Terbinafine-vertex 250 mg 10 pcs. Vertex ao tablets

Terbinafine-vertex 250 mg 10 pcs. Vertex ao tablets

pharmachologic effect

Terbinafine is an allylamine that has a broad spectrum of activity against fungi that cause diseases of the skin, hair and nails, including dermatophytes.
At low concentrations it has a fungicidal effect on dermatophytes Trychophyton spp. (T. rubrum, T. mentagrophytes, T. verrucosum, T. tonsurans, T. violaceum), Microsporum canis, Epidermophyton floccosum, molds (for example, Aspergillus, Cladosporium, Scopulariopsis brevicaulis), yeasts, mainly Candida albicans. In low concentrations, terbinafine has a fungicidal effect against dermatophytes, molds and some dimorphic fungi. Activity against yeast fungi, depending on their type, can be fungicidal or fungistatic. Terbinafine specifically inhibits the early stage of sterol biosynthesis in the fungal cell. This leads to ergosterol deficiency and intracellular accumulation of squalene, which causes the death of the fungal cell. Terbinafine works by inhibiting the enzyme squalene epoxidase in the cell membrane of the fungus. This enzyme does not belong to the cytochrome P450 system. Terbinafine does not affect the metabolism of hormones or other drugs.

When Terbinafine is taken orally, concentrations of the drug are created in the skin, hair and nails, providing a fungicidal effect.

When administered orally, it is not effective in the treatment of pityriasis versicolor caused by Pityrosporum ovale, Pityrosporum orbiculare (Malassezia furfur).

Composition and release form Terbinafine-vertex 250 mg 10 pcs. Vertex ao tablets

Tablets - 1 tablet:

• Active ingredients: terbinafine (in the form of hydrochloride) - 250 mg;
• Excipients: microcrystalline cellulose 0.08 g, hyprolose (hydroxypropylcellulose) 0.025 g, croscarmellose sodium 0.08 g, colloidal silicon dioxide 0.01 g, calcium stearate 0.005 g, lactose monohydrate to obtain a tablet weighing 0.5 g.

Description of the dosage form

Tablets of white or white with a yellowish tint with a chamfer and a score.

Directions for use and doses

For adults:

Inside, after eating. Usual dose: 250 mg 1 time per day.

Children over 3 years old:

For body weight from 20 to 40 kg - 125 mg 1 time per day.

For body weight more than 40 kg - 250 mg 1 time per day.

The duration of the course of treatment and dosage regimen are established individually and depend on the localization of the process and the severity of the disease.

Onychomycosis: duration of therapy is on average 6-12 weeks. If the nails of the fingers and toes are affected (with the exception of the big toe), or if the patient is young, the duration of treatment may be less than 12 weeks. For a big toe infection, a 3-month course of treatment is usually sufficient.

Some patients whose nail growth rate is reduced may require a longer treatment period.

Fungal skin infections: the duration of treatment for interdigital, plantar or “sock” localization of infection is 2-6 weeks; for mycoses of other parts of the body: legs - 2-4 weeks, torso - 2-4 weeks; for mycoses caused by fungi of the genus Candida - 2-4 weeks; for mycoses of the scalp caused by fungi of the genus Microsporum - more than 4 weeks.

The duration of treatment for mycoses of the scalp is about 4 weeks; for infection with Microsporum canis, it may be longer.

Elderly patients are prescribed the drug in the same doses as adults.

For patients with liver or kidney failure - 125 mg 1 time per day.

Pharmacokinetics

After a single oral dose of terbinafine at a dose of 250 mg, its Cmax in plasma is reached after 2 hours and is 0.97 mcg/ml. The half-life of absorption is 0.8 hours, the half-life of distribution is 4.6 hours. Communication with blood plasma proteins - 99%. When taken simultaneously with food, no dose adjustment is required.

Terbinafine quickly penetrates the skin and accumulates in the sebaceous glands. High concentrations are created in the hair follicles and hair; after a few weeks of use it penetrates into the nail plates. Accumulates in the stratum corneum of the skin (the concentration increases 10 times on day 2 after taking 250 mg, 70 times on day 12) and nails (the diffusion rate exceeds the rate of nail growth) in concentrations that provide a fungicidal effect.

