Terbinafine - instructions for use, doses, side effects, contraindications

Active substance: terbinafine hydrochloride in recalculation with terbinafine - 0.25 g; auxiliary substances: microcrystalline cellulose - 0.08 g; giprolose (hydroxypropylcellulose) 0.025 g; croscarmellose sodium - 0.025 g; silicon dioxide colloidal - 0.01 g; calcium stearate - 0.005 g; lactose monohydrate - to obtain a tablet weighing 0.5 g.

Description:Round flat-cylindrical tablets of white or almost white color with a facet and a risk.

Pharmacotherapeutic group:Antifungal agent.

ATX: & nbsp

D.01.A.E.15 Terbinafine

Pharmacodynamics:

Turbabinine is an allylamine, has a broad spectrum of action against fungi that cause skin, hair and mole diseases, including dermatophytes such as Trichophyton (e.g., T. rubrum, T. mentagrophytes, T. verrucosum, T. tonsurans, T. violacium), Microsporum (e.g., M. canis), Hpidermophiton floccosum, as well as yeast fungi of the genus Candida (e.g., O. albicans) and Pityrosporum. In low concentrations terbinafine has a fungicidal effect against dermatophytes, molds and some dimorphic fungi. Activity with respect to yeast fungi, depending on their type, may be fungicidal or fungistatic.

Terbinafine specifically suppresses the early stage of biosynthesis of sterols in the fungal cell. Ego leads to a deficit of ergotheter and to intracellular accumulation of squalor, which calls the death of the fungal cell. The action of terbinafine is carried out by inhibiting the enzyme squalene oxidase in the cell membrane of the fungus. This enzyme does not belong to the cytochrome P450 system. Terbinafine has no influence on metabolism of hormones or other medications.

When taking the drug Terbinafine Inside in the skin, hair and nails are created concentrations of the drug, providing fungicidal action.

Pharmacokinetics:

Suction and distribution

After oral administration terbinafine is well absorbed (> 70%); absolute bioThe availability of terbinafine due to the "first pass" effect through the liver is approximately 50%.

July single-dose terbinafine intake at a dose of 250 mg its maximum concentration in blood plasma (C_max) is achieved after 1.5 hours and is 1.3 μg / ml. With a constant intake of terbinafine, its C_max on average increases by 25%, compared with a single admission; area under the curve "concentration-time" (AUC) increases by 2.3 times. The effective half-life is 30 hours. Food intake moderately affects the bioavailability of the drug (AUC increases by less than 20%), but adjusting the dose of terbinafine with simultaneous intake with food is not required.

Terbinafine is largely associated with blood plasma proteins (99%). It quickly penetrates the dermal layer of the skin and is concentrated in the lipophilic stratum corneum. Terbinafine also penetrates into the secretion of the sebaceous glands, which leads to the creation of high concentrations in the hair follicles, hair and in the skin, rich in sebaceous glands. It is also shown that terbinafine penetrates the nail plate in the first few weeks after the initiation of therapy.

Metabolism and excretion

Terbinafine is metabolized rapidly and to a significant extent with the participation of at least seven cytochrome P450 isofermites, with the main role being played by isozymes CYP2C9. CYP1A2, CYP3A4, CYP2C8 and CYP2C19. As a result of biotransformation Terbinafine produces metabolites that do not possess antifungal activity and excreted mainly by the kidneys. Multiple application of terbinafine, leading to an increase in its concentration in the blood plasma, is accompanied by a three-phase excretion with a finite half-life of about 16.5 days. It is excreted by the kidneys in the form of metabolites (about 70%), the rest - through the intestine.

Do not cumulate. Excreted in breast milk.

Pharmacokinetics in specific patient groups

Elderly patients

There were no changes in the equilibrium concentration of terbinafine in blood plasma at depending on age.

Patients with impaired hepatic and / or renal function

In pharmacokinetic studies of a single dose of terbinafine in patients with concomitant renal dysfunction (creatinine clearance (CC) less than: 0 ml / min) and with liver diseases, the possibility of reducing the clearance of the drug by 50% was demonstrated.

