Active substanceVoriconazoleVoriconazole
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  • Dosage form: & nbspfilm-coated tablets
    Composition:

    Dosage 50 mg

    1 A film coated tablet contains:

    active substance: voriconazole 50 mg;

    Excipients: starch corn pregelatinized 30 mg, croscarmellose sodium 5.5 mg, mannitol 30 mg, magnesium stearate 1 mg, cellulose microcrystalline 23.5 mg;

    film sheath: opadrai II white 4 mg, including: polyvinyl alcohol 1,876 mg, macrogol (polyethylene glycol 4000) 0.944 mg, talc 0.696 mg, titanium dioxide 0.484 mg.

    Dosage 200 mg

    1 tablet, film-coated, contains:

    active substance: voriconazole 200 mg;

    Excipients: starch corn pregelatinized 81 mg, croscarmellose sodium 18 mg, mannitol 83 mg, magnesium stearate 3 mg, cellulose microcrystalline 65 mg;

    film sheath: opadrai II white 13 mg, including: polyvinyl alcohol 6.097 mg, macrogol (polyethylene glycol 4000) 3.068 mg, talc 2.262 mg, titanium dioxide 1.573 mg.

    Description:Round, biconvex tablets, covered with a film shell of white or almost white color. On the cross-section - almost white.
    Pharmacotherapeutic group:Antifungal agent
    ATX: & nbsp

    J.02.A. C.03   Voriconazole

    Pharmacodynamics:

    Voriconazole is a broad-spectrum antifungal agent from the group of triazoles. The mechanism of action of voriconazole is associated with the inhibition of demethylation of 14α-sterol, indirectly through fungal cytochrome P450, which is a key stage in the biosynthesis of ergosterol. The accumulation of 14α-methylsterol correlates with the subsequent loss of ergosterol in fungal cell membranes, which determines the antifungal activity of voriconazole. It was found that voriconazole more selective for cytochrome P isoenzymes450 fungi than with respect to various enzymatic systems of cytochrome R450 mammals.

    A positive relationship between the mean, maximum and minimum values ​​of voriconazole concentration in blood plasma and the effectiveness of the drug in therapeutic studies was not revealed and this relationship in preventive studies has not been studied.

    Pharmacodynamic and pharmacokinetic analysis of these clinical studies revealed a positive relationship between the concentration of voriconazole in blood plasma and a deviation from the norm of biochemical parameters of liver function, as well as visual disturbances.

    In vitro voriconazole has a broad spectrum of antifungal action: active against Candida spp. (including strains FROM. krusei, resistant to fluconazole, and resistant strains FROM. glabrata and FROM. albicans), and also shows a fungicidal effect against all strains studied Aspergillus spp., and pathogenic fungi that have become relevant in recent times, including Scedosporium spp., or Fusarium spp., which are limitedly sensitive to existing antifungal agents.

    Clinical efficacy (with partial or complete response) of voriconazole has been demonstrated in infections caused by Aspergillus spp., including A. flavus, A. fumigatus, A. terreus, A. niger, A. nidulans, Candida spp., including FROM. albicans, FROM. glabrata, FROM. krusei, FROM. parapsilosis, FROM. tropicalis, as well as for a limited number of strains FROM. dubliniensis, FROM. inconspicua, FROM. guilliermondii, Scedosporium spp., including S. apiospermum, S. prolificans and Fusarium spp.

    Other fungal infections in which voriconazole (sometimes with a partial or complete response) included individual cases of infections, caused by Alternaria spp., Blastomyces dermatitidis, Blastoschizomyces capitatus, Cladosporium spp., Coccidioides immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum, Exophiala spinifera, Fonsecaea pedrosoi, Madurella mycetomatis, Paecilomyces lilacinus, Penicillium spp., including P. marneffei, Phialophora richardsiae, Scopulariopsis brevicaulis and Trichosporon spp., including T. beigelii.

    Voriconazole activity was demonstrated in vitro in relation to clinical strains Acremonium spp., Alternaria spp., Bipolaris spp., Cladophialophora spp., Histoplasma capsulatum. The growth of most strains was suppressed at voriconazole concentrations from 0.05 μg / ml to 2 μg / ml.

    The activity of voriconazole in vitro in a relationship Curvularia spp. and Sporothrix spp., but the clinical significance of this effect is unknown.

    Pharmacokinetics:

    general characteristics

    Pharmacokinetic parameters of voriconazole are characterized by significant interindividual variability.

    The pharmacokinetics of voriconazole is nonlinear due to the saturation of its metabolism.When the dose is increased, a disproportionate (more pronounced) increase in the area under the concentration-time curve (AUCt). An increase in the oral dose from 200 mg twice a day to 300 mg twice daily leads to an increase AUCt on average 2.5 times. Effects of voriconazole when administered a maintenance dose of 200 mg (or 100 mg for patients weighing less than 40 kg), corresponds to the effect of voriconazole when applied intravenously in a dose of 3 mg / kg. If administered orally at a maintenance dose of 300 mg (or 150 mg for patients weighing less than 40 kg), the exposure is consistent with voriconazole when administered intravenously at a dose of 4 mg / kg.

    With the intake of saturating doses of voriconazole, its concentration in the blood plasma approaches equilibrium within the first 24 hours. If the drug is prescribed twice a day in moderate (but not saturating) doses, then voriconazole is cumulated, and equilibrium concentrations are reached by the sixth day in the majority patients.

    Suction and distribution

    Voriconazole is rapidly and almost completely absorbed after oral administration; the maximum concentration in the blood plasma (CmOh) is achieved 1-2 hours after admission.Bioavailability of voriconazole for oral administration is 96%. When reoccurring voriconazole with oily poor CmOh and AUCt decrease by 34% and 24%, respectively. Absorption of voriconazole does not depend on the pH of the gastric juice. The average volume of distribution of voriconazole in the equilibrium state is 4.6 l / kg. Binding to plasma proteins is 58%. Voriconazole penetrates the blood-brain barrier and is determined in the cerebrospinal fluid.

    Metabolism

    According to research data in vitro voriconazole is metabolized by isozymes CYP2C19, CYP2C9, CYP3A4. An important role in the metabolism of voriconazole is played by isoenzyme CYP2C19, showing a pronounced genetic polymorphism, and therefore, a reduced metabolism of voriconazole is possible in 15-20% of representatives of Asian descent and 3-5% of representatives of Caucasoid and Negroid races. The main metabolite of voriconazole is Noxide, the proportion of which is 72% of the total number of metabolites circulating in the blood plasma with a radioactive label. This metabolite has minimal antifungal activity and does not contribute to the clinical effect of voriconazole.

