Lamifen®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LAMIPHEN® (LAMIPHEN)

Composition:

Active substance: terbinafine;

1 tablet contains terbinafine hydrochloride in a dose equivalent to 250 mg of terbinafine;

Excipients: microcrystalline cellulose, copovidone, polyethylene glycol (macrogol) 6000, potato starch, hypromellose (hydroxypropylmethylcellulose 50 cP), sodium starch glycolate (type A), sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: flat cylindrical tablets with a score line and bevel, white or almost white.

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. This leads to ergosterol deficiency and intracellular accumulation of squalene, resulting in fungal cell death. The action of terbinafine is mediated by inhibition of the enzyme squalene epoxidase in the fungal cell membrane. 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%); due to presystemic metabolism, the absolute bioavailability of terbinafine in Lamisil® tablets 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. With repeated dosing, maximum terbinafine concentration is on average 25% higher than after a single dose, and plasma AUC increases by a factor of 2.3. With increasing plasma AUC, the effective elimination half-life is 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.

Concomitant intake of high-fat meals 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 and thereby achieves high concentrations in sebaceous 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 via at least seven CYP isoenzymes, among which the most actively involved are: CYP2C9, CYP1A2, CYP3A4, CYP2C8, and CYP2C19. The metabolites formed during biotransformation of terbinafine have no antifungal activity and are primarily excreted in urine.

No significant changes in the pharmacokinetics of the drug related to patient age have been observed; however, the elimination rate of the drug may be reduced in patients with impaired renal or hepatic function, leading to elevated blood levels of terbinafine.

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

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

Contraindications.

Hypersensitivity to terbinafine or to any excipients of the medicinal product. Chronic or acute liver disease.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on terbinafine

The metabolism of terbinafine involves cytochrome P450 (CYP450) isoenzymes. The plasma clearance of terbinafine may be increased by drugs that induce these enzymes and may be decreased by drugs that inhibit cytochrome P450. If concomitant treatment with such drugs is necessary, the dosage of Lamifen® should be adjusted accordingly.

Enzyme inhibitors

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

Fluconazole increased Cmax and AUC of terbinafine by 52% and 69%, respectively, due to inhibition of CYP2C9 and CYP3A4 enzymes. A similar increase in these parameters may occur when terbinafine is used concomitantly with drugs that inhibit CYP2C9 and CYP3A4, such as azole antifungals, macrolide antibiotics, or amiodarone.

Enzyme inducers

Rifampicin (a CYP3A4 inducer) 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 primarily metabolized by this enzyme, especially those with a narrow therapeutic index (see section "Special precautions"). This applies, for example, to certain drugs within 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 CYP2D6 rapid metabolizers, terbinafine increased the urinary metabolic interaction ratio of dextromethorphan/dextrorphan by 16−97 times on average. 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 the cytochrome P450 system (e.g., terfenadine, triazolam, or oral contraceptives).

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

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

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

Special precautions for use.

Lamifen® for oral administration should only be used when topical application of the drug is not feasible.

Liver function

Lamifen® tablets are contraindicated in patients with chronic or acute liver disease. Prior to prescribing Lamifen® tablets, all pre-existing liver conditions 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 prior liver disease; therefore, periodic monitoring of liver function is recommended (after 4–6 weeks of treatment). Treatment with Lamifen® tablets should be discontinued immediately if liver function tests show increased activity. In very rare cases, severe liver failure (some of which were fatal or required liver transplantation) has been reported in patients receiving oral terbinafine. In most cases of liver failure, patients had serious underlying systemic diseases (see sections "Contraindications" and "Adverse reactions").

Patients taking Lamifen® should be advised to immediately inform their physician of any signs or symptoms suggestive of liver dysfunction, such as persistent nausea, loss of appetite, jaundice, vomiting, increased fatigue, right upper abdominal pain, dark urine, or pale stools. Patients experiencing such 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 (such as 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. If progressive skin rash or other possible symptoms of hypersensitivity occur, treatment with Lamifen® tablets should be discontinued.

Lupus erythematosus/psoriasis

Lamifen® should be used with caution in patients with psoriasis or cutaneous or systemic lupus erythematosus, as there have been reports of exacerbation of these conditions.

Hematological effects

Very rare cases of hematological abnormalities (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 Lamifen® tablets.

Pharmacokinetic studies of single doses in patients with liver disease have shown that the clearance of terbinafine may be reduced by approximately 50%.

Renal function

The use of Lamifen® 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 should be closely monitored if they are concurrently receiving drugs primarily metabolized by CYP2D6 (e.g., tricyclic antidepressants, beta-blockers, selective serotonin reuptake inhibitors, antiarrhythmic agents (including class 1A, 1B, and 1C), or monoamine oxidase type B inhibitors), 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 Lamisil® in pregnant women is very limited; therefore, Lamifen® 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 receive treatment with Lamifen®.

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 "Adverse reactions") should avoid driving 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. 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 duration. Inadequate duration of treatment and/or irregular use of the medication may lead to recurrence of infection. Personal hygiene measures should be followed to prevent reinfection (from underwear, socks, footwear, etc.).

Recommended treatment duration:

• Athlete's foot (interdigital, plantar/"moccasin" type) – 2–6 weeks;
• Tinea corporis (ringworm of glabrous skin) – 4 weeks;
• Tinea cruris (jock itch) – 2 to 4 weeks;
• Cutaneous candidiasis – 2 to 4 weeks;
• Tinea capitis (scalp ringworm) – 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.

Infection of the big toe: in most cases, 12 weeks of treatment are sufficient.

For fungal nail infections, clinical improvement usually occurs several months after mycological cure due to the time required for healthy nail regrowth.

Special Populations

Patients with hepatic impairment

Lamifen® tablets are contraindicated in patients with chronic or acute liver disease.

Patients with renal impairment

The use of Lamifen® 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, potential hepatic or renal impairment should be taken into consideration when using the medication.

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 the medication in children are limited; therefore, its use 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 the drug, primarily with activated charcoal, and, if necessary, symptomatic and supportive therapy.

Side effects.

To assess the frequency of occurrence of various side effects, the following classification is used: 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).

Shelf life. 3 years.

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

Packaging.

7 tablets per blister; 1, 2, or 4 blisters per carton.

Prescription status.

By prescription only.

Manufacturer. JSC "FITOPHARM".

Manufacturer's address and location of business operations.

2 Sybirtseva Street, Bakhmut, Donetsk region, 84500, Ukraine.

Marketing Authorization Holder. JSC "FITOPHARM".

Address of the Marketing Authorization Holder.

7, Verkhovnoyi Rady Boulevard, premises 18, 3rd floor, Kyiv, 02100, Ukraine.