Flukonazol-Darnitsa

General characteristics. Structure:

Active ingredient: fluconazole; 1 capsule contains a flukonazol (in terms of 100% substance) 50 mg, 100 mg;

excipients: potato starch, lactoses monohydrate, silicon dioxide colloid anhydrous, sodium lauryl sulfate, magnesium stearate.

Pharmacological properties:

Pharmacodynamics. Flukonazol is the representative of a class of triazolny antifungal means. It is powerful selection inhibitor of synthesis of stirol in cells of mushrooms. Drug shows activity at the mycoses caused by Candida spp., Cryptococcus neoformans., M_crosporum spp., Tychophyton spp., Blastomyces dermatitides, Cocc_dioides іmmіtis H_stoplasma capsulatum.

Pharmacokinetics. After intake флуконазол it is well soaked up, its level in plasma and the general bioavailability is exceeded by 90% of levels of a flukonazol in plasma at intravenous administration. The simultaneous use of food does not influence absorption of drug at intake. Concentration in a blood plasma is proportional to a dose, it reaches the maximum size in 0,5-1,5 hours after reception of a flukonazol on an empty stomach. Equilibrium concentration (for equal 90%) is reached for the 4-5th days of treatment by drug (at reception once a day).

Reception for the first day of a shock dose which twice exceeds a usual daily dose, allows to reach equilibrium 90% of concentration for the second day. The volume of distribution approaches the general contents of water in an organism. Extent of linkng of a flukonazol with blood proteins does not exceed 11-12%.

Flukonazol gets into all liquids of an organism. Drug levels in saliva and a phlegm the same most, as well as its concentration in a blood plasma. At patients with fungal meningitis the level of a flukonazol in cerebrospinal fluid reaches 80% of its concentration in a blood plasma.

In a corneous layer, epidermis, a derma and stalemate liquid high concentration which exceed serumal are reached. Flukonazol collects in a corneous layer of skin. At reception of a dose of 50 mg/days concentration of a flukonazol in a corneous layer in 12 days made 73 mkg/g, and in 7 days after completion of treatment – 5,8 mkg/g. At use in a dose of 150 mg once a week concentration of a flukonazol in a corneous layer for the seventh day reached 23,4 mkg/g, and in 7 days after reception of the second dose – 7,1 mkg/g. Concentration of a flukonazol in nails after four-months use in a dose of 150 mg made 4,05 mkg/g in healthy nails and 1,8 mkg/g once a week – in struck; in     6 months after the end of therapy флуконазол still was defined in nails.

Drug is completely removed by kidneys, and about 80% of the entered dose appear in urine in not changed look. Clearance of a flukonazol proportional to clearance of creatinine. The circulating metabolites are not revealed.

Long plasma elimination half-life of blood (about 30 hours) allows to accept флуконазол at the same time at vaginal candidiasis and to apply once a day or once a week at other diseases caused by sensitive mushrooms.

At people of advanced age, in the absence of the phenomena of a renal failure, pharmacokinetic parameters of a flukonazol without changes.

Indications to use:

• A cryptococcosis, including cryptococcal meningitis and infections of other localization (for example, skin, lungs). Treatment can be carried out as at patients with a normal immune response, and at patients with acquired immunodeficiency syndrome (AIDS), recipients of transplanted organs and patients who receive therapy by imunnosupressant. Flukonazol-Darnits can be applied as a maintenance therapy for the purpose of prevention of a recurrence of a cryptococcosis at patients with AIDS.

• Generalized candidiasis, including a kandidemiya, the disseminated candidiasis, fungal infections of an abdominal cavity, an endocardium, eyes, respiratory and urinary tract. Treatment of patients with malignant tumors which are in intensive care unit and is received by cytotoxic or immunosuppressive means, or will visit under the influence of other factors that does them more inclined to development of candidiasis.