Indications:

- onychomycosis caused by mushrooms dermatophytes;

- Mycosis of the scalp;

- fungal skin infections - treatment of dermatomycosis of the trunk, shins, groans, as well as yeast infections of the skin caused by fungi of the genus Candida (eg. Candida albicans) - In those cases where the localization, severity or prevalence of infection determines the advisability of oral therapy.

Contraindications:

- hypersensitivity to terbinafine or other components of the drug;

- severe, chronic or active liver disease;

- chronic renal failure (CC less than 50 ml / min or creatinine concentration in the blood plasma more than 300 μmol / l);

children's age (up to 3 children, with a body weight of up to 20 kg); the period of breastfeeding; deficiency of lactase, lactose intolerance, malabsorption.

Carefully:

impaired liver function;

renal failure (QC more than 50 ml / min);

alcoholism;

oppression of bone marrow hematopoiesis;

cutaneous lupus erythematosus or systemic lupus erythematosus;

psoriasis;

metabolic diseases;

occlusive diseases of the vessels of the extremities.

Pregnancy and lactation:

Pregnancy

The data of experimental studies of nc give grounds for assuming the presence of undesirable phenomena with respect to toxic effects on the fetus. Since the experience of using terbiafin in pregnant women is limited, the drug should not be used during pregnancy, except when the expected benefit of providing therapy for the mother exceeds the potential risk to the fetus.

Breastfeeding period

Terbinafine is excreted in breast milk, so women who receive the drug Terbinafine inside, should not feed piles.

Impact on fertility

Data on the effect of the drug Terbinafine people do not have fertility. Studies of rats did not reveal an undesirable effect on fertility and reproductive capacity.

Dosing and Administration:

Inside, regardless of food intake, washed down with water.

Duration of treatment depends on the indication and severity of the course of the disease, it is desirable to take the drug at the same time.

Adults

250 mg once a day.

Infections of the skin recommended duration of treatment:

- dermatomycosis of the foot (interdigital, plantar or as a socks) - 2-6 weeks;

- dermatomycosis of the trunk, shins - 2-4 weeks;

- Candidiasis of the skin - 2-4 weeks.

Complete disappearance of manifestations of infection and complaints associated with it can occur not earlier than a few weeks after mycological cure.

Hair and scalp infections

The recommended duration of treatment for mycosis of the scalp is 4 of the week.

Mycoses of the scalp are mainly seen in children.

Onychomycosis:

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

With onychomycosis, brushes in most cases are sufficient for 6 weeks of treatment.

In the onychomycosis of feet, in most cases, 12 weeks of treatment are sufficient.

Some patients who have a reduced rate of nail growth, can longer treatment is required.

The optimal clinical effect is observed several months after mycological cure and discontinuation of therapy. This is determined by the time period that is necessary for the growth of a healthy nail.

Elderly patients

There is no reason to believe that elderly patients need to change the dosage regimen of the drug or that they have side effects that are different from those in younger patients; if this drug is used in this age group, the possibility of concomitant liver and / or kidney dysfunction .

Children

In children older than 3 years, the drug is prescribed once a day. A single dose depends on the body weight and is:

- for children with a body weight of 20 to 40 kg - 125 mg (1/2 tablet 250 mg);

- for children with a body weight of more than 40 kg - 250 mg.

Side effects:

Classification of the incidence of adverse events according to the World Health Organization (WHO): very often> 1/10; frequentlyabout from> 1/100 to <1/10; I infrequently from> 1/1000 to <1/100; rarely from> 1/10000 to <1/1000; very rarely <1/10000. including individual messages; frequency unknown - by the available data to establish the frequency of occurrence is not possible.

According to clinical studies

Violations of the blood and lymphatic system: infrequently, anemia;

very rarely - neutron, agranulocytosis, pancytopenia, thrombocytopenia.

Immune system disorders:

Very rarely - anaphylactoid reactions (including angioedema), cutaneous and systemic lupus erythematosus (or their exacerbation).

Disorders from the psyche:

Often - depression; infrequent anxiety.

Impaired nervous system: very often - headache;

often - dizziness; disturbances of taste, up to their loss (usually recovery occurs within a few weeks after cessation of treatment); infrequently - paresthesia, hypoesthesia;

very rarely - long disturbances of taste sensations, exhaustion.

