Lamisil tablets 250 mg blister No. 14

Instructions for Lamisil tablets 250 mg blister No. 14

Composition

active ingredient: terbinafine;

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

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

Dosage form

Pills.

Main physicochemical properties:

The tablets are round, biconvex, with beveled edges, from white to white with a yellow tint, with a smooth or slightly uneven surface, with a score on one side and the inscription LAMISIL 250 (in a circle) on the other side of the tablet.

Pharmacotherapeutic group

Antifungal drugs for use in dermatology. Antifungal drugs for systemic use. Terbinafine.

ATX 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 yeasts of the genus Candida (e.g. Candida albicans) and Pityrosporum. At low concentrations, terbinafine has fungicidal activity against dermatophytes, molds and some dimorphic fungi. The activity against yeasts, depending on their species, can be fungicidal or fungistatic.

Terbinafine specifically promotes the early stage of sterol biosynthesis in the fungal cell. Terbinafine acts by inhibiting the enzyme squalene epoxidase in the fungal cell membrane. This leads to ergosterol deficiency and intracellular accumulation of squalene, which causes fungal cell death. This enzyme does not belong to the cytochrome P450 system.

When used internally, the drug accumulates in the skin in concentrations that provide the fungicidal effect of the drug.

Pharmacokinetics.

Terbinafine is well absorbed after oral administration (> 70%); the absolute bioavailability of terbinafine, which is part of Lamisil® tablets, as a result of presystemic metabolism is approximately 50%. A single oral dose of 250 mg terbinafine showed a mean peak plasma concentration of 1.30 μg/ml 1.5 hours after administration. With continuous administration, compared with a single dose, the maximum concentration of terbinafine was on average 25% higher, and the plasma AUC increased 2.3-fold. Based on the increase in plasma AUC, an effective half-life (30 hours) can be calculated. Food intake has a moderate effect on the bioavailability of terbinafine (increase in AUC by less than 20%), but this does not lead to the need for dose adjustment. Concomitant intake of a high-fat meal slows down 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 diffuses rapidly through the dermis and concentrates in the lipophilic stratum corneum.

Terbinafine accumulates in the lipophilic stratum corneum. Terbinafine is also secreted into sebum and thus reaches high concentrations in hair follicles, hair and sebum-rich skin. Terbinafine has also been shown to be distributed into the nail plate during the first weeks after initiation of therapy. There is 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. Terbinafine biotransformation produces metabolites that have no antifungal activity and are excreted mainly in the urine. The elimination half-life of the drug is 17 hours. There is no evidence of accumulation of the drug in the body.

No changes in the pharmacokinetics of the drug are observed depending on the patient's age, but the rate of drug elimination from the body may be reduced in patients with impaired renal or hepatic function, leading to increased levels of terbinafine in the blood.

Single-dose pharmacokinetic studies in patients with renal impairment (creatinine clearance < 50 mL/min) or pre-existing liver disease have shown that the clearance of Lamisil® may be reduced by approximately 50%.

Indication

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:

Ringworm (trichophytosis of smooth skin, trichophytosis of the perineum and dermatophytosis of the feet), when the localization of the lesion, severity or prevalence of the infection determine the feasibility of oral therapy.

Onychomycosis.

Contraindication

Acute or chronic liver disease.

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

Interaction with other medicinal products and other types of interactions

Terbinafine is metabolized by cytochrome P450 (CYP450) isoenzymes. 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 Lamisil® 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 the Cmax and AUC of terbinafine by 52% and 69%, respectively. The same increase may be observed when terbinafine is co-administered with drugs that inhibit CYP2C9 and CYP3A4, such as azole fungicides, macrolide antibiotics, or amiodarone.

Enzyme inducers

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

Effect of terbinafine on the pharmacokinetics of other drugs

CYP2D6 substrates: In vitro and in vivo studies have shown that terbinafine inhibits CYP2D6. These findings are more relevant for substances that are predominantly metabolised by this enzyme, especially if they have a narrow therapeutic index (see section 4.4). This applies, for example, to certain classes of drugs: tricyclic antidepressants, beta-blockers, selective serotonin reuptake inhibitors, antiarrhythmics (including class 1A, 1B and 1C) or monoamine oxidase inhibitors type B.

Terbinafine reduced desipramine clearance by 82% and increased AUC 5-fold.

In CYP2D6 extensive metabolizers, terbinafine increased the urinary dextromethorphan/dextrorphan metabolic interaction ratio by an average of 16-97-fold. This suggests that terbinafine slows the metabolism of CYP2D6 substrates in CYP2D6 extensive metabolizers (“extensive metabolizers”), i.e., the metabolism in these patients is maximally similar to that in poor metabolizers (i.e., “poor metabolizers”).

Substrates of other CYP450 enzymes: In vitro studies in healthy volunteers indicate that terbinafine has little potential to inhibit or increase the clearance of most drugs metabolized by other cytochrome P450 isoforms (e.g. terfenadine, triazolam or oral contraceptives).

Other metabolic pathways: terbinafine increased the clearance of cyclosporine by 15% (decrease in AUC by 13%).

The possibility of interactions between terbinafine and commonly prescribed anticoagulants has not been studied. No interactions were observed in a study with warfarin.

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

Application features

Lamisil® for oral use should only be used when topical application of the drug is not possible.

