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 250mg terbinafine.
For excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet.
White to off-white, round, biconvex tablet with “TF” scoreline “250” on one side and “G” on the other.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
1. Treatment of terbinafine sensitive fungal infections such as Tinea corporis, Tinea cruris and Tinea pedis (caused by Dermatophytes 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.
Consideration should be given to official guidance on the appropriate use of antifungal agents.
4.2. Posology and method of administration
Route of administration:
Oral use
The duration of treatment is dependant on the indication and the degree of severity of the infection.
Adults
250mg once daily.
Skin infections
The likely durations of treatment for Tinea pedis, Tinea corporis and Tinea cruris are 2 - 4 weeks.
For Tinea pedis (interdigital, plantar/moccasin-type): recommended treatment periods may be up to 6 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 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.
Additional information on special populations
Children and Adolescents (0-17 years)
There is limited experience with oral terbinafine in children and adolescents and therefore its use cannot be recommended.
Liver impairment
Terbinafine tablets are not recommended for patients with chronic or active hepatic disease (see section 4.4).
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 and section 5.2).
Elderly
There is no evidence to suggest that elderly patients require different dosages or experience different side effects than younger patients. When prescribing terbinafine tablets for patients in this age group, the possibility of pre-existing impairment of hepatic or kidney function should be considered (see section 4.4).
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 tablets are not recommended for patients with chronic or active hepatic disease.
Single dose pharmacokinetic studies in patients with pre-existing liver disease have shown that the clearance of terbinafine can be reduced by 50% (see section 5.2).
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 liver failure (some with a fatal outcome, or requiring liver 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).
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 any signs and symptoms suggestive of liver dysfunction such as pruritus, unexplained persistent nausea, decreased appetite, anorexia or fatigue, vomiting, right upper abdominal pain, or jaundice, dark urine or pale faeces. Patients with these symptoms should discontinue taking oral terbinafine and the patient's hepatic function should be immediately evaluated (see section 4.8). Pretreatment serum transaminase tests (ALT, AST) are advised for all patients before taking terbinafine.
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 reactions.
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.
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).
Terbinafine should be used with caution in patients with pre-existing psoriasis or 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 medicinal products which induce metabolism (such as rifampicin) and may be inhibited by medicinal products which inhibit cytochrome P450 (such as cimetidine). Where co-administration of such medicinal products 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 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.
Some cases of irregular menstruation have been reported in patients taking terbinafine tablets 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. For this reason, it is important to monitor patients who are treated simultaneously with medicinal products that are predominantly metabolised by this enzyme, e.g. certain members of the following drug classes, tricyclic antidepressants (TCAs), beta-blockers, selective serotonin re-uptake inhibitors (SSRIs), antiarrhythmics (including class 1A, 1B and 1C) and monoamine oxidase inhibitors type B, especially if they also have a narrow therapeutic window (see section 4.4).
• Terbinafine decreased the clearance of desipramine by 82%.
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 undesirable effects.
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.
Breast-feeding:
Terbinafine is excreted in breast milk and therefore mothers should not receive treatment with 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
Adverse effects are generally mild to moderate in severity and transient.
The following adverse reactions have been observed in the clinical trials or during post marketing experience.
Adverse reactions are ranked under heading of frequency, the most frequent first, 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 (cannot be estimated from the available data).
|
Frequency System Organ Class l |
Very Commo n |
Common |
Uncommon |
Rare |
Very Rare |
Not Known |
|
Blood and lymphatic system disorders |
Neutropenia, agranulocytos is, thrombocytop enia, pancytopenia |
Anaemia | ||||
|
Immune system disorders |
Anaphylact ic reactions, serum sicknesslike reaction |
Anaphylactoi d reaction, angioedema, manifestation or aggravation of cutaneous or systemic lupus erythematosu s | ||||
|
Metabolis m and nutrition disorders |
Decreas ed appetite | |||||
|
Psychiatric disorders |
Anxiety, depression* | |||||
|
Nervous system disorders |
Headach e |
Hypogeusia *** ? ageusia***, dysgeusia** |
Dizziness, hypoaesthe sia, paraesthesi a |
Anosmia | ||
|
Ear and labyrinth disorders |
Hypoacusi s, hearing impaired, tinnitus | |||||
|
Vascular disorders |
Vasculitis | |||||
|
Gastrointe stinal disorders |
Abdomi nal distensi on, abdomi nal pain, diarrhoe a, dyspeps ia, nausea |
Pancreatiti s | ||||
|
Hepatobili ary disorders |
Hepatic failure (some with fatal |
|
Frequency System Organ Class l |
Very Commo n |
Common |
Uncommon |
Rare |
Very Rare |
Not Known |
|
outcome), hepatic enzymes increased, cholestasis (see 4.4), hepatic function abnormal (see 4.4), hepatitis (see 4.4), jaundice (see 4.4) | ||||||
|
Skin and subcutane ous tissue disorders |
Rash, urticaria |
Erythema multiforme, Stevens- Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematou s pustulosis (AGEP)). Psoriasiform eruptions or exacerbation of psoriasis (see 4.4). Alopecia. Photosensitivi ty reaction. |
Photoderm atosis, photosensi tivity allergic reaction and polymorph ic light eruption | |||
|
Musculosk eletal and connective tissue disorders |
Arthral gia, myalgia |
Rhabdomy olysis | ||||
|
Reproducti ve system and breast disorders |
Menstruation irregular, breakthrough bleeding (see 4.5) | |||||
|
General disorders and administra tion site |
Fatigue, malaise |
Influenza like illness, pyrexia |
|
Frequency System Organ Class l |
Very Commo n |
Common |
Uncommon |
Rare |
Very Rare |
Not Known |
|
conditions | ||||||
|
Investigati ons |
Hepatic enzyme increased (see 4.4) |
Blood creatinine phosphoki nase increased, weight decreased **** |
* Anxiety and depressive symptoms secondary to dysgeusia.
** can persist for a long period (up to 2 years)
*** Hypogeusia, including ageusia, which usually recover within several weeks after discontinuation of the drug. Isolated cases of prolonged hypogeusia have been reported.
**** Weight decreased secondary to hypogeusia.
4.9. Overdose
A few cases of overdose (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 active substance, primarily by the administration of activated charcoal, and giving symptomatic supportive therapy if needed.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Dermatologicals; antifungals for systemic use ATC code: D01 B 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 fungi 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 range (pg/ml) |
|
Trichophyton rubrum |
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 |
|
Epidermophyton floccosum |
0.001 - 0.05 |
erbinafine 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 0.97mcg/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 the first few weeks of 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.
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 69mg/kg a day, 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
Silica, colloidal anhydrous Croscarmellose sodium
Magnesium stearate Microcrystalline cellulose Povidone K29-32 Talc
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PVC/Aluminium blister pack, containing 7, 8, 14, 28, 30, 42, 56, 98, 100 or 250 tablets
HDPE bottles with PP caps, containing 7, 8, 14, 28, 30, 42, 56, 98, 100, or 250 tablets
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Generics [UK] Limited t/a Mylan
Station Close
Potters Bar
Hertfordshire
EN6 1TL
United Kingdom
MARKETING AUTHORISATION NUMBER(S)
PL 04569/0837
9
10
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
28 July 2004
DATE OF REVISION OF THE TEXT
17/01/2013