Mycofin®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MICOFIN® (MYCOFIN)

Composition:

Active substance: terbinafine;

1 tablet contains terbinafine hydrochloride equivalent to 250 mg of terbinafine;

Excipients: hypromellose, sodium croscarmellose, microcrystalline cellulose, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round tablets with a score line on one side.

Pharmacotherapeutic group.

Antifungal agents for systemic use. ATC code D01B A02.

Pharmacological properties.

Pharmacodynamics.

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

Terbinafine specifically inhibits an early step in the biosynthesis of sterols within the fungal cell. This leads to a deficiency of ergosterol and intracellular accumulation of squalene, resulting in fungal cell death. The mechanism of action of terbinafine involves inhibition of the enzyme squalene epoxidase in the fungal cell membrane. This enzyme is not part of the cytochrome P450 system.

When administered systemically, the drug accumulates in the skin, hair, and nails at concentrations sufficient to exert a fungicidal effect.

Pharmacokinetics.

After oral administration, taking into account first-pass metabolism in the liver, terbinafine is well absorbed (> 70%), and absolute bioavailability 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 continuous dosing compared to single dosing, the maximum concentration of terbinafine was on average 25% higher, and plasma AUC increased by a factor of 2.3. 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. 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 and thus reaches high concentrations in sebum-rich areas such as hair follicles, hair, and skin. Distribution of terbinafine into nail plates has also been demonstrated 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. 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 significant changes in pharmacokinetics related to patient age have been observed; however, the rate of drug elimination may be reduced in patients with impaired renal or hepatic function, leading to increased blood levels of terbinafine.

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 cruris, and tinea pedis) when the site of infection, severity, or extent of infection warrants systemic therapy.
2. Onychomycosis.

Contraindications.

Hypersensitivity to terbinafine or to any of the excipients of the 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

The metabolism of terbinafine involves cytochrome P450 isoenzymes (CYP450). 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 therapy with such drugs is necessary, the dosage of Mycofin® should be adjusted accordingly.

Enzyme inhibitors

Cimetidine decreased 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 in these parameters may be observed 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"). This applies, for example, to certain drugs in the following classes: tricyclic antidepressants, beta-blockers, selective serotonin reuptake inhibitors, antiarrhythmic agents (including class 1A, 1B, and 1C), or monoamine oxidase inhibitors type B.

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

In rapid metabolizers of CYP2D6, terbinafine increased the urinary metabolic interaction ratio of dextromethorphan/dextrorphan on average by 16–97 times. This indicates that terbinafine slows the metabolism of CYP2D6 substrates in rapid metabolizers (i.e., "extensive metabolizers"), meaning their metabolism resembles that of slow metabolizers (i.e., "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 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 possibility of interaction between terbinafine and commonly prescribed anticoagulants has not been studied. No interactions were observed in a study with warfarin.

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

Special precautions for use

Mikofin**®** for oral administration should only be used when topical treatment is not feasible.

Liver function

Mikofin**®** tablets are contraindicated in patients with chronic or acute liver disease. Prior to initiating treatment with Mikofin**®** tablets, any pre-existing liver disorders should 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. Mikofin**®** tablets should be discontinued immediately if liver function tests show increased activity. Very rare cases of severe hepatic failure (some with fatal outcome or requiring liver transplantation) have been reported in patients treated with Mikofin**®** tablets. In most cases of liver failure, patients had serious underlying systemic diseases (see sections "Contraindications" and "Adverse reactions").

Patients 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 part of the abdomen, dark urine, or pale stools. Patients experiencing such symptoms should discontinue oral terbinafine immediately and undergo prompt liver function testing.

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 Mikofin**®** 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 signs of hypersensitivity occur, treatment with Mikofin**®** tablets should be discontinued.

Lupus erythematosus/psoriasis

Mikofin 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 abnormalities (neutropenia, agranulocytosis, thrombocytopenia, pancytopenia) have been reported in patients receiving Mikofin**®** tablets. The cause of any blood abnormality should be evaluated in patients, and consideration should be given to modifying the treatment regimen, including discontinuation of Mikofin**®** tablets.

Renal function

The use of Mikofin**®** 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 taking concomitant medications that are 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 Mikofin in pregnant women is very limited; therefore, Mikofin should not be used during pregnancy except when clearly necessary.

A small amount of terbinafine passes into breast milk; therefore, women who are breastfeeding should not receive Mikofin 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 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 independently 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. It is important to ensure that treatment is continued for the appropriate period. 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 (from underwear, socks, footwear, etc.).

Recommended treatment duration:

• Tinea pedis (interdigital, plantar/moccasin type) – 2–6 weeks;
• Trichophytia of smooth skin – 4 weeks;
• Trichophytia of the groin area – 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: in most cases, 6 weeks of treatment is sufficient.
* Infections of the toenail (great toe): in most cases, 12 weeks of treatment is sufficient.

In 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
Mycofin**®** tablets are contraindicated in patients with chronic or active liver disease.

Patients with renal impairment
The use of Mycofin**®** 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 dosages compared to younger patients. However, in this age group, potential impairment of liver or kidney function should be taken into consideration when administering the medication.

Procedure in case of missed dose
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 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 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.

Adverse reactions.

The following classification is 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 from the available data).

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

14 tablets in a blister pack, 1 or 2 blisters per cardboard box.

4 tablets in a blister pack, 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer.

NOBEL ILAC SANAYI VE TICARET A.S.

Manufacturer's address.
Sankaklar Quarter, Eskia kacakoca Avenue, No. 299, 81100, Duzce, Turkey.