Disorders from the side of the organ of vision: infrequently - impaired vision.

Hearing disorders and labyrinthine disturbances: infrequently, noise in the ears.

Disorders from the liver and bile ducts:

rarely hepatobiliary dysfunction (mainly of the cholestagic nature), including hepatic insufficiency, including very rare cases of severe hepatic insufficiency (some with fatal outcome or requiring liver transplantation, in most cases, when hepatic insufficiency developed,patients had serious concomitant systemic diseases and the cause-and-effect relationship of hepatic insufficiency with terbinafine was doubtful), hepatitis, jaundice, cholestasis, increased activity of "hepatic" enzymes.

Disorders from the digestive system.

very often - bloating, decreased appetite, indigestion, nausea, mild abdominal pain, diarrhea.

Disturbances from the skin and subcutaneous tissue: very often - a rash, hives; infrequently - photosensitivity reactions;

very rarely - Stevens-Johnson syndrome, toxic epidermal necrolysis, ostium generalized exanthematous pustulosis, erythema multiforme, toxic skin rash, exfoliative dermatitis, bullous dermatitis, psoriasis-like skin rashes or exacerbation of psoriasis, alopecia.

Disturbances from the musculoskeletal and connective tissue: very often - arthralgia, myalgia.

General disorders:

often a feeling of fatigue;

HOften - an increase in body temperature.

Laboratory and instrumental data:

HOften - weight loss (secondary to the violation of taste).

According to the post-registration application (frequency of adverse events re can be installed)

Immune system disorders:

anaphylactic reactions; a syndrome similar to serum sickness.

Disorders from the side of the organ of vision:

Зatumanization of vision, reduction of visual acuity.

Disturbances from the skin and subcutaneous tissue:

drug rash with eosinophilia and systemic symptoms (rash, swelling, fever and swelling of the lymph nodes).

Hearing disorders and labyrinthine disturbances:

Deafness, hearing loss.

Vascular disorders: whines.

Impaired nervous system:

Loss of smell, including for a long period of time; decrease in olfaction.

Disorders from the digestive system: pancreatitis.

Disturbances from the musculoskeletal and connective tissue: rhabdomyolysis.

General disorders: influenza-like syndrome.

Laboratory and instrumental data:

increased activity of creatine phosphokinase in blood plasma.

Overdose:

Symptoms

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

Treatment

Measures for the removal of the drug (gastric lavage, reception of activated charcoal); if necessary, symptomatic and supportive therapy.

Interaction:

The plasma clearance of terbinafine can be accelerated by the influence of drugs-inducers of metabolism and suppressed under the influence inhibitors of cytochrome P450. If it is necessary to simultaneously apply the above drugs and terbinafine, a corresponding correction of the dosage regimen of the latter may be required.

Cimetidine can enhance the action of terbinafine or increase its concentration in the blood plasma. Cimetidine reduces terbinafine clearance by 33%.

Fluconazole increases C_max and AUC terbinafine by 52% and 69%, respectively, due to the inhibition of isoenzymes CYP2C9 and CYP3A4. Such an increase in terbinafine exposure may occur with the use of other drugs inhibiting enzymes CYP2C9 and CYP3A4, for example, ketoconazole and amiodarone.

Rifampicin can reduce the effect of terbinafine or reduce its concentration in the blood plasma. Rifampicin increases the terbinafine clearance by 100%.

The effect of terbinafine on other drugs

P studies in vivo and in vitro it has been shown that terbinafn inhibits metabolism mediated by an isoenzyme 2D6 (CYP2D6). These data can be clinically significant for those drugs that are metabolized primarily by this enzyme: tricyclic antidepressants, beta-adrenoblockers (megarrolol, gropranolol), selective serotonin reuptake inhibitors, antiarrhythmic drugs (IA, IB, IC class), antipsychotic drugs (chlorpromazine, haloperidol) and monoamine oxidase B inhibitors of type (selegiline), - if the drug used simultaneously has a small range of therapeutic concentration.

Terbinafine reduces clearance desipramine on 82%.

