Terbinafine

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TERBINAFIN (TERBINAFIN)

Composition:

Active substance: terbinafin;

1 tablet contains terbinafine hydrochloride (equivalent to terbinafine) 250 mg;

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

Pharmaceutical form. Tablets.

Main physicochemical properties: intact, regular, round cylindrical tablets with flat upper and lower surfaces, beveled edges, a dividing score line, white to off-white in color.

Pharmacotherapeutic group.

Antifungal agents for systemic use.

ATC 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, as well as yeast-like fungi of the genus Candida (e.g., Candida albicans) and Pityrosporum. At low concentrations, terbinafine exerts a fungicidal effect against dermatophytes, molds, and some dimorphic fungi. Activity against yeast fungi may be either fungicidal or fungistatic, depending on the species.

Terbinafine specifically inhibits an early stage of sterol biosynthesis in fungal cells. This leads to ergosterol deficiency and intracellular accumulation of squalene, resulting in fungal cell death. The mechanism of action of terbinafine involves inhibition of the enzyme squalene epoxidase in the fungal cell membrane. This enzyme does not belong to the cytochrome P450 system.

When administered systemically, the drug accumulates in the skin, hair, and nails at concentrations sufficient to exert a fungicidal effect.

Pharmacokinetics

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

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

Terbinafine is highly bound to plasma proteins (99%). It rapidly diffuses through the dermis and concentrates in the lipophilic stratum corneum. Terbinafine is also excreted in sebum and reaches high concentrations in hair follicles, hair, and skin. It has been demonstrated that terbinafine distributes into the nail plates within the first weeks of therapy.

Terbinafine is rapidly metabolized by at least seven isoenzymes of the cytochrome P450 system, with CYP2C9, CYP1A2, CYP3A4, CYP2C8, and CYP2C19 playing the major roles. No changes in the plasma equilibrium concentration of terbinafine have been observed related to age. However, in patients with impaired renal or hepatic function, the elimination rate of the drug may be reduced, leading to higher plasma concentrations of terbinafine.

As a result of biotransformation, terbinafine produces metabolites that lack antifungal activity and are primarily excreted in urine.

Pharmacokinetic studies of single doses in patients with renal impairment (creatinine clearance < 50 mL/min) or pre-existing liver disease have shown that the clearance of terbinafine may be reduced by approximately 50%.

Clinical characteristics.

Indications.

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. Oral terbinafine is indicated for the treatment of dermatophytosis (tinea corporis, tinea cruris, and tinea pedis) in cases where the location, severity, or extent of the infection warrants systemic therapy.
2. Oral terbinafine is indicated for the treatment of onychomycosis.

Contraindications.

Hypersensitivity to terbinafine or to any of the excipients of the medicinal product.

Acute or chronic liver disease.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on the pharmacokinetics of terbinafine

Cytochrome P450 (CYP450) isoenzymes are involved in the metabolism of terbinafine. The plasma clearance of terbinafine may be increased by drugs that induce these enzymes and may be decreased by drugs that inhibit cytochrome P450. When concomitant therapy with such drugs is necessary, the dosage of terbinafine should be adjusted accordingly.

Enzyme inhibitors

Cimetidine reduced the clearance of terbinafine by 30% and increased AUC by 34%.

Fluconazole (an inhibitor of CYP3A4 and CYP2C9) increased Cmax and AUC of terbinafine by 52% and 69%, respectively. Similar increases may be observed when terbinafine is used concomitantly with drugs that inhibit CYP2C9 and CYP3A4, such as azole antifungals, macrolide antibiotics, or amiodarone.

Enzyme inducers

Rifampicin (an inducer of CYP3A4) increased the clearance of terbinafine by 100%. AUC and Cmax were reduced by 50% and 45%, respectively.

