Vfend - instructions for use, doses, side effects, contraindications

Excipients: sucrose 542.40 mg, silicon dioxide colloid 1.00 mg, titanium dioxide 1.00 mg, xanthan gum 2.00 mg, sodium citrate dihydrate 3.00 mg, citric acid 4.20 mg, sodium benzoate 2.40 mg, orange flavoring 4.00 mg.

Description:

Powder white or almost white.

Suspension white or almost white.

Pharmacotherapeutic group:Antifungal agent

ATX: & nbsp

J.02.A. C.03 Voriconazole

Pharmacodynamics:

Mechanism of action

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 mediated via fungal cytochrome P450, which is the key ethane of ergosterol biosynthesis. 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 P450 isoenzymes of fungi than for various enzyme systems of mammalian cytochrome P450.

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 S. krusei, resistant to fluconazole, and resistant strains C. glabrata and C. 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 C. albicans, FROM. glabrata , S. krusei, C. parapsilosis and C. tropicalis, as well as for a limited number of strains C. dubliniensis, C. inconspicua. and C. 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 brevicatdis 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 capsulation. 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. However, 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 (AUC_t). An increase in the oral dose from 200 mg twice a day to 300 mg twice daily leads to an increase AUC_ton 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.

When receiving the saturating doses of voriconazole equilibrium concentration achieved within 24 hours. If the drug is administered 2 times a day in medium (but not saturating) doses of voriconazole cumulation then occurs, and the equilibrium concentration achieved by day 6 in the majority of patients.

Suction and distribution

Voriconazole quickly and almost completely absorbed after ingestion: the maximum concentration in the blood plasma (FROM_max) is achieved 1-2 hours after admission. Bioavailability of voriconazole for oral administration is 96%. With repeated administration of voriconazole with food with a high fat content FROM_maxand AUC_tdecrease 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 about 4.6 l / kg, which indicates the active distribution of voriconazole in the tissue. Binding to plasma proteins is 58%.

Voriconazole penetrates the blood-brain barrier (BBB) and is determined in the cerebrospinal fluid.

Metabolism

According to research data in vitro voriconazole metabolized under the action of isoenzymes CYP2C19, CYP2C9, CYP3A4. An important role in the metabolism of voriconazole is played by the CYP2C19 isoenzyme, exhibiting 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 the N-oxide, whose proportion is about 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.

Half-life (T_1/2) 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 T_1/2does not allow to predict the cumulation or excretion of voriconazole.

Pharmacokinetics in special groups

Floor

With multiple administration of voriconazole inside FROM_maxand AUC_t in healthy young women were 83% and 113%, respectively, higher than in healthy young men (18-45 years).Significant differences FROM_maxand AUC_tin healthy elderly men and healthy elderly women (≥65 years) do not. The equilibrium concentration of voriconazole in blood plasma in women was 91% higher than in men after taking the drug as a suspension. There is no need to adjust the dose of voriconazole depending on the sex. Concentrations in blood plasma in men and women are similar.

Age

With multiple administration of voriconazole inside FROM_maxand AUC_t in healthy elderly men (≥65 years) by 61% and 86%, respectively, higher than in healthy young men (18-45 years). Significant differences FROM_maxand AUC_tin 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.

If necessary, dose correction voriconazole, depending on age, no.

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 when taking voriconazole by mouth 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. Nevertheless, fewer concentrations of voriconazole in the blood plasma were observed in some adolescents with a low body weight in comparison with adults and were closer to the values of the same index 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

When taking voriconazole once in a dose of 200 mg by patients with normal night function and patients with renal dysfunction from mild (creatinine clearance <41-60 ml / min) to severe (KC <20 ml / min) degree of pharmacokinetics of voriconazole significantly does not depend on the degree of impaired renal function. The binding of voriconazole with plasma proteins is approximately the same in patients with varying degrees of renal insufficiency.sections "Method of administration and dose" and "Special instructions").

