Atifin - instructions for use, dose, side effects, contraindications

Pharmacodynamics:Terbinafine belongs to the group of allylamines, it has a wide spectrum of action against fungi that cause skin, hair and nail diseases, including dermatophytes. In low concentrations has a fungicidal effect on Dermatophytes Trichophyton spp. (T. rubrum, T. mentagrophytes, T. tonsurans, T. verrucosum, T.violaceum), Microsporum canis, Epidermophyton jloccosum, molds (for example, Scopulariopsis brevicalius), yeast fungi, mainly, Candida albicans, and some dimorphic fungi. On mushrooms Candida spp. and its mycelial forms, depending on the type of fungus, fungicidal or fungistatic action.

Terbinafine disrupts the early stage of biosynthesis of the main component of the cell membrane of the ergosterol fungus by inhibiting the enzyme squalene epoxidase. The squalene epoxidase is not bound to the isoenzyme CYP450, so terbinafine does not affect the metabolism of hormones and drugs, the metabolism of which is associated with the isoenzyme CYP450.

When taking the drug inside in the skin, hair and nails are created concentrations of terbinafine, providing fungicidal effect.

When ingestion is not effective in the treatment of varicolored lichen caused by Pityrosporum ovale, Pityrosporum orbiculare (Malassezia furfur).

Pharmacokinetics:After oral administration terbinafine is well absorbed (> 70%), the absolute bioavailability of terbinafine due to the effect of "primary transmission" through the liver is approximately 50%. After a single administration of terbinafine inwards at a dose of 250 mg, its maximum concentration (C_m_Oh) in the blood plasma is achieved after 1.5 hours and is 1.3 μg / ml. FROM_m_Oh terbinafine in blood plasma with its constant application, on average, increased by 25% compared with a single dose, the value of the area under the curve "concentration-time" (AUC) increased by 2.3 times. Based on the increase AUC, it is possible to calculate the effective half-life (30 h). Food intake moderately affects the bioavailability of the drug (value 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 accumulates in the lipophilic stratum corneum of the epidermis. Terbinafine also penetrates into the secretion of sebaceous glands, which provides a high concentration 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.

Metabolised quickly and to a significant extent with the participation of at least seven isoenzymes of cytochrome P450. The main role is played by isozymes CYP2C9, CYP1A2, CYP3A4, CYP2C8 and CYP2C19. As a result of the biotransformation of terbinafine, metabolites are formed that do not possess antifungal activity and are excreted mainly by the kidneys.

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

In patients with concomitant renal dysfunction (creatinine clearance [CK] <50 ml / min) and with liver disease, terbinafine clearance can be reduced by 50%.

Excreted in breast milk.

Indications:

Superficial mycoses caused by microorganisms sensitive to terbinafine: onychomycosis caused by mushrooms by dermatophytes; mycosis of the scalp; dermatomycosis of the trunk, legs, feet; candidiasis of the skin, when the localization, severity or prevalence of infection causes the expediency of oral therapy.

Contraindications:

- Hypersensitivity to terbinafine and other components of the drug.

- Children under 3 years of age and / or children weighing less than 20 kg (for this dosage form);

- Deficiency of lactase, lactose intolerance, glucose-galactose malabsorption syndrome;

- Chronic or active liver disease;

- It is not recommended to use Atifin® in patients with impaired renal function (CC less than 50 ml / or serum creatinine concentration more than 300 μmol / L), since the use of the drug in this category of patients is not sufficiently studied.

Carefully:

Violation of kidney function (QC more than 50 ml / min), oppression of bone marrow hematopoiesis, psoriasis, cutaneous lupus erythematosus, systemic lupus erythematosus, pregnancy.

Pregnancy and lactation:

Pre-clinical data suggest that there are undesirable effects on fertility and toxic effects on the fetus. Since the clinical experience of terbinafine in pregnant women is very limited.

Do not use Atifin® during pregnancy, except when the expected benefit of providing therapy for the mother exceeds the potential risk to the fetus.

Terbinafine is excreted in breast milk, so if you need to use the drug Atifin®, you should stop breastfeeding.

Dosing and Administration:

Inside, regardless of the time of eating, drink with water. It is advisable to apply the drug at the same time of day.

The duration of the course of treatment and the dosage regimen is set individually and depends on the localization of the process and the severity of the disease.

Adults: 250 mg (1 tablet) once a day.

Children:

Weight of child's body	Dose
20-40 kg	125 mg (1/2 250 mg tablets) once a day
More than 40 kg	250 mg (1 tablet) once a day

Duration of treatment is different and depends on the indications and severity of the infection.