Effect of terbinafine on the pharmacokinetics of other medicinal products

CYP2D6 substrates: In vitro and in vivo studies have shown that terbinafine inhibits CYP2D6. These findings are particularly relevant for substances predominantly metabolized by this enzyme, especially those with a narrow therapeutic index (see section "Special warnings and precautions for use"). Examples include certain drugs from the following classes: tricyclic antidepressants, beta-blockers, selective serotonin reuptake inhibitors, antiarrhythmics (including class 1A, 1B, and 1C), or monoamine oxidase inhibitors type B.

Terbinafine reduced the clearance of desipramine by 82% and increased AUC fivefold.

In rapid metabolizers of CYP2D6, terbinafine increased the urinary metabolic interaction ratio of dextromethorphan/dextrorphan on average by 16–97 times. This indicates that terbinafine slows the metabolism of CYP2D6 substrates in rapid metabolizers ("extensive metabolizers"), so that metabolism in these patients closely resembles that in slow metabolizers ("poor metabolizers").

Substrates of other CYP450 enzymes: Results from in vitro studies and studies in healthy volunteers indicate that terbinafine has minimal potential to inhibit or enhance the clearance of most drugs metabolized by other cytochrome P450 isoenzymes (e.g., terfenadine, triazolam, or oral contraceptives).

Other metabolic pathways: Terbinafine increased the clearance of cyclosporine by 15% (reducing AUC by 13%).

The potential for interaction between terbinafine and commonly prescribed anticoagulants has not been studied. During a study with warfarin, no interactions were observed.

During clinical trials, no relevant effect on the pharmacokinetics of co-trimoxazole (trimethoprim and sulfamethoxazole), digoxin, fluconazole, phenazone, theophylline, or zidovudine was observed.

Special precautions for use

Oral terbinafine should only be used when topical treatment is not feasible.

Liver function

Terbinafine tablets are contraindicated in patients with chronic or acute liver disease. Prior liver disease must be assessed before initiating treatment. Baseline levels of ALT (alanine aminotransferase) and AST (aspartate aminotransferase) should be determined to allow comparison with values obtained during treatment. In patients with pre-existing liver disease, terbinafine clearance may be reduced by approximately 50%.

Hepatotoxicity has been observed in patients both with and without a history of liver disease; therefore, periodic monitoring of liver function (after 4–6 weeks of treatment) is recommended. Treatment should be discontinued immediately if liver function tests show elevated enzyme activity. Rare cases of severe hepatic failure (some fatal or requiring liver transplantation) have been reported in patients treated with terbinafine tablets. In most cases of liver failure, patients had serious underlying systemic conditions (see sections "Contraindications" and "Side effects").

Patients taking terbinafine should be advised to immediately inform their physician if they experience any signs or symptoms suggestive of liver dysfunction, such as persistent nausea, loss of appetite, jaundice, vomiting, increased fatigue, pain in the upper right part of the abdomen, dark urine, or pale stools. Patients experiencing these symptoms should discontinue oral terbinafine immediately, and liver function should be evaluated promptly.

Hypersensitivity reactions / severe skin reactions

Very rare cases of severe skin reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms [DRESS syndrome]) have been reported in patients receiving terbinafine tablets. Like skin reactions and eosinophilia, DRESS syndrome may involve one or more organs, leading to hepatitis, interstitial nephritis, interstitial pneumonitis, myocarditis, or pericarditis. Treatment with terbinafine tablets should be discontinued if progressive skin rashes or other possible signs of hypersensitivity occur.

Lupus erythematosus / psoriasis

Terbinafine should be used with caution in patients with psoriasis or cutaneous or systemic lupus erythematosus, as post-marketing reports have described exacerbations of these conditions.

Hematological effects

Very rare cases of blood disorders (neutropenia, agranulocytosis, thrombocytopenia, pancytopenia) have been reported in patients receiving terbinafine tablets. The cause of any pathological blood changes should be evaluated, and a possible change in treatment regimen, including discontinuation of terbinafine tablets, should be considered.

Renal function

The use of terbinafine tablets in patients with impaired renal function (creatinine clearance less than 50 mL/min or serum creatinine levels exceeding 300 µmol/L) has not been adequately studied and is therefore not recommended.