Impaired liver function

After a single intake of the drug in a dose of 200 mg AUC_tvoriconazole in patients with mild or moderate severity of liver function (classes A and B according to the Child-Pyo classification) was 233% higher than in patients with normal liver function. Dysfunction of the liver does not affect the binding of voriconazole with plasma proteins.

With repeated intake of the drug inside AUC_tvoriconazole is comparable in patients with an average degree of impaired liver function (class B according to the Child-Pugh classification) who received the drug at a maintenance dose of 100 mg 2 times / day, and in patients with normal liver function receiving voriconazole in a dose of 200 mg twice a day. There is no information on the pharmacokinetics of voriconazole in patients with severe hepatic impairment (class C according to the Child-Pugh classification). For recommendations on how to dose the drug, see "Method of administration and dose".

Indications:

- ANDInvasive aspergillosis;

- Candida in patients without neutropenia;

- severe invasive forms of candidiasis (including FROM. krusei);

- Candidiasis of the esophagus;

- severe 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 high-risk groups (allogeneic bone marrow recipients, patients with relapse of leukemia).

Contraindications:

Vfend® is contraindicated in patients with hypersensitivity to voriconazole or any other component of the drug.

Contraindicated simultaneous use of Vfend® and the following drugs: substrates isoenzyme CYP3A4-terfenadine, astemizole, cisapride, pimozide or quinidine; sirolimus; rifampicin, carbamazepine and long-acting barbiturates (phenobarbital); rifabutin; efavirenz in high doses (400 mg and higher once a day); ritonavir (400 mg and higher twice a day); ergot alkaloids (ergotamine, dihydroergotamine) which are substrates of the isoenzyme CYP3A4; St. John's wort (the cytochrome P inducer₄₅₀ and P-glycoprotein).

Vfend® is contraindicated in children under 2 years of age.

Deficiency of sugar / isomaltase, fructose intolerance, glucosogalactose malabsorption.

Carefully:

Hypersensitivity to other drugs - derivatives of azoles.

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

Electrolyte disorders such as hypokalemia, hypomagnesemia and hypocalcemia.

Diabetes.

Voriconazole should be used with caution in patients with proarrhythmic conditions:

- congenital or acquired interval increase QT;

- cardiomyopathy, especially with heart failure;

- sinus bradycardia;

- presence of symptomatic arrhythmia;

- simultaneous administration of drugs that cause lengthening of the interval QT.

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, except when the expected benefit to the mother clearly exceeds the possible risk to the fetus.

The excretion of voriconazole with breast milk has not been studied. Voriconazole Do not use in women who are breast-feeding. For the duration of the drug, breastfeeding should be discontinued.

Women of reproductive age using Vfend® should use reliable contraceptive methods.

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 use of Vfend® 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 administration 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 medication for oral administration. Given the high bioavailability of the drug when ingested, 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 withoutdose adjustment.

The table provides detailed information on the dosing of the drug:

	Intravenously	Inside
	Intravenously	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
The maintenance dose (after the first 24 hours)
Prevention of invasive fungal infections in patients (adults and children over 12 years) at high risk groups, such as pexciseTrainsimplantationand hematopoietic stem cells / prevention of "breakthrough" fungal infections in febrile patients	3-4 mg / kg every 12 hours	200 mg (5 ml) every 12 hours	100 mg (2.5 ml) 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 (5 ml) every 12 hours	100 mg (2.5 ml) every 12 hours
Candidemia in patients without neutropenia	3-4 mg / kg every 12 h	200 mg (5 ml) every 12 hours	100 mg (2.5 ml) every 12 hours
Esophageal candidiasis	Not installed	200 mg (5 ml) every 12 hours	100 mg (2.5 ml) every 12 hours

Selection of dose for oral administration

If treatment is not effective, a maintenance dose of Vfend® for oral administration may be increased from 200 mg (5 ml suspension) every 12 hours to 300 mg (7.5 ml suspension) every 12 hours.In patients with a body weight of less than 40 kg, the dose may be increased from 100 mg (2.5 ml suspension) to 150 mg (3.75 ml) every 12 hours.