Disease	Duration of treatment
Skin Infections
Dermatomycosis of the foot (interdigital, plantar or by the type of socks)	2-6 weeks
Dermatomycosis of the trunk, shins and inguinal dermatomycosis	2-4 weeks
Candidiasis of the skin	2-4 weeks
Complete disappearance of manifestations of infection and complaints associated with it can occur no earlier than a few weeks after mycological cure.
Hair and scalp infections
Mycosis of the scalp	4 weeks
Mycosis of the scalp is observed mainly in children.
Onychomycosis	6-12 weeks
Onychomycosis of brushes	6 weeks
Onychomycosis of the feet	In most cases, 12 weeks of treatment are sufficient. Some patients who have a reduced rate of nail growth may require longer treatment. 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 assume that elderly people need to change the dosage regimen of the drug, or that they have side effects that differ from those in younger patients. In case of use in this age group of the drug in tablets, the possibility of concomitant impairment of liver or kidney function should be considered.

Side effects:

Classification of the incidence of side effects recommended by the World Health Organization (WHO):

very often ≥ 1/10

often from ≥ 1/100 to <1/10

infrequently from ≥ 1/1000 to <1/100

rarely from ≥1 / 10000 to <1/1000

very rarely <1/10000

the frequency of the unknown can not be estimated from the available data.

According to clinical studies

Violations from the blood and lymphatic system:

very rarely: neutropenia, agranulocytosis, pancytopenia, thrombocytopenia. In the case of qualitative or quantitative changes in the blood constituents, the cause of the impairment should be determined and the question of reducing the dose of the drug or, if necessary, discontinuing therapy with Atifin® should be considered.

Immune system disorders:

very rarely: anaphylactoid reactions (including angioedema), cutaneous and systemic lupus erythematosus (or exacerbation).

Impaired nervous system:

often: headache;

infrequently: a violation of taste, including their loss (usually recovery occurs within a few weeks after cessation of treatment);

very rarely: dizziness, paresthesia, hypoesthesia;

the frequency is unknown: there are separate reports of cases of prolonged violations of taste sensations. In some cases, while taking the drug, a decrease in food intake was noted, which led to a significant reduction in weight.

Disorders from the digestive system:

very often: a feeling of overflow of the stomach, loss of appetite, indigestion, nausea, mild abdominal pain, diarrhea.

Disorders from the sides of the liver and bile ducts:

rarely: hepatobiliary dysfunction (predominantly of a cholestatic nature);

very rarely: cases of severe hepatic insufficiency (some with a fatal outcome or requiring liver transplantation). In most cases, when hepatic insufficiency developed, patients had serious co-occurring systemic diseases, and the causal relationship of hepatic insufficiency with terbinafine was questionable.

Disturbances from the skin and subcutaneous tissues:

very often: non-severe skin reactions (skin rash, urticaria);

very rarely: serious skin reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis), psoriasis-like skin rashes or exacerbation of psoriasis, hair loss (cause-and-effect relationship with taking the drug is not established). If a progressive skin rash develops, treatment with Atifin® should be discontinued.

Disturbances from musculoskeletal and connective tissue:

very often: arthralgia, myalgia.

General disorders and disorders at the site of administration:

very rarely: feeling tired.

Post-registration application (frequency of adverse events can not be established)

Violations from the blood and lymphatic system: anemia.

Immune system disorders: anaphylactic reactions, a syndrome similar to serum sickness.

Disorders of the psyche: symptoms of anxiety and depression are secondary to taste disorders.

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

Hearing disorders and labyrinthine disturbances: hearing loss, tinnitus.

Vascular disorders: vasculitis.

Disorders from the digestive system: pancreatitis.

Disturbances from the skin and subcutaneous tissues: photosensitivity reactions (eg, photodermatosis, photosensitivity and polymorphic light rash).

Disturbances from the musculoskeletal and connective tissue: rhabdomyolysis.

General disorders and disorders at the site of administration: flu-like syndrome, fever.

Laboratory and instrumental data: increased activity kreatinfosfokinazy in the blood serum.

Overdose:

Symptoms: there have been reports of several cases of overdose (the accepted dose of terbinafine to 5 g), which included headache, nausea, epigastric pain and dizziness.

Treatment: gastric lavage followed by the use of activated charcoal, if necessary - symptomatic and supportive therapy.

Interaction:

The effect of other drugs on terbinafine

The terbinafine plasma clearance can be accelerated under the influence of drugs of metabolism inducers and suppressed under the influence of inhibitors of the cytochrome P450 system. If it is necessary to simultaneously apply the above preparations and the drug Atifin®, 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_m_Oh and AUC terbinafine by 52% and 69%, respectively, due to the inhibition of isoenzymes CYP2C9 and CYP3A4. Such an increase in exposure Terbinafine may occur when other isozyme inhibitory drugs are used CYP2C9 and CYP3F4, for example, ketoconazole and amiodarone.