Terbinafine is metabolized in the liver to form inactive metabolites. T1/2 is 16-18 hours. T1/2 of the terminal phase is 200-400 hours. It is excreted mainly by the kidneys (70%) in the form of metabolites, as well as through the skin. There is no evidence of drug accumulation in the body. Excreted in breast milk. There have been no changes in steady-state plasma concentrations of terbinafine with age, but patients with impaired renal or hepatic function may have a slower rate of elimination of the drug, resulting in higher blood concentrations of terbinafine.

Indications for use Terbinafine-vertex 250 mg 10 pcs. Vertex ao tablets

• fungal diseases of the skin and nails (onychomycosis) caused by Trychophyton spp. (T. rubrum, T. mentagrophytes, T.
• verrucosum, T. tonsurans, T. violacium), Microsporum spp. (M. canis, M. gypseum) and Epidermophyton floccosum;
• mycoses of the scalp (trichophytia, microsporia);
• severe, widespread dermatomycosis of smooth skin of the trunk and extremities, requiring systemic treatment;
• candidiasis of the skin and mucous membranes.

Contraindications

• chronic or active liver disease;
• chronic renal failure (creatinine clearance less than 50 ml/min);
• children's age (up to 3 years) and with a body weight of up to 20 kg (for this dosage form);
• lactation period;
• lactase deficiency, lactose intolerance, glucose-galactose malabsorption;
• hypersensitivity to terbinafine or other components of the drug.

Caution should be used when:

• renal failure (with CC more than 50 ml/min);
• alcoholism;
• inhibition of bone marrow hematopoiesis;
• tumors;
• metabolic diseases;
• occlusive diseases of the vessels of the extremities;
• cutaneous lupus erythematosus or systemic lupus erythematosus.

Application Terbinafine-vertex 250 mg 10 pcs. Vertex AO tablets during pregnancy and breastfeeding

Since no studies have been conducted on the safety of Terbinafine in pregnant women, the drug should not be prescribed during pregnancy. Terbinafine is excreted in breast milk, so its use is contraindicated during breastfeeding. Contraindicated in children under 3 years of age and weighing up to 20 kg.

special instructions

Irregular use or early termination of treatment increases the risk of relapse.

The duration of therapy can be influenced by factors such as the presence of concomitant diseases, the condition of the nails with onychomycosis at the beginning of the course of treatment.

If after 2 weeks of treatment of a skin infection there is no improvement in the condition, it is necessary to re-determine the causative agent of the disease and its sensitivity to the drug.

Systemic use for onychomycosis is justified only in the case of total damage to most nails, the presence of severe subungual hyperkeratosis, and the ineffectiveness of previous local therapy.

When treating onychomycosis, a laboratory-confirmed clinical response is usually observed several months after mycological cure and cessation of treatment, which is due to the rate of regrowth of a healthy nail.

Removal of nail plates is not required when treating onychomycosis of the hands for 3 weeks and onychomycosis of the feet for 6 weeks.

In the presence of liver disease, the clearance of terbinafine may be reduced. During treatment, it is necessary to monitor the activity of “liver” transaminases in the blood serum.

In rare cases, cholestasis and hepatitis occur after 3 months of treatment. If signs of liver dysfunction occur (weakness, persistent nausea, decreased appetite, excessive abdominal pain, jaundice, dark urine or discolored stools), the drug should be discontinued.

Prescribing terbinafine to patients with psoriasis requires caution, because in very rare cases, terbinafine can cause an exacerbation of psoriasis.

When treating with terbinafine, general hygiene rules should be observed to prevent the possibility of re-infection through underwear and shoes. During treatment (after 2 weeks) and at the end it is necessary to carry out antifungal treatment of shoes, socks and stockings.

Impact on the ability to drive vehicles and operate machinery

There is no data on the effect of Terbinafine on the ability to drive vehicles and machines.

Overdose

Symptoms: headache, dizziness, nausea, vomiting, epigastric pain, frequent urination, rash.

Treatment: measures to eliminate the drug (gastric lavage, taking activated charcoal); if necessary, symptomatic maintenance therapy.

