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TERBINAFINE 125MG TABLETS

Active substance(s): TERBINAFINE HYDROCHLORIDE / TERBINAFINE HYDROCHLORIDE / TERBINAFINE HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
TERBINAFINE 125 mg tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 125 mg terbinafine (as hydrochloride).
For the full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM
Tablet
White, or almost white round, biconvex tablets with a breakline on one side and 125
engraved on the other.
The tablet can be divided into equal doses.

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) where oral therapy 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
Method of administration: Oral use

The duration of treatment is dependent on the indication and the degree of severity of
the infection.
Adults: 250mg once daily.
Patients with impaired renal function (creatinine clearance less than 50ml/minute or
serum creatinine of more than 300 micromol/l) should receive half the normal dose.
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 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.
Children
There is no experience with oral terbinafine in children and its use cannot therefore be
recommended.
Use in the 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 liver or kidney
function impairment must be considered in this age group (see sections 4.4 and 4.8).
Liver impairment
Terbinafine tablets are not recommended for patients with chronic or active hepatic
disease (see sections 4.3 and 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 4.3, 4.4
and 5.2).

4.3

Contraindications

Hypersensitivity to terbinafine the active substance or to any of the
excipients listed in section 6.1.

Severe renal impairment

Chronic or acute 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 sections 4.3 and 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 of unexplained persistent nausea, decreased appetite, fatigue,
vomiting, right upper abdominal pain, or jaundice, dark urine, pruritus 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).

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.
Terbinafine should be used with caution in patients with psoriasis or lupus
erythematosus, as very rare cases of exacerbation have been reported.

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.
If severe changes in blood count, taste disorders or loss of the sense of taste or
worsening skin reactions occur during terbinafine therapy, treatment must be stopped
immediately.
Patients on terbinafine who develop a high fever or sore throat should be examined
concerning possible haematological reactions.
A complete blood count should be considered in patients with known or presumed
immune system weakness, which take terbinafine longer than 6 weeks.
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).

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 drugs 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 CYP2D6mediated metabolism. For this reason, it is important to monitor patients who are
treated simultaneously with drugs that are mainly metabolised by this enzyme, such
as tricyclic antidepressants (TCAs), β-blockers, selective serotonin re-uptake

inhibitors (SSRIs), antiarrhythmics (including class 1A, 1B and 1C) and monoamine
oxidase inhibitors (MAO-Is) type B and if the co-medication has a narrow therapeutic
index. Dose adjustments may be necessary.
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.
Breast-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 undesirable 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 reactions 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).
Blood and lymphatic system disorders
Very rare: Neutropenia, Agranulocytosis, Thrombocytopenia, Pancytopenia
Not known: Anaemia
Immune system disorders
Rare: Anaphylactic reaction, Serum sickness like reaction, Angio-oedema
Very rare: Anaphylactoid reaction, Manifestation or aggravation of cutaneous
or systemic lupus erythematosus
Metabolism and nutrition disorders

Very common: Decreased appetite
Common: Loss of appetite
Psychiatric disorders
Very rare: Anxiety, Depression (secondary to dysgeusia)
Nervous system disorders
Common: Headache
Uncommon: Dysgeusia, Hypogeusia, Ageusia (Hypogeusia, including ageusia,
which usually recover within several weeks after discontinuation of the drug.
Isolated cases of prolonged hypogeusia have been reported.)
Rare: Dizziness, Hypoaesthesia, Paraesthesia
Not known: Anosmia
Ear and labyrinth disorders
Not known: Hypoacusis, hearing impaired, tinnitus
Vascular disorders
Not known: Vasculitis
Gastrointestinal disorders
Very common: Abdominal distension, Dyspepsia, Nausea, Abdominal pain,
Diarrhoea
Not known: Pancreatitis
Hepatobiliary disorders
Rare: Cholestasis*, Hepatic function abnormal*, Hepatitis*, Jaundice*,
Hepatic enzymes increased*, Hepatic failure, followed by liver transplantation
or death. In the majority of these cases patients suffered from a severe
underlying disease.
Skin and subcutaneous tissue disorders
Very common: Rash, Urticaria
Very rare: Erythema exsudativum multiforme (EEM), Stevens-Johnson
syndrome, Toxic epidermal necrolysis, acute generalised exanthematous
pustulosis (AGEP), Photosensitivity reaction, Psoriasiform eruptions or
exacerbation of psoriasis*, Alopecia
Not known: Photodermatosis, Photosensitivity allergic reaction and
polymorphic light eruption
Musculoskeletal and connective tissue disorders
Very common: Arthralgia, Myalgia
Not known: Rhabdomyolysis
Reproductive system and breast disorders
Very rare: Menstruation irregular, Breakthrough bleeding
General disorders and administration site conditions
Common: Fatigue, Malaise
Not known: Influenza like illness, pyrexia