If the patient does not tolerate the drug in high dose (i.e., 300 mg orally every 12 hours), the maintenance dose for ingestion gradually reduce in increments of 50 mg to 200 mg every 12 hours (for patients weighing less than 40 kg - 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 is possible only if immunosuppressive therapy is continued or the development of the "graft-versus-host" reaction (TPH).

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.

Instructions for preparing a suspension:

1. Gently shake the vial of powder, then open it.

2. Add only 46 ml of water: measure 23 ml of water with a measuring cup (fill the cup until the risks). Add water to the vial. Using the same measuring cup, measure another 23 ml of water. Add this amount to the vial.

3. Close the vial and vigorously shake for 1 minute.

4. Remove the protective cover from the children. Insert the adapter into the neck of the vial.

5. Attach the lid back.

6. Write on the label the expiration date of the suspension (the shelf life of the finished suspension is 14 days).

Instructions for the use of suspension:

Before each use, the vial with suspension should be shaken for 10 seconds. A ready-made suspension should be used using the measuring syringe, presented in each package.

Impaired renal function

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

Impaired liver function

In acute liver damage, manifested by increased activity of "liver" transaminases: alanine aminotransferase (ALT) and aspartate aminotransferase (ACT), dose adjustment is not required, it is recommended to continue monitoring liver function indicators.

Patients with mild or moderate hepatic impairment (Child-Pugh class A and B classes) should be given a standard satiating dose of Vfend® and a two-fold reduction in the maintenance dose.

Patients with severe hepatic impairment (class C but Child-Pugh classifications) should be prescribed Vfend® only in cases where the expected benefit exceeds the possible risk, and under constant monitoring to detect signs of toxic effects of the drug.

Elderly patients

Dose adjustments in the elderly are not required.

Use in children

The efficacy and safety of voriconazole in children younger than 2 years of age have not been established.

The dosage regimen of voriconazole in children (aged 2 to 12 years) and adolescents aged 12 to 14 years and weighing less than 50 kg:

	Intravenously	Inside
Saturated dose (first 24 h)	9 mg / kg every 12 hours	Not recommended
The 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 start therapy with intravenous administration of the drug, and the possibility of oral administration of the drug Vfend^® should be considered only after clinical improvement and the patient's ability to take oral medications. It should be taken into account that the effect of the drug when administered intravenously at a dose of 8 mg / kg is approximately twice as high as when administered intravenously at a dose of 9 mg / kg.

Pharmacokinetics and tolerability of higher doses of voriconazole for oral administration in children have not been studied.

The use of voriconazole in children aged 2 to 12 years with violations of the 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 increments of 1 mg / kg (or 50 mg if a maximum oral dose of 350 mg was initially used).

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.

Criteria for frequency estimation: 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.

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

From the side of the vessels: often - arterial hypotension, phlebitis; rarely thrombophlebitis.

On the part of the hematopoiesis 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.

From the nervous system: highly often - headache; often - syncope, tremor, paresthesia, drowsiness, dizziness, convulsions, nystagmus; infrequently - cerebral edema, encephalopathy, extrapyramidal disorder, peripheral neuropathy, ataxia, hypesthesia, dysgeusia (impaired taste perception); rarely - hepatic encephalopathy, Guillain-Barre syndrome.

From the side of the organ of vision: very often - a violation of the sight (including blurred vision, blurred vision, photophobia, chloropsy, chromatopsy, photophobia, color blindness, cyanopsy,presence in the field of vision of iridescent circles around light sources, night blindness, oscilloscopy, photopsy, scintillation scotoma, visual acuity decrease, visual field defect, floating vitreous opacities and xantopsy); often - hemorrhage in the retina of the eye; infrequently - optic neuritis, edema of the nipple of the optic nerve, oculogic crisis, diplopia, scleritis, blepharitis; rarely - atrophy of the optic nerve, corneal opacity.