    Excretion

    Voriconazole is excreted as metabolites after biotransformation in the liver; In unchanged form, less than 2% of the administered dose is excreted by the kidneys. After repeated administration of voriconazole or intravenous administration in urine, about 83% and 80% of the dose of the drug are detected, respectively. Most (> 94%) of the total dose is excreted within the first 96 hours after ingestion and intravenously. The half-life (T1/2) voriconazole is dose dependent and is approximately 6 hours when taken internally at a dose of 200 mg. In connection with the nonlinearity of pharmacokinetics, the magnitude T1/2 does not allow to predict the cumulation or excretion of voriconazole.

    Pharmacokinetics of special groups of patients

    Floor: with repeated intake of the drug inside Cmax and AUCt in healthy young women were 83% and 113%, respectively, higher than in young healthy men (18-45 years). Significant differences CmOh and AUCt in healthy elderly men and healthy elderly women (≥65 years) do not. The equilibrium concentration of voriconazole in blood plasma in women was 100% higher than that of men. There is no need for dose adjustment depending on sex. Plasma concentrations in men and women are similar.

    Age: with repeated administration of voriconazole inward in the form of tablets CmOh and AUCt in healthy elderly men (≥65 years) by 61% and 86%, respectively, higher than in healthy young men (18-45 years). Significant differences CmOh and AUCt in healthy elderly women (≥65 years of age) and healthy young women (18-45 years) do not.

    The safety profile of voriconazole in young and elderly patients is no different. There is no need to adjust the dose of voriconazole according to age.

    Children: The estimated total concentration of voriconazole in children with oral administration of a maintenance dose of 9 mg / kg (maximum 350 mg) twice a day is comparable to that of adults with oral voriconazole at a dose of 200 mg twice daily. The concentration of voriconazole with intravenous administration at a dose of 8 mg / kg is twice as high as when ingested at a dose of 9 mg / kg. Bioavailability of voriconazole for oral administration in children may be limited by a malabsorption and a sufficiently low body weight at this age, and in this case intravenous administration may be indicated.

    In most adolescents, the concentration of voriconazole in the blood plasma corresponds to this parameter in adult patients.However, fewer voriconazole concentrations in plasma were observed in some adolescents with a low body weight compared to adults and were closer to the same values ​​in children. Based on the population pharmacokinetic analysis, adolescents aged 12 to 14 years with a body weight of less than 50 kg should receive a dose of voriconazole recommended for use in children.

    Impaired renal function: with single dose oral dose of voriconazole of 200 mg in patients with normal renal function and patients with renal dysfunction from mild (creatinine clearance (CC) 41-60 ml / min) to severe (creatinine clearance <20 mL / min) degree pharmacokinetics of voriconazole is not substantially depends on the degree of impaired renal function. The binding of voriconazole to plasma proteins is approximately the same in patients with varying degrees of renal insufficiency (see the sections on "Dosage and administration" and "Special instructions").

    Impaired liver function: after a single oral intake at a dose of 200 mg AUCt voriconazole in patients with mild to moderate severity of liver cirrhosis (classes A and B according to the classification Child-Pugh) was 233% higher than in patients with normal liver function. Violation of the function of the liver does not affect the binding of voriconazole with plasma proteins.With repeated intake of the drug inside AUCt voriconazole is comparable in patients with an average severity of liver cirrhosis (class B according to the Child-Pugh classification) who received the drug at a maintenance dose of 100 mg twice a day, and in patients with normal liver function receiving voriconazole in a dose of 200 mg twice a day. There is no information about the pharmacokinetics of voriconazole in patients with severe liver cirrhosis (class C according to the Child-Pugh classification). For recommendations on dosing, see "Dosage and Administration".

    Indications:

    - Invasive aspergillosis.

    - Candidemia in patients without neutropenia.

    - Severe invasive candidiasis infections (including FROM. krusei).

    - Candidiasis of the esophagus.

    - Heavy fungal infections caused by Scedosporium spp. and Fusarium spp.

    - Other severe invasive fungal infections with intolerance or refractory to other medicines.

    - Prevention of "breakthrough" fungal infections in patients with reduced immune system function, fever and neutropenia from the high-risk group (recipients of hematopoietic stem cell transplantation, patients with relapse of leukemia).

    - Prevention of invasive fungal infections in patients (adults and children over 12 years) at high risk,such as recipients of hematopoietic stem cell transplantation.

    Contraindications:

    - The drug Voriconazole Canon is contraindicated in patients with hypersensitivity to voriconazole or any other component of the drug.

    - Simultaneous use of the drug Voriconazole Canon and the following drugs (see "Interaction with other drugs.") Substrates isoenzyme SYP3A4 - terfenadine, astemizole, cisapride, pimozide or quinidine; sirolimus; rifampicin, carbamazepine and long-acting barbiturates (phenobarbital), rifabutin; efavirenz in doses of 400 mg and higher once a day (with voriconazole in standard doses); ritonavir in high doses (400 mg and higher twice a day); ergot alkaloids (ergotamine, dihydroergotamine), which are substrates of the isoenzyme CYP3A4; St. John's wort (the inductor of cytochrome P450 and P-glycoprotein).

    - The drug Voriconazole Canon is contraindicated in children under the age of 3 years (for this dosage form).

    Carefully:

    Hypersensitivity to other drugs - derivatives of azoles.

    Severe failure of the liver, severe failure of kidney function.

    The drug Voriconazole Canon should be used with caution in patients with proarrhythmic conditions: congenital or acquired increase in the interval QT, Cardiomyopathy, especially heart failure, sinus bradycardia, presence symptomatic arrhythmia, simultaneous administration of drugs that cause elongation interval QT.

    Care should also be taken when using the drug Voriconazole Canon in patients with electrolyte disorders, such as hypokalemia, hypomagnesemia and hypocalcemia.

    Pregnancy and lactation:

    There is no sufficient information about the use of voriconazole in pregnant women. In animal studies, it has been established that the drug has a toxic effect on reproductive function. The possible risk to man is unknown.

    Voriconazole should not be used in pregnant women unless the expected benefit to the mother clearly exceeds the risk to the fetus.

    The excretion of voriconazole with breast milk has not been studied. For the duration of the drug, breastfeeding should be discontinued.

    Women of reproductive age when using Voriconazole Canon should use reliable methodscontraception.

    Dosing and Administration:

    Inside, 1 hour before meals or 1 hour after meals.

    Before the start of therapy, it is necessary to correct such electrolyte abnormalities as hypokalemia, hypomagnesemia and hypocalcemia (see also the "Side effect" section).

    Adult patients

    The appointment of voriconazole should be started with intravenous administration at the recommended saturating dose, in order to achieve an adequate concentration in the blood plasma on the first day. Intravenous should be continued for at least 7 days, after which it is possible to switch to oral intake of the drug, provided that the patient is able to take medicines for oral administration. Given the high bioavailability of the drug with oral intake, reaching 96% (see the section "Pharmacokinetics"), in the presence of clinical indications, it is possible to switch from intravenous to oral administration of the drug without dose correction.

