Flumenin

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

Composition:

Active substance: efinaconazole;

1 g of solution contains efinaconazole 100 mg;

Excipients: ethanol 96%, anhydrous citric acid, butylhydroxytoluene,
C12-15 alkyl lactate, cyclomethicone, diisopropyl adipate, disodium edetate, purified water.

Pharmaceutical form. Topical solution.

Main physicochemical properties: clear solution ranging from colorless to pale yellow.

Pharmacotherapeutic group.

Antifungal agents for topical use. Imidazole and triazole derivatives. Efinaconazole.

ATC code D01AC19.

Pharmacological Properties

Pharmacodynamics

Efinakonazole is a triazole antifungal agent. Efinakonazole inhibits fungal lanosterol-14α-demethylase, an enzyme involved in ergosterol biosynthesis. Accumulation of 14α-methylsterols and the resulting deficiency of ergosterol in the fungal cell wall may account for the fungistatic and fungicidal activity of efinakonazole. It has been shown that in vitro, efinakonazole is largely adsorbed onto keratin, but the binding to keratin is weak. The low affinity of efinakonazole for keratin is expected to increase the availability of unbound drug at the site of the infected nail.

Microbiological Properties

Efinakonazole is an azole antifungal agent. Efinakonazole inhibits fungal lanosterol-14α-demethylase, an enzyme involved in the biosynthesis of ergosterol, a component of fungal cell membranes.

In vitro and in vivo Activity

Efinakonazole has been found to be active against isolates of the following microorganisms both in vitro and in the treatment of clinical infections. Efinakonazole demonstrates in vitro minimum inhibitory concentrations (MICs) of 0.06 µg/mL or lower against most (≥ 90%) isolates of the following microorganisms: Trichophyton rubrum, Trichophyton mentagrophytes.

Mechanism of Resistance

Development of resistance to efinakonazole has been studied in vitro for T. mentagrophytes, T. rubrum, and C. albicans. Serial passages of fungal cultures in the presence of efinakonazole concentrations insufficient to inhibit microbial growth resulted in up to a 4-fold increase in MIC. The clinical significance of these in vitro findings is currently unknown.

Pharmacokinetics

Absorption

Topical application of efinakonazole results in low systemic concentrations of the drug. Systemic absorption of efinakonazole was evaluated in 18 patients with severe onychomycosis following once-daily application of efinakonazole for 28 days to 10 toenails and adjacent skin of each patient. Plasma concentrations of efinakonazole were measured at multiple time points over 24-hour periods on Day 1, Day 14, and Day 28. The mean Cmax of efinakonazole in plasma on Day 28 was 0.67 ng/mL. The plasma concentration-time curve was generally flat throughout the treatment period. In patients with onychomycosis, steady-state plasma concentrations ranged from 0.1 to 1.5 ng/mL for efinakonazole and from 0.2 to 7.5 ng/mL for its metabolite H3. In a separate study conducted in healthy volunteers, the plasma half-life of efinakonazole on Day 10 after multiple applications to all 10 toenails was 29.9 hours.

Distribution

The extent of plasma protein binding of efinakonazole in humans in vitro is high: 95.8%–96.5%. Due to the low systemic levels, plasma protein binding of efinakonazole is not clinically significant. Plasma protein binding was independent of concentration over the range of 50–2500 ng/mL. In vitro, efinakonazole binds to human serum albumin (95.2%), α1-acid glycoprotein (85.5%), and γ-globulin (4.4%). Given the high plasma concentration of albumin relative to other proteins, efinakonazole in humans is expected to bind predominantly to serum albumin in vivo.

In vitro, efinakonazole penetrates through nails following topical application, indicating drug penetration through the fungal-infected nail and nail bed, although the clinical significance of these findings is currently unknown. Penetration of efinakonazole was assessed in an in vitro study following daily application of radiolabeled efinakonazole (10%) at a dose of 55.1 µL/cm² to human nails for 28 days. After 28 days of application, cumulative radioactivity in the receptor fluid and nail plate was 0.03% and 0.16% (3.11 mg·eq/g) of the total applied radioactivity, respectively. The flux rate was relatively stable from Day 18 to Day 28, with a mean value of 1.40 µg·eq/cm² per day, indicating steady-state absorption.

