Terbinafine (tablets, spray, cream)

Pharmacotherapeutic group

antifungal agent

Pharmacodynamics

Terbinafine is an allylamine that has a broad spectrum of activity against fungi that cause diseases of the skin, hair and nails, including dermatophytes such as Trichophyton (for example, Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton verrucosum, Trichophyton violaceum, Trichophyton tonsurans), Microsporum (eg Microsporum canis), Epidermophyton floccosum, as well as yeast fungi of the genus Candida (eg C. albicans) and Malassezia.

At low concentrations, terbinafine has a fungicidal effect against dermatophytes, molds and some dimorphic fungi.Activity against yeast fungi, depending on their type, can be fungicidal or fungistatic

Terbinafine, by inhibiting squalene epoxidase in the fungal cell membrane (not related to the cytochrome P450 system), specifically inhibits the early stage of sterol biosynthesis in the fungal cell, which leads to ergosgerin deficiency, intracellular accumulation of squalene and death of the fungal cell.

When using the drug inside in the skin, hair and nails, concentrations of the drug are created that provide a fungicidal effect.

Pharmacokinetics

After oral administration, terbinafine is well absorbed (> 70%), the absolute bioavailability is about 50% (first pass effect).After a single dose of terbinafine orally at a dose of 250 mg, the maximum plasma concentration (Cmax) is 1.3 μg / ml, the time to reach the maximum concentration (TCmax) is 1.5 hours. With a constant intake of terbinafine, its Cmax increased by an average of 25%, compared with a single dose;the area under the concentration-time curve (AUC) increased by 2.3 times.Based on the increase in AUC, the effective half-life (30 hours) can be calculated.Food intake moderately affects the bioavailability of the drug (AUC increases by less than 20%), but dose adjustment of Terbinafine is not required when taken with food.

Communication with plasma proteins - 99%.Terbinafine rapidly penetrates into the dermal layer of the skin and concentrates in the lipophilic stratum corneum.Terbinafine also penetrates the secretion of the sebaceous glands, which leads to the creation of high concentrations in the hair follicles, hair and skin rich in sebaceous glands.It has also been shown that terbinafine penetrates the nail plate in the first few weeks after the start of therapy.

Terbinafine is metabolized rapidly and to a significant extent with the participation of at least seven isoenzymes of cytochrome P450, while the isoenzymes CYP2C9, CYP1A2, CYP3A4, CYP2C8, CYP2C19 play the main role.As a result of the biotransformation of terbinafine, metabolites are formed that do not have antifungal activity and are excreted mainly by the kidneys.Repeated use of terbinafine, leading to an increase in its concentration in blood plasma, is accompanied by a three-phase elimination with a final half-life of about 16.5 days.There were no changes in the equilibrium concentration of terbinafine in plasma depending on age.In pharmacokinetic studies in patients with concomitant impaired renal function (creatinine clearance < 50 ml / min) and liver disease, the possibility of reducing the clearance of the drug by 50% was shown.

Indications

- Onychomycosis caused by dermatophyte fungi

- Mycosis of the scalp.

- Fungal infections of the skin - treatment of dermatomycosis of the trunk, legs, feet, as well as yeast infections of the skin caused by fungi of the genus Candida (for example, Candida albicans) - in cases where the localization, severity or prevalence of the infection determine the appropriateness of oral therapy.

Contraindications

Hypersensitivity to terbinafine or to any other component of the drug;breastfeeding period;lactose intolerance, lactase deficiency, glucose-galactose malabsorption;children under 3 years of age, weighing up to 20 kg for this dosage;chronic or active liver disease;impaired renal function (creatinine clearance less than 50 ml / min or plasma creatinine concentration more than 300 μmol / l), since the use of the drug in this category of patients has not been sufficiently studied

Carefully:

Inhibition of bone marrow hematopoiesis, cutaneous lupus erythematosus or systemic lupus erythematosus, psoriasis.