    The table provides detailed information on the dosage of voriconazole:

    Intravenously

    Inside

    Patients with a body weight of 40 kg and more

    Patients weighing less than 40 kg

    Saturated dose - all indications (first 24 h)

    6 mg / kg

    every 12 hours

    Not recommended

    Not recommended

    Maintenance dose - all indications (after the first 24 hours)

    Prevention of invasive fungal infections in patients (adults and children over 12 years) at high risk, such as recipients of hematopoietic stem cell transplantation / prevention of breakthrough fungal infections in febrile patients

    3-4 mg / kg

    every 12 hours.

    200 mg

    every 12 hours

    100 mg

    every 12 hours

    Invasive aspergillosis / infections caused by Scedosporium spp. and Fusarium spp. / other severe invasive fungal infections

    4 mg / kg

    every 12 hours.

    200 mg

    every 12 hours

    100 mg

    every 12 hours

    Candidemia in patients without neutropenia

    4 mg / kg

    every 12 hours.

    200 mg every 12 hours

    100 mg

    every 12 hours

    Candidiasis of the esophagus

    Not

    is established

    200 mg

    every 12 hours

    100 mg

    every 12 hours

    Selection of dose for oral administration: with insufficient effectiveness of treatment, the maintenance dose of Voriconazole canon for oral administration may be increased from 200 mg every 12 hours to 300 mg every 12 hours. In patients with a body weight of less than 40 kg, the dose may be increased from 100 mg to 150 mg every 12 hours.

    If the patient does not tolerate the drug in a high dose (300 mg every 12 hours), the maintenance dose for oral administration is gradually reduced in increments of 50 mg to 200 mg every 12 hours (for patients weighing less than 40 kg, up to 100 mg every 12 hours ).

    The duration of treatment should be as short as possible, depending on the clinical effect and the results of mycological examination. The duration of treatment should not exceed 180 days.

    Prevention in adults and children

    Prophylactic use of the drug should be started on the day of transplantation and can be continued up to 100 days. To prolong prophylaxis up to 180 days after transplantation, it is only possible if immunosuppressive therapy is continued or the development of the "graft-versus-host" (TPH) reaction.

    The safety and efficacy of voriconazole for more than 180 days in clinical trials have not been adequately studied.

    The dosage regimen for prevention is the same as for treatment in the appropriate age groups.

    Impaired renal function

    Correction of the dose of voriconazole for oral administration in patients with mild or severe renal impairment is not required.

    Impaired liver function

    In acute liver damage, manifested by an increase in the activity of "liver" transaminases: alanine aminotransferase (ALT), aspartate aminotransferase (ACT), dose adjustment is not required, but it is recommended to continue monitoring the liver function.

    Patients with mild or moderate hepatic impairment (Child-Pugh class A and B classes) should be prescribed a standard saturating dose of voriconazole, and the maintenance dose should be reduced by a factor of 2.

    Patients with severe liver function disorder (class C according to Child Pugh classification) drug Voriconazole Canon should be prescribed only in cases where the expected benefit exceeds the possible risk, and under constant monitoring to identify signs of toxic effects of the drug.

    Elderly patients

    Correction of dose in elderly patients is not required.

    Use in children

    The drug in the form of tablets is prescribed to children in the event that a child can swallow tablets.

    The dosage regimen of voriconazole in children (aged 3 (for a given dosage form) to 12 years) and adolescents aged 12 to 14 years and weighing less than 50 kg:

    Intravenously

    Inside

    The saturation dose

    (first 24 hours)

    9 mg / kg

    every 12 hours.

    Not recommended

    Maintenance dose

    (after the first 24 hours)

    8 mg / kg

    2 times a day

    9 mg / kg twice daily

    (maximum dose of 350 mg twice daily)

    It is recommended to begin therapy with intravenous introduction of voriconazole,and the possibility of oral administration of the drug Voriconazole Canon should be considered only after the clinical improvement and the patient's ability to take oral medications. It should be taken into account that the effect of voriconazole with intravenous administration at a dose of 8 mg / kg is approximately twice as high as when administered intravenously at a dose of 9 mg / kg.

    The pharmacokinetics and tolerability of higher doses of voriconazole in children have not been studied.

    Recommendations for the use of voriconazole in children are given on the basis of studies of its use in the form of a powder for the preparation of a suspension for oral administration. The bioequivalence of voriconazole in the form of a powder for the preparation of a suspension for ingestion and tablets when used in children has not been studied. Given that children have slowed down the passage of food through the gastrointestinal tract, it is likely that the absorption of voriconazole when ingested will be different than in adults. The use of voriconazole in children aged 2 to 12 years with impaired liver or kidney function has not been studied.

    In adolescents (aged 12 to 14 years with a body weight of 50 kg or more, 15 to 18 years, regardless of body weight) voriconazole dosed the same way as for adults.

    Correction of dose: In case of inadequate clinical response of the patient, the dose may be increased in steps of 1 mg / kg (or 50 mg if a maximum dose of 350 mg was initially administered). If the child does not tolerate therapy at the prescribed dose, it should be reduced in steps of 1 mg / kg (or 50 mg if a maximum oral dose of 350 mg was initially used).

    Side effects:

    The safety data for voriconazole are based on the results of a study of more than 2000 people (1655 patients using voriconazole for therapeutic purposes and 279 for prophylactic purposes) represented by a heterogeneous population (patients with malignant blood growths, HIV-infected patients with esophageal candidiasis and refractory fungal infections, patients without neutropenia with candidemia or aspergillosis, and healthy volunteers).

    The most common adverse reactions are abnormalities in the eyes, abnormal results of functional liver tests, fever, rash, vomiting, nausea, diarrhea, headache, peripheral edema, abdominal pain and respiratory depression.Undesirable reactions were usually easily or moderately expressed.

    Clinically significant dependence of drug safety on age, race or sex was not revealed.

    Classification of WHO frequency of development of side effects:

    very often> 10%;

    often> 1% and <10%;

    infrequently> 0.1% and <1%;

    rarely> 0.01% and <0.1%,

    very rarely <0.01%,

    frequency is unknown - it is impossible to determine the frequency based on the available data.

    Heart Disease

    often - supraventricular arrhythmia, tachycardia, bradycardia; infrequently - ventricular fibrillation, ventricular extrasystole, ventricular tachycardia, supraventricular tachycardia; rarely - arrhythmia in the form of "pirouette", complete atrioventricular blockade, blockage of the bundle branch, nodular arrhythmias.

    Vascular disorders

    often - arterial hypotension, phlebitis; infrequently - thrombophlebitis.

    Violations of the blood and lymphatic system

    often - agranulocytosis (including febrile neutropenia and neutropenia), pancytopenia, thrombocytopenia (including immune thrombocytopenic purpura), anemia; infrequently - bone marrow depression, leukopenia, lymphadenopathy, eosinophilia, disseminated intravascular coagulation syndrome.

