Instructions Terbinorm tablets 250 mg blister No. 14
Composition
active ingredient: terbinafine;
1 tablet contains terbinafine (in the form of hydrochloride) 250 mg;
excipients: microcrystalline cellulose, corn starch, colloidal anhydrous silicon dioxide, hypromellose, talc, magnesium stearate.
Dosage form
Pills.
Main physicochemical properties: round flat tablets from white to yellowish-white in color.
Pharmacotherapeutic group
Antifungal drugs for use in dermatology. Antifungal drugs for systemic use. 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 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 administered orally, terbinafine accumulates in the skin in concentrations that provide its fungicidal effect.
Pharmacokinetics
Absorption
Terbinafine is well absorbed after oral administration (> 70%). Its absolute bioavailability as a result of first-pass metabolism is approximately 50%. A single oral dose of 250 mg terbinafine showed a mean maximum plasma concentration (Cmax) of 1.30 μg/ml 1.5 hours after administration. At steady state, compared with a single dose, Cmax of terbinafine was on average 25% higher and the area under the concentration-time curve (AUC) increased 2.3-fold. Based on the increase in plasma AUC, the effective half-life (T1/2) (30 hours) can be calculated. Food intake has a moderate effect on the bioavailability of terbinafine (increase in AUC by less than 20%), but not enough to require dose adjustment. Concomitant intake of a high-fat meal slows down the absorption of terbinafine and increases bioavailability by approximately 20%.
Distribution
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. 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 plates 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.
Metabolism
Terbinafine is rapidly and extensively metabolized by at least 7 CYP isoenzymes with significant contributions from CYP2C9, CYP1A2, CYP3A4, CYP2C8 and CYP2C19.
Breeding
As a result of biotransformation of terbinafine, metabolites are formed that have no antifungal activity and are excreted mainly in the urine. T1/2 is 17 hours. There is no evidence of accumulation of terbinafine in the body.
No changes in the pharmacokinetics of terbinafine are observed depending on the patient's age, but the rate of excretion from the body may be reduced in patients with impaired renal or hepatic function, leading to increased plasma levels.
Single-dose pharmacokinetic studies of terbinafine in patients with renal impairment (creatinine clearance <50 mL/min) or pre-existing liver disease have shown that its clearance 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
hypersensitivity to the active substance or to other components of the drug; acute or chronic liver diseases.
Interaction with other medicinal products and other types of interactions
Effect of other drugs on the pharmacokinetics of terbinafine
Terbinafine is metabolized by cytochrome P450 (CYP450) isoenzymes. Plasma clearance of terbinafine may be increased by agents that induce these enzymes and may be decreased by agents that inhibit cytochrome P450. If concomitant use of such agents is necessary, the dosage of terbinafine should be adjusted accordingly.
Cytochrome P450 enzyme inhibitors
Fluconazole (an inhibitor of CYP2C9 and CYP3A4) increased the Cmax and AUC of terbinafine by 52% and 69%, respectively, due to inhibition of CYP2C9 and CYP3A4 enzymes. The same increase may be observed when terbinafine is co-administered with agents that inhibit CYP2C9 and CYP3A4, such as azole fungicides (ketoconazole), macrolide antibiotics, or amiodarone.
Inducers of cytochrome P450 enzymes
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-mediated metabolism. 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 some of the following classes of agents: 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 enzymes
In vitro studies in healthy volunteers indicate that terbinafine has little potential to inhibit or increase the clearance of most drugs metabolized by the cytochrome P450 system (e.g. terfenadine, triazolam, tolbutamine or oral contraceptives).
Other metabolic pathways
Terbinafine increases the clearance of cyclosporine by 15% (decrease in AUC by 13%).
The possibility of interaction between terbinafine and commonly prescribed anticoagulants has not been studied. No interactions were observed in a study of interaction with warfarin.
In clinical studies, no relevant effect of terbinafine on the pharmacokinetics of co-trimoxazole (trimethoprim and sulfamethoxazole), digoxin, fluconazole, phenazone, theophylline or zidovudine was found.
Application features
The drug should only be used when topical application of terbinafine is not possible.
Liver reactions
The drug is contraindicated for use in patients with chronic or acute liver disease. Any pre-existing liver disease should be evaluated before use. 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). The drug should be discontinued immediately if liver function tests become elevated. Serious hepatic failure (some fatal or requiring liver transplantation) has been reported very rarely in patients receiving oral terbinafine. In most cases of hepatic failure, the patients had serious underlying systemic diseases (see sections 4.3 and 4.8).
Patients should be advised to report any signs or symptoms of liver dysfunction, such as pruritus, unexplained persistent nausea, loss of appetite, anorexia, jaundice, vomiting, fatigue, right upper abdominal pain, dark urine, or discolored stools, to their physician immediately while taking the drug. 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 with oral terbinafine. As well as skin reactions and eosinophilia, DRESS can involve one or more organs, causing hepatitis, interstitial nephritis, interstitial pneumonitis, myocarditis, pericarditis. If progressive skin rash or other possible signs of hypersensitivity occur, the drug should be discontinued.
Hematological reactions
Hematological abnormalities (neutropenia, agranulocytosis, thrombocytopenia, pancytopenia) have been reported very rarely with oral terbinafine. Patients should be evaluated for the cause of any hematological abnormality and consider possible changes in treatment regimen, including discontinuation of the drug.