Liver function

Lamisil® tablets are contraindicated in patients with chronic or acute liver disease. Any pre-existing liver disease should be evaluated before prescribing Lamisil® tablets. At a minimum, ALT and AST levels should be determined to obtain baseline values for comparison with values to be 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 with and without pre-existing liver disease, therefore periodic monitoring of liver function is recommended (after 4-6 weeks of treatment). Lamisil® tablets should be discontinued immediately if liver function tests become elevated. Very rare cases of serious liver failure (some fatal or requiring liver transplantation) have been reported in patients taking Lamisil® tablets. In most cases of liver failure, patients had serious underlying systemic diseases (see sections 4.3 and 4.8).

Patients taking Lamisil® should be advised to report any signs or symptoms suggestive of liver dysfunction, such as persistent nausea, loss of appetite, jaundice, vomiting, fatigue, upper right abdominal pain, dark urine, or discolored stools, to their physician immediately. Patients with these symptoms should discontinue oral terbinafine and have their liver function evaluated promptly.

Hypersensitivity reactions/serious skin reactions

Serious skin reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis, rash with eosinophilia and systemic symptoms [DRESS]) have been reported very rarely in patients receiving Lamisil® tablets. As well as skin reactions and eosinophilia, DRESS syndrome can involve one or more organs, causing hepatitis, interstitial nephritis, interstitial pneumonitis, myocarditis, pericarditis. If a progressive skin rash or other possible signs of hypersensitivity develop, Lamisil® tablets should be discontinued.

Lamisil® should be used with caution in patients with psoriasis or cutaneous or systemic lupus erythematosus, as cases of exacerbation of these diseases have been reported in the post-marketing period.

Hematological effects

Blood abnormalities (neutropenia, agranulocytosis, thrombocytopenia, pancytopenia) have been reported very rarely in patients receiving Lamisil® tablets. The cause of any blood abnormality in patients should be evaluated and a possible change in treatment regimen, including discontinuation of Lamisil® tablets, should be considered.

Kidney function

The use of Lamisil® tablets in patients with renal impairment (creatinine clearance less than 50 ml/min or serum creatinine level 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 carefully monitored if they are concomitantly taking drugs that are metabolized primarily by the CYP2D6 enzyme (e.g. tricyclic antidepressants, beta-blockers, selective serotonin reuptake inhibitors, antiarrhythmics (including class 1A, 1B and 1C) or monoamine oxidase type B inhibitors), especially if these drugs have a narrow therapeutic window (see section "Interaction with other medicinal products and other forms of interaction").

Use during pregnancy or breastfeeding

Animal reproductive toxicity studies have shown no risk to the fetus, however, controlled clinical studies in pregnant women have not been conducted. Clinical experience with Lamisil® in pregnant women is very limited, therefore Lamisil® should not be used during pregnancy unless clearly necessary.

Small amounts of terbinafine pass into breast milk, and therefore women who are breastfeeding should not be treated with Lamisil®.

Ability to influence reaction speed when driving vehicles or other mechanisms

No relevant studies have been conducted. Patients who experience dizziness and visual disturbances as an undesirable effect of the drug (see section "Adverse reactions") should avoid driving vehicles and operating other mechanisms.

Method of administration and doses

The drug is intended for oral use. The tablets should be swallowed with water, preferably at the same time of day. The tablets can be taken regardless of meals.

Adults are prescribed 1 tablet of 250 mg once a day.

The duration of treatment depends on the nature and severity of the disease. Care should be taken to ensure that the treatment is carried out for the appropriate period of time. Inadequate duration of treatment and/or irregular use of the drug may lead to a relapse of the infection. Personal hygiene rules should be observed to prevent reinfection (from underwear, socks, shoes, etc.).

Recommended duration of treatment:

dermatophytosis of the feet (interdigital, plantar/moccasin type) – 2−6 weeks;

trichophytosis of smooth skin – 4 weeks;

Trichophytosis of the perineum – from 2 to 4 weeks;

cutaneous candidiasis – from 2 to 4 weeks;

trichophytosis of the scalp – 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.

Big toe infections: 12 weeks of treatment is sufficient in most cases.

In the case of fungal nail infections, the clinical effect usually occurs several months after mycological treatment. This is due to the regrowth of a healthy nail.

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 doses than younger patients. In this age group, the possibility of impaired liver or kidney function should be taken into account when using the drug.

Procedure in case of missed dose

If the patient forgets to take a dose, the next dose should be taken as soon as possible after the patient remembers. However, given the pharmacokinetic properties of terbinafine, the missed dose should not be taken if the interval between the missed dose and the next dose is less than 4 hours.

Children

Data on the use of the drug in children are limited, therefore its use is not recommended for this age group of patients.

Overdose

Several cases of overdose (up to 5 g of Lamisil® taken orally) have been reported. Headache, nausea, epigastric pain and dizziness were reported. Treatment recommended in case of overdose includes removal of the drug, primarily with activated charcoal, and symptomatic supportive therapy if necessary.

Side effects

The following classification was 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 (≥ 1/10000, ≤ 1/1000); very rare (≤ 1/10000), frequency unknown (cannot be estimated from the available data).

Expiration date

3 years.

Storage conditions

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

Incompatibility

Unknown.

Packaging

14 tablets in a blister, 1 blister in a cardboard box.

Vacation category

According to the recipe.

Producer

1. Novartis Pharma Produktions GmbH (production, quality control, packaging, batch release).

2. Lek Pharmaceuticals dd, PE Proizvodnja Lendava (quality control, primary packaging, secondary packaging, batch release).

Address

1. Oeflinger Strasse 44, 79664 Wehr, Germany.

2. Trimlini 2D, Lendava, 9220, Slovenia.