    Disturbances from the nervous system

    Often - headache; often - syncope, tremor, paresthesia, drowsiness, dizziness, convulsions, nystagmus; infrequently - cerebral edema, encephalopathy, extrapyramidal disorder, peripheral neuropathy, ataxia, hypoesthesia, dysgeusia (a violation of taste perception); rarely - hepatic encephalopathy, Hyenna-Barre syndrome.

    Disturbances on the part of the organ of sight

    Often - visual impairment (including blurred vision, blurred vision, photophobia, chloropsy, chromatopsy, photophobia, color blindness, cyanopsy, presence of iridescent circles around the light sources, night blindness, oscilloscopy, photopsy, scintillation scotoma, visual acuity reduction, visual brightness, visual field defect, floating vitality and xanthopia; often - hemorrhage into the retina of the eye; infrequently - neuritis of the optic nerve, edema of the nipple of the optic nerve, oculogic crisis, scleritis, diplopia, blepharitis; rarely - atrophy of the optic nerve, corneal opacity

    Violations of the hearing and vestibular organs

    infrequently - Vertigo, hypoacusia, tinnitus.

    Disturbances from the respiratory system, chest and mediastinal organs

    Often - respiratory depression; often - pulmonary edema, acute respiratory distress syndrome.

    Disorders from the gastrointestinal tract

    Often - nausea, vomiting, diarrhea, abdominal pain; often - cheilitis, indigestion, constipation; infrequently - duodenitis, glossitis, pancreatitis, edema of the tongue.

    Disorders from the kidneys and urinary tract

    often acute renal failure, hematuria; infrequently - Necrosis of the renal tubules, proteinuria, nephritis.

    Disturbances from the skin and subcutaneous tissues

    Often - a rash; often - exfoliative dermatitis, alopecia, itchy skin, maculopapular rash, erythema; infrequently - Stevens-Johnson syndrome, photosensitivity, urticaria, eczema, toxic epidermal necrolysis, angioedema, erythema multiforme, psoriasis, allergic dermatitis, purpura, papular rash, macular rash; rarely - pseudoporphyria, persistent drug erythema; frequency unknown - dermal form of systemic lupus erythematosus.

    Disorders from the musculoskeletal system and connective tissue

    often - backache; infrequently - arthritis; frequency unknown - periostitis.

    Disorders from the endocrine system

    infrequently - insufficiency of the adrenal cortex, hypothyroidism; rarely - hyperthyroidism.

    Metabolic and nutritional disorders

    Often - peripheral edema; often - hypokalemia, hypoglycemia, hyponatremia (identified in post-registration studies).

    Infections and invasions

    often - sinusitis, gastroenteritis, gingivitis; infrequently - pseudomembranous colitis, lymphangitis, peritonitis.

    General disorders and disorders at the site of administration

    Often - fever; often - chills, asthenia, chest pain, flu-like illness, facial edema (including periorbital edema, swelling of the lips and swelling of the mouth); infrequently - reaction / inflammation at the injection site.

    Immune system disorders

    infrequently - allergic reactions; rarely - anaphylactoid reactions.

    Disorders from the hepatobiliary system

    Often - Deviations from the norm of the results of functional hepatic tests (increased activity of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyltransferase, lactate dehydrogenase, hyperbilirubinemia); often - jaundice, cholestatic jaundice, hepatitis; infrequently - cholecystitis, cholelithiasis, liver enlargement, hepatic insufficiency.

    Mental disorders

    often - hallucinations, depression, anxiety, insomnia, agitation, confusion.

    Neoplasms are benign, malignant and unspecified neoplasms (including cysts and polyps)

    frequency unknown - squamous cell carcinoma of the skin.

    Research

    often - increasing the concentration of creatinine in the blood; infrequently - lengthening of the interval QT on an electrocardiogram, an increase in the concentration of urea in the blood, an increase in the concentration of cholesterol in the blood.

    Side effect when applied the children:

    it was found that the undesirable effects of the drug in children aged 3 (for a given dosage form) to 12 years are similar to those in adults. Children had a higher frequency of hepatic enzyme activity. In the course of post-registration studies, the development of pancreatitis in children with voriconazole therapy was revealed, as well as the more frequent occurrence of skin reactions.

    Overdose:

    There are three cases of accidental overdose. All of these cases occurred in children who received a dose of voriconazole intravenously, five times the recommended dose.

    There is a report of a single case of photophobia, lasting 10 minutes.

    The antidote of voriconazole is unknown. In case of an overdose, symptomatic and supportive therapy is indicated. Voriconazole is deduced in the course of hemodialysis with a clearance of 121 ml / min. In case of an overdose, hemodialysis can help to remove voriconazole from the body.

    Interaction:

    Inhibitors or inducers of cytochrome P isoenzymes450 (CYP2C19, CYP2C9 and CYP3A4) can cause, respectively, an increase or decrease in the concentration of voriconazole in the blood plasma.

    Voriconazole inhibits the activity of cytochrome P isoenzymes450 - FROMYP2C19, CYP2C9 and CYP3A4, - and can increase plasma concentrations of substances that are metabolized with the participation of cytochrome P isoenzymes450.

    The interaction of voriconazole with other drugs and recommendations for simultaneous use are presented in the table below:

    Drug (mechanism of interaction)

    Interaction: changes in pharmacokinetic parameters (%)

    Recommendations for simultaneous application

    Astemizole, cisapride, pimozide, quinidine and terfenadine

    [Pro-enzyme substrates CYP3A4]

    Interaction has not been studied, but there is a high probability,that increased concentrations of these drugs may lead to lengthening of the interval QTC and in rare cases, the occurrence of ventricular tachycardia of the type "pirouette"

    Contraindicated

    Carbamazepine and long-acting barbiturates (for example, phenobarbital, mefobarbital)

    [powerful inducers of cytochrome P450]

    Interaction has not been studied, however carbamazepine and long-acting barbiturates are likely to significantly reduce plasma concentrations of voriconazole

    Contraindicated

    Efavirenz (non-nucleoside reverse transcriptase inhibitor)

    [inducer of cytochrome P450; inhibitor and isoenzyme substrate CYP3A4]

    Simultaneous use of efavirenz in a dose of 400 mg once a day and voriconazole at a dose of 200 mg twice a day *

    FROMmOh efavirenz ↑ 38%

    AUCτ efavirenz ↑ 44%

    FROMmOh voriconazole ↓ 61%

    AUCτ voriconazole ↓ 77%

    The use of standard doses of voriconazole and efavirenz 400 mg once a day is contraindicated.

    Simultaneous application of 300 mg of efavirenz once a day and voriconazole 400 mg twice daily

    In comparison with efavirenz 600 mg once a day:

    FROMmOh efavirenz ↔

    AUCτ efavirenz ↑ 17%

    Simultaneous application is possible if the maintenance dose of voriconazole is increased to 400 mg

    twice a day, and the dose of efavirenz is reduced to 300 mg once a day. With the withdrawal of voriconazole therapy, the initial dose of efavirenz should be restored.

