Not known |
Vertigo Hypoacusis, impaired hearing, 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 Not known |
Gastrointestinal symptoms (feeling of fullness, loss of appetite, dyspepsia, nausea, mild abdominal pain, diarrhoea). Pancreatitis |
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Hepatobiliary disorders | |
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Rare |
Cases of serious hepatic dysfunction, including heaptic failure, hepatic enzymes increased, jaundice, cholestasis and hepatitis. If hepatic dysfunction develops, treatment with Terbinafine Tablets should be discontinued (see 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 casual association with the intake of Terbinafine Tablets was uncertain. |
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Skin and subcutaneous tissue disorders | |
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Very common Very rare |
Non-serious forms of skin reactions (rash, urticaria). Serious skin reactions (e.g. 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, Terbinafine treatment should be discontinued. Psoriasiform eruptions or exacerbation of psoriasis. Serious skin reactions (e.g. acute generalized exanthematous |
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Not Known |
pustulosis (AGEP)). |
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Musculoskeletal and connective tissue disorders | |
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Very common Not known |
Musculoskeletal reactions (arthralgia, myalgia). Rhabdomyolysis |
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General disorders | |
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Rare |
Malaise |
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Not known |
Fatigue Influenza-like illness, pyrexia |
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Investigations | |
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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 the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard.
4.9 Overdose
A few cases of overdose (up to 5g) have been reported giving rise to headache, nausea, upper abdominal pain and dizziness.
The recommended treatment of overdosage consists of eliminating the drug, primarily by the administration of activated charcoal and giving symptomatic supportive therapy if needed.
5 PHARMACOLOGICAL PROPERTIES
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.
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 mean peak plasma concentrations of 1.30pg /ml within 1.5 hours after administration.
Plasma concentrations decline in a triphasic manor, with a terminal half-life of 16.5 days. At 28 days, when around 70% steady state levels have been achieved, peak concentrations of terbinafine was on average 25% higher and plasma AUC increased by a factor of 2.3 when compared to single dose administration. 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.
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
No clinically relevant 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.
Single dose pharmacokinetic studies in patients with renal impairment (creatinine clearance <50 ml/min) or with pre-existing liver disease have shown that clearance of terbinafine may be reduced by about 50%.
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, an increased incidence of liver tumours was 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 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 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Microcrystalline Cellulose Croscarmellose Sodium Anhydrous Colloidal Silica Hypromellose Magnesium Stearate
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years
6.4 Special precautions for storage
HDPE bottle: Do not store above 25°C. Store in the original package.
Blister pack: Do not store above 25°C. Keep the blister in the outer carton.
6.5 Nature and contents of container
Aluminium foil/PVC/PVdC blisters in cartons of 14, 28, 42, 56 or 98 tablets White HDPE bottle with a polypropylene child resistant cap containing 60 or 500 tablets
6.6 Special precautions for disposal
No special requirements
7 MARKETING AUTHORISATION HOLDER
Dr Reddy’s Laboratories (UK) Ltd
6 Riverview Road
Beverley
HU17 0LD
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 08553/0186
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
Date of first authorisation: 08/01/2004 Date of last renewal: 23/09/2009
10 DATE OF REVISION OF THE TEXT
05/05/2015