• Candidiasis of mucous membranes, including an oral cavity, a throat, a gullet, noninvasive bronchopulmonary infections, a kandiduriya, the skin and mucous and chronic oral atrophic candidiasis (connected using dentures). Treatment can be carried out at patients with the normal or suppressed immune function. Prevention of a recurrence of oropharyngeal candidiasis at patients with AIDS.

• Genital candidiases: acute or recurrent candidiasis of a vagina, candidosis balanitis. Preventive use for the purpose of reduction of frequency of a recurrence of candidiasis of a vagina (rub or more recurrence in a year).

• Prevention of fungal infections which can develop owing to cytotoxic chemotherapy or radiation therapy at patients with malignant new growths.

• Dermatomycoses, mycoses of feet, mycosis of smooth skin, a pakhovy dermatomycosis, multi-colored deprive, an onychomycosis and skin candidosis infections.

• Deep local mycoses at patients with undisturbed immune system, кокцидиомикоз, паракокцидиомикоз, a sporotrichosis and histoplasmosis.

Route of administration and doses:

Adults.

 - At cryptococcal meningitis and cryptococcal infections of other localizations in the first day appoint 400 mg, and then continue treatment, applying doses from 200 mg to 400 mg once a day. Duration of treatment of cryptococcal infections depends on clinical and anti-mycotic effects; at cryptococcal meningitis it is continued by at least 6-8 weeks. For the purpose of prevention of a recurrence of cryptococcal meningitis at patients with AIDS after end of a full course of primary treatment Flukonazolom-Darnits's therapy in a dose of 200 mg/days can be continued during very long time.

 - At a kandidemiya, the disseminated candidiasis and other forms of an invaziyny candidosis infection the dose, as a rule, makes 400 mg in the first days, and further – on 200 mg/days. Depending on degree of manifestation of clinical effect it is possible to increase a dose to 400 mg/days. Duration of therapy depends on clinical performance.

 - At oropharyngeal candidiasis of Flukonazol-Darnits, as a rule, appoint   50-100 mg for 7-14 days once a day. As necessary, at patients with the expressed oppression of immune function treatment can be continued throughout a long time. At the atrophic candidiasis of an oral cavity connected using dentures, drug, as a rule, appoint in a dose 50 mg/days for 14 days in combination with local antiseptic agents for processing of prostheses. At other candidosis infections of mucous membranes (except for genital candidiasis), for example, a candidosis esophagitis, noninvasive bronchopulmonary infections, a kandiduriya, candidiasis of skin and mucous membranes, etc., the effective dose, as a rule, makes 50-100 mg/days lasting treatment of 14-30 days. For prevention of a recurrence of oropharyngeal candidiasis at patients with AIDS after end of a full course of primary therapy of Flukonazol-Darnits about 150 mg once a week can be appointed.

 - At vaginal candidiasis of Flukonazol-Darnits accept once in a dose 150 mg. For decrease in frequency of a recurrence of vaginal candidiasis drug can be used in a dose of 150 mg once a month. Duration of therapy is determined individually, it varies from 4 to 12 months. Some patients need more frequent use of drug. At the balanitis caused by Sapdida, Flukonazol-Darnits is appointed once in a dose of 150 mg.

 - For prevention of candidiasis the recommended Flukonazola-Darnits's dose represents 50-400 mg once a day, depending on a risk degree of development of a fungal infection. With high risk of a generalized infection (for example, at patients with the expected, expressed or dolgodeystvuyushchy neutropenia) the recommended dose makes 400 mg once a day. Flukonazol-Darnits is appointed some days before the expected neutropenia; after increase in number of neutrophils over 1000 in 1 mm3 treatment is continued within 7 days.

 - At skin infections, including mycoses of feet, mycosis of smooth skin, a pakhovy dermatomycosis, and also at candidosis infections the recommended dose makes 150 mg once a week or 50 mg once a day. In such cases therapy lasts     2-4 weeks, however at mycoses of feet there can be a need of longer therapy (up to 6 weeks).