From the side of the hearing and vestibular organs: infrequently - vertigo, hypoacusia, tinnitus.

From the respiratory system, thorax and mediastinum: very often - respiratory depression; often - pulmonary edema, acute respiratory distress syndrome.

From the gastrointestinal tract: very often - nausea, vomiting, diarrhea, abdominal pain; often - cheilitis, indigestion, constipation; infrequently - duodenitis, glossitis, pancreatitis, edema of the tongue.

From the kidneys and urinary system: often - acute renal insufficiency, hematuria; infrequently necrosis of renal tubules, proteinuria, nephritis.

From the skin and subcutaneous tissues: very often - a rash; frequent exfoliative dermatitis, alopecia, itchy skin,maculopapular rash, erythema; infrequently - Stevensjonson's 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.

From the side of the musculoskeletal system and connective tissue: often - backache; infrequently - arthritis; frequency is unknown - periostitis.

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: very 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.

From the immune system: infrequently - allergic reactions; rarely anaphylactoid reactions.

From the hepatobiliary system: very 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 - hepatic insufficiency, cholecystitis, cholelithiasis, enlargement of the liver.

Mental disorders: often hallucinations, confusion, depression, anxiety, insomnia, agitation.

Neoplasms are benign, malignant and unspecified (including cysts and polyps): frequency unknown - squamous cell carcinoma of the skin.

Research: often - an increase in the concentration of creatinine in the blood; infrequent - prolongation of QT interval on electrocardiogram, increase of urea concentration in blood, increase of cholesterol concentration in blood.

