Document: Terbinafin Bluefish tablet ENG SmPC change

• Terbinafin Bluefish tablet SmPC
• Terbinafin Bluefish tablet ENG SmPC

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1. NAME OF THE MEDICINAL PRODUCT

Terbinafin Bluefish 250 mg tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 250 mg terbinafine (as terbinafine hydrochloride).

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL form

Tablet

Terbinafin Bluefish 250 mg tablets are white, circular, biconvex tablets with “TF” on one side and a score line on the other side.

The tablet can be divided into equal halves.

4. Clinical particulars

4.1 Therapeutic indications

Note. 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

Posology

The duration of treatment is dependent on the indication and the degree of severity of the infection.

Additional information on special population

Method of administration

Oral use

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 successful 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 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 and is only seen several months after stopping treatment, which is the time for growth of a healthy nail.

Children

There is limited experience with oral terbinafine in children and its use cannot therefore be recommended.

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).

Use in hepatic impairment

For patients with hepatic impairment, see section 4.3 and 4.4.

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).

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. Special warnings and precautions for use).

4.3 Contraindications

Known hypersensitivity to terbinafine or to any of the excipients of terbinafine tablets.

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. 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 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).

Patients prescribed terbinafine tablets should be warned to report immediately any signs and symptoms of unexplained persistent nausea, decreased appetite, 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.

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.

Patients on terbinafine who develop a high fever or sore throat should be examined concerning possible haematological reactions

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 Pharmacokinetic properties).

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 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 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. This finding may be of clinical relevance for compounds predominantly metabolised by CYP2D6, e.g. certain members of the following drug classes, tricyclic antidepressants (TCAs), beta-blockers, selective serotonine 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%.

Terbinafine may decrease the effect or plasma concentration of the following medicinal products

Terbinafine increased the clearance of ciclosporin by 15%.

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.

Brest- feeding

Terbinafine is excreted in breast milk; mothers receiving oral 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.

The following adverse reactions have been observed in the clinical trials or during post marketing experience.

Adverse reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following conventions:

.

Frequency → Primary System Organ Class (MedDRA 9.1) ↓	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)
Blood and lymphatic system disorders					Agranulocytosis Neutropenia Thrombocytopenia Pancytopenia	Anaemia
Immune system disorders				Anaphylactic reaction	Anaphylactoid reaction, angioedema, Manifestation or aggravation of cutaneous and systemic lupus erythematosus	Anaphylactic reactions, serum sickness-like reaction
Metabolism and nutrition disorders	Decreased appetite
Psychiatric disorders						Anxiety, Depression*
Nervous system disorders		Headache	Ageusia** Hypogeusia**		Dizziness, paraesthesia and Hypoaesthesia	Anosmia
Ear and labyrinth disorders						Hypoacusis, Hearing impaired, tinnitus
Vascular disorders						Vasculitis
Gastrointestinal disorders	Abdominal distension, Abdominal pain Diarrhoea, Dyspepsia, Nausea Fullness					Pancreatitis
Hepatobiliary disorders				Hepatic failure Hepatic enzymes increased		Hepatitis, Jaundice, Cholestasis
Skin and subcutaneous tissue disorders	Rash Urticaria			Angioneurotic oedema-	Erythema multiforme, Psoriasiform eruptions or exacerbation of psoriasis, Stevens-Johnson syndrome, Toxic epidermal necrolysis, acute generalized exanthematous pustulosis (AGEP), Alopecia,	Photosensitivity reaction, Photodermatosis, Photosensitivity allergic reaction and Polymorphic light eruption.
Musculoskeletal and connective tissue disorders	Arthralgia Myalgia					Rhabdomyolysis
Reproductive system and breast disorders					Menstruation irregular Break-through bleeding
General disorders and administration site conditions		Malaise			Fatigue	Influenza like illness, pyrexia
Investigations						Blood creatinine phosphokinase increased, weight decreased ***

* Anxiety and depressive symptoms secondary to dysgeusia.

** 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.

Musculo-skeletal disorders including arthralgia and myalgia may occur as part of a hypersensitivity reaction in association with allergic skin reactions.

Some cases of menstrual disturbance (breakthrough bleeding and irregular cycle) have been reported in patients taking terbinafine concomitantly with oral contraceptives (see section 4.5).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefits/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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 overdose 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: Dermatologicals, antifungals for systemic use

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 selectively with fungal sterol biosynthesis at an early stagethrough inhibition of the enzyme squalene epoxidase. This leads to a deficiency in ergosterol and to an intracellular accumulation of squalene in the fungal cell membrane. Both the deficiency inergosterol and the accumulation ofsqualene 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 (μg/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
Epidermorphyton floccosum	0.001 – 0.05

Terbinafine 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 250 mg terbinafine results in mean plasma concentrations of 0.97 mg/ml within 1-2 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 lipohilic stratum corneum. Terbinafine is also secreted in the 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 a few weeks after 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 about 17 hours.

There is no evidence of accumulation in the plasma.

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

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 dose level of 69 mg/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 might 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 reproductive parameters were observed in studies in rats or rabbits.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Microcrystalline cellulose

Sodium starch glycolate (type A).

Hypromellose

Colloidal anhydrous silica

Magnesium stearate

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.

Blister (PVC/Al): 7, 10, 14, 20, 28, 30, 49, 50, 56, 60, 98, 100, 112, 250 and 500 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Bluefish Pharmaceuticals AB

Torsgatan 11

111 23 Stockholm

Sweden

8. MARKETING AUTHORISATION NUMBER(S)

To be completed nationally

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

To be completed nationally

10. DATE OF REVISION OF THE TEXT

21 May 2015