    In comparison with voriconazole 200 mg twice a day:

    FROMmOh voriconazole ↑ 23%

    AUCτ voriconazole 7%

    Ergot alkaloids (eg, ergotamine and dihydroergotamine)

    [isoenzymatic substrates CYP3A4]

    The interaction of voriconazole with ergot alkaloids (ergotamine and dihydroergotamine) has not been studied, but there is a high probability that voriconazole can cause an increase in the concentrations of these drugs in the blood plasma and lead to ergotism.

    Contraindicated

    Rifabutin

    [powerful cytochrome P450 inducer]

    300 mg once daily

    FROMmOh voriconazole ↓ 69%

    AUC τ voriconazole ↓ 78%

    FROMmOh rifabutin ↑ 195%

    AUC τ rifabutin ↑ 331%

    Contraindicated

    300 mg once a day (with simultaneous application with voriconazole 400 mg twice daily) *

    In comparison with voriconazole 200 mg twice a day:

    FROMmOh voriconazole ↑ 104%

    AUCτ voriconazole ↑ 87%

    Rifampicin

    (600 mg once daily)

    [powerful cytochrome inducer P450]

    FROM mOh voriconazole ↓ 93%

    AUCτ voriconazole 96%

    Contraindicated

    Ritonavir (protease inhibitor)

    [powerful cytochrome P450 inducer; inhibitor and isoenzyme substrate CYP3A4]

    High doses

    (400 mg twice daily)

    FROMmOh AUCτ ritonavir ↔

    FROMmOh voriconazole 66%

    AUCτ voriconazole 82%

    Simultaneous use of voriconazole and high doses of ritonavir (400 mg and more twice a day) is contraindicated.

    Low doses

    (100 mg twice daily) *

    FROMmOh ritonavir 25%

    AUCτ ritonavir 13%

    FROMmOh voriconazole 24%

    AUCτ voriconazole 39%

    Apply simultaneously voriconazole and ritonavir in low doses (100 mg twice a day) should be given only if the expected benefit from taking voriconazole significantly exceeds the risk of their combined use.

    St. John's wort perforated

    [inducer of cytochrome P450 and P-glycoprotein] 300 mg three times daily

    (simultaneous use with a single dose of voriconazole 400 mg)

    According to an independent study:

    AUC0-∞ voriconazole ↓ 59%

    Contraindicated

    Everolimus

    [isoenzymatic substrate CYP3A4 and P-glycoprotein]

    Interaction has not been studied, however voriconazole, probably, can significantly increase the plasma concentrations of everolimus.

    Simultaneous use is not recommended, as it is expected that voriconazole significantly increases the concentration of everolimus in the blood plasma. At the moment, there is not enough information to recommend a correction of the dosing regimen.

    Fluconazole

    (200 mg once daily)

    [inhibitor of isoenzymes CYP2C9, CYP2CJ9 and CYP3A4]

    FROMmOh voriconazole ↑ 57%

    AUCτ voriconazole ↑ 79%

    Changes in CmOh and AUCτ fluconazole not established

    A suitable regimen for dose adjustment and / or reception frequency of voriconazole and fluconazole is not established. In case if voriconazole is used after fluconazole, it is recommended that careful monitoring of unwanted reactions associated with the use of voriconazole is recommended.

    Phenytoin

    [isoenzymatic substrate CYP2C9 and a powerful inducer of cytochrome P450]

    300 mg once daily

    FROMmOh voriconazole 49%

    AUCτ voriconazole ↓ 69%

    Avoid simultaneous administration of voriconazole and phenytoin, unless the patient's benefit exceeds the risk. It is recommended to monitor plasma concentrations of phenytoin.

    300 mg once daily

    (simultaneous application with voriconazole at a dose of 400 mg twice a day) *

    FROMmOh phenytoin ↑ 67%

    AUCτ phenytoin ↑ 81%

    In comparison with voriconazole, 200 mg twice daily

    FROMmOh voriconazole ↑ 34%

    AUCτ voriconazole | ↑ 39%

    Simultaneous application is possible only if the maintenance dose of voriconazole is increased to 5 mg / kg intravenously or 200 mg to 400 mg orally twice a day (in patients weighing less than 40 kg from 100 mg to 200 mg orally twice a day day).

    Anticoagulants Warfarin

    (30 mg once with voriconazole 300 mg twice daily)

    [isoenzymatic substrate CYP2C9]

    The increase in the maximum prothrombin time was approximately two-fold.

    If patients receiving coumarin preparations are prescribed voriconazole, it is necessary to monitor prothrombin time at short intervals and appropriately select doses of anticoagulants.

    Other oral anticoagulants, for example, fenprokumone, acenocoumarol

    [Substrates isoenzymes CYP2C9 and CYP3A4]

    It is assumed that voriconazole can increase plasma concentrations of coumarins, which may lead to an increase in prothrombin time.

    Benzodiazepines (e.g., midazolam, triazolam, alprazolam)

    [Substrates isoenzyme CYP3A4]

    In vitro voriconazole may cause an increase in plasma concentrations of benzodiazepines that are metabolized by isoenzyme CYP3A4, and cause the development of prolonged sedation.

    It is recommended to evaluate the appropriateness of dose adjustment for benzodiazepines.

    Immunosuppressants

    [isoenzymatic substrates CYP3A4]

    Sirolimus

    (2 mg once)

    According to an independent study:

    FROMmOh sirolimus ↑ 6,6 times

    AUC0-∞ sirolimus ↑ 11 times

    The simultaneous use of voriconazole and sirolimus is contraindicated.

    Cyclosporin (in patients who underwent kidney transplantation and are in a stable state)

    FROMmOh cyclosporine ↑ 13%

    AUCτ cyclosporine ↑ 70%

    When prescribing voriconazole, patients receiving ciclosporin, it is recommended to reduce the dose of cyclosporine by half and monitor its concentration in the blood plasma.

    An increase in the concentration of cyclosporine is accompanied by nephrotoxicity.

    After voriconazole cancellation, it is necessary to control the concentration of cyclosporine and, if necessary, increase its dose.

    Tacrolimus

    (0.1 mg / kg once)

    FROMmOh tacrolimus 117%

    AUCτ tacrolimus ↑ 221%

    When prescribing voriconazole, patients receiving tacrolimus, it is recommended to reduce the dose of the latter to one third and monitor its concentration in the blood plasma. Increased concentration of tacrolimus is accompanied by nephrotoxicity. After voriconazole cancellation, it is necessary to monitor the concentration of tacrolimus and, if necessary, increase its dose.

