Onhofin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ONCHOFIN (ONCHOFIN)

Composition:

Active substance: terbinafine;

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

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

Pharmaceutical form. Tablets.

Main physicochemical characteristics: round, biconvex white to almost white tablets with bevelled edges, with a score line and imprint D on one side and 74 on the other side.

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 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 yeast fungi may be either fungicidal or fungistatic, depending on the species.

Terbinafine specifically targets an early stage in the biosynthesis of sterols 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 contained in Onychofine tablets is approximately 50% due to presystemic metabolism. 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 the plasma AUC increased by a factor of 2.3. Based on the increase in plasma A游戏副本, the effective elimination half-life can be estimated at ~30 hours. Food intake has a moderate effect on terbinafine bioavailability (less than 20% increase in AUC), but this does not necessitate dose adjustment. Concurrent 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 secreted in sebum and thus reaches 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 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 elevated 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:

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

Contraindications.

Acute or chronic liver disease.

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

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on terbinafine pharmacokinetics

Terbinafine is metabolized by 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 Onchophin 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 occur when terbinafine is co-administered with drugs that inhibit CYP2C9 and CYP3A4, such as azole antifungals, macrolide antibiotics, or 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 applies, for example, to certain drugs in the following classes: tricyclic antidepressants, beta-blockers, selective serotonin reuptake inhibitors (SSRIs), 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 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 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 other cytochrome P450 isoenzymes (e.g., terfenadine, triazolam, or oral contraceptives).

Other metabolic pathways: Terbinafine increased cyclosporine clearance by 15% (reduction in AUC by 13%).

The potential for interaction between terbinafine and commonly prescribed anticoagulants has not been studied. No interaction was observed in a study with warfarin.

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

Special precautions for use.

Oral Onhofin should only be used when topical treatment is not feasible.

Liver function

Onhofin tablets are contraindicated in patients with chronic or acute liver disease. Prior to initiating Onhofin tablets, any pre-existing liver conditions 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, 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 Onhofin tablets should be discontinued immediately if liver function tests show increased activity. Very rare cases of severe liver failure (some of which were fatal or required liver transplantation) have been reported in patients taking oral terbinafine. In most cases of liver failure, patients had serious underlying systemic diseases (see sections "Contraindications" and "Adverse reactions").

Patients taking Onhofin 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, pain in the upper right abdomen, 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 (e.g., 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 pneumonia, myocarditis, or pericarditis. Treatment with Onhofin tablets should be discontinued if progressive skin rash or other possible signs of hypersensitivity occur.

Lupus erythematosus/psoriasis

Onhofin 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 terbinafine tablets. The cause of any blood disorder in patients should be evaluated, and consideration should be given to modifying the treatment regimen, including discontinuation of Onhofin tablets.

Renal function

The use of Onhofin tablets in patients with impaired renal function (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 closely monitored when concomitantly receiving drugs that are primarily metabolized by the CYP2D6 enzyme (e.g., tricyclic antidepressants, beta-blockers, selective serotonin reuptake inhibitors [SSRIs], antiarrhythmics [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, there are no adequate controlled clinical studies in pregnant women. Clinical experience with the use of terbinafine in pregnant women is very limited; therefore, Onhofin 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 Onhofin treatment.

Ability to affect reaction speed when driving or operating machinery

No specific studies have 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.

Dosage and Administration

The medication is intended for oral use. The tablets should be swallowed with water, preferably at the same time each day. The 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 type and severity of the infection. Treatment should be continued for the appropriate length of time. Inadequate duration of treatment and/or irregular administration may lead to recurrence of infection. Personal hygiene measures should be followed to prevent reinfection (e.g., underwear, socks, footwear).

Recommended duration of treatment:

• 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: In most cases, 6 weeks of treatment are sufficient.

Infections of the great toe: In most cases, 12 weeks of treatment are 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

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

Patients with renal impairment

The use of Onhofin tablets in patients with renal impairment has not been adequately studied and is therefore not recommended in this patient group.

Elderly patients

It is unknown whether dose adjustment is required in elderly patients. However, in this age group, potential hepatic or renal impairment should be taken into consideration when administering the drug.

Missed dose

If a patient forgets to take 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 this 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.

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 in a place protected from light and inaccessible to children at a temperature not exceeding 25 °C.

Packaging.

7 tablets per blister, 2 blisters per cardboard box.

Prescription status.

By prescription only.

Manufacturer.

Aurobindo Pharma Limited – Unit III.

Manufacturer's address and location of its business operations.

Survey No.: 313, 314 - Blocks I, II, III, IV, Bachupally, Bachupally Mandal, Medchal-Malkajgiri District, Telangana State, 500090, India.