Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: NOVARTIS PHARMACEUTICALS UK LIMITED, Frimley Business Park, Frimley, Camberley, Surrey, GU16 7SR
Known hypersensitivity to terbinafine or to any of the excipients of Lamisil tablets.
Chronic or active hepatic disease.
Lamisil tablets are contraindicated for patients with chronic or active hepatic disease. Before prescribing Lamisil 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. Lamisil 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 Lamisil tablets. In the majority of liver failure cases the patients had serious underlying systemic conditions (see sections 4.3 Contraindications and 4.8 Undesirable effects).
Patients prescribed Lamisil 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.
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 Lamisil tablets. If progressive skin rash occurs, Lamisil tablets treatment should be discontinued.
Lamisil should be used with caution in patients with pre-existing psoriasis, as very rare cases of exacerbation of psoriasis have been reported.
Very rare cases of blood dyscrasias (neutropenia, agranulocytosis, thrombocytopenia, pancytopenia) have been reported in patients treated with Lamisil tablets. Aetiology of any blood dyscrasias that occur in patients treated with Lamisil tablets should be evaluated and consideration should be given for a possible change in medication regimen, including discontinuation of treatment with Lamisil tablets.
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 Lamisil tablets has not been adequately studied, and therefore, is not recommended (see section 5.2 Pharmacokinetic properties).
Lamisil should be used with caution in patients with lupus erythematosus as very rare cases of lupus erythematosus have been reported.
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 Lamisil 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%.
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), β-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 97-fold on average. Thus, terbinafine may convert extensive CYP2D6 metabolisers (genotype) to poor metaboliser status (phenotype).
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 metabolized 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 Lamisil 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.
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.
Terbinafine is excreted in breast milk and therefore mothers should not receive Lamisil treatment whilst breast-feeding.
Foetal toxicity and fertility studies in animals suggest no adverse effects.
No studies on the effects of Lamisil 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.
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).
Very rare: Neutropenia, agranulocytosis, thrombocytopenia.
Not known: Anaemia Pancytopenia
Very rare: Anaphylactoid reactions (including angioedema), cutaneous and systemic lupus erythematosus.
Not known: Anaphylactic reaction, serum sickness-like reaction.
Very common: Decreased appetite
Not known: Anxiety and depressive symptoms
Common: Headache
Uncommon: Dysgeusia* including ageusia*
* Hypogeusia, including ageusia, which usually recover within several weeks after discontinuation of the drug. Isolated cases of prolonged hypogeusia have been reported.
Rare: Paraesthesia, hypoaesthesia, dizziness
Not known: Anosmia including permanent anosmia, hyposmia.
Not known: Visual impairment, vision blurred, visual acuity reduced
Very rare: Vertigo
Not known: Hypoacusis, impaired hearing, tinnitus
Not known: Vasculitis
Very common: Gastrointestinal symptoms (feeling of fullness abdominal distension, dyspepsia, nausea, abdominal pain, diarrhoea).
Not known: Pancreatitis
Rare: Cases of serious hepatic dysfunction, including hepatic failure, hepatic enzymes increased, jaundice, cholestasis and hepatitis. If hepatic dysfunction develops, treatment with Lamisil 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 Lamisil was uncertain.
Very common: Rash, urticaria
Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, toxic skin eruption, dermatitis exfoliative, dermatitis bullous. Photosensitivity reactions. Alopecia
If progressive skin rash occurs, Lamisil treatment should be discontinued.
Not known: Psoriasiform eruptions or exacerbation of psoriasis. Serious skin reactions (e.g. acute generalized exanthematous pustulosis (AGEP)). Drug rash with eosinophilia and systemic symptoms
Very common: Musculoskeletal reactions (arthralgia, myalgia).
Not known: Rhabdomyolysis
Rare: Malaise
Not known: Fatigue, Influenza-like illness, pyrexia
Uncommon: Weight decreased**
** weight decreased secondary to dysgeusia
Not known: Blood creatine phosphokinase increased
Reporting 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.
None known.
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