    Long-acting opiates

    [Substrates isoenzyme CYP3A4]

    Oxycodone

    (10 mg once)

    According to an independent study:

    FROMmOh oxycodone ↑ 1.7 times

    AUC0-∞ oxycodone ↑ 3,6 times

    The possibility of reducing the dose of oxycodone and other long-acting opiates metabolized by the CYP3A4 isoenzyme (eg, hydrocodone) should be evaluated. It may be necessary to monitor the patient's condition at short intervals for the development of unwanted reactions associated with opiates.

    Methadone

    (32-100 mg once daily)

    [isoenzymatic substrate CYP3A4]

    FROMmOh R-metadone (active metabolite) ↑ 31%

    AUCτ R-metadone (active metabolite) ↑ 47%

    FROMmOh S-methanone ↑ 65%

    AUCτ Smethadone ↑ 103%

    An increase in the concentration of methadone in the blood plasma leads to the appearance of toxic effects, including lengthening of the interval QT. It is recommended that frequent monitoring of the patient's condition for the development of unwanted reactions and toxicity (including lengthening of the interval QT) associated with methadone.

    You may need to reduce the dose of methadone.

    Non-steroidal anti-inflammatory drugs (NSAIDs)

    [isoenzymatic substrates CYP2C9]

    Patients should be monitored to identify possible toxic effects and, if necessary, adjust the dose of NSAIDs.

    Ibuprofen

    (400 mg once) Diclofenac

    (50 mg once)

    FROMmOh S-ibuprofen ↑ 20%

    AUC0-∞ Sibuprofen ↑ 100%

    FROMmOh diclofenac ↑ 114%

    AUC0-∞ diclofenac ↑ 78%

    Omeprazole

    (40 mg once daily) *

    [inhibitor of isoenzyme CYP2 С19; isoenzyme substrate CYP2C19 and CYP3A4]

    FROMmOh omeprazole ↑ 116%

    AUCτ omeprazole ↑ 280%

    FROMmOh voriconazole ↑ 15%

    AUCτvoriconazole ↑ 41% Voriconazole can also inhibit the action of other proton pump inhibitors, which are substrates of the isoenzyme CYP2C19, which can lead to an increase in the plasma concentrations of these drugs.

    Correction of the dose of voriconazole is not required. When starting voriconazole in patients who are already receiving omeprazole therapy at doses of 40 mg or higher, a dose reduction of omeprazole is recommended in half.

    Oral contraceptives *

    [substrates of the isoenzyme CYP3A4; inhibitors of the isoenzyme CYP2C19]

    Norethisterone / ethinylestradiol

    (1 mg / 0.35 mg, one

    once a day)

    FROMmOh ethinylestradiol ↑ 36%

    AUCτ ethinyl estradiol ↑ 61%

    FROMmax norethisterone ↑ 15%

    AUCτ norethisterone ↑ 53%

    FROMmOh voriconazole ↑ 14%

    AUCτ voriconazole ↑ 46%

    It is recommended to monitor the patient's condition for the development of unwanted reactions associated with the use of oral contraceptives and voriconazole.

    Narcotic analgesics of short action

    [isoenzymatic substrates CYP3A4]

    The possibility of reducing the dose of alfentanil, fentanyl and other short-acting narcotic analgesics having a chemical structure similar to alfentanil and metabolized by the CYP3A4 isoenzyme (eg, sufentanil) should be evaluated. Patients should be under constant surveillance to prevent respiratory depression or other side effects associated with the use of short-acting narcotic analgesics and, if necessary, their dose should be reduced.

    Alfentanil (a single dose of 20 mcg / kg with the simultaneous use of naloxone)

    According to an independent study:

    AUC0-∞ alfentanil ↑ 6 times

    Fentanyl

    (a single dose of 5 μg / kg)

    According to an independent study:

    AUC0-∞ fentanyl ↑ 1,34 times

    Statins (for example, lovastatin)

    [Substrates isoenzyme CYP3A4]

    The interaction was not studied, however, voriconazole can increase plasma concentrations of statins that are metabolized by an isoenzyme CYP3A4 and can lead to rhabdomyolysis.

    It should be assessed the possibility of reducing the dose of statins.

    Derivatives of sulfonylureas (for example, tolbutamide, glipizide, glibenclamide)

    [Substrates isoenzyme CYP2C9]

    The interaction was not studied, however, voriconazole can increase plasma concentrations of sulfonylureas and cause hypoglycemia.

    It is necessary to carefully monitor the concentration of glucose in the blood plasma.

    Vinca alkaloids (for example, vincristine and vinblastine)

    [Substrates isoenzyme CYP3A4]

    Voriconazole can increase the vinca alkaloids (vincristine and vinblastine) in the blood plasma and cause neurotoxicity.

    It is recommended to evaluate the feasibility of correcting the dose of vinca alkaloids.

    Other HIV protease inhibitors (PIs) (eg, saquinavir, amprenavir and nelfinavir)*

    [inhibitors and substrates of the isoenzyme CYP3A4]

    Research in vitro evidence that voriconazole can inhibit the metabolism of HIV protease inhibitors: saquinavir, amprenavir and nelfinavir. In turn, HIV protease inhibitors can suppress the metabolism of voriconazole.

    It is recommended that the patient be carefully monitored for any manifestation of drug toxicity and / or lack of action. Probably, correction of a dose of preparations is required.

    Other non-nucleoside reverse transcriptase inhibitors (NNRTIs) (eg, delavirdine, nevirapine)*

    [inhibitors or inducers of cytochrome P450 and isoenzymatic substrates CYP3A4]

    Research in vitro showed that voriconazole metabolism may be inhibited by NNRTI, and voriconazole in turn, can inhibit the metabolism of the NNRTI.

    Based on the results of the study of the effect of efavirenz on voriconazole, it can be assumed that NNRTIs can enhance the metabolism of voriconazole.

    It is recommended to carefully monitor the patient's condition for the development of drug toxicity and / or lack of action.You may need to adjust the dose of drugs.

    Cimetidine

    (400 mg twice daily) [nonspecifically inhibits cytochrome P450 and increases the pH of the gastric juice]

    FROMmOh voriconazole ↑ 18%

    AUCτ voriconazole ↑ 23%

    Dose correction is not required

    Digoxin

    (0.25 mg once daily)

    [P-glycoprotein substrate]

    FROMmOh digoxin

    AUCτ digoxin

    Dose correction is not required

    Indinavir

    (800 mg three times a day)

    [inhibitor and substrate of isoenzyme CYP3A4]

    FROMmOh indinavir ↔

    AUCτ indinavir ↔

    FROMmOh voriconazole ↔

    AUCτ voriconazole ↔

    Dose correction is not required

    Antibiotics of the macrolide group

    Dose correction is not required

    Erythromycin

    (1 g twice daily)

    [inhibitor isoenzyme CYP3A4]

    Azithromycin

    (500 mg once daily)

    FROMmOh voriconazole ↔

    AUCτ voriconazole ↔

    FROMmOh voriconazole ↔

    AUCτ voriconazole ↔

    The effect of voriconazole on the metabolism of erythromycin or azithromycin is unknown.