Metabolism and Elimination

Efinakonazole is extensively metabolized in the body via oxidative-reductive processes, with potential additional glucuronidation of metabolites. Analysis of human plasma confirmed that H3 is the major metabolite of efinakonazole. Efinakonazole is considered neither an inhibitor nor an inducer of CYP450 enzymes. In vitro studies using human liver microsomes showed that efinakonazole inhibited the activity of CYP2C8, CYP2C9, CYP2C19, and CYP3A4 at concentrations exceeding clinical levels of systemic exposure. Furthermore, in vitro studies demonstrated that efinakonazole did not induce the activity of CYP1A2 or CYP3A4 in isolated human hepatocytes. Therefore, it is unlikely that efinakonazole affects the pharmacokinetics of substrates of major CYP450 isoenzymes via inhibition or induction mechanisms. Efinakonazole metabolites are excreted in urine and bile/feces.

Clinical characteristics.

Indications.

Indicated for topical treatment of onychomycosis of toenail(s) without nail bed involvement (mild to moderate degree), caused by Trichophyton rubrum and Trichophyton mentagrophytes in adult patients with normal immune response.

Contraindications.

Contraindicated in patients with known hypersensitivity to efinaconazole or to any of the excipients of the medicinal product, or to any component of the packaging.

Interaction with other medicinal products and other forms of interaction.

In vitro studies have shown that efinaconazole at therapeutic concentrations does not cause either inhibitory or inductive effects on cytochrome P450 (CYP450) enzymes.

Efinaconazole is considered a non-inhibitor of CYP450 enzymes. In vitro studies using human liver microsomes demonstrated that efinaconazole did not inhibit the activity of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 enzymes at concentrations expected in systemic circulation under clinical use of the drug. In vitro studies showed that efinaconazole does not induce the activity of CYP1A2 or CYP3A4 enzymes in isolated human hepatocytes.

Special precautions for use.

The overall safety and efficacy of the medicinal product Fliamena have not been studied in patients with a history of immunosuppression and/or current clinical signs of immunosuppression, in patients with HIV infection, uncontrolled diabetes mellitus, in pregnant and breastfeeding women, in patients with other fungal infections of the toenails (except Candida), in patients with toenail infections involving the nail matrix, in patients with lateral nail involvement only, or in patients with severe plantar ("moccasin") tinea pedis ("athlete's foot"). Concomitant use of other antifungal agents together with the medicinal product Fliamena has not been evaluated. The safety and efficacy of daily use of the medicinal product for periods longer than 48 weeks have not been established.

Use outside nail areas.

The medicinal product Fliamena is not intended for oral, ophthalmic, otic, or mucosal use.

It is indicated for topical application only to toenails and immediately adjacent skin areas.

The medicinal product Fliamena is highly flammable; it should be stored away from sources of heat and flame.

Application site irritation.

If a reaction indicating hypersensitivity or severe irritation occurs during use of the medicinal product, treatment with this agent should be discontinued and appropriate therapy initiated according to physician recommendations.

Use during pregnancy or breastfeeding.

Pregnancy period.

Currently, adequate and well-controlled studies on the use of the medicinal product in pregnant women have not been conducted. The medicinal product Fliamena should not be used during pregnancy except when the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding period.

It is not known whether efinaconazole is excreted in human breast milk. Efinaconazole has been detected in the milk of lactating rats following repeated subcutaneous administration. Since many medicinal products are excreted in human breast milk, the medicinal product should not be used in breastfeeding women except when the expected benefit to the mother outweighs the potential risk to the infant.

Ability to affect reaction rate when driving or operating machinery.

No effect.

Method of administration and dosage.

Dosage and administration

General recommendations.