Side effect when used in children: it was found that The undesirable effects of the drug in children aged 2 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 excreted during hemodialysis with a clearance of 121 ml / min. In case of an overdose, hemodialysis can promote the removal of voriconazole and begadex sulfobutylate 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 - CYP2C19, 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 [isoenzymatic substrates CYP3A4]	Interactions have not been studied, but there is a high probability that elevated concentrations of these drugs may lead to an extension of the QTc interval and in rare cases, the occurrence of ventricular tachycardia of the type "pirouette"	Contraindicated
Carbamazepine and long-acting barbiturates (for example, phenobarbital, mefobarbital) [powerful cytochrome inducers R₄₅₀]	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 R_450;inhibitor and substrate of isoenzyme 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 *	FROM_max efavirenz ↑ 38% AUC_τ efavirenz ↑ 44% FROM_max voriconazole ↓61% AUC_τ voriconazole ↓77%	The use of standard doses of voriconazole and efavirenz 400 mg once a day is contraindicated.
	In comparison with efavirenz 600 mg once a day:	Simultaneous application is possible if
Simultaneous application of 300 mg of efavirenz once a day and voriconazole 400 mg two once a day *	FROM_maxefavirenz ↔ AUC_τ efavirenz ↑ 17%	the maintenance dose of voriconazole will be increased to 400 mg twice per day, and the dose of efavirenz is reduced to 300 mg once a day. With the withdrawal of therapy with voriconazole, the initial dose of efavirenz should be restored.
	In comparison with voriconazole 200 mg twice a day: FROM_max voriconazole ↑23% AUC_τ voriconazole ↓ 7%
Ergot alkaloids (eg, ergotamine and dihydroergotamine) [substrates of isoenzyme 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 concentration of these drugs in the blood plasma and lead to ergotism.	Pcontraindicated
Rifabutin [powerful cytochrome inducer R₄₅₀]
300 mg once daily	FROM_max voriconazole ↓ 69% AUC_τ voriconazole ↓78% FROM_max 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 daily: FROM_max voriconazole ↑ 104% AUC_τ voriconazole ↑ 87%
Rifampicin (600 mg once daily) [powerful cytochrome inducer R₄₅₀]	FROM_max voriconazole ↓ 93% AUC_τ voriconazole ↓ 96%	Contraindicated
Ritonavir (protease inhibitor) [a powerful inducer of cytochrome P₄₅₀; inhibitor and substrate of isoenzyme CYP3A4]
High doses (400 mg twice daily)	FROM_max and AUC_τ ritonavir ↔ FROM_maxvoriconazole ↓ 66% AUC_τvoriconazole ↓ 82%	The simultaneous use of voriconazole at high doses of ritonavir (400 mg and higher twice daily) is contraindicated.
Low doses (100 mg twice daily) *	FROM_maxpitonavir ↓ 25% AUC_τ ritonavir ↓ 13% FROM_max voriconazole ↓ 24% AUC_τ voriconazole ↓ 39%	Apply simultaneously voriconazole and ritonavir 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 a day (simultaneous application with a single dose of voriconazole 400 mg)	According to an independent study: AUC_0-∞ 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, FROMYP2C19 and CYP3A4]	FROM_max voriconazole ↑ 57% AUC_τ voriconazole ↑ 79% Changes FROM_max and AUC_τ, 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 cytochrome inducer R₄₅₀]
300 mg once daily	FROM_max voriconazole ↓ 49% AUC_τ 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 a day (simultaneous application with voriconazole at a dose of 400 mg twice a day) *	FROM_max phenytoin ↑ 67% AUC_τ fenitopna ↑ 81% In comparison with voriconazole 200 mg twice a day, FROM_max voriconazole ↑ 34% AUC_τ 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 with a zebra less than 40 kg from 100 mg to 200 mg orally twice a day day).
Anticoagulants		If the patient receiving preparations of coumarin, appoint voriconazole. it is necessary to monitor the prothrombin time with short intervals and appropriately select doses of anticoagulants.
Warfarin (30 mg once with voriconazole 300 mg twice daily) [substrate of proenzyme CYP2C9]	The increase in the maximum prothrombin time was approximately two-fold.
Other oral anticoagulants, for example, fenprocumone, acenocoumarol [substrates of proenzymes CYP2C9 and CYP3A4]	It is assumed that voriconazole can increase plasma concentrations of coumarins, which can lead to an increase in pro thrombin time.
Benzodiazepines (e.g., midazolam, triazolam, alprazolam) [Pro-enzyme substrates 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 Benzodiazepines.
Immunosuppressants [isoenzymatic substrates CYP3A4]
Sirolimus (2 mg once)	According to an independent study: FROM_max sirolimus ↑ 6,6 times AUC_0-∞ sirolimus ↑ 11 times	The simultaneous use of voriconazole and sirolimus is contraindicated.