    Mycophenolic acid

    (1 g once)

    [substrate uridine-5 diphosphate-glucuronyl transferase]

    FROMmOh mycophenolic acid

    AUCτ mycophenolic acid

    Dose correction is not required

    Prednisolone

    (60 mg once)

    [isoenzymatic substrate CYP3A4]

    FROMmOh prednisolone ↑ 11%

    AUCτ prednisolone 34%

    Dose correction is not required

    Ranitidine

    (150 mg twice daily)

    [increases the pH of gastric juice]

    FROMmOh voriconazole ↔

    AUCτ voriconazole ↔

    Dose correction is not required

    The pharmacokinetic parameter based on 90% confidence interval of the mean geometric value is inside (↔), higher (↑) or lower (↓) of the interval 80% -125%.

    * Mutual effect.

    AUCτ, AUCt, AUC0-∞ - area under the curve "concentration-time" during the dosing period, from the moment of administration of the drug to the visible concentration in the blood plasma, from the moment of drug administration to infinity, respectively.

    Special instructions:

    Taking the material for sowing and other laboratory tests (serology, histopathology) for the purpose of isolating and identifying pathogens should be performed before the start of treatment. Treatment can begin before the results of laboratory tests. However, after receiving these results, it is necessary to adjust the antifungal therapy.

    The types that most often cause infection in humans include FROM. albicans, FROM. parapsilosis, FROM. tropicalis, FROM. glabrata and FROM. torusei, while for all of them the minimal suppressive concentration (MIC) of voriconazole is usually less than 1 mg / ml. but in vitro voriconazole activity against fungi of different species Candida is not the same.In particular, the MIC of voriconazole for fluconazole-resistant isolates FROM. glabrata is proportionally higher than the MIC for isolates sensitive to fluconazole. In connection with this, fungi of the genus Candida in all possible cases, identify to the species level. If it is possible to determine the sensitivity of fungi to antifungal drugs, the values ​​of the MIC should be interpreted using threshold criteria.

    Undesirable effects from the cardiovascular system

    The use of voriconazole is associated with lengthening of the interval QT on an electrocardiogram, which is accompanied by rare cases of ventricular fibrillation / flutter in severely ill patients with multiple risk factors, such as cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant therapy, which could contribute to the development of this complication.

    Voriconazole should be used with caution in patients with the following potentially proarrhythmic conditions:

    - congenital or acquired lengthening interval QT;

    - Cardiomyopathy, especially in combination with heart failure;

    - sinus bradycardia;

    - existing arrhythmias with clinical manifestations;

    - simultaneous use of drugs that extend the interval QT (see section "Interaction with other drugs").

    Electrolyte disorders, for example, hypokalemia, hypomagnesemia and hypocalcemia, if necessary, should be monitored and eliminated before and during therapy with voriconazole.

    When tested on healthy volunteers, the effects of voriconazole on the interval QT on the ECG using single doses exceeding the usual daily dose no more than 4 times, it was found that none of the subjects had an increase in the interval QT at 60 or more milliseconds from the norm. Also, none of the subjects had an exceedance of the interval above the clinically significant threshold of 500 msec.

    Hepatotoxicity

    The frequency of a clinically significant increase in the activity of "liver" transaminases in patients receiving voriconazole, is 13.4%. In most cases, the liver function parameters are normalized both during the continuation of treatment without changing the dose or after its correction, and after the cessation of therapy.With the use of voriconazole, cases of severe hepatotoxicity (jaundice, hepatitis and hepatic cell failure leading to death) were rare in patients with serious underlying diseases.

    Undesirable phenomena from the liver are observed, mainly, in patients with serious diseases, mainly malignant blood tumors. Patients without any risk factors have transient liver reactions, including hepatitis and jaundice. Dysfunction of the liver is usually reversible and pass after discontinuation of treatment.

    Monitoring of liver function

    During treatment with voriconazole, it is recommended to constantly monitor liver function in both children and adults. Clinical management of such patients should include a laboratory assessment of liver function (in particular, activity determination ACT and ALT) at the beginning of treatment with voriconazole and at least once a week during the first month of therapy. In the case of continuation of treatment in the absence of changes in the biochemical parameters of liver function, the frequency of laboratory testing can be reduced to once a month.With a marked increase in biochemical parameters of liver function voriconazole should be discarded, unless the benefit-risk ratio of therapy according to the medical evaluation does not justify its continued use (see "Application and dose" section).

    Visual disorders

    In the treatment with voriconazole, approximately 21% of patients have visual impairment: blurred vision, changes in color vision or photophobia. Visual disturbances are transient and completely reversible; in most cases they spontaneously disappear within 60 minutes. With repeated use of voriconazole, there is a weakening of their severity. Visual disturbances are usually easily expressed, rarely require discontinuation of treatment and do not lead to any remote consequences.

    The mechanism of development of visual disturbances is unknown. Determined that voriconazole reduces the amplitude of waves on the electroretinogram (ERG) in healthy volunteers. These changes do not grow ERG with continued treatment for 29 days and completely disappeared after withdrawal of voriconazole.

    Long-term therapy with voriconazole (an average of 169 days) in patients with paracoccidioidosishad a clinically significant effect on visual function, which was confirmed by the results of tests for visual acuity, visual fields, color perception and contrast sensitivity.

    According to post-marketing research, there are reports of the development of cases of visual disturbances that persist for a long time, in particular, the appearance of a "veil" before the eyes, optic neuritis and edema of the optic disc. It should be noted that these disorders develop most often in seriously ill patients and / or receiving concomitant therapy, which can cause such undesirable phenomena.

    Undesirable effects of the kidneys

    In seriously ill patients receiving voriconazole, there were cases of development of acute renal failure, which was probably associated with therapy of primary or concomitant diseases with nephrotoxic drugs.

    Monitoring of kidney function. Patients should be observed to identify signs of impaired renal function. To do this, it is necessary to conduct laboratory tests, in particular, to determine the concentration of creatinine in the blood serum (see section "Method of administration and dose").

    Monitoring of pancreatic function

    Adults and children with risk factors for acute pancreatitis (recent chemotherapy, hematopoietic stem cell transplantation) should undergo a screening (determination of amylase and lipase activity in the blood serum) to address the issue of voriconazole therapy.

    Undesirable skin effects

    When voriconazole therapy often develop skin reactions, mostly in patients with serious underlying diseases, while taking other medicines. In most cases, a mild to moderate skin rash was noted.

    During treatment with voriconazole, patients experienced rare cases of exfoliative skin reactions, such as Stevens-Johnson syndrome. If the patient develops exfoliative skin reactions, then voriconazole should be canceled. Since during the therapy with voriconazole the development of photosensitization is possible, during treatment, patients (including children) are advised to avoid exposure to direct sunlight and take protective measures such as wearing clothes and applying sunscreens with a high UV-protection factorSPF).

