Terbinafine tablets 250 mg No. 10

Translation of the instructions can be

Instruction

For medical use of the medicinal product

Terbinafine

(Terbinafine)

Composition:

Active ingredient: terbinafine;

1 tablet contains terbinafine hydrochloride (as terbinafine) 250 mg;

Excipients: lactose monohydrate; magnesium stearate; microcrystalline cellulose; colloidal anhydrous silica; polyethylene glycol-1500; croscarmellose sodium.

Dosage form.

Pills.

Main physicochemical properties: solid, regular, round cylinders, the upper and lower surfaces of which are flat, the edges of the surfaces are beveled, with a dividing line, white with a yellowish tint.

Pharmacotherapeutic group.

Antifungal drugs for systemic use.

PBX code D01B A02.

Pharmacological properties.

Pharmacodynamics.

Terbinafine is an allylamine with a broad spectrum of activity against fungal infections of the skin, hair and nails caused by dermatophytes such as Trichophyton (e.g. T. rubrum, T. mentagrophytes, T. verrucosum, T. tonsurans, T. violaceum), Microsporum (e.g. Microsporum canis), Epidermophyton floccosum and yeasts of the genus Candida (e.g. Candida albicans) and Pityrosporum. At low concentrations, terbinafine has fungicidal activity against dermatophytes, molds and some dimorphic fungi. The activity against yeasts, depending on their species, can be fungicidal or fungistatic.

Terbinafine specifically inhibits the early stage of sterol biosynthesis in the fungal cell. This leads to ergosterol deficiency and intracellular accumulation of squalene, which causes fungal cell death. Terbinafine acts by inhibiting the enzyme squalene epoxidase in the fungal cell membrane. This enzyme does not belong to the cytochrome P450 system.

When taken orally, the drug accumulates in the skin, hair, and nails in concentrations that provide a fungicidal effect.

Pharmacokinetics.

After oral administration, taking into account first-pass metabolism, terbinafine is well absorbed (70%), and the absolute bioavailability of terbinafine is approximately 50%. A single oral dose of 250 mg of terbinafine showed a mean maximum plasma concentration (Cmax) of 1.3 μg/ml 1.5 hours after administration.

At steady state, compared with a single dose, Cmax of terbinafine was on average 25% higher, and the area under the plasma concentration-time curve (AUC) increased 2.3-fold. Based on the increase in AUC in plasma, an effective half-life of 30 hours can be calculated. Food has little effect on the bioavailability of terbinafine (increase in AUC by approximately 20%), which does not require dose adjustment.

Terbinafine is highly bound to plasma proteins (99%). It diffuses rapidly through the dermis and is concentrated in the lipophilic stratum corneum. Terbinafine is also secreted into sebum and reaches high concentrations in hair follicles, hair and skin. Terbinafine has been shown to be distributed into the nail plate during the first weeks after initiation of therapy.

Terbinafine is rapidly metabolized with the participation of at least 7 cytochrome P450 isoenzymes, with the main role played by CYP2C9, CYP1A2, CYP3A4, CYP2C8, CYP2C19 isoenzymes. No changes in the equilibrium concentration of Terbinafine in blood plasma have been detected depending on age, but in patients with impaired renal or hepatic function, the rate of drug excretion may be slowed, leading to higher concentrations of terbinafine in the blood.

As a result of the biotransformation of terbinafine, metabolites are formed that have no antifungal activity and are excreted mainly in the urine.

Single-dose pharmacokinetic studies in patients with renal impairment (creatinine clearance

Clinical characteristics.

Indication.

Fungal infections of the skin and nails caused by Trichophyton (e.g. T. rubrum, T. mentagrophytes, T. verrucosum, T. violaceum), Microsporum canis and Epidermophyton floccosum.

1. Terbinafine for oral use is indicated for the treatment of ringworm (trichophytosis of smooth skin, trichophytosis of the perineum and dermatophytosis of the feet) in cases where the localization of the lesion, severity or prevalence of the infection make oral therapy appropriate.

2. Oral terbinafine is indicated for the treatment of onychomycosis.

Contraindication.

Hypersensitivity to terbinafine or to any of the excipients of the drug.

Acute or chronic liver disease.

Interaction with other drugs and other types of interactions.

Effects of other drugs on terbinafine

The plasma clearance of terbinafine may be increased by drugs that induce metabolism and may be decreased by drugs that inhibit cytochrome P450. If concomitant treatment with such drugs is necessary, the dosage of terbinafine should be adjusted.