The drug should be used with caution in such patients, as very rare cases of exacerbation of these diseases have been reported.
Use in patients with renal impairment
The use of the medicinal product in patients with renal impairment (creatinine clearance less than 50 ml/min or plasma creatinine level greater than 300 μmol/l) has not been adequately studied and is therefore not recommended.
Interactions with other drugs
In vitro and in vivo studies have shown that terbinafine is an inhibitor of the CYP2D6 enzyme. 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").
Ability to influence reaction speed when driving vehicles or other mechanisms
No relevant studies have been conducted. Patients who experience dizziness as an adverse effect of the drug (see section "Adverse reactions") should avoid driving or operating machinery.
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 oral terbinafine in pregnant women is very limited. The drug should not be used during pregnancy unless clearly necessary.
Small amounts of terbinafine pass into breast milk. The drug should not be used during breastfeeding.
Method of administration and doses
The medicine is intended for oral use. The tablets should be swallowed with water, preferably at the same time of day, regardless of meals.
Adults
The drug should be used at a dose of 250 mg (1 tablet) once a day.
If a dose is missed, the next dose should be taken as soon as possible. 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.
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 – 2–4 weeks; cutaneous candidiasis – 2–4 weeks; trichophytosis of the scalp – 4 weeks; onychomycosis caused by dermatophytes – 6–12 weeks (longer treatment may be required in patients with slow-growing nails); nail infections – 6 weeks are sufficient in most cases; infections of the big toe – 12 weeks are sufficient in most cases.
In the case of fungal nail infections, the clinical effect usually occurs several months after treatment. This is due to the regrowth of a healthy nail.
Patients with hepatic impairment
The drug is contraindicated in patients with chronic or acute liver disease.
Patients with renal impairment
The use of terbinafine in patients with renal impairment has not been adequately studied, therefore the drug is not recommended for use in such patients.
Elderly patients
There is no evidence that elderly patients require a different dose of terbinafine or that they experience different adverse reactions than younger patients. In this age group, the possibility of impaired liver or kidney function should be taken into account when using the drug.
Children
Data on the use of oral terbinafine in children are limited, therefore the use of the drug is not recommended in this age group of patients.
Overdose
Several cases of overdose (oral administration of up to 5 g of terbinafine) have been reported. Headache, nausea, epigastric pain and dizziness were observed. The treatment recommended in case of overdose includes removal of terbinafine, primarily with the use of adsorbents and, if necessary, symptomatic supportive therapy.
Adverse reactions
Adverse reactions are usually mild to moderate and transient in nature. The following adverse reactions have been observed during clinical trials with terbinafine or during post-marketing surveillance.
Blood and lymphatic system disorders:
infrequently - anemia; very rarely - neutropenia, agranulocytosis, thrombocytopenia, pancytopenia.
On the part of the immune system:
very rarely - anaphylactoid reactions (including Quincke's edema), progression and exacerbation of cutaneous and systemic lupus erythematosus; unknown - anaphylactic reaction, reactions similar to serum sickness symptoms (including rash, itching, urticaria, edema, arthralgia, fever and lymphadenopathy).
Metabolism and nutrition:
very common – loss of appetite; uncommon – weight loss (due to dysgeusia).
Severe isolated cases of decreased food intake leading to significant weight loss have been reported.
From the psyche:
often - depression; infrequently - anxiety.
From the nervous system:
very often - headache; often - dizziness, dysgeusia up to loss of taste; infrequently - paresthesia, hypoesthesia; very rarely - persistent dysgeusia; unknown - hyposmia, anosmia, including permanent anosmia.
On the part of the organs of vision:
often - visual impairment; unknown - blurred vision, decreased visual acuity.
On the part of the organs of hearing and balance:
uncommon – tinnitus; unknown – hearing loss.
From the vascular side:
unknown – vasculitis.
From the digestive tract:
very common - feeling of fullness of the stomach, dyspepsia, nausea, moderate abdominal pain, diarrhea; unknown - pancreatitis.
From the hepatobiliary system:
Rare: hepatic failure, increased liver enzymes, jaundice, cholestasis and hepatitis (including fatal cases or cases requiring liver transplantation) (see section "Special warnings and precautions for use").
Skin and subcutaneous tissue disorders:
very common - rash, urticaria; infrequent - photosensitivity; very rare - alopecia, psoriatic-like rash or exacerbation of psoriasis, toxicoderma, exfoliative and bullous dermatitis, erythema multiforme, Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis), acute generalized exanthematous pustulosis; unknown - drug rash with eosinophilia and systemic symptoms.
Musculoskeletal and connective tissue disorders:
very common – arthralgia, myalgia; unknown – rhabdomyolysis; increased plasma creatine phosphokinase.
On the part of the body as a whole and reactions at the injection site:
often - fatigue; infrequently - fever; unknown - influenza-like illness.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions that occur after the marketing authorisation of a medicinal product is very important. This allows the benefit/risk balance of the medicinal product to be continuously monitored. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
Expiration date
3 years.
Storage conditions
Store at a temperature not exceeding 25 ºС in a place inaccessible to children.
Packaging
7 tablets in a blister, 2 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
K.O. SLAVIA FARM S.R.L.
Location of the manufacturer and its business address
Teodor Palladi Boulevard No. 44 C, Sector 3, 032266, Bucharest, Romania.