    Long-term treatment

    In patients with skin photosensitivity reactions and additional risk factors, the development of squamous cell carcinoma of the skin and melanoma against a background of prolonged therapy is reported. If a patient experiences phototoxic reactions, he should be consulted by appropriate specialists and sent to a dermatologist. Voriconazole should be considered. With the continuation of therapy with voriconazole, despite the occurrence of phototoxic skin lesions, the patient should regularly undergo a dermatological examination for the early detection and treatment of precancerous skin diseases. If the patient develops skin lesions associated with precancerous skin diseases, squamous cell carcinoma of the skin or melanoma, consideration should be given to discontinuing voriconazole therapy.

    Noninfectious periostitis

    There have been reports of cases of periostitis in patients after transplantation receiving long-term therapy with voriconazole. The therapy with voriconazole should be discontinued if the patient has bone pain and the radiograph shows changes that are characteristic of periostitis.

    Use in children

    Voriconazole is indicated for use in children aged 3 years (for a given dosage form) and older with continuous monitoring of liver function. In children, an increase in the activity of liver enzymes is more common. Bioavailability of voriconazole for oral administration in children aged 3 (for a given dosage form) to 12 years can be reduced by impaired absorption or decreased body weight. In such cases intravenous administration of voriconazole is indicated.

    The frequency of phototoxic reactions in children is higher. Due to the fact that phototoxic lesions can degenerate into squamous cell carcinoma (PKC), children should take strict measures to protect the skin from ultraviolet radiation. Children with signs of photoaging of the skin, such as lentigo or freckles, are advised to avoid the sun and be examined by a dermatologist even after discontinuation of treatment.

    Narcotic analgesics of short action (substrates of isoenzyme CYP3A4)

    Since the half-life of alfentanil when it is used simultaneously with voriconazole is increased 4-fold, careful monitoring of undesirable phenomena associated with the use of narcotic analgesics,including longer monitoring of respiratory function.

    Long-acting narcotic analgesics (substrates isoenzyme CYP3A4)

    It should be possible to reduce the dose of oxycodone and other long-acting narcotic analgesics, which are metabolized by the isoenzyme CYP3A4 (hydrocodone) with simultaneous application with voriconazole. It is necessary to carefully monitor undesirable phenomena associated with the use of narcotic analgesics (see section "Interaction with other drugs").

    Phenytoin (powerful cytochrome P450 inducer and isoenzyme substrate CYP2C9)

    With the simultaneous use of phenytoin and voriconazole, it is recommended that the concentration of phenytoin be monitored continuously. If possible, simultaneous use of voriconazole and phenytoin should be avoided, unless the anticipated benefit exceeds the potential risk (see "Interactions with Other Drugs").

    Efavirenz (non-nucleoside reverse transcriptase inhibitor, cytochrome P450 inducer inhibitor and isoenzyme substrate CYP3A4)

    In case of simultaneous use of voriconazole and efavirenz, the dose of voriconazole should be increased to 400 mg twice a day, and the dose of efavirenz should be reduced to 300 mg every 24 hours (see section "Interaction with other drugs").

    Rifabutin

    The simultaneous use of voriconazole and rifabutin is contraindicated, since rifabutin significantly reduces the concentration of voriconazole in blood plasma.

    Ritonavir (a powerful inducer of cytochrome P450 inhibitor and substrate of isoenzyme CYP3A4)

    Apply simultaneously voriconazole and ritonavir in low doses (100 mg twice a day) should be given only if the expected benefit from taking voriconazole significantly exceeds the risk of their combined use (see the sections "Contraindications" and "Interaction with other medicines").

    Everolimus (isoenzymatic substrate CYP3A4 and P-glycoprotein)

    The simultaneous use of voriconazole and everolimus is not recommended, since it is expected that voriconazole significantly increases the concentration of everolimus in the blood plasma. At the moment, there is not enough information to recommend a correction of the dosing regimen.

    Methadone (isoenzymatic substrate CYP3A4)

    An increase in the concentration of methadone in the blood plasma leads to the appearance of toxic effects, including lengthening of the interval QT. With simultaneous use of voriconazole and methadone, it is necessary to closely monitor the manifestation of undesirable and toxic effects. If necessary, the dose of methadone may be reduced (see section "Interaction with other drugs").

    Fluconazole (inhibitor of isoenzymes CYP2C9, CYP2C19 and CYP3A4)

    Simultaneous use of voriconazole and fluconazole inside of healthy volunteers leads to a significant increase in Cmax and AUCt voriconazole. A suitable regimen for dose adjustment and / or reception frequency of voriconazole and fluconazole is not established. In case if voriconazole is used after fluconazole, it is recommended that careful monitoring of unwanted reactions associated with the use of voriconazole is recommended.
    Effect on the ability to drive transp. cf. and fur:

    Voriconazole can cause transient and reversible visual impairment, including the appearance of a "veil" in front of the eyes, impaired / increased visual perception and / or photophobia. In the presence of such symptoms, patients should avoid performing potentially dangerous actions, in particular,motor vehicle management or the use of complex equipment requiring speed of psychomotor reactions. When taking voriconazole, patients should not drive the car at night.

    Form release / dosage:

    Tablets coated with a film coating, 50 mg and 200 mg.

    Packaging:

    Dosage 50 mg: 2, 7, 10, 20, 28 or 30 tablets into a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

    1 contour pack of 2 tablets or 1, 2, 4, 8 contour packs of 7 tablets, or 1, 3, 5, 10 contiguous cell packs of 10 tablets, or 5 circuit packs of 20 tablets each, or 1,2 contourcell packs of 28 tablets, or 1 contour pack of 30 tablets together with the instructions for use are placed in a pack of cardboard.

    Dosage of 200 mg: 2, 7, 10, 14 or 15 tablets into a contoured cell packaging made of a polyvinylchloride film and aluminum foil printed lacquered.

    1 contour pack of 2 tablets or 1, 2, 4, 8 contour cell packs of 7 tablets, or 1, 3, 5, 10 contiguous cell packs of 10 tablets, or 1, 2, 4 contiguous cell packs 14 tablets, or 2 contour packs of 15 tablets together with the instructions for use are placed in a pack of cardboard.

    Storage conditions:

    At a temperature of no higher than 25 ° C, in the manufacturer's packaging.

    Keep out of the reach of children.

    Shelf life:

    3 years.

    Do not use after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-002331
    Date of registration:13.12.2013
    Expiration Date:13.12.2018
    The owner of the registration certificate:CANONFARMA PRODUCTION, CJSC CANONFARMA PRODUCTION, CJSC Russia
    Manufacturer: & nbsp
    Representation: & nbspCANONFARMA PRODUCTION CJSC CANONFARMA PRODUCTION CJSC Russia
    Information update date: & nbsp26.03.2017
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