At multi-colored herpes the recommended dose makes 300 mg once a week for 2 weeks; also the third week with the same dosage can be necessary for some patients; (in certain cases it is enough also a single dose of 300-400 mg). The alternative scheme of treatment are 50 mg paranteralno once a day within 2-4 weeks.

At an onychomycosis the recommended dose makes 150 mg once a week. Treatment needs to be continued before substitution of the infected nail (growth of not infected nail). Repeated growth of nails on fingers of hands and legs lasts respectively 3-6 months and 6-12 months. Nevertheless growth rate varies with the broad range at different people, and also depends on age. After successful treatment of long persistent infections change of a shape of nails is sometimes observed.

 - At deep local mycoses there can be a need for course use of drug for doses of 200-400 mg a day for nearly 2 years. Duration of therapy is determined individually; as a rule, within         11-24 months at a koktsidiomikoza, 2-17 months – at a parakoktsidiomikoza, 1-16 months – at a sporotrichosis and 3-17 months – at histoplasmosis.

Use to people of advanced age.

In the absence of symptoms of a renal failure drug is appointed in usual doses.

Use by the patient with a renal failure.

Flukonazol is brought generally with urine in not changed look. At single use it is not necessary to change a dose. At patients (including children) with a renal failure at repeated use of drug it is necessary to enter at first an initial dose which makes up to 400 mg.

After introduction of an initial dose the daily dose (depending on indications) is determined by the table.

Clearance of creatinine (ml/min.)                Percent of the recommended dose

 
>                                                                       50 100%

 
<50 (without dialysis)                                                    50%

 
Patients who it is regular

are on dialysis                             of 100% after each session of dialysis

 

Children.

Flukonazol-Darnits is appointed to children 5 years are more senior.

The dose should not exceed the highest day dose for adults.

At candidiasis of mucous membranes the recommended dose - 3 mg/kg a day. In the first day purpose of a shock dose – 6 mg/kg a day for bystry achievement of equilibrium concentration is possible. For treatment of generalized candidiasis and a cryptococcal infection the recommended dose makes 6-12 mg/kg a day, depending on disease severity.

For prevention of fungal infections at patients with reduced immunity at which the risk of development of an infection is connected with a neutropenia owing to cytotoxic chemotherapy or radiation therapy drug is appointed on 3 - 2 mg/kg a day, depending on manifestations and duration of a neutropenia.

Treatment duration, both for children, and for adults depends on clinical conditions and anti-mycotic efficiency.

Features of use:

The insufficient term of treatment can lead to reinfection.

As флуконазол it is removed generally with urine, it is necessary to be careful at treatment of patients with a renal failure. The daily dose of active agent needs to be adjusted depending on clearance of creatinine.

It is necessary to be careful at purpose of a flukonazol the patient with an abnormal liver function. During treatment it is regularly necessary to carry out monitoring of level of liver enzymes and to watch the patient for the purpose of identification of possible toxic effects. At increase in level of liver enzymes the doctor has to define advantage of performing therapy and risk of development of more severe damage of a liver.

In case of substantial increase of activity of liver enzymes or emergence of clinical signs of deterioration in function of a liver treatment flukonazoly needs to be stopped.

During treatment flukonazoly exfoliative skin reactions, such as Stephens-Johnson's syndrome and a toxic epidermal necrolysis very seldom occurred at patients. Patients with AIDS are more inclined to development of heavy skin reactions at use of many drugs. If the patient with a superficial fungal infection has a rash which can be connected with flukonazoly, drug it is necessary to cancel. At emergence of rash in patients with invasive/system fungal infections behind them it is necessary to observe and cancel carefully флуконазол at emergence of violent defeats or a multiformny erythema.

Considering developing of the expressed arrhythmias connected with lengthening of an interval of QT at patients who received azolny antifungal means in combination with terfenadiny special researches were conducted. Co-administration of a flukonazol in doses of 400 mg a day and more with terfenadiny is contraindicated. Treatment flukonazoly in doses is less than 400 mg in days in association with terfenadiny it is necessary to carry out under careful control.