Drugs that may reduce the effects or plasma concentrations of terbinafine

Rifampicin increased the clearance of terbinafine by 100%. AUC and Cmax decreased by 50% and 45%, respectively.

Drugs that may increase the exposure or plasma concentrations of terbinafine

Cimetidine reduced the clearance of terbinafine by 30%.

Fluconazole increased the Cmax and AUC of terbinafine by 52% and 69%, respectively, due to inhibition of CYP2C9 and CYP3A4 enzymes. The same increase may be observed when terbinafine is co-administered with drugs that inhibit CYP2C9 and CYP3A4, such as azole fungicides (ketoconazole), macrolide antibiotics, and amiodarone.

The results of studies conducted in vitro and in healthy volunteers show that terbinafine has a negligible potential to inhibit or increase the clearance of drugs metabolized by the cytochrome P450 system (e.g. terfenadine, triazolam, tolbutamide or oral contraceptives), with the exception of those drugs metabolized by CYP2D6.

CYP2D6 substrates:

In vitro and in vivo studies have shown that terbinafine inhibits CYP206-mediated metabolism. These findings are more relevant for substances that are predominantly metabolized by this enzyme, especially if they have a narrow therapeutic range. These findings may be clinically relevant for patients receiving the following classes of drugs: tricyclic antidepressants, β-blockers, selective serotonin reuptake inhibitors, antiarrhythmics (including class 1A, 1B and 1C) or monoamine oxidase type B inhibitors.

Terbinafine reduced desipramine clearance by 82% and increased AUC 5-fold.

In CYP2D6 extensive metabolizers, terbinafine increased the urinary dextromethorphan/dextrorphan metabolic interaction ratio by an average of 16-97-fold. This suggests that terbinafine slows the metabolism of CYP2D6 substrates in CYP2D6 extensive metabolizers (“extensive metabolizers”), i.e., the metabolism in these patients is maximally similar to that in poor metabolizers (“poor metabolizers”).

Other metabolic pathways

Terbinafine increases the clearance of cyclosporine by 15% (decrease in AUC by 13%).

Terbinafine does not affect the clearance of antipyrine or digoxin.

No effect of terbinafine on the pharmacokinetics of fluconazole was observed. Furthermore, no clinically significant interaction was observed between terbinafine and concomitantly administered medicinal products with possible interaction potential, such as co-trimoxazole (trimethoprim and sulfamethoxazole), zidovudine or theophylline.

Some cases of menstrual disorders (intermenstrual bleeding and irregular menstrual cycles) have been reported in patients taking terbinafine concomitantly with oral contraceptives, although the frequency of these disorders remains within the range of adverse reactions in patients taking oral contraceptives alone.

Medicinal products whose effects or plasma concentrations may be increased by terbinafine

In studies in healthy volunteers who were extensive metabolizers of dextromethorphan (an antitussive and CYP2D6 marker substrate), terbinafine increased the urinary dextromethorphan/dextrorphan metabolic interaction ratio by an average of 16-97-fold. Thus, terbinafine may result in a change in the status of CYP2D6 extensive metabolizers to poor metabolizers.

Terbinafine may increase the effects or plasma concentrations of the following drugs:

Caffeine: Terbinafine reduces the clearance of intravenous caffeine by 21%. Terbinafine reduces the clearance of desipramine by 82%.

Drugs whose effects or plasma concentrations may be reduced by terbinafine: terbinafine increased the clearance of cyclosporine by 15%.

In patients receiving terbinafine concomitantly with warfarin, changes in international normalized ratio (INR) and/or prothrombin time have been reported in very rare cases.

Application features.

liver function

Terbinafine tablets are contraindicated in patients with chronic or acute liver disease. Any pre-existing liver disease should be evaluated before prescribing the drug. In patients with pre-existing liver disease, the clearance of terbinafine may be reduced by approximately 50%.

Hepatotoxicity may occur in patients with and without a history of liver disease, therefore periodic monitoring of liver function is recommended (after 4-6 weeks of treatment). The drug should be discontinued immediately if liver function tests become elevated. In patients taking terbinafine tablets, cases of serious liver failure (some of which required liver transplantation or were fatal) have been reported very rarely. In most cases of liver failure, the patients had serious underlying systemic diseases, and the causal relationship to terbinafine tablets was questionable.

