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

Excipients: lactose monohydrate 62,50 mg / 250,00 mg, pregelatinized starch 21.00 mg / 84.00 mg, croscarmellose sodium 7.50 mg / 30.00 mg, povidone 7.50 mg / 30.00 mg, magnesium sttarate 1.50 mg / 6.00 mg;

film sheath: opadrai white OY-LS-28914 (gigromellose, titanium dioxide, lactose monohydrate, triacetin) 3.75 mg / 15.00 mg.

Description:

Dosage 50 mg: round biconvex tablets, covered with a film shell, white or almost white, with engraving "VORSO" on one side and "Pfizer" - on the other side.

Dosage of 200 mg: oblong biconvex tablets, covered with a film shell, white or almost white, with engraving "VOR200" on one side and "Pfizer" - on the other side.

The core of the tablets on the cross-section is white or almost white in color.

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 methylation of 14α-sterol mediated via fungal cytochrome P₄₅₀, which is a key stage in the biosynthesis of ergostrotal. Accumulation 14α-methylsterol correlate the subsequent loss of ergosterol in fungal cell membranes, which causes the antifungal activity of voriconazole. It was found that voriconazole more selective for cytochrome isoenzymes R₄₅₀ 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 with respect to 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. lerreus, A. niger, A. nidulans, Candida spp.. including FROM. albicans, FROM. glabrata, FROM. krusei, FROM. parapsilosis and FROM. tropicalis, as well as with a limited number of strains FROM. dubliniensis, FROM. inconspicua, and 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 capital us. Cladosporium spp., Coccidioides immitis, FROMonidiobolus 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., Cladophialopliora spp.. Hisloplasma 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 characteristic

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 is observed (AUCτ). An increase in the oral dose from 200 mg twice a day to 300 mg twice a day leads to an increase AUC, on average 2.5 times. The effect of voriconazole when administered at a maintenance dose of 200 mg (or 100 mg for patients with a body weight of less than 40 kg) corresponds to the effect of voriconazole when administered intravenously at 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 taking saturating doses of voriconazole, the equilibrium concentration is reached within the first 24 hours. If the drug is prescribed 2 times a day in medium (but not in saturating) doses, then voriconazole is cumulated. and equilibrium concentrations are reached by the 6th day in most patients.

Suction and distribution

Voriconazole quickly and almost completely absorbed after oral administration: the maximum concentration in the blood plasma (C_m_Oh) 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 C_m_Oh and AUCτ 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 about 4.6 l / kg, indicating the active distribution of voriconazole in the tissue. Binding to plasma proteins is 58%. Voriconazole penetrates the blood-brain barrier (BBB) and is defined in cerebrospinal fluid.

Metabolism

According to research data in vitro voriconazole is metabolized by isofermpts CYP2C19, CYP2C9, CYP3A4. Important role in the metabolism of voriconazole is isoenzyme CYP2C19, showing a pronounced genetic polymorphism, in connection with which 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 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,nery or intravenously, about 83% and 80% of the dose of the drug are detected in urine, respectively.Most (> 94%) of the total dose is excreted within the first 96 hours after ingestion and intravenously.

The half-life (T_1/2) voriconazole depends on the dose and is approximately 6 hours when taking the drug vagrone in a dose of 200 mg. In connection with the nonlinearity of pharmacokinetics, the quantity T_1/2 does not allow to predict the cumulation or excretion of voriconazole.

Pharmacokinetics in special groups

Floor

With multiple administration of voriconazole inside C_m_Oh and AUCτ in healthy young women were 83% and 113%, respectively, higher than in healthy young men (18-45 years). Significant differences C_m_Oh and AUCτ in healthy elderly men and healthy elderly women (≥ 65 years) no. The equilibrium concentration of voriconazole in blood plasma in women was 100% higher than that of men. 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 in the form of tablets inside C_m_Oh and AUCτ in healthy elderly men (≥ 65 years old) by 61% and 86%, respectively, higher than in healthy young men (18-45 years). Significant differences C_m_Oh and AUCτ in healthy elderly women (≥ 65 years old) 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 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. 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 admission in children.

Violation of the function of the nights

With a single admission of voriconazole inside at a dose of 200 mg by patients with normal renal function and patients with impaired renal function from mild (creatinine clearance (KK) -41-60 ml / min) to severe (KK <20 ml / min), the degree of pharmacokinetics of voriconazole is not significantly affected by the degree of renal impairment. 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 intake of the drug in a dose of 200 mg AUCτ voriconazole in patients with mild or moderate severity of liver cirrhosis (classes A and B according to the Child-Pugh 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 AUCτ voriconazole is comparable in patients with cirrhotic liver of moderate severity (Child-Pugh class B) who received the drug at a maintenance dose of 100 mg 2 times / su g, and in patients with normal liver function receiving voriconazole in a dose of 200 mg twice a day.There is no information about the pharmacokinics of voriconazole in patients with severe liver cirrhosis (Class C but Child-Pugh classification). For recommendations on how to dose the drug, see "Method of administration and dose".

