Terbinorm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TERBINORM (TERBINORM)

Composition:

Active substance: terbinafine;

1 tablet contains terbinafine (as hydrochloride) 250 mg;

Excipients: microcrystalline cellulose, maize starch, colloidal anhydrous silicon dioxide, hypromellose, talc, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: round, flat tablets of white to yellowish-white color.

Pharmacotherapeutic group.

Antifungal agents for dermatological use. Systemic antifungal agents. Terbinafine. ATC code D01B A02.

Pharmacological Properties

Pharmacodynamics

Terbinafine is an allylamine with a broad spectrum of antifungal activity against skin, hair, and nail infections 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 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 yeasts may be either fungicidal or fungistatic, depending on the species.

Terbinafine specifically targets an early stage in the biosynthesis of sterols within the fungal cell. Its action is mediated by inhibition of the enzyme squalene epoxidase in the fungal cell membrane. This leads to a deficiency of ergosterol and intracellular accumulation of squalene, resulting in fungal cell death. This enzyme is not part of the cytochrome P450 system.

After oral administration, terbinafine accumulates in the skin at concentrations sufficient to exert its fungicidal effect.

Pharmacokinetics

Absorption

After oral administration, terbinafine is well absorbed (>70%). Due to presystemic metabolism, its absolute bioavailability is approximately 50%. A single oral dose of 250 mg terbinafine results in a mean maximum plasma concentration (C_max) of 1.30 µg/mL, reached 1.5 hours after administration. At steady state, compared to a single dose, the C_max of terbinafine was on average 25% higher, and the area under the plasma concentration–time curve (AUC) increased by a factor of 2.3. Based on the increase in plasma AUC, the effective elimination half-life (T_1/2) is estimated to be approximately 30 hours. Food intake has a moderate effect on terbinafine bioavailability (increasing AUC by less than 20%), but not to an extent requiring dose adjustment. Concurrent intake of a high-fat meal slows the absorption of terbinafine and increases bioavailability by approximately 20%.

Distribution

Terbinafine is highly bound to plasma proteins (99%). The volume of distribution exceeds 2000 L. It rapidly diffuses through the dermis and concentrates in the lipophilic stratum corneum. It accumulates in the lipophilic stratum corneum. Terbinafine is also secreted in sebum and thus achieves high concentrations in sebum-rich skin, hair follicles, and hair. It has also been demonstrated to distribute into the nail plates within the first weeks of therapy. There are insufficient data on whether terbinafine crosses the placental barrier. Less than 0.2% of the administered dose is excreted in breast milk.

Metabolism

Terbinafine is rapidly and extensively metabolized by at least 7 CYP isoenzymes, with significant contributions from CYP2C9, CYP1A2, CYP3A4, CYP2C8, and CYP2C19.

Elimination

As a result of biotransformation, terbinafine is converted into metabolites that lack antifungal activity and are primarily excreted in urine. The elimination half-life (T_1/2) is 17 hours. There is no evidence of terbinafine accumulation in the body.

No significant age-related changes in terbinafine pharmacokinetics have been observed; however, elimination may be reduced in patients with impaired renal or hepatic function, leading to increased plasma levels.

Pharmacokinetic studies of single terbinafine doses in patients with renal impairment (creatinine clearance <50 mL/min) or pre-existing liver disease have shown that its clearance 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:

• Dermatophytosis (tinea of smooth skin, tinea cruris, and tinea pedis) when the location, severity, or extent of the infection warrants systemic therapy;
• Onychomycosis.

Contraindications.

• Hypersensitivity to the active substance and/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.

Terbinafine metabolism involves cytochrome P450 (CYP450) isoenzymes. The plasma clearance of terbinafine may be increased by agents that induce these enzymes and decreased by agents that inhibit cytochrome P450. If concomitant administration of such medicinal products is necessary, the dosage of terbinafine should be adjusted accordingly.

Inhibitors of cytochrome P450 enzymes.

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

Fluconazole (an inhibitor of CYP2C9 and CYP3A4) increased Cmax and AUC of terbinafine by 52% and 69%, respectively, due to inhibition of CYP2C9 and CYP3A4 enzymes. Similar increases in these parameters may occur when terbinafine is co-administered with medicinal products that inhibit CYP2C9 and CYP3A4, such as azole antifungals (ketoconazole), macrolide antibiotics, or amiodarone.

Inducers of cytochrome P450 enzymes.

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

Effect of terbinafine on the pharmacokinetics of other medicinal products.

Substrates of CYP2D6.