Cyclosporin (in patients who have undergone kidney transplantation and are in stable state)	FROM_max cyclosporine ↑ 13% AUC_τ cyclosporine ↑ 70%	When voriconazole is prescribed to patients receiving ciclosporin, it is recommended to reduce the dose of cyclosporine by half and control 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)	FROM_max tacrolimus ↑ 117% AUC_τ tacrolimus ↑ 221%	When voriconazole is prescribed to 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 [isoenzymatic substrates CYP3A4]
Oxycodone (10 mg once)	According to an independent study: FROM_max oxycodone ↑ in 1,7 times AUC_0-∞ oxycodone ↑ 3,6 times	The possibility of reducing the dose of oxycodone and other long-acting describemetabolized by the CYP3A4 isoenzyme (eg, hydrocodone). 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]	FROM_max R-methadone (active metabolite) ↑ 31% AUC_τ R-methadone (active metabolite) ↑ 47% FROM_max S-methadone ↑ 65% AUC_τ S-methadone ↑103%	An increase in the concentration of methadone in the blood plasma leads to the appearance of toxic effects, including the prolongation of the QT interval. It is recommended that the patient be monitored frequently for the development of unwanted reactions and toxicity (including prolongation of the QT interval) associated with methadone. You may need to reduce the dose of methadone.
Nonsteroidal anti-inflammatory drugs (HBPP) [isoenzymatic substrates CYP2C9]		Patients should be observed to identify possible toxic effects and, if necessary, adjust the dose of NSAIDs.
Ibuprofen (400 mg once)	FROM_max S-ibuprofen ↑ 20% AUC_0-∞ S-ibuprofen ↑ 100%
Diclofenac (50 mg once)	FROM_max diclofenac ↑ 114% AUC_0-∞ diclofenac ↑ 78%
Omeprazole (40 mg once daily) * [inhibitor of isoenzyme CYP2C19; isoenzyme substrate CYP2C19 and CYP3A4]	FROM_max omeprazole ↑ 116% AUC_τ omeprazole ↑ 280% FROM_max voriconazole ↑ 15% AUC_τ voriconazole ↑ 41%. Voriconazole can also inhibit the action of other inhibitors of the purine pump, which are substrates of the CYP2C19 isoenzyme.which can lead to an increase in the plasma concentrations of these drugsMr.funds.	Correction of the dose of voriconazole is not required. When you start taking voriconazole the patients already receiving omeprazole therapy at doses of 40 mg or above, a dose reduction of omeprazole is recommended in half.
Oral contraceptives * [isoenzymatic substrates CYP3A4; inhibitors of the isoenzyme CYP2S19] Norethisterone / ethinylestradiol (1 mg / 0.35 mg once daily)	FROM_max ethinylestradiol ↑ 36% AUC_τ ethinyl estradiol ↑ 61% FROM_max norethisterone ↑ 15% AUC_τ norethisterone ↑ 53% FROM_max voriconazole ↑ 14% AUC_τ 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 should be evaluated. fentanyl and other short-acting narcotic analgesics having a chemical structure similar to alfentanil and metabolized by the CYP3A4 isoenzyme (eg, sufentanil). Patients should be under constant supervision to prevent oppression of respiratory function 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: AUC_0-∞ alfentanil ↑ 6 times
Fentanyl (a single dose of 5 μg / kg)	According to an independent study: AUC_0-∞ fentanyl ↑ in 1,34 times
Statins (for example, lovastatin) [isoenzymatic substrates CYP3A4]	The interaction was not studied, however, voriconazole can increase plasma concentrations of statins that are metabolized by the CYP3A4 isoenzyme and can lead to rhabdomyolysis.	It should be assessed the possibility of reducing the dose of statins.
Derivatives sulfonylureas (for example, tolbutamide, glipizide, glibenclamide) [isoenzymatic substrates 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) [isoenzymatic substrates 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 isoenzyme substrates 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]	FROM_max voriconazole ↑ 18% AUC_τ voriconazole ↑ 23%	Dose correction is not required
Digoxin (0.25 mg once daily)	FROM_max digoxin ↔ AUC_τ digoxin ↔	Dose correction is not required
Indinavir (800 mg three times a day) [inhibitor and substrate of isoenzyme CYP3A4]	FROM_max indinavir ↔ AUC_τ indinavir ↔ FROM_max voriconazole ↔ AUC_τ voriconazole ↔	Dose correction is not required
Antibiotics of the macrolide group		Dose correction is not required
Erythromycin (1 g twice daily) [inhibitor of isoenzyme CYP3A4]	FROM_max and AUC_τ voriconazole ↔
Azithromycin (500 mg once daily)	FROM_max and AUC_τ , voriconazole ↔ The effect of voriconazole on the metabolism of erythromycin or azithromycin is unknown.
Mycophenolic acid (1 g once) [uridine-5'-diphosphate-glucuronyl transferase substrate]	FROM_max mycophenolic ACID ↔ AUC_τ mycophenolic acid ↔	Dose correction is not required
Prednisolone (60 mg once) [isoenzymatic substrate CYP3A4]	FROM_max prednisolone ↑11% AUC_0-∞ prednisolone ↑ 34%	Dose correction is not required
Ranitidine (150 mg twice daily) [increases the pH of gastric juice]	FROM_max and AUC_τ voriconazole	Dose correction is not required