Indications:

Invasive aspergillosis.

Candidemia in patients without neutropenia.

Severe invasive candidiasis infections (including C. 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) of high-risk groups, such as recipients of hematopoietic stem cell transplantation.

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 (see the section "Interaction with other drugs"): substrates isoenzyme CYP3A4 - 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 inducer of cytochrome R₄₅₀ and P-glycoprotein).

The drug Vfend® is contraindicated in children under 3 years of age (for this dosage form).

Contraindicated in patients with lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

Carefully:

Hypersensitivity to other drugs - derivatives of azoles.

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

Voriconazole should be used with caution in patients with proarrhythmic conditions: congenital or acquiredincreased QT interval, cardiomyoathy, especially with heart failure, sinus bradycardia, the presence of symptomatic arrhythmia, simultaneous reception of drugs that cause prolongation of the QT interval.

Care should also be taken when using Vfend 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 Do not use in pregnant women, except in those cases where 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. 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 beginning of therapy it is necessary to correct such electrolyte disturbances as hypocalysis, hypomagnesemia and hypocalcemia (see also the "Side effect" section).

Adult patients

Appointment 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 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 Vfend®:

	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, such as recipients of hematopoietic stem cell transplantation / prevention of breakthrough fungal infections in febrile patients	3-4 mg / kg every 12 h	200 mg every 12 hours	100 mg every 12 h
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	3-4 mg / kg every 12 hours	200 mg every 12 hours	100 mg every 12 hours
Candidiasis of the esophagus	Not installed	200 mg every 12 hours	100 mg 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 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 (ie, 300 mg orally 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 possible only in case of continuation of immunosuppressive therapy or 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 well as with the purpose of 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 increased activity of "liver" transaminases: alanine aminotransfsrazy (ALT) and aspartate aminotransferase (ACT), correction of the dose is not required, but it is recommended to continue monitoring the indicators of liver function.

Patients with mild or moderate hepatic impairment (class A and B according to Child-Pugh classification) should be given a standard saturating dose of Vfend®, and the maintenance dose should be reduced by a factor of 2.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 elderly patients are 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)

X mg / kg 2 times per 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 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.

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 the Vfend® preparation in powder form for the preparation of oral suspension and tablets when used in children has not been studied. Given that the children are slowed through the passage of the stomach through the gastrointestinal tract, it is likely that the absorption of voriconazole when taken in the form of tablets 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, from 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 neoplasms of blood, HIV-infected patients with esophageal candidiasis and refractory fungal infections, patients without neutropenia with candidemia or aspergillosis, and also 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 ileal 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%, the frequency is unknown - it is impossible to determine the frequency based on the available data.

Disorders from the heart: often - supraventricular arrhythmia, tachycardia, bradycardia; infrequently - ventricular fibrillation, ventricular extrasystole, ventricular tachycardia, supraventricular tachycardia; rarely - arrhythmia of the type "pirouette", complete atrioventricular block, blockade of the bundle of the bundle, node arrhythmias.

Vascular disorders: often - arterial hypotension, phlebitis; infrequently - thrombophlebitis.

Disturbances from 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.

Disorders from the nervous system: very 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, Hyenna-Barre syndrome.

Disorders from the side of the organ of vision: very 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 from the organ of hearing and vestibular apparatus: infrequently - vertigo, hypoacusia, tinnitus.

Disturbances from the respiratory system, chest and mediastinal organs: very often -respiratory depression; often - pulmonary edema, acute respiratory distress syndrome.

Disorders from the gastrointestinal tract: very 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 renal tubules, proteinuria, nephritis.

Disturbances from the skin and subcutaneous tissues: very often - rash; often - exfoliative dermatitis, alopecia, itching, maculopapular rash, erythema; infrequently - Stevens-Johnson syndrome, photosensitivity, urticaria, eczema, toxic epidermal necrolysis, angioedema, erythema multimorph, psoriasis, allergic dermatitis, purpura, papular rash, macular rash; rarely - pseudoporphyria, persistent drug erythema;frequency unknown - cutaneous systemic lupus erythematosus.

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

General disorders and disorders at the injection site: 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.

Immune system disorders: infrequently - allergic reactions; rarely anaphylactoid reactions.

Infringements from 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, gillerbilirubinemia); often - jaundice, cholestatic jaundice, hepatitis; infrequently - cholecystitis, cholelithiasis, liver enlargement, liver failure.