Investigations
Not known: Blood creatinine phosphokinase increased, weight decreased
(secondary to hypogeusia)
*see section 4.4
Musculo-skeletal disorders including arthralgia and myalgia have been
reported. These may occur as part of a hypersensitivity reaction in association
with allergic skin reactions.
Serious skin reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis,
photosensitivity
Manifestation or aggravation of cutaneous or systemic lupus erythematosus.
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 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.
4.9

Overdose
A few cases of overdose (up to 5g) have been reported, giving rise to headache,
nausea, abdominal pain and dizziness.
Treatment: eliminating the drug (e.g. activated charcoal) and symptomatic supportive
treatment, if needed.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Dermatologicals; antifungals for systemic use

ATC code: D01B 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
fungal 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 rang
(μg/ml)

Trichophyton rubrum
Trichophyton mentagrophytes
Trichophyton verrucosum
Trichophyton violaceum

0.001 – 0.15
0.0001 – 0.05
0.001 – 0.006
0.001 – 0.1

Microsporum canis

0.0001 – 0.1

Epidermophyton 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

Following oral administration, terbinafine is well absorbed (>70 %) and the absolute
bioavailability of terbinafine from terbinafine tablets as a result of first-pass
metabolism is approximately 50 %. A single oral dose of 250 mg terbinafine resulted
in mean peak plasma concentrations of 1.30μg/ml within 1.5 hours after
administration. At steady-state, in comparison to a single dose, peak concentration of
terbinafine was on average 25 % higher and plasma AUC increased by a factor of 2.3.
From the increase in plasma AUC an effective half-life of ~30 hours can be
calculated. The bioavailability of terbinafine is moderately affected by food (increase
in the AUC of less than 20%), but not sufficiently to require dose adjustments.
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.
Terbinafine is metabolised rapidly and extensively by at least seven CYP isoenzymes
with major contributions from CYP2C9, CYP1A2, CYP3A4, CYP2C8 and
CYP2C19. Biotransformation results in metabolites with no antifungal activity, which
are excreted predominantly in the urine.
No clinically-relevant 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.
Single dose pharmacokinetic studies in patients with renal impairment (creatinine
clearance <50 ml/min) or with pre-existing liver disease have shown that clearance of
terbinafine may be reduced by about 50%.

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 69 mg/kg, 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 speciesspecific 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
Cellulose microcrystalline
Hypromellose
Sodium starch glycolate
Silica colloidal anhydrous
Magnesium stearate

6.2

Incompatibilities
None known

6.3

Shelf life
5 years

6.4

Special precautions for storage
Store in original container.

6.5

Nature and contents of container
The folded carton of Terbinafine 125 mg tablet contains 7, 14, 28, 42, 56, 84 and 98
tablets. The blister is made of aluminium/PVC.

6.6

Special precautions for disposal
None

7

MARKETING AUTHORISATION HOLDER
Stada Arzneimittel AG
STADASTRASSE 2-18

BAD VILBEL
D-61118
GERMANY

8

MARKETING AUTHORISATION NUMBER(S)
PL 11204/0197

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
07/04/2009

10

DATE OF REVISION OF THE TEXT
06/02/2015

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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