In studies on healthy volunteers with active metabolism dextromethorphan (antitussive and substrate CYP2D6) terbinafnn increased the metabolic coefficient of dextromethorphan / dextrorphan in urine 16-97 times. Thus, terbinafine in individuals with high isoenzyme activity (FROMYP2D6 can reduce the activity of the latter.

Terbinafine reduces clearance caffeine when administered intravenously by 19%.

When combined with ethanol or drugs that have a hepatotoxic effect, there is a risk of developing drug damage to the liver.

When used simultaneously with warfarin terbinafnn reduces prothrombin three (cause-effect relationship not established).

Terbinafnn increases clearance cyclosporine by 15%.

Drug interactions that do not or have little effect

The results of studies conducted in vitro and in healthy volunteers, showthen terbinafine has little potential for suppressing or enhancing the clearance of most drugs that are metabolized by the cytochrome P450 system (for example, Terfenadine, triazolam, tolbutamide, oral contraceptives), except for those that are metabolized with the participation of isoenzyme CYP2D6.

Terbinafnn does not affect the clearance phenazone or digoxin.

Terbinafnn does not significantly affect the pharmacokinetics fluconazole.

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

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

Interaction with food products and drinks

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

Special instructions:

Irregular application or early termination of treatment increases the risk of developing rschidiva.

If, after 2 weeks of treatment, there is an improvement in the condition, it is necessary to repeatedly determine the causative agent of the disease and its sensitivity to the drug.

Before and during the treatment (4-6 weeks after the start of treatment), it is necessary to monitor the indicators of liver function. Hepatotoxicity can occur both in patients with previous liver diseases and without them. In the case of increased activity of "hepatic" samples and / or in the detection of symptoms,suggesting a violation of liver function (decreased appetite, persistent nausea, jaundice, dark urine, light feces, excessive fatigue), it is necessary to cancel the drug.

Care should 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) were extremely rare when terbinafine was used.

When terbinafine was used in tablets, extremely rare cases of changes in the cellular composition of the blood (neutropenia, agranulocytosis, thrombocytopenia, pancytopenia) were noted. In case of qualitative or quantitative changes in the blood constituents, the cause of the impairment should be determined and the issue of reducing the dose of the drug or, if necessary, stopping therapy with Terbabinia should be considered (see the subsection "Pharmacokinetics").

Since the use of terbinafine in patients with renal dysfunction of KK less than 50 ml / min or a creatinine concentration in the blood plasma of more than 300 μmol / l) is notis sufficiently studied, the drug Terbinafii is not recommended for patients with impaired renal function.

Three patients with a history of psoriasis should use Terbinafia cautiously. since there are data on cases of exacerbation of the disease. Systemic use in onychomycosis is justified only in case of total defeat of most nails, the presence of pronounced subungual hyperkeratosis, ineffectiveness of previous local therapy.

Removal of nail plates in the treatment of onychomycosis of the brushes for 3 weeks and onychomycosis of the feet for 6 weeks is not required.

In the process of treatment (after 2 weeks) and at the end it is necessary to produce antifungal treatment of shoes, socks and stockings.

Effect on the ability to drive transp. cf. and fur:

There is no data on the effect of terbinafine on the ability to drive vehicles and mechanisms. With the development of vertigo on the background of Terbinafia therapy, patients should not drive vehicles and / or engage in potentially hazardous activities requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Tablets 250 mg.

7 evil 10 tablets in a planar cell packaging made of a polyvinylchloride film made of aluminum foil.

1, 2 or 4 contour packs of 7 tablets or 1, 2 or 3 contour packs of 10 tablets together with instructions for use in a pack of cardboard.

Packaging:

Tablets 250 mg.

7 or 10 tablets in a planar cell packaging made of a polyvinylchloride film made of aluminum foil.

1, 2 or 4 contour packs of 7 tablets or 1, 2 or 3 contour packs of 10 tablets together with instructions for use in a pack of cardboard.

Storage conditions:

Store in a dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-000653

Date of registration:28.09.2011

The owner of the registration certificate:VERTEKS, AO VERTEKS, AO Russia

Manufacturer: & nbsp

VERTEKS, AO Russia

Information update date: & nbsp20.09.2015

Illustrated instructions

Instructions

Terbinafine (Terbinafine)