Interactions

In vitro and in vivo studies have shown that terbinafine is an inhibitor of the hepatic enzyme CYP2D6. Patients should be closely monitored when concomitantly receiving drugs primarily metabolized by CYP2D6 (e.g., tricyclic antidepressants, beta-blockers, selective serotonin reuptake inhibitors, antiarrhythmics (including class 1A, 1B, and 1C), or monoamine oxidase inhibitors type B), especially if these drugs have a narrow therapeutic index (see section "Interaction with other medicinal products and other forms of interaction").

Excipients

The sodium content of one tablet of this medicinal product is less than 1 mmol (23 mg), i.e., essentially sodium-free.

This medicinal product contains lactose and therefore should not be used in patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding

Reproductive toxicity studies in animals have shown no risk to the fetus; however, controlled clinical studies in pregnant women have not been conducted. Clinical experience with terbinafine use in pregnant women is very limited; therefore, terbinafine should not be used during pregnancy except when clearly necessary.

A small amount of terbinafine passes into breast milk; therefore, women who are breastfeeding should not receive terbinafine treatment.

Ability to affect reaction speed when driving or operating machinery

Appropriate studies have not been conducted. Patients who experience adverse effects such as dizziness or visual disturbances (see section "Side effects") should avoid driving or operating machinery.

Method of Administration and Dosage

The medicinal product is intended for oral administration. The tablets should be swallowed with water, preferably at the same time each day. The tablets may be taken independently of food intake.

The recommended dose for adults is 1 tablet of 250 mg once daily.

The duration of treatment depends on the nature and severity of the disease. Treatment should be continued for the appropriate length of time. Inadequate duration of treatment and/or irregular use of the medication may lead to recurrence of infection. Personal hygiene measures should be observed to prevent reinfection (from underwear, socks, footwear, etc.).

Recommended duration of treatment:

• Tinea pedis (interdigital, plantar/"moccasin" type) — 2–6 weeks;
• Tinea corporis (dermatophytosis of smooth skin) — 4 weeks;
• Tinea cruris — 2 to 4 weeks;
• Cutaneous candidiasis — 2 to 4 weeks;
• Tinea capitis — 4 weeks;
• Onychomycosis caused by dermatophytes — 6–12 weeks. Longer treatment may be required in patients with slow nail growth.

Nail infections: In most cases, 6 weeks of treatment are sufficient.

Infections of the great toe: In most cases, 12 weeks of treatment are sufficient.

In fungal nail infections, clinical improvement usually occurs several months after completion of mycological treatment, due to the time required for healthy nail regrowth.

Special Populations

Patients with hepatic impairment. Terbinafine tablets are contraindicated in patients with chronic or acute liver disease.

Patients with renal impairment. 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 doses different from those used in younger adults. However, in this age group, potential impairment of liver or kidney function should be taken into account when administering the drug.

Missed dose

If a patient misses a dose, the next dose should be taken as soon as remembered. However, considering the pharmacokinetic properties of terbinafine, a missed dose should not be taken if the interval between the missed dose and the next scheduled dose is less than 4 hours.

Children

Data on the use of this medicinal product in children are limited; therefore, it is not recommended for use in this age group.

Overdose

There have been several reported cases of overdose (oral intake of up to 5 g of terbinafine). Symptoms observed included headache, nausea, epigastric pain, and dizziness.

In case of overdose, elimination of the drug using activated charcoal is recommended, followed, if necessary, by symptomatic and supportive therapy.

Side effects.

The following classification is used to assess the frequency of occurrence of various side effects:

very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated based on available data).

Reporting of suspected adverse reactions.

Reporting of adverse reactions following registration of a medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 4 years.

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

Keep out of reach of children.

Packaging. 10 tablets per blister; 1 blister per cardboard pack.

Prescription status. Prescription only.

Manufacturer. JSC "Lubnifarm".

Manufacturer's address and location of business activity. 16, Barvinkova Street, Lubny, Poltava region, 37500, Ukraine.