Side effects Terbinafine-vertex 250 mg 10 pcs. Vertex ao tablets

Frequency: very often - more than 1/10, often - more than 1/100 and less than 1/10, infrequently - more than 1/1000 and less than 1/100, rarely - more than 1/10000 and less than 1/1000, very rarely - less 1/10000, including individual cases.

From the digestive system: very often - a feeling of fullness in the stomach, loss of appetite, dyspepsia, nausea, abdominal pain, diarrhea; rarely - liver dysfunction; very rarely - liver failure, even death.

From the hematopoietic organs: very rarely - neutropenia, agranulocytosis, thrombocytopenia, pancytopenia.

Allergic reactions: very rarely - anaphylactoid reactions (including angioedema).

From the nervous system: often - headache; Uncommon: taste disturbance, including ageusia.

From the skin: very often - skin reactions (including rash, urticaria); very rarely - Stevens-Johnson syndrome, toxic epidermal necrolysis, psoriasis-like rash, exacerbation of existing psoriasis, alopecia.

From the musculoskeletal system: very often - arthralgia, myalgia.

Other: very rarely - fatigue; cutaneous lupus erythematosus, SLE or their exacerbation.

Drug interactions

Inhibits the CYP2D6 isoenzyme and disrupts the metabolism of drugs such as tricyclic antidepressants and selective serotonin reuptake inhibitors (for example, desipramine, fluvoxamine), beta-blockers (metoprolol, propranolol), antiarrhythmics (flecainide, propafenone), monoamine oxidase B inhibitors (for example, selegiline ) and antipsychotic (eg, chlorpromazine, haloperidol) agents.

Drugs that induce cytochrome P450 isoenzymes (for example, rifampicin) can accelerate the metabolism and elimination of terbinafine from the body. Medicines that are inhibitors of cytochrome P450 isoenzymes (for example, cimetidine) can slow down the metabolism and elimination of terbinafine from the body. If these drugs are used concomitantly, a dose adjustment of terbinafine may be required.

Menstrual irregularities are possible when taking terbinafine and oral contraceptives simultaneously. Terbinafine reduces the clearance of caffeine by 21% and prolongs its half-life by 31%. Does not affect the clearance of phenazone, digoxin, warfarin.

When used together with ethanol or drugs that have hepatotoxic effects, there is a risk of developing drug-induced liver damage.

Dermatophyte infections, especially onychomycosis, firmly occupy a niche among the most common dermatological diseases. For many years, onychomycosis was not treated or was difficult to treat. Only in recent decades, with the advent of well-known oral systemic antifungal drugs, has it been possible to significantly improve the effectiveness of treatment. Traditionally, systemic therapy for dermatophytosis is recommended for widespread, recurrent, chronic processes that do not respond well to the use of topical antimycotics. Conventional regimens for the use of systemic drugs for the treatment of onychomycosis require long-term administration and are associated with toxicity and low compliance in patients. This is primarily due to the lack of accurate data on the duration of therapy and the degree of recovery. For example, in Europe and North America, the standard treatment regimen for onychomycosis using terbinafine is a 3-month course with a dose of 250 mg/day. In Japan, treatment of dermatophytic onychomycosis is usually carried out with terbinafine at a dose of 125 mg/day for 5-6 months. It is obvious that in practical mycology there is a need to develop new highly effective and well-tolerated regimens. In this regard, in foreign mycological practice, the range of available doses for oral administration has increased, and methods of intermittent treatment (pulse therapy) and short-term therapy have been developed, which can replace the long-term continuous use of drugs for oral administration [1-3].

In Russia, itraconazole is traditionally used for pulse therapy. Pulse therapy with itraconazole has been shown to be an effective treatment method and is characterized by good patient adherence to treatment [4, 5]. However, in long-term treatment of fungal infections of the toenails caused by dermatophytes, terbinafine was more effective than itraconazole. Based on the results of local post-clinical observations of the LION program, it can be concluded that 5 years after the start of therapy, the number of relapses in patients taking itraconazole was approximately 2 times higher than in patients taking terbinafine. At the same time, in patients previously treated with itraconazole, whose tests during the observation period turned out to be positive, when switching to terbinafine therapy, a good level of clinical and mycological healing was revealed [6]. The cost-effectiveness studies that prioritized terbinafine in five of the six countries are also based on the LION program. According to clinical trial data, the price/effectiveness ratio of terbinafine was more favorable than that of itraconazole [7].