Patients taking Terbinafine should be advised to immediately report to their physician any unexplained persistent nausea, anorexia, fatigue, vomiting, right upper abdominal pain, jaundice, dark urine or light-colored stools, or itching. Patients with these symptoms should discontinue Terbinafine and have their liver function evaluated promptly.

taste disturbance

Taste disturbances and loss of taste have been reported with terbinafine. This may lead to decreased appetite, weight loss, fainting, and depressive symptoms. If symptoms of taste disturbances occur, the drug should be discontinued.

impaired sense of smell

Disturbances and loss of smell have also been reported. These disturbances may resolve after discontinuation of therapy, but may also be persistent (more than 1 year) or permanent. If olfactory disturbances occur, the drug should be discontinued.

During treatment with the drug, depressive symptoms may occur, which may require treatment.

hematological effects

Blood abnormalities (neutropenia, agranulocytosis, thrombocytopenia, pancytopenia) have been reported very rarely in patients taking terbinafine hydrochloride tablets. In the event of any blood abnormality in patients taking terbinafine, a possible change in drug therapy, including discontinuation of the drug, should be recommended.

dermatological effects

Serious skin reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported very rarely in patients taking terbinafine hydrochloride tablets. If a progressive skin rash develops, terbinafine treatment should be discontinued.

The drug should be used with caution in patients with psoriasis or cutaneous or systemic lupus erythematosus, as very rare cases of exacerbation of these diseases have been reported.

Single-dose pharmacokinetic studies in patients with liver disease have shown that the clearance of terbinafine may be reduced by approximately 50%.

kidney function

The use of terbinafine tablets in patients with renal impairment (creatinine clearance less than 50 ml/min or serum creatinine level greater than 300 μmol/l) has not been adequately studied and is therefore not recommended.

general

Personal hygiene rules should be followed to prevent reinfection (from infected underwear, socks, shoes, etc.).

The drug contains lactose monohydrate, therefore, patients with galactose intolerance, lactase deficiency or glucose-galactose malabsorption should use the drug with caution.

interactions

In vitro and in vivo studies have shown that terbinafine is an inhibitor of the CYP2D6 enzyme. Patients should be carefully monitored if they are concomitantly taking drugs that are metabolized primarily by the CYP2D6 enzyme (e.g. tricyclic antidepressants, β-blockers, selective serotonin reuptake inhibitors, antiarrhythmics (including class 1A, 1B and 1C) or monoamine oxidase type B inhibitors), especially if these drugs have a narrow therapeutic window.

Use during pregnancy or breastfeeding.

Animal studies on the toxic effects of terbinafine on the fetus and fertility did not reveal any adverse effects.

Clinical experience with terbinafine in pregnant women is limited. During pregnancy, the drug should be used only if the expected benefit to the mother outweighs the potential risk to the fetus.

Terbinafine passes into breast milk, so if necessary, breastfeeding should be discontinued.

The ability to influence the reaction speed when driving vehicles or other mechanisms.

There are no data on the effect of terbinafine on the ability to drive and use other mechanisms. However, if patients experience dizziness as an undesirable effect of the drug, they should refrain from driving or operating other mechanisms.

Method of administration and doses.

Apply internally.

adults

250 mg once a day.

The duration of treatment depends on the nature and severity of the disease.

children

A review of the safety data for oral terbinafine in children has shown that the adverse event profile in children is similar to that in adults. There is no evidence of any new, unusual, or more serious reactions than those observed in adult patients. However, as data on the use of the drug are still limited to date, its use is not recommended in this age group.

skin infections

Recommended duration of treatment:

Complete disappearance of symptoms of infection may occur only a few weeks after the absence of pathogens is detected through laboratory control.

Scalp infections

The recommended duration of treatment for fungal infections of the scalp is 4 weeks.

Fungal infection of the scalp is observed mainly in children.

onychomycosis

The duration of treatment for most patients is from 6 weeks to 3 months.

Treatment periods of less than 3 months may be considered for patients with fingernails, toenails other than the big toe, or younger patients. For toenails, 3 months is usually sufficient, although some patients may require treatment for 6 months or longer. Patients requiring longer treatment may be identified by decreased nail growth during the first few weeks of treatment.

Complete disappearance of infection symptoms may occur only a few weeks after laboratory testing has shown the absence of pathogens. This is due to the regrowth of a healthy nail.

special populations

Patients with liver dysfunction

Terbinafine tablets are not recommended for use in patients with chronic or active liver disease.

The use of terbinafine tablets in patients with renal impairment has not been adequately studied and is therefore not recommended in this patient group.