In vitro and in vivo studies have shown that terbinafine inhibits CYP2D6-mediated metabolism. These findings are particularly relevant for substances primarily metabolized by this enzyme, especially those with a narrow therapeutic range (see section "Special warnings and precautions for use"). This includes, for example, certain medicinal products from the following classes: tricyclic antidepressants, beta-blockers, selective serotonin reuptake inhibitors, antiarrhythmics (including class IA, IB, and IC), or monoamine oxidase inhibitors type B.

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

In CYP2D6 extensive metabolizers, terbinafine increased the urinary metabolic ratio of dextromethorphan/dextrorphan on average by 16–97 times. This indicates that terbinafine slows the metabolism of CYP2D6 substrates in extensive metabolizers, meaning that metabolism in these patients resembles that in poor metabolizers.

Substrates of other enzymes.

Results from in vitro studies in healthy volunteers indicate that terbinafine has low potential to inhibit or enhance the clearance of most medicinal products metabolized by the cytochrome P450 system (e.g., terfenadine, triazolam, tolbutamide, or oral contraceptives).

Other metabolic pathways.

Terbinafine does not affect the clearance of antipyrine or digoxin.

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

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

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

Cases of menstrual cycle disturbances (intermenstrual bleeding and irregular menstrual cycles) have been reported in women receiving terbinafine concomitantly with oral contraceptives, although the frequency of these events remains within the range of adverse reaction rates observed in patients taking oral contraceptives alone.

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

Special precautions for use.

The medicinal product should be used only when topical application of terbinafine is not possible.

Hepatic reactions.

The medicinal product is contraindicated in patients with chronic or acute liver disease. Prior existing liver disorders should be evaluated before initiating treatment. At a minimum, baseline levels of ALT and AST should be determined to allow comparison with values obtained during treatment. In patients with pre-existing liver disease, the clearance of terbinafine may be reduced by approximately 50%.

Hepatotoxicity may occur in patients both with and without prior liver disease; therefore, periodic monitoring of liver function (after 4–6 weeks of treatment) is recommended. The medicinal product should be discontinued immediately if liver function tests show increased activity. In patients who have taken oral terbinafine, very rare cases of severe hepatic failure (some of which were fatal or required liver transplantation) have been reported. In most cases of liver failure, patients had serious underlying systemic diseases (see sections "Contraindications" and "Side effects").

Patients should be advised to immediately inform their physician about any signs or symptoms indicating impaired liver function, such as pruritus, unexplained persistent nausea, loss of appetite, anorexia, jaundice, vomiting, increased fatigue, right upper abdominal pain, dark urine, or pale stools. Patients experiencing these symptoms should discontinue the medicinal product immediately, and liver function should be assessed promptly.

Hypersensitivity reactions/severe skin reactions.

During the use of oral terbinafine, 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. Like skin reactions and eosinophilia, DRESS syndrome may involve one or more organs, leading to hepatitis, interstitial nephritis, interstitial pneumonia, myocarditis, or pericarditis. If progressive skin rash or other possible symptoms of hypersensitivity occur, the medicinal product should be discontinued.

Hematological reactions.

During the use of oral terbinafine, very rare cases of blood disorders (neutropenia, agranulocytosis, thrombocytopenia, pancytopenia) have been reported. The cause of any blood disorder in patients should be evaluated, and consideration should be given to modifying the treatment regimen, including discontinuation of the medicinal product.

Use in patients with systemic lupus erythematosus/psoriasis.

The medicinal product should be used with caution in such patients, as very rare cases of exacerbation of these conditions have been reported.

Use in patients with renal impairment.

The use of the medicinal product in patients with renal impairment (creatinine clearance less than 50 mL/min or plasma creatinine level greater than 300 µmol/L) has not been adequately studied and is therefore not recommended.

Interactions with other medicinal products.

In vitro and in vivo studies have shown that terbinafine is an inhibitor of the CYP2D6 enzyme. Patients should be closely monitored when concomitantly using drugs that are primarily metabolized by the CYP2D6 enzyme (e.g., tricyclic antidepressants, beta-blockers, selective serotonin reuptake inhibitors, antiarrhythmic agents (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 types of interactions").

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 the use of oral terbinafine in pregnant women is very limited. The medicinal product should not be used during pregnancy except in cases of clear necessity.

A small amount of terbinafine passes into breast milk. The medicinal product should not be used during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

The medicinal product is intended for oral use. Tablets should be swallowed with water, preferably at the same time each day, regardless of food intake.

Adults.