The pharmacokinetic properties of terbinafine are close to those of itraconazole. In addition, the fungicidal activity of terbinafine makes it an ideal drug for the treatment of dermatophyte onychomycosis. When terbinafine is administered orally at a dose of 250 mg/day for 6–12 weeks, this substance remains in the nail plate for an additional 30–36 weeks in concentrations exceeding the minimum inhibitory value for most types of dermatophytes [8, 9]. Based on these data, researchers suggested that pulse therapy with terbinafine may be effective in the treatment of onychomycosis [10–16].

In foreign practice, several regimens of pulse therapy using terbinafine are used for the treatment of onychomycosis: weekly intermittent therapy (500 mg/day 1 week for 4 months), on a principle similar to pulse therapy with itraconazole, single dose (1000 mg simultaneously once a month in for 4 months), monthly intermittent therapy (250 mg/day for a month, the next month without an antimycotic, then a repeated course of terbinafine at a dose of 250 mg/day for 4 weeks) [17].

The first publications on the effectiveness of single doses of systemic antimycotics and pulse therapy with terbinafine appeared in the 90s of the 20th century [10-12]. In 1996, A. Tosti et al. [11] published data from an open randomized study of the comparative effectiveness of intermittent therapy for dermatophytic onychomycosis with terbinafine and itraconazole. After daily administration of terbinafine at a dose of 250 mg for 4 months, the treatment effectiveness rate for mycological indicators was 95.0%, after 4 cycles of pulse therapy with terbinafine at a dose of 500 mg/day - 80.0% and after 4 cycles of pulse therapy itraconazole at a dose of 400 mg/day - 76.0%, while there were no significant statistical differences between these three groups. When conducting 4 cycles of pulse therapy with terbinafine at a dose of 500 mg/day, E. Alpsoy et al. [12] obtained good results comparable to those with continuous administration of terbinafine 250 mg/day for 3 months. In the table

The results of comparative studies of different regimens of terbinafine and itraconazole are presented. A total of 1073 patients participated in these studies. The selection of studies was based on the duration of follow-up of patients undergoing treatment. Undoubtedly, this better reflects the picture of daily clinical practice than projecting data only on patients who completed the study.

In most studies, the assessment of the cure of the process was based on the results of mycological studies (culture and microscopy). The rate of clinical recovery is difficult to assess, since different criteria are applied in the analyzed scientific works regarding clinical healing. Quite often, nails remain deformed, undeveloped, or have abnormalities even after mycological recovery. As a rule, authors take as a basis the length of a healthy nail, the percentage of its area, the generalized rate of recovery, or the proportion of nails whose recovery exceeds 90% [16, 18]. That is why the data reflecting the results of clinical recovery in the table vary widely.

A. Gupta et al. [19], when conducting a meta-analysis of the effectiveness of continuous and intermittent terbinafine regimens in the treatment of onychomycosis of the feet, concluded that the results of mycological cure are better when using continuous regimens than with pulse therapy. At the same time, the authors recommended the pulse therapy regimen as the final stage of prolonged administration of terbinafine, which significantly increases its effectiveness.

In our country, the intermittent scheme has not yet received widespread recognition [20]. In a study conducted by I.G. Bogush et al. [21], the clinical and mycological effectiveness after 6 cycles of pulse therapy with terbinafine at a dose of 500 mg/day was 67.3%. Positive experience of using Exifin

the pulse therapy method is presented in the monograph by V.M.
Rukavishnikova. However, the author noted better tolerability of high doses when taking the original terbinafine [22]. The choice of Exifin
was not accidental: it is a generic analogue of terbinafine, which has existed on the Russian market and in 8 other countries for a long time (since 1999), and also has a solid evidence base of effectiveness and safety [22, 23].

The search for optimal treatment regimens for onychomycosis is based on the understanding that existing treatment options do not completely solve the problem of fungal infections. Despite the proven effectiveness of recommended antifungal agents and the relatively slow development of resistance in fungi, the epidemiological situation with onychomycosis in the world is not improving. Perhaps under-accounted features of the interaction between fungi and drugs in vivo

. One cannot deny the influence of another parameter - the patient’s discipline in the use of medications, since treatment of onychomycosis in most cases occurs on an outpatient basis. It is around the fashionable concept of “compliance” (from English compliance), which denotes adherence to treatment, that all the factors that influence the success of activities performed by patients independently are united.

