Lamisil

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

Composition:

Active substance: terbinafine;

1 tablet contains terbinafine hydrochloride 281.25 mg, which corresponds to 250 mg of terbinafine;

Excipients: magnesium stearate, colloidal anhydrous silicon dioxide, hypromellose, sodium starch glycolate (type A), microcrystalline cellulose.

Pharmaceutical form. Tablets.

Main physicochemical characteristics:

round, biconvex tablets with beveled edges, white to off-white in color, with a smooth or slightly uneven surface, marked with a score line on one side and the inscription LAMISIL 250 (in a circle) on the other side of the tablet.

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 exhibits fungicidal activity 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 of sterol biosynthesis in fungal cells. Its action is mediated by inhibition of the enzyme squalene epoxidase in the fungal cell membrane. This leads to ergosterol deficiency 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 providing fungicidal activity.

Pharmacokinetics.

After oral administration, terbinafine is well absorbed (> 70%); the absolute bioavailability of terbinafine in Lamisil® tablets, due to presystemic metabolism, is approximately 50%. A single oral dose of 250 mg terbinafine resulted in a mean peak plasma concentration of 1.30 µg/mL, reached 1.5 hours after administration. With continuous dosing compared to single dosing, the maximum concentration of terbinafine was on average 25% higher, and plasma AUC increased 2.3-fold. Based on the increase in plasma AUC, the effective elimination half-life is estimated to be approximately 30 hours. Food intake has a moderate effect on terbinafine bioavailability (an increase in AUC of less than 20%), but this does not necessitate dose adjustment. Concomitant 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 and thus achieves high concentrations in sebum-rich skin, hair follicles, and hair. 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 seven CYP isoenzymes, with significant contributions from CYP2C9, CYP1A2, CYP3A4, CYP2C8, and CYP2C19. As a result of biotransformation, metabolites are formed that 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 the pharmacokinetics of the drug have been observed; however, the rate of elimination may be reduced in patients with impaired renal or hepatic function, leading to increased blood levels of terbinafine.

Studies on the pharmacokinetics of single doses in patients with impaired renal function (creatinine clearance < 50 mL/min) or pre-existing liver disease showed 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:

• Tinea infections (tinea of smooth skin, tinea cruris, tinea pedis) when the site, severity, or extent of infection warrants systemic therapy.
• Onychomycosis.

Contraindications.

Acute or chronic liver disease.

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

Interaction with other medicinal products and other forms of interactions.

Effect of other medicinal products on the pharmacokinetics of 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 decreased by drugs that inhibit cytochrome P450. If concomitant treatment with such drugs is necessary, the dosage of Lamisil® 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 occur 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 primarily metabolized by this enzyme, especially those with a narrow therapeutic index (see section "Special precautions for use"). This applies, for example, to certain drugs in 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 metabolic interaction ratio of dextromethorphan/dextrorphan in urine by an average of 16–97 times. This indicates that terbinafine slows the metabolism of CYP2D6 substrates in rapid metabolizers (i.e., "extensive metabolizers"), making their metabolism resemble that of 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 isoenzymes of 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. No interactions were observed in a study with warfarin.

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

Special precautions for use

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

Liver function

Lamisil® tablets are contraindicated in patients with chronic or acute liver disease. Prior to prescribing Lamisil® 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 with Lamisil® tablets should be discontinued immediately if liver function tests show elevated activity. Very rare cases of severe hepatic failure (some of which were fatal or required liver transplantation) have been reported in patients taking Lamisil® tablets. In most cases of hepatic failure, patients had serious underlying systemic diseases (see sections "Contraindications" and "Adverse reactions").

Patients taking Lamisil® 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, pain in the upper right 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 Lamisil® 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 rashes or other possible signs of hypersensitivity occur, treatment with Lamisil® tablets should be discontinued.

Lupus erythematosus/psoriasis

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

Hematological effects

Very rare cases of blood disorders (neutropenia, agranulocytosis, thrombocytopenia, pancytopenia) have been reported in patients receiving Lamisil® tablets. Any blood dyscrasia in patients should be evaluated, and consideration should be given to modifying the treatment regimen, including discontinuation of Lamisil® tablets.

Renal function

The use of Lamisil® 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 when concomitantly receiving drugs 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 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, Lamisil® should not be used during pregnancy except when clearly necessary.

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

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 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.

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 infection. Treatment should be continued for the appropriate length of time. Inadequate duration of treatment and/or irregular dosing may lead to recurrence of infection. Personal hygiene measures should be followed to prevent reinfection (e.g., from underwear, socks, footwear, etc.).

Recommended treatment duration:

• Tinea pedis (interdigital, plantar/moccasin type) – 2–6 weeks;
• Tinea corporis (cutaneous ringworm) – 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 is sufficient.

Infection of the great toe: In most cases, 12 weeks of treatment is sufficient.

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

Special Populations

Patients with hepatic impairment

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

Patients with renal impairment

The use of Lamisil® 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 different dosing regimens compared to younger patients. However, in this age group, potential hepatic or renal impairment should be taken into consideration when administering the drug.

Missed dose procedure

If a patient misses a dose, the next dose should be taken as soon as remembered. However, due to 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 drug 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 Lamisil®). Symptoms observed included headache, nausea, epigastric pain, and dizziness. Recommended treatment in case of overdose includes elimination of the drug, primarily by administration of activated charcoal, and, if necessary, symptomatic and supportive therapy.

Adverse reactions.

The following classification is used to assess the frequency of occurrence 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).

Shelf life.

3 years.

Storage conditions.

Keep out of reach of children. Store in the original packaging at a temperature not exceeding 30 °C.

Incompatibility.

Unknown.

Packaging. 14 tablets per blister, 1 blister per cardboard carton.

Prescription status. Prescription only.

Manufacturer.

1. Novartis Pharma Produktions GmbH / Novartis Pharma Produktions GmbH (manufacturing, quality control, packaging, batch release).
2. Lek Pharmaceuticals d.d., Lendava production site / Lek Pharmaceuticals d.d.,
   PE Proizvodnja Lendava (quality control, primary packaging, secondary packaging, batch release).

Manufacturer's location and address of business operation.

1. Oeflinger Strasse 44, 79664 Wehr, Germany.
2. Trimlini 2D, Lendava, 9220, Slovenia.