The medicinal product should be administered at a dose of 250 mg (1 tablet) once daily.

If a dose is missed, the next dose should be taken as soon as possible. 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.

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

Recommended duration of treatment:

• Tinea pedis (interdigital, plantar/moccasin type) – 2–6 weeks;
• Tinea corporis – 4 weeks;
• Tinea cruris – 2–4 weeks;
• Cutaneous candidiasis – 2–4 weeks;
• Tinea capitis – 4 weeks;
• Onychomycosis caused by dermatophytes – 6–12 weeks (longer treatment may be required for patients with slow nail growth);
• Nail infections – in most cases, 6 weeks is sufficient;
• Infections of the great toenail – in most cases, 12 weeks is sufficient.

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

Patients with hepatic impairment.

The medicinal product is contraindicated in patients with chronic or acute liver disease.

Patients with renal impairment.

The use of terbinafine in patients with renal impairment has not been adequately studied; therefore, the medicinal product is not recommended for use in such patients.

Elderly patients.

There is no evidence that dosage adjustment of terbinafine is required in elderly patients or that adverse reactions differ from those observed in younger patients. However, in this age group, potential hepatic or renal impairment should be taken into consideration when using the medicinal product.

Children.

Data on the use of oral terbinafine in children are limited; therefore, the use of the medicinal product is not recommended 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. Recommended treatment in case of overdose includes elimination of terbinafine, primarily through the use of adsorbents, and, if necessary, symptomatic and supportive therapy.

Adverse reactions.

Adverse reactions are usually mild to moderate in intensity and transient in nature. The undesirable effects listed below were observed during clinical trials with terbinafine or during post-marketing surveillance.

The following classification was used to assess the frequency of various adverse reactions: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated based on available data).

Blood and lymphatic system disorders:

uncommon – anaemia; very rare – neutropenia, agranulocytosis, thrombocytopenia, pancytopenia.

Immune system disorders:

very rare – anaphylactoid reactions (including Quincke's edema), exacerbation and worsening of cutaneous and systemic lupus erythematosus; frequency not known – anaphylactic reaction, serum sickness-like reactions (including rash, pruritus, urticaria, angioedema, arthralgia, fever, and lymphadenopathy).

Metabolism and nutrition disorders:

very common – loss of appetite; uncommon – weight loss (due to dysgeusia).

Severe individual cases of reduced food intake leading to significant weight loss have been reported.

Psychiatric disorders:

common – depression; uncommon – restlessness.

Nervous system disorders:

very common – headache; common – dizziness, dysgeusia up to complete loss of taste; uncommon – paraesthesia, hypesthesia; very rare – persistent dysgeusia (taste disturbance, including loss of taste, usually reversible after discontinuation of terbinafine); frequency not known – hyposmia, anosmia, including persistent anosmia.

Eye disorders:

common – visual disturbances; frequency not known – blurred vision, decreased visual acuity.

Ear and labyrinth disorders:

uncommon – tinnitus; frequency not known – hearing impairment.

Vascular disorders:

frequency not known – vasculitis.

Gastrointestinal disorders:

very common – epigastric fullness, dyspepsia, nausea, mild abdominal pain, diarrhoea; frequency not known – pancreatitis.

Hepatobiliary disorders:

rare – hepatic failure, increased liver enzymes, jaundice, cholestasis, and hepatitis (including cases with fatal outcome or requiring liver transplantation) (see section "Special precautions for use").

Skin and subcutaneous tissue disorders:

very common – rash, urticaria; uncommon – photosensitivity; very rare – alopecia, psoriasiform rash or exacerbation of psoriasis, toxicoderma, exfoliative and bullous dermatitis, erythema multiforme, Stevens–Johnson syndrome, Lyell’s syndrome (toxic epidermal necrolysis), acute generalized exanthematous pustulosis; frequency not known – drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Musculoskeletal and connective tissue disorders:

very common – arthralgia, myalgia; frequency not known – rhabdomyolysis; increased plasma creatine phosphokinase.

General disorders and administration site conditions:

common – fatigue; uncommon – fever; frequency not known – influenza-like illness.

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals should report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25°C, in a place inaccessible to children.

Packaging.

7 tablets in a blister pack, 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

K.O. SLAVIA PHARM S.R.L., Romania /
S.C. SLAVIA PHARM S.R.L., Romania.

Manufacturer's address and place of business.

Boulevard Theodor Pallady № 44 C, sector 3, 032266, Bucharest /
Boulevard Theodor Pallady № 44 C, sector 3, 032266, Bucharest.

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine