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 terbinafine hydrochloride equivalent to terbinafine 250 mg For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Capsule shaped biconvex tablets.
White to off-white, capsule shaped, biconvex tablets debossed with ‘T’ and ‘250’ on either side of the breakline on one side and a deep breakline on the other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Terbinafine is indicated for treatment of fungal infections of the skin and nails caused by Trichophyton (e.g. Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton verrucosum, Trichophyton 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
250 mg once daily. The duration of treatment varies according to the indication and theseverity of the 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 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 in whom longer therapy is required.
Complete resolution of the signs and symptoms of infection may not occur until several weeks after mycological cure.
Paediatric population
In children above 2 years of age, terbinafine tablets have been found to be well tolerated. Safety experience with oral terbinafine in children, which included patients involved in a UK 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 than those seen in the adult population have been noted. However, as data are still limited its use is not recommended.
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).
Elderly
There is no evidence to suggest that elderly patients require different dosages or experience different side-effects than younger patients. When prescribing terbinafinetablets for patients in this age group, the possibility of pre-existing impairment of hepatic or kidney function should be considered (see section 4.4. Special warnings and precautions for use).
Method of administration Via the oral route.
4.3 Contraindications
Terbinafine tablets are contra-indicated in patients with known hypersensitivity to terbinafine or to any of the excipients of terbinafine tablets.
4.4 Special warnings and precautions for use
Liver function
The therapeutic use of terbinafine in patients with chronic or active hepatic disease has not been studied in prospective clinical trials, and therefore cannot be recommended. 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. 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). Rarely, cases of cholestasis and hepatitis have been reported, these usually occur within two months of starting treatment. Patients prescribed terbinafine tablets should be warned to report immediately anysigns or symptoms suggestive of liver dysfunction such as pruritus, unexplained persistent nausea, anorexia or tiredness, or jaundice, vomiting, fatigue, right upper abdominal pain or dark urine, or pale stools, hepatic origin should be verified and terbinafine therapy should be discontinued (see Section 4.8). Terbinafine should be immediately discontinued in case of elevation of liver function test. 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.
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.
Renal function
In patients with renal impairment(creatinine clearance less than 50 ml/minute or serum creatinine of more than 300pmol/l) the use of terbinafine tablets has not been adequately studied, and therefore, is not recommended (see section 5.2 Pharmacokinetic properties)..
Terbinafine should be used with caution in patients with pre-existing psoriasis or lupus erythematous, as very rare cases of exacerbation of psoriasis and exacerbation of lupus erythematous 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
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 enzymes (e.g. cyclosporin, tolbutamide, 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 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 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 (MAOIs) Type B, especially if they also have a narrow therapeutic window (see 4.4. Special warnings and precautions for use).
Terbinafine decreased the clearance of desipramine by 82%.
In studies in healthy subjects characterised 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 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
Pregnancy
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.
Breast-feeding
Terbinafine metabolites are excreted in humanmilk;mothers receivingoral treatment with terbinafine should therefore not breast-feed.
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
The following adverse reactions have been observed in the clinical trials or during post marketing experience. Side effects are generally mild to moderate, and transient. Adverse reactions (Table 1) are ranked under heading of frequency, the most frequent first, 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 the available data)
|
Very Common |
Common |
Uncommon |
Rare |
Very Rare |
Not known | |
|
Blood and lymphatic system disorders |
Neutropenia, Thrombocytop enia, Agranulocytosi s, |
Pancytopenia | ||||
|
Immune system |
Anaphylactoid reactions |
|
Very Common |
Common |
Uncommon |
Rare |
Very Rare |
Not known | |
|
disorders |
(including angioedema), cutaneous and systemic lupus erythematosus | |||||
|
Psychiatric disorders |
Depression and anxiety symptoms secondary to taste disturbances | |||||
|
Nervous system disorders |
Headache |
Taste disturbances , including taste loss, which usually recover slowly after discontinuat ion of the drug, |
Dizziness, Paraesthesi a, Hypoaesthe sia |
Very rare cases of prolonged taste disturbances have been reported, sometimes leading to a decrease of food intake and significant weight loss. | ||
|
Ear and labyrinth disorders |
Vertigo | |||||
|
Gastrointestina l disorders |
Gastrointe stinal symptoms (dyspepsia , feeling of fullness, loss of appetite nausea, mild abdominal pain, diarrhoea) | |||||
|
Hepatobiliary disorders |
Cases of serious hepatic dysfunction , including jaundice, cholestasis, Hepatitis. If |
|
Very Common |
Common |
Uncommon |
Rare |
Very Rare |
Not known | |
|
hepatic dysfunction develops, treatment with terbinafine should be discontinue d (see also Section 4.4 Special Warnings and Precautions for Use). Very rare cases of serious liverfailure have been reported (some with a fatal outcome, or requiring liver transplant). In the majority of cases the patients had serious underlying systemic conditions and a causal association with the intake of terbinafine was uncertain.H epaticenzy mes increased | ||||||
|
Skin and subcutaneous tissue disorders |
Nonserious forms of skin reactions (rash, |
Erythema multiforme, Serious skin reactions (e.g. Steven-Johnson |
Psoriasiform eruptions or exacerbation of Psoriasis. Serious skin reactions (e.g. |
|
Very Common |
Common |
Uncommon |
Rare |
Very Rare |
Not known | |
|
Urticaria) |
syndrome, Toxic epidermal necrolysis). Photosensitivit y (eg. photodermatosi s, photosensitivit y allergic reaction and polymorphic light eruption). If progressive skin rash occurs, terbinafine treatment should be discontinued.A lopecia |
acute generalised exanthematou s pustulosis (AGEP). | ||||
|
Musculoskelet al and connective tissue disorders |
Musculos keletal reactions (Arthralgi a, Myalgia) | |||||
|
General disorders and administration site conditions |
Malaise, |
Fatigue |
Other adverse drug reactions from post-marketing spontaneous reports
The following adverse drug reactions have been identified based on post marketing spontaneous reports and are organized by system organ classes. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.
Blood and lymphatic system disorders: anaemia.
Immune system disorders: anaphylactic reaction, serum sickness-like reaction.
Ear and labyrinth disorders:hypoacusis, impaired hearing, tinnitus.
Nervous system disorders: anosmia including permanent anosmia, hyposmia. Vascular disorders: vasculitis.
Gastrointestinal disorders: pancreatitis.
Musculoskeletal and connective tissue disorders: rhabdomyolysis.
General disorders and administration site conditions: influenza-like illness, pyrexia.
Investigations: blood creatine phosphokinase increased.
4.9 Overdose
A few cases of overdose with terbinafine (up to 5 g) have been reported, giving rise to headache, nausea, upper abdominal 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
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
A single oral dose of 250 mg terbinafine results in mean peak plasma concentrations of 0.97mg/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. 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. 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.
The bioavailability of terbinafine is unaffected by food.
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 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 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 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 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Microcrystalline cellulose Sodium starch glycollate Hypromellose Colloidal anhydrous silica Magnesium stearate Talc
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 25°C. Store in the original package in order to protect from light.
6.5 Nature and contents of container
Blister packs comprising of white opaque PVC film coated with PVdC on the inner side with a backing of aluminium foil coated with heat seal lacquer.
In packs of 14, 28, 42, 56 or 98 tablets
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Not applicable
7 MARKETING AUTHORISATION HOLDER
Ranbaxy (UK) Limited 5th floor, Hyde Park, Hayes 3 11 Millington Road Hayes, UB3 4AZ United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 14894/0279
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
29/09/2005
10 DATE OF REVISION OF THE TEXT
22/07/2016