Surgical intervention for debridement of the affected area is not required when treating onychomycosis with the medicinal product Fliemenai. There is no need to wash off the previously applied medicinal product, as it does not accumulate with daily use. Patients should trim the toenails every 4 weeks and dispose of the clipped fragments. Unaffected toenails should be trimmed before affected toenails.

Fliemenai is intended for topical use only. The solution must not be used orally, in the eyes, ears, or on mucous membranes.

Recommended dosage and dosage adjustment.

The medicinal product Fliemenai should be applied to clean, dry nails. The product should be applied topically once daily (preferably before bedtime) to the affected toenails using the built-in applicator brush on the bottle, through which the solution is dispensed from the container. One drop of the solution should be applied to each affected nail. If the big toenail is affected, two drops of the medicinal product Fliemenai should be applied to it.

Complete clinical recovery may take several months after achieving mycological cure, depending on the time required for healthy nail regrowth.

Recommendations for application of the medicinal product Fliemenai.

Missed dose.

Physicians should act based on clinical judgment depending on the severity of infection.

If the patient misses an application of Fliamenai:

• Apply the missed dose as soon as remembered;
• If remembered close to the time of the next dose, skip the missed dose and apply the next dose at the regular time;
• Do not apply two doses at once or extra doses.

Use in elderly individuals

Of the total number of participants evaluated in clinical trials of efinaconazole, 8.3% were aged 65 years and older, and no participant was aged 75 years or older. Overall, no differences in safety and efficacy of the medication were observed in these participants compared to younger participants. Additional clinical experience reports have not revealed any differences in treatment response between elderly and younger patients; however, increased sensitivity to the medication in some elderly individuals cannot be ruled out.

Pediatric use.

The safety and efficacy of efinaconazole in children under 18 years of age have not been established.

Overdose.

Absorption of the medication into the bloodstream from the site of application results in low systemic concentrations of the drug in the body. There are no data on the bioavailability of the drug following oral administration in humans; however, oral bioavailability in rats is very low (0.4%).

No cases of overdose were reported in clinical trials, either with topical or oral administration. However, overdose with topical use is unlikely due to low systemic drug concentrations. There is no specific antidote for this medication.

Adverse Reactions

Adverse reactions observed in patients treated with efinaconazole were:

• Dermatitis at the site of application (2.0%);
• Vesicles at the site of application (1.4%).

Most of the adverse events observed in the efinaconazole treatment group were mild to moderate in severity. The most common adverse reaction leading to discontinuation of treatment was dermatitis at the site of application.

Less common adverse reactions reported in clinical trials (occurring in > 0.1% to < 1% of patients):

Cardiac disorders: ventricular extrasystoles (0.1%).

Eye disorders: blepharitis (0.1%), eye pruritus (0.1%), and blurred vision (0.1%).

General disorders and administration site conditions: application site reactions: discoloration (0.3%), eczema (0.2%), erythema (0.8%), desquamation (0.6%), irritation (0.3%), pain (0.4%), paresthesia (0.3%), pruritus (0.4%), and swelling (0.5%).

Infections and infestations: nasopharyngitis (0.2%).

Nervous system disorders: headache (0.2%).

Skin and subcutaneous tissue disorders: onychomadesis (0.3%).

Since clinical trials are conducted under highly specific conditions, the adverse reaction frequencies observed in clinical trials may not reflect the frequencies observed in clinical practice and should not be compared to frequencies from clinical trials of other medicinal products. Information on adverse reactions obtained from clinical trials is useful for identifying adverse events related to the use of this medicinal product and for estimating their frequency.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

2 years.

After opening the bottle – 45 days.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Do not freeze. Keep the bottle tightly closed, in an upright position, away from heat sources and flames.

Keep out of reach of children.

Packaging.

4 ml or 8 ml in a bottle with an applicator brush, closed with a cap, one bottle per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

EnCUBE Ethicals Private Limited.

Manufacturer's address and location of operations.

Plot No. C-1, Madkaim Industrial Estate, Madkaim, Post MarDol, Ponda, Goa - 403 404, India.