MEDOFLORAN Tablet Ref.[28281] Active ingredients: Terbinafine

Liver Function

Terbinafine is not recommended for patients with chronic or active liver disease. Before prescribing Medofloran, 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. Medofloran 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. 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 (see section 4.8).

Patients prescribed Medofloran 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. If progressive skin rash occurs, Medofloran treatment should be discontinued.

Medofloran 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. Aetiology of any blood dyscrasias that occur in patients treated with Medofloran should be evaluated and consideration should be given for a possible change in medication regimen, including discontinuation of treatment with Medofloran.

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 has not been adequately studied, and therefore, is not recommended (see section 5.2).

Other

Medofloran should be used with caution in patients with lupus erythematosus as very rare cases of lupus erythematosus have been reported.

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 Medofloran 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 C_max 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), 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).

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 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 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.

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 terbinafine treatment whilst breast-feeding.

Fertility

Foetal toxicity and fertility studies in animals suggest no adverse effects.

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.

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 (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 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 tissue disorders

Very common: Non-serious forms of skin reactions (rash, urticaria).

Very rare: 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.

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

Not known: Fatigue. Influenza-like illness, pyrexia.

Investigations

Not known: Blood creatine phosphokinase increased

Reporting of suspected adverse reactions

Reporting suspected adverse reactions is an important way to gather more information to continuously monitor the benefit/risk balance of the medicinal product. Any suspected adverse reactions should be reported to Pharmaceutical Services, Ministry of Health, CY-1475, www.moh.gov.cy/phs, Fax: +357 22608649.

None known.