Lamictal

INSTRUCTIONS for medical use of the medicinal product LamIcoN® (LamIcoN)

Composition:

active substance: terbinafine;

1 tablet contains terbinafine hydrochloride 281 mg (0.281 g), equivalent to 100% anhydrous terbinafine 250 mg (0.250 g);

excipients: microcrystalline cellulose, maize starch, colloidal anhydrous silicon dioxide, sodium starch glycolate (type A), hydroxypropylmethylcellulose, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white or with a yellowish tint, round-shaped tablets with a flat surface, bevelled edges, and a score line.

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, 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 targets an early stage in sterol biosynthesis 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 does not belong to the cytochrome P450 system.

When administered orally, the drug accumulates in the skin at concentrations sufficient to exert a fungicidal effect.

Pharmacokinetics.

After oral administration, terbinafine is well absorbed (>70%); the absolute bioavailability of terbinafine in Lamicon® tablets, due to presystemic metabolism, is approximately 50%. A single oral dose of 250 mg terbinafine results in a mean peak plasma concentration of 1.30 µg/mL reached 1.5 hours after administration. At steady state, compared to a single dose, the maximum plasma concentration (Cmax) of terbinafine is on average 25% higher, and the area under the plasma concentration–time curve (AUC) increases by a factor of 2.3. Based on the increased plasma AUC, the effective half-life is estimated at 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%.

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.

Terbinafine accumulates in the lipophilic stratum corneum. It is also excreted in sebum, thereby achieving high concentrations in hair follicles, hair, and sebum-rich skin. It has also been demonstrated that terbinafine distributes into 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. Terbinafine is rapidly and extensively metabolized by at least 7 CYP isoenzymes, with significant contributions from CYP2C9, CYP1A2, CYP3A4, CYP2C8, and CYP2C19. The metabolites formed during biotransformation lack antifungal activity and are primarily excreted in urine. The elimination half-life of the drug is 17 hours. There is no evidence of drug accumulation in the body.

No age-related changes in pharmacokinetics have been observed; however, the rate of elimination may be reduced in patients with renal or hepatic impairment, leading to increased blood levels of terbinafine.

The bioavailability of Lamicon® is not affected by food intake.

Pharmacokinetic studies of single doses in patients with impaired renal function (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 skin and nails caused by Trichophyton (e.g., T. rubrum, T. mentagrophytes, T. verrucosum, T. violaceum), Microsporum canis, and Epidermophyton floccosum.

1. Tinea infections (tinea of smooth skin, tinea of the groin, and tinea pedis), when the site, severity, or extent of infection warrants systemic (oral) therapy.
2. Onychomycosis.

Contraindications.

Acute or chronic liver disease.

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

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 drugs that induce these enzymes and decreased by drugs that inhibit cytochrome P450. If concomitant administration of such drugs is necessary, the dosage of Lamicon® should be adjusted accordingly.

Enzyme inhibitors

Cimetidine reduced terbinafine clearance 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 (ketoconazole), macrolide antibiotics, and amiodarone.

Enzyme inducers

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

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

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

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

CYP450 other enzyme substrates: results from in vitro studies in healthy volunteers indicate that terbinafine has minimal potential to inhibit or enhance the clearance of 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% (AUC decreased by 13%).

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

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

Special precautions for use.

Lamicon® for oral use should only be used when topical treatment is not feasible.

Liver function

Lamicon® tablets are contraindicated in patients with chronic or acute liver disease. Prior to prescribing Lamicon® tablets, any pre-existing liver disorders must be evaluated. 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 pre-existing liver disease; therefore, periodic monitoring of liver function (after 4–6 weeks of treatment) is recommended. Treatment should be discontinued immediately if liver function test parameters increase. In patients treated with terbinafine tablets, very rare cases of severe liver 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 taking Lamicon® should be advised to immediately inform their physician of any signs or symptoms suggesting impaired liver function, such as persistent nausea, loss of appetite, jaundice, vomiting, increased fatigue, right upper abdominal pain, dark urine, or pale stools. Patients experiencing these symptoms should discontinue oral terbinafine immediately, and liver function should be assessed promptly.

Hypersensitivity reactions/severe skin reactions

Very rare cases of serious skin reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash 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 pneumonia, myocarditis, or pericarditis. If progressive skin rash or other possible signs of hypersensitivity occur, treatment with Lamicon® tablets should be discontinued.

Lupus erythematosus/psoriasis

Lamicon® should be used with caution in patients with psoriasis, cutaneous or systemic lupus erythematosus, as there have been reports of exacerbation 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 hematological abnormality in patients should be evaluated, and consideration should be given to modifying the treatment regimen, including discontinuation of Lamicon® tablets.

Renal function

The use of terbinafine tablets in patients with impaired renal function (creatinine clearance less than 50 mL/min or serum creatinine levels greater than 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 receiving concomitant medications that are primarily metabolized by the CYP2D6 enzyme (e.g., tricyclic antidepressants, beta-blockers, selective serotonin reuptake inhibitors, antiarrhythmics (including class 1A, 1B, and 1C), or monoamine oxidase inhibitors type B) should be closely monitored, especially if these drugs have a narrow therapeutic index (see section "Interaction with other medicinal products and other forms of interaction").

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 terbinafine in pregnant women is very limited; therefore, Lamicon® should not be used during pregnancy except in cases of clear necessity.

A small amount of terbinafine passes into breast milk; therefore, women who are breastfeeding should not use Lamicon®.

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 drug (see section "Side effects") should avoid driving vehicles or operating machinery.

Method of Administration and Dosage

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

For adults, the recommended dose 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 period of time. Inadequate duration of treatment and/or irregular administration of the medication may lead to recurrence of infection. Personal hygiene measures should be followed to prevent reinfection (e.g., underwear, socks, footwear).

Skin Infections

Recommended treatment duration:

• Tinea pedis (interdigital, plantar/moccasin type) – 2–6 weeks;
• Tinea corporis – 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 of the fingers: In most cases, 6 weeks of treatment are sufficient.

Nail infections of the big toe: In most cases, 12 weeks of treatment are sufficient.

In patients with fungal nail infections, clinical improvement typically occurs several months after mycological cure, due to the time required for healthy nail regrowth.

Special Populations

Patients with Hepatic Impairment

Lamicon®, tablets, is contraindicated in patients with chronic or acute liver disease.

Patients with Renal Impairment

The use of Lamicon® 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 patients. However, in this age group, possible hepatic or renal impairment should be taken into account when administering the medication.

Missed Dose Procedure

If a patient forgets to take 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 terbinafine in children are limited; therefore, its use is not recommended in this age group.

Overdose

Several cases of overdose (oral intake up to 5 g of terbinafine) have been reported. Symptoms observed included headache, nausea, epigastric pain, and dizziness. Recommended treatment in case of overdose includes elimination of the drug, primarily with activated charcoal, and, if necessary, 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 (≥ 1/10,000, < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated based on available data).

Shelf life. 3 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibility. Unknown.

Packaging. 7 tablets in a blister. 2 blisters in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's name and address of the place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.