Use during pregnancy and during breastfeeding:

The data of experimental studies do not give grounds to assume the presence of adverse effects in relation to fertility and toxic effects on the fetus.Since the clinical experience with the use of terbinafine in pregnant women is very limited, the drug should not be used during pregnancy, unless the expected benefit of therapy for the mother outweighs the potential risk to the fetus.

Terbinafine is excreted in breast milk, so women receiving Terbinafine by mouth should not continue breastfeeding.

Dosage and administration

The drug is taken orally, regardless of the meal, washed down with water.It is advisable to use the drug at the same time.The duration of treatment depends on the indication and severity of the disease.

adults

250 mg 1 time per day

Skin infections

Recommended duration of treatment:

Ringworm of the feet (interdigital, plantar, or sock type): 2-6 weeks.

Dermatomycosis of the trunk, legs: 2-4 weeks.

Skin candidiasis: 2-4 weeks.

The complete disappearance of the manifestations of infection and complaints associated with it may occur no earlier than a few weeks after mycological cure.

Hair and scalp infections

Recommended duration of treatment:

Mycosis of the scalp: 4 weeks.

Mycoses of the scalp are observed mainly in children.

Onychomycosis

The duration of treatment is in most patients from 6 to 12 weeks.

With onychomycosis of the hands, in most cases, 6 weeks of treatment is sufficient.

With onychomycosis of the feet, in most cases, 12 weeks of treatment is sufficient.

Some patients who have a reduced nail growth rate may require longer treatment.The optimal clinical effect is observed several months after mycological cure and cessation of therapy.This is determined by the period of time that is necessary for the growth of a healthy nail.

Use in children

In children older than 3 years and weighing more than 20 kg, the drug is used 1 time per day.

A single dose depends on body weight and is: for children weighing 20 to 40 kg - 125 mg (1/2 tablet 250 mg);more than 40 kg - 250 mg.

Use in the elderly

There is no reason to assume that elderly people need to change the dosing regimen of the drug or that they have side effects that differ from those in younger patients.In the case of use in this age group of the drug in tablets, the possibility of concomitant impaired liver or kidney function should be considered.

Side effects

The drug is generally well tolerated.Side effects are usually mild or moderate and transient.

When assessing the incidence of side effects, the following gradations were used: "very often" (? 1/10), "often" (? 1/100 <1/10), "infrequently" (? 1/1000 <1/100), " rarely" (? 1/10000 <1/1000), "very rarely" (<1/10000), including individual messages

On the part of the hematopoietic system: infrequently - anemia, very rarely - neutropenia, agranulocytosis, thrombocytopenia, pancytopenia.

Immune system disorders: very rarely - anaphylactoid reactions (including angioedema), cutaneous and systemic lupus erythematosus (or their exacerbation).

Nervous system disorders: very often - headache;often - dizziness, taste disturbances, up to their loss (usually recovery occurs within a few weeks after stopping treatment);infrequently - paresthesia, hypesthesia.There are isolated reports of cases of long-term taste disturbances.In some cases, against the background of taking the drug, exhaustion was noted.

Mental disorders: often - depression;infrequently - anxiety.

On the part of the organ of vision: infrequently - visual impairment.

On the part of the organ of hearing and labyrinth disorders: infrequently - tinnitus.

Liver and biliary tract disorders: rarely - hepatobiliary dysfunction (mainly of a cholestatic nature), incl.liver failure, including very rare cases of severe liver failure (some fatal or requiring liver transplantation; in most cases, when liver failure developed, patients had serious concomitant systemic diseases and a causal relationship of liver failure with taking terbinafine was doubtful), hepatitis, jaundice, cholestasis, increased activity of "liver" enzymes.

Digestive system disorders: very often - bloating, loss of appetite, dyspepsia, nausea, mild abdominal pain, diarrhea.

Skin and subcutaneous tissue disorders: very common - rash, urticaria; infrequently - photosensitivity reactions;very rarely - Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, erythema multiforme, toxic skin rash, exfoliative dermatitis, bullous dermatitis, psoriasis-like skin rashes or exacerbations of psoriasis, alopecia.

Musculoskeletal and connective tissue disorders: very common - arthralgia, myalgia

General disorders: often - a feeling of fatigue;infrequently - an increase in body temperature.

Laboratory and instrumental data: infrequently - weight loss (secondary to a violation of taste sensations).

Based on spontaneous reports received in the post-registration period and literature data, the following adverse events were identified, the frequency of which, due to an inaccurate number of patients, cannot be established:

Immune system disorders: anaphylactic reactions, serum sickness-like syndrome.

On the part of the organ of vision: blurred vision, decreased visual acuity.

Skin and subcutaneous tissue disorders: drug rash with eosinophilia and systemic symptoms (rash, edema, fever, and swollen lymph nodes).

Hearing disorders and labyrinth disorders: hearing loss, hearing impairment.

Vascular disorder: vasculitis.

Violation of the nervous system: loss of smell, including for a long period of time, decreased sense of smell.

Gastrointestinal disorders: pancreatitis.

Violation of the side of the musculoskeletal and connective tissue: rhabdomyolysis.

General disorders: influenza-like syndrome.

Blood and lymphatic system disorders: anemia.

Laboratory and instrumental data: increased activity of creatine phosphokinase in blood plasma.

If any of the side effects listed in the instructions get worse, or if you notice any other side effects not listed in the instructions, tell your doctor.

Overdose

There are reports of several cases of overdose (the accepted dose of terbinafine was up to 5 g), in which headache, dizziness, nausea, pain in the epigastric region, frequent urination, rash were noted.

Treatment recommended in case of overdose includes measures to remove the drug, primarily by prescribing activated charcoal and gastric lavage;if necessary, carry out symptomatic and supportive therapy.

drug interaction

Effect of other medicinal products on terbinafine

Plasma clearance of terbinafine may be accelerated by metabolic inducers and suppressed by cytochrome P450 inhibitors.If necessary, the simultaneous use of the above drugs and the drug Terbinafine may require an appropriate correction of the dosing regimen of the latter.

Cimetidine may enhance the effect of terbinafine or increase its plasma concentration.Cimetidine reduces the clearance of terbinafine by 33%

Fluconazole increases Cmax and AUC of terbinafine by 52% and 69%, respectively, due to inhibition of CYP2C9 and CYP3A4 isoenzymes.A similar increase in terbinafine exposure may occur with the use of other drugs that inhibit CYP2C9 and CYP3A4 isoenzymes, for example, ketocoiazole and amiodarone.

Rifampicin may weaken the effect of terbinafine or reduce its plasma concentration.Rifampicin increases the clearance of terbinafine by 100%.

Effect of terbinafine on other medicinal products

In vivo and in vitro studies have shown that terbinafine inhibits metabolism mediated by the 2D6 isoenzyme (CYP2D6).These data may be clinically significant for those drugs that are metabolized mainly by this isoenzyme: tricyclic antidepressants, beta-blockers (metoprolol, propranolol), selective serotonin reuptake inhibitors, antiarrhythmic drugs of the class (IA, IB, IC class), antipsychotic drugs (chlorpromazine , haloperidol) and type B monoamine oxidase inhibitors (seleginine) - if the drug used simultaneously has a small therapeutic concentration range.

Terbinafine reduces the clearance of desipramine by 82%.

In studies in healthy volunteers with an active metabolism of dextromethorfap (an antitussive agent and CYP2D6 substrate), terbinafine increased the urinary metabolic ratio of dextromethorphan/dextrorphan by 16-97 times.Thus, terbinafine in individuals with high activity of the CYP2D6 isoenzyme may reduce the activity of the latter.

Terbinafine reduces the clearance of caffeine when administered intravenously by 19%.

With simultaneous use with warfarin, rare cases of changes in INR and / or prothrombin time have been noted.

Drug interactions with little or no effect

The results of in vitro and healthy volunteer studies indicate that terbinafine has little potential to suppress or increase the clearance of most drugs that are metabolized by the cytochrome P450 system (for example, terfenadine, triazolam, tolbutamide, or oral contraceptives), with the exception of those which are metabolized with the participation of CYP2D6.Terbinafine does not affect the clearance of phenazone or digoxin.