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

* Mutual effect.

AUC_τ, AUC_t, AUC_0-∞ - 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 S. krusei, 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.

Isolated clinical strains of microorganisms, which have a reduced sensitivity to voriconazole. However, increased minimal inhibitory concentrations (MICs) do not always allow predicting clinical inefficiency: there are cases when voriconazole was effective in patients infected with microorganisms resistant to other azoles.

To evaluate the correlation between voriconazole activity under conditions in vitro and clinical treatment outcomes are difficult, given the complexity of patients who have been included in clinical trials.The borderline concentrations of voriconazole, which make it possible to assess the sensitivity to this drug, have not been established.

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, such as 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 of no more than 4 times, it was found that none of the subjects showed 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 clinically significant increase in the activity of "hepatic" 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.

When voriconazole was used, cases of severe hepatotoxicity (jaundice, hepatitis and hepatic-cell insufficiency 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.

In patients without any risk factors, transient reactions from the liver, including hepatitis and jaundice, are observed. 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 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 abolished, unless the ratio of the benefits and risks of therapy according to medical evaluation does not justify its continued use.

Visual disorders

In the treatment with voriconazole, approximately 21% of patients experience 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 paracoccidioidosis did not have 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 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, it is recommended that patients (including children) avoid exposure to direct sunlight and take protective measures such as wearing clothes and using 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 with a view to 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

The efficacy and safety of voriconazole in children under 2 years of age have not been studied. Voriconazole is indicated for use in children aged 2 years and older with continuous monitoring of liver function. Children had a higher frequency of hepatic enzyme activity than in adults.

Bioavailability of voriconazole for oral administration in children aged 2 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 skin aging, 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 simultaneously administered with voriconazole is increased 4-fold, careful monitoring of undesirable phenomena associated with the use of narcotic analgesics, including longer monitoring of respiratory function, is necessary.

Long-acting narcotic analgesics (substrates of isoenzyme CYP3A4)

It should be possible to reduce the dose of oxycodone and other narcotic analgesics for a long timeThe actions that 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 (a powerful inducer of cytochrome P₄₅₀ 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, inducer of cytochrome P₄₅₀, inhibitor and substrate of isoenzyme 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 reduce the concentration of voriconazole in the 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 C_mOh and AUC_τ 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.

The sodium content

Each vial of the drug contains 217.6 mg of sodium, this must be taken into account when using the drug in patients who adhere to a diet with a reduced sodium content.

Reactions, associated with the introduction

When intravenously administered voriconazole, there are infusions associated with infusion, in particular, "tides" of blood to the skin of the face and nausea. If these symptoms are expressed, then the expediency of stopping treatment should be discussed (see the "Side effect" section).

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, driving or using complex equipment. When taking voriconazole, patients should not drive the car at night.

Form release / dosage:

Powder for suspension for oral administration, 40 mg / ml.

Packaging:

45 g of powder into a 100 ml high-density polyethylene bottle capped with a polypropylene lid with a low density polyethylene liner with protection from children and controlled by the first opening.

1 bottle with a 5 ml syringe, adapter, measuring cup for 23 ml and instructions for use in a cardboard box.

Storage conditions:

Powder - at a temperature of 2 to 8 ° C.

Finished suspension - at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:

Powder - 2 years.

Finished suspension - no more than 14 days.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002080

Date of registration:28.05.2013 / 05.05.2015

Expiration Date:28.05.2018

The owner of the registration certificate: Pfizer Inc. Pfizer Inc. USA

Manufacturer: & nbsp

Fareva Amboise France

Representation: & nbspPfizer H. Si. Pi. CorporationPfizer H. Si. Pi. Corporation

Information update date: & nbsp16.03.2017

Illustrated instructions

Instructions

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