Thus, according to Chinese researchers Y. Hu et al. [24], factors influencing treatment adherence among patients with onychomycosis were age, severity of damage to the nail plate (assessed by the SCIO or KIOTOS index) and treatment regimen. All patients in this study (330 people) were randomized into three groups: those treated with itraconazole pulse therapy (A), those receiving continuous terbinafine (B) and pulse therapy regimen (C). The average compliance rate was only 55.15%. The frequency of patients' negative attitude towards doctor's recommendations in groups A, B and C was 22.73, 21.43 and 23.15%, respectively (differences in indicators are statistically insignificant; p>0.1). Most negative reactions to medical prescriptions occurred in the 1st month of therapy.

The patient’s resistance to treatment directly depends on the extent to which medical prescriptions interfere with the usual routine of life.

On average, only 1/3 of patients strictly follow all medical recommendations. According to a systematic review [25], which combined the results of 76 studies, compliance deteriorates in parallel with an increase in the frequency of taking/using medications: if a single dose is necessary, 79% of patients comply with medical recommendations, 69% - 69% - 2 times, 65% - 3 times. It is not surprising that in the study by V. Sanmano et al. [14], which provided a combination of weekly pulse therapy with terbinafine at a dose of 250 mg/day and daily topical application of 1% terbinafine cream, achieved high results of clinical and mycological cure (83.7%), and also demonstrated good patient adherence to this regimen treatment.

Another parameter that the practitioner has to take into account is the tolerability and safety of long-term use of the antimycotic. Most scientists [26-31] noted that the use of intermittent regimens using terbinafine best solves this problem, demonstrating high clinical and mycological effectiveness.

The use of terbinafine pulse therapy regimens is not limited to the treatment of onychomycosis. Interesting are the results of the intermittent treatment regimen for dermatophytosis of the smooth skin of the trunk, used by V. Shivakumar et al. [32] (1 tablet (250 mg) of terbinafine once every 3 days, course of 7 tablets). At the end of treatment, clinical recovery was observed in 93.4% of patients. After 3 months, clinical and mycological cure was 91.3%. Mycological examination included microscopy and obtaining a fungal culture on Sabouraud dextrose agar.

There are optimistic attempts to use pulse therapy to treat mycosis of the scalp caused by fungi of the genus Microsporum

spp., including
Microsporum canis
.
It is known that Microsporum canis
and other pathogens that infect hair of the “ectothrix” type are less sensitive to terbinafine than micromycetes that infect hair of the “endothrix” type.
In a double-blind, randomized study conducted by R. Ungpakorn et al., a standard treatment regimen for mycosis of the scalp with terbinafine or a double dose of terbinafine for 1 week was provided. After 3 weeks, pulse therapy was repeated, the recommended number of pulses being 2-3. Researchers have shown that an increased dose of terbinafine does not affect the effectiveness of treatment, while at the same time, the duration of terbinafine therapy is an important factor determining the prognosis of clinical recovery. According to the authors [33], 2 courses of pulse therapy with standard doses of terbinafine are sufficient to cure most cases caused by Microsporum
spp.
and Trichophyton
spp. The effectiveness of pulse therapy with terbinafine was 92.3%. Prescription of a 3rd pulse may be necessary if there is no clinical improvement after 8 weeks of therapy. The need to increase the duration of treatment with terbinafine from 8 to 12 weeks for mycosis of the scalp caused by Microsporum canis is indicated by A. Gupta [34] and other researchers [35, 36].

Conclusion

The above analysis of data from individual studies, as well as meta-analyses summarizing the results of intermittent terbinafine regimens, clearly reflects the international desire to develop optimal treatment protocols. By systematizing the experience of colleagues, it is possible to determine the indications for the use of terbinafine pulse therapy:

1) onychomycosis of dermatophyte etiology in patients with low adherence to therapy;

2) use as a final stage of prolonged administration of terbinafine in the treatment of onychomycosis of the feet;

3) dermatophytosis of smooth skin and scalp caused by Microsporum

spp.
and Trichophyton
spp.