Elderly patients

There is no evidence that elderly patients require a different dose or that they experience different side effects than younger patients. In this age group, the possibility of impaired liver or kidney function should be taken into account when using the drug.

Procedure in case of missed dose

If the patient forgets to take a dose, the next dose should be taken as soon as possible after remembering. However, due to the pharmacokinetic properties of terbinafine, the missed dose should not be taken if the interval between the missed dose and the next dose is less than 4 hours.

Children.

Since data on the use of the drug in children are still limited, it is not recommended for use in this age group of patients.

Overdose.

Several cases of overdose (oral administration of up to 5 g of terbinafine) have been reported, with headache, nausea, epigastric pain and dizziness.

Treatment: removal of the drug primarily with activated charcoal and use of symptomatic therapy if necessary.

Adverse reactions.

Terbinafine is well tolerated. Adverse reactions are usually mild to moderate and transient.

From the blood system: neutropenia, agranulocytosis, thrombocytopenia, pancytopenia, anemia.

Immune system disorders: anaphylactoid reactions (including angioedema); cutaneous and systemic manifestations of lupus erythematosus; anaphylactic reaction; serum sickness-like reactions (including rash, itching, urticaria, oedema, arthralgia, fever and lymphadenopathy).

Psychiatric: depression, anxiety.

Nervous system: headache, dizziness; dysgeusia up to loss of taste. Taste disturbances, including loss of taste sensations, which usually recover within a few weeks after discontinuation of the drug. Very rarely, prolonged taste disturbances have been reported, sometimes leading to reduced food intake and significant weight loss. Paresthesia, hypoesthesia, permanent dysgeusia; hyposmia and anosmia, including permanent anosmia and hyposmia.

From the organs of hearing and balance: vertigo, tinnitus, hearing loss, hearing impairment.

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

Gastrointestinal tract: gastrointestinal symptoms (feeling of fullness of the stomach, dyspepsia, nausea, abdominal pain, diarrhea), pancreatitis.

Metabolic disorders: decreased appetite, weight loss (resulting in dysgeusia). Severe cases of decreased food intake leading to significant weight loss have been reported.

Hepatobiliary: Cases of serious liver dysfunction, including hepatic failure, elevated liver enzymes, jaundice, cholestasis and hepatitis. If liver dysfunction develops, terbinafine treatment should be discontinued. Very rare cases of serious liver failure have been reported (some fatal or requiring liver transplantation). In most cases of liver failure, patients had serious underlying systemic diseases, and the causal relationship to terbinafine was questionable.

Skin: mild skin reactions (rash, urticaria), severe skin reactions (e.g. erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity); alopecia; acute generalized exanthematous pustulosis, psoriatic rash or exacerbation of psoriasis, hair loss, although a causal relationship has not been proven. Rash with eosinophilia and systemic symptoms. If a progressive skin rash occurs, treatment with the drug should be discontinued.

Musculoskeletal system: arthralgia, myalgia, rhabdomyolysis.

General disorders: fatigue, malaise, vasculitis, influenza-like illness, pyrexia.

Laboratory indicators: increased blood creatine phosphokinase level.

Other adverse drug reactions that were reported during post-marketing studies based on spontaneous reports.

The adverse drug reactions listed below were identified based on post-marketing spontaneous reactions and are classified by system organ class.

Because these reactions were reported voluntarily from an unknown number of patients, it is not always possible to reliably estimate their frequency.

On the part of the immune system: anaphylactic reactions, serum sickness-like reactions, hypersensitivity reactions, including allergic reactions (including anaphylaxis).

From the nervous system: anosmia, including permanent anosmia, hyposmia, hypoesthesia, paresthesia.

From the organs of vision: blurred vision, decreased visual acuity.

Vascular disorders: vasculitis.

Gastrointestinal tract: pancreatitis.

Skin and subcutaneous tissue disorders: rash with eosinophilia and systemic symptoms, exfoliative and bullous dermatitis.

Musculoskeletal system: rhabdomyolysis.

Laboratory indicators: increased blood creatine phosphokinase levels, changes in prothrombin time (prolongation, reduction) in patients who were simultaneously taking warfarin.

Expiration date.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets in a blister; 1 blister in a cardboard pack.

Vacation category.

According to the recipe.

Producer.

PJSC Lubnyfarm.

Location of the manufacturer and address of its place of business.

Ukraine, 37500, Poltava region, M lubny, Barvinkovy St., 16.