Terbinafine has no significant effect on the pharmacokinetics of fluconazole.

There were no clinically significant interactions between terbinafine and the components of co-trimoxazole (trimethoprim and sulfamethoxazole), zidovudine or theophylline.

There are reports of several cases of menstrual irregularities in patients taking the drug together with oral contraceptives, although the frequency of these disorders does not exceed the average frequency of such disorders in patients taking only oral contraceptives.

Terbinafine may reduce plasma concentrations or clinical effects of the following drugs.

Terbinafine increases the clearance of cyclosporine by 15%.

Interactions with food and drink

Food has little effect on the bioavailability of terbinafine (increase in AUC <20%), which does not require a change in the dose of the drug.

special instructions

Irregular use or early termination of treatment increases the risk of relapse

If after 2 weeks of treatment there is no improvement in the condition, it is necessary to re-determine the causative agent of the disease and its sensitivity to terbinafine.

Before starting the use of the drug Terbinafine in tablets, it is necessary to monitor liver function parameters.Hepatotoxicity may occur in patients with or without pre-existing liver disease.During therapy, a periodic study of liver function is recommended (4-6 weeks after the start of treatment).Treatment with Terbinafine should be discontinued immediately if liver function tests increase.Patients who are prescribed the drug Terbinafine should be warned that it is necessary to immediately inform the attending physician about the occurrence of symptoms such as persistent nausea, loss of appetite, fatigue, vomiting, pain in the right hypochondrium, jaundice, dark urine or light cal.

Care must be taken when using the drug in patients with oppression of bone marrow hematopoiesis, cutaneous lupus erythematosus or systemic lupus erythematosus.

Serious skin reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms) have been extremely rare during the use of terbinafine.

When using terbinafine, extremely rare cases of changes in the cellular composition of the blood (neutropenia, agranulocytosis, thrombocytopenia, pancytopenia) were noted.In the event of the development of qualitative or quantitative changes in the blood cells, the cause of the violations should be established and consideration should be given to reducing the dose of the drug or, if necessary, stopping therapy with Terbinafine.

Since the use of the drug in patients with impaired renal function (creatinine clearance less than 50 ml / min or plasma creatinine concentration more than 300 μmol / l) has not been sufficiently studied, Terbinafine is not recommended for use in this category of patients.

If the patient has a history of psoriasis, Terbinafine should be used with caution, since there are data on cases of exacerbation of the disease.

Systemic use in onychomycosis is justified only in the case of total damage to most nails, the presence of pronounced subungual hyperkeratosis, and the ineffectiveness of previous local therapy.

In the treatment of onychomycosis, a clinical response is usually observed several months after mycological cure and discontinuation of treatment, due to the rate of growth of a healthy nail.Removal of nail plates in the treatment of onychomycosis of the hands for 3 weeks and onychomycosis of the feet for 6 weeks is not required.

Terbinafine has been shown to inhibit metabolism mediated by isoenzyme 2D6 (CYP2D6).Therefore, it is necessary to constantly monitor patients receiving concomitant treatment with terbinafine with drugs predominantly metabolized with the participation of this isoenzyme (tricyclic antidepressants, beta-blockers, selective serotonin reuptake inhibitors, antiarrhythmic drugs of the class (IA, IB, IC class), antipsychotic drugs and type B monoamine oxidase inhibitors) if the drug used simultaneously has a small therapeutic concentration range.

When treating with terbinafine, general hygiene rules should be observed to prevent the possibility of re-infection through underwear and shoes.In the process of treatment (after 2 weeks) and at the end, it is necessary to carry out antifungal treatment of shoes, socks and stockings.

Influence on the ability to drive vehicles and other mechanisms:

The effect of terbinafine on the ability to drive vehicles and operate machinery has not been studied.With the development of dizziness during drug therapy, patients should not drive vehicles and / or work with mechanisms.

Storage temperature

2℃ to 25℃