Flukonazol-Darnits's drug contains lactose that persons need to consider with disturbance of digestion of lactose, glucose or galactose.

Ability to influence the speed of reactions at control of motor transport or work with other mechanisms. Drug does not influence speed of response at control of motor transport or work with other mechanisms.

Use during pregnancy or feeding by a breast. It is necessary to avoid drug use, except cases when the potential advantage for mother exceeds possible risk for a fruit. It is allocated in breast milk therefore during treatment it is necessary to stop feeding by a breast.

Children. To children apply, since 5 years.

Side effects:

Central and peripheral nervous systems: headache, dizziness, spasms.

Skin and its derivatives: an alopecia, exfoliative skin reactions, including Stephens-Johnson's syndrome and a toxic epidermal necrolysis, a rash, a dermahemia.

Digestive tract: digestion disturbance, nausea, abdominal pain, vomiting, diarrhea, meteorism, dyspepsia.

Hemopoietic and lymphatic systems: a leukopenia, including a neutropenia and a granulocytosis, thrombocytopenia.

Cardiovascular system: lengthening of an interval of QT, Bouveret's ventricular disease on the pirouette type.

Allergic reactions: urticaria, skin itch, Quincke's disease, face edema, bronchospasm, acute anaphylaxis.

Liver / желчевыделительная system: toxic damages of a liver, liver failure, increase in level of an alkaline phosphatase, bilirubin, alaninaminotranspherase (ALT) and aspartate aminotransferase (nuclear heating plant), hepatitis, hepatocellular necrosis, jaundice.

Metabolic processes: hypercholesterolemia, gipertriglitseridemiya, hypopotassemia.

Sense bodys: disturbance of flavoring feelings.

Interaction with other medicines:

Antitrombotichesky means, antagonists of vitamin K.

The effect of antitrombotichesky means, antagonists of vitamin K amplifies (formation of bleedings: hematomas, bleeding from a nose, gastrointestinal bleeding, etc.).

Benzodiazepines (short action).

At purpose of midazolam inside use of a flukonazol leads to substantial increase of concentration of the first and to emergence of psychomotor reactions. This effect of midazolam is more expressed at reception of a flukonazol in capsules, compared with flukonazoly that it was entered intravenously. If the patient who receives treatment flukonazoly needs to appoint benzodiazepine, the dose of the last needs to be reduced, and for the patient to establish careful supervision.

Tsizaprid.

At simultaneous use of a flukonazol and tsizaprid single cases of undesirable reactions from heart are described, such as paroxysms of ventricular tachycardia. Purpose of a tsizaprid is contraindicated to patients to whom apply флуконазол.

Cyclosporine.

According to a kinetic research, at recipients of the replaced kidneys флуконазол in a dose of 200 mg/days slowly increases concentration of cyclosporine. At reusable reception of a flukonazol on 100 mg/days of changes of level of cyclosporine at recipients of marrow did not note. At treatment flukonazoly it is recommended to define concentration of cyclosporine in blood.

Hydrochlorothiazide.

Reusable use of a hydrochlorothiazide led to increase in concentration of a flukonazol in plasma for 40%, but it is not the reason of change of the mode of dosing of a flukonazol at patients who at the same time receive diuretics.

 

Oral contraceptives.

Studying of pharmacokinetics of the combined peroral contraceptive drug in combination with reusable reception of a flukonazol was carried out in two researches. At reception of 50 mg of a flukonazol no significant effect at the level of hormones whereas at reception of 200 mg/days increase in the area under a curve "concentration time" (AUC) of ethinylestradiol for 40% and a levonorgestrola – for 24% was observed was noticed. Reception of a flukonazol in a dose of 300 mg significantly does not influence efficiency of the combined peroral contraceptive drug.

Phenytoinum.