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

The effect of terbinafine on other drugs

The results of studies conducted in conditions in vitro and in healthy volunteers, show that terbinafine has little potential to suppress or enhance the clearance of most drugs that are metabolized by the cytochrome P450 system (eg, terfenadine, triazolam, tolbutamine or oral contraceptives), except for those that are metabolized with isoenzyme 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 co-trimoxazole components (trimethoprim and sulfamethoxazole), zidovudine, or theophylline.

There are reports of several cases of menstrual irregularities (acute bleeding and menstrual irregularity) in patients,who took the drug Atifin® concurrently with contraceptives for oral administration. At the same time, the frequency of these disorders does not exceed the average frequency in patients taking only oral contraceptives.

Terbinafine can enhance the effect of caffeine or increase its concentration in the blood plasma. Terbinafine reduces caffeine clearance by intravenous administration by 19%.

In studies in vivo and in vitro it was shown that terbinafine suppresses metabolism mediated by isoenzyme CYP2D6. These data can be clinically significant for those drugs that are metabolized primarily by this isoenzyme: tricyclic antidepressants, beta-blockers. selective serotonin reuptake inhibitors, antiarrhythmics IA, IB, IC class and monoamine oxidase type B inhibitors, if the concomitant drug has a small range of therapeutic concentration.

Terbinafine reduces the clearance of desipramine by 82%.

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

Terbinafine can weaken the action of cyclosporine and reduce its concentration in the blood plasma. Terbinafine increases the clearance of cyclosporine by 15%.

Special instructions:

The drug Atifin® in the dosage form of the tablet is not effective in multicolored (pityriasis) lichen.

Irregular application or early termination of treatment with Atifin® increases the risk of relapse. If after 2 weeks of using the drug Atifin®, there is no improvement, it is necessary to re-determine the pathogen and its sensitivity to the drug.

Before beginning therapy with the drug Atifin® in tablets, it is necessary to determine whether the patient has a history of liver disease. Hepatotoxicity can occur both in patients with previous liver diseases, and without them. Therefore, it is recommended to monitor liver function before the start of therapy and 4-6 weeks after the start of therapy. Terbinafine should be lifted immediately in the event of increased activity of "liver" enzymes in the blood serum.

Patients should be warned that you should immediately inform your doctor of the occurrence in patients receiving the drug symptoms such as persistent nausea, anorexia, fatigue, vomiting, pain in the right upper quadrant, jaundice, fatigue, dark urine or light cal . In case of appearance of such symptoms, it is necessary to immediately stop taking the drug and conduct a study of liver function.

It is not recommended to use the drug Atifin® in patients with chronic liver disease.

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

It is necessary to carry out continuous monitoring of the patients receiving both drugs that are metabolized mainly isoenzyme CYP2D6 (such as tricyclic antidepressants, beta-blockers. Selective serotonin reuptake inhibitor, antiarrhythmics IA, IB, IC class and monoamine oxidase type B inhibitors) in the case where the concomitant drug has a small range of therapeutic concentration.

In patients with psoriasis terbinafine should be used with extreme caution, since in very rare cases terbinafine can provoke an exacerbation of the disease.

Dermatological effects

When terbinafine is used in very rare cases, serious skin reactions are possible (including Stevens-Johnson syndrome, toxic epidermal necrolysis). When the skin rash progresses, the drug should be discarded.

Hematological effects

When terbinafine was taken orally, changes in the blood were very rarely recorded (neutropenia, agranulocytosis, thrombocytopenia, pancytopenia). In the case of qualitative or quantitative changes in the blood constituents, the cause of the impairment should be determined and the question of reducing the dose of the drug or, if necessary, discontinuing therapy with Atifin® should be considered.

Impaired renal function

Since the use of terbinafine in patients with impaired renal function (QC less than 50 ml / min or a serum creatinine concentration of more than 300 μmol / L) is insufficientAtifin® is not recommended for use in this category of patients (see the subsection "Pharmacokinetics").

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

The effect of Atifin® on the ability to drive vehicles and work with mechanisms has not been studied. When dizziness develops against the background of drug therapy, patients should not drive vehicles or work with mechanisms.

Form release / dosage:

Tablets, 250 mg.

Packaging:

For 7 tablets in a blister of the combined material of a PVC / PVDC-aluminum foil (PVC/PVDC and Al-Folga).

For 2 or 4 blisters in a pack of cardboard along with instructions for use.

Storage conditions:At a temperature of no higher than 25 ° C, in the original packaging.

Keep out of the reach of children.

Shelf life:

5 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-000090

Date of registration:31.05.2007 / 07.02.2014

Expiration Date:Unlimited

The owner of the registration certificate:KRKA, dd, Novo mesto, AOKRKA, dd, Novo mesto, AO

Manufacturer: & nbsp

KRKA, d.d. Slovenia

Representation: & nbspKRKA KRKA Slovenia

Information update date: & nbsp20.10.2017

Illustrated instructions

Instructions

Atifin® (Atifin®)