Co-administration of a flukonazol and Phenytoinum can be followed by increase in concentration of Phenytoinum to clinically significant degree. If combined use of two drugs, the necessary monitoring of level of Phenytoinum and selection of its dose is necessary for ensuring therapeutic concentration in blood serum.

Rifabutin.

It was reported about interaction of a flukonazol and rifabutin which result was an increase in serumal levels of the last. At co-administration of a flukonazol and rifabutin uveitis cases are described. It is necessary to watch patients who receive рифабутин and флуконазол at the same time attentively.

Rifampicin.

Co-administration of a flukonazol and rifampicin reduces AUC by 25% and duration of an elimination half-life of a flukonazol for 20%. At patients who receive at the same time rifampicin and флуконазол it is necessary to consider expediency of increase in a dose of the last.

Sulfonilmochevinny means.

Flukonazol at a concomitant use with Chlorproramidum, Glibenclamidum, glipizidy and Tolbutamidum extends an elimination half-life of oral sulfonilmochevinny drugs. Flukonazol and oral sulfonilmochevinny drugs it is possible to appoint jointly a sick diabetes mellitus, but at the same time it is necessary to consider possible development of a hypoglycemia.

Takrolimus.

At interaction of a flukonazol and takrolimus there is an increase in serumal levels of the last. At co-administration of a flukonazol and takrolimus cases of increase in nephrotoxicity are described. It is necessary to watch the patients receiving такролимус and флуконазол at the same time carefully.

Terfenadin.

Considering developing of the expressed arrhythmias connected with lengthening of an interval of QT at patients who received azolny antifungal means in combination with terfenadiny special researches were conducted. If флуконазол appointed in a dose 200 mg a day, lengthening of an interval of QT was not observed. At use of doses of 400 mg and 800 mg it was shown what флуконазол in a dose of 400 mg a day and more considerably increases concentration of a terfenadin in a blood plasma. Co-administration of a flukonazol in doses of 400 mg a day and more with terfenadiny is contraindicated. Treatment flukonazoly in doses is less than 400 mg in days in association with terfenadiny it is necessary to carry out under careful control.

Theophylline.

At treatment flukonazoly patients who receive theophylline in high doses, or patients with the increased risk of toxic effect of theophylline need to be watched theophylline overdose symptoms; at their emergence therapy needs to be changed properly.

Zidovudine.

Kinetic researches showed increase in levels of a zidovudine which, most likely, were connected with decrease in transformation of the last on its main metabolite. It is necessary to watch patients who receive such combination for the purpose of identification of side effect of a zidovudine.

Astemizol.

Simultaneous use of a flukonazol by patients who receive астемизол or other drugs who are metabolized by system of P450 cytochrome can be followed by increase in serumal concentration of these means. In the absence of final information it is necessary to be careful at co-administration of the specified medicines.

One-time or reusable reception of a flukonazol in a dose of 50 mg did not influence metabolism of antipyrine at their simultaneous use.

Contraindications:

Patients should not appoint drug with hypersensitivity to a flukonazol or other azolny substances, and also any excipients. Protipokazanny simultaneous use of a terfenadin by patients who apply флуконазол in a dosage 400 mg/days and above. Contraindicated simultaneous use of a tsizaprid. Drug is contraindicated during pregnancy and feeding by a breast.

Overdose:

Symptoms: nausea, vomiting, diarrhea, in more hard cases – spasms, hallucinations, eksgibitsionichesky paranoid behavior.

Treatment: gastric lavage and symptomatic treatment. Flukonazol is brought with urine therefore the artificial diuresis can accelerate drug removal. The session of a hemodialysis lasting 3 hours reduces the level of a flukonazol in plasma approximately by 50%.

Storage conditions:

To store drug in dry, protected from light and the place, unavailable to children, at a temperature from 15 to 25 °C. A period of validity - 2 years.

Issue conditions:

Without recipe

Packaging:

On 1 capsule in a blister strip packaging; on 1 blister strip packaging in a pack.