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

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

Research: often - Increase in the concentration of creatinine in the blood; infrequently - interval lengthening 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 used in 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 excreted during 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 P450 isoenzymes (CYP2C19, CYP2C9 and CYP3A4) can cause, respectively, an increase or decrease in the concentration of voriconazole in the blood plasma.

Voriconazole inhibits cytochrome P isoferment activity₄₅₀ - 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:

Medicinal affinity (mechanism of interaction)

Interaction: changes in pharmacokinetic parameters (%)

Recommendations for simultaneous application

Astemizole, cisapride, pimozide, quinidine and terfenadine [isoenzyme substrates CYP3A4]

Interactions have not been studied, but there is a high probability that elevated 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 cytochrome P inducers₄₅₀]

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

Contraindicated

Medicine

(the mechanism of interaction)

Interaction: change

pharmacokinetic

parameters (%)

Recommendations for

simultaneous application

Efavirenz (non-nucleoside

reverse inhibitor

transcriptase)

[inducer of cytochrome P450;

inhibitor and substrate

isoenzymes CYP3A4]

Simultaneous application

efavirenz 400 mg once

per day and voriconazole in a dose of 200

mg twice a day *

Simultaneous application of 300

mg of efavirenz once a day and

voriconazole 400 mg twice daily

day)

Cmax efavirenz ↑ 38%

AUCτ efavirenz ↑ 44%

Cmax voriconazole ↓ 61%

AUCτ voriconazole ↓ 77%

In comparison with efavirenz

600 mg once a day:

Cmax efavirenz ↔

AUCτ efavirenz ↑ 17%

In comparison with voriconazole

200 mg twice daily:

Cmax voriconazole ↑ 23%

AUCτ voriconazole ↓ 7%

The use of standard doses

voriconazole and efavirenz in

a dose of 400 mg once a day

it is contraindicated.

Simultaneous application

perhaps if

maintenance dose

voriconazole will be

increased to 400 mg twice

per day, and the dose of efavirenz

reduced to 300 mg once in

day. With cancellation of therapy

with voriconazole.

The dose of efavirenz should be

restored.

Ergot alkaloids (for example,

ergotamine and dihydroergotamine)

[isoenzymatic substrates

CYP3A4]

Interaction of voriconazole with

alkaloids of ergot

(ergotamine and

digindroergotamine) is not

studied, but there is

high probability, h

voriconazole may cause

concentration increase

of these preparations to plasma blood and lead to ergotism.

Contraindicated

Rifabutin

[powerful cytochrome inducer

P450]

300 mg once daily

300 mg once a day (with

simultaneous application with

voriconazole 400 mg twice daily day)*

Cmax voriconazole ↓ 69%

AUCτ voriconazole ↓ 78%

Cmax rifabutin ↑ 195%

AUCτ rifabutin ↑ 331%

In comparison with voriconazole

200 mg twice daily:

Cmax voriconazole ↑ 104%

AUCτ voriconazole ↑ 87%

Contraindicated

Rifampicin (600 mg once every

day)

[powerful cytochrome inducer

P450]

Cmax voriconazole ↓ 93%

AUCτ voriconazole ↓ 96%

Contraindicated

Ritonavir (protease inhibitor)

[powerful cytochrome inducer

P450; inhibitor and substrate of the isoenzyme CYP3A4]

High doses (400 mg twice a day

day)

Low doses (100 mg twice a day

day)*

Cmax and AUCτ of ritonavir ↔

Cmax voriconazole ↓ 66%

AUCτ voriconazole ↓ 82%

Cmax of ritonavir ↓ 25%

AUCτ of ritonavir ↓ 13%

Cmax voriconazole ↓ 24%

AUCτ voriconazole ↓ 39%

Simultaneous application

voriconazole and high doses

ritonavir (400 mg and higher

twice a day)

it is contraindicated.

Apply simultaneously

voriconazole and ritonavrinv

low doses (100 mg 2 times in

day) follows only in that

If the expected The benefits of taking voriconazole significantly exceed the risk of their combined use.

St. John's wort perforated [cytochrome P450 inducer and P-glycoprotein]

300 mg three times a day (simultaneous application with a single dose of voriconazole 400 mg)

According to an independent study:

AUC0-∞ voriconazole ↓ 59%

Contraindicated

Everolimus

[a substrate of the isoenzyme 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, CYP2C19 and CYP3A4]

Cmax voriconazole ↑ 57%

AUCτ voriconazole ↑ 74% No changes in Cmax and AUCτ of fluconazole

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

Phenytoin

[substrate of isoenzyme CYP2C9

and a powerful cytochrome inducer

P450]

300 mg once daily

(simultaneous use with

voriconazole at a dose of 400 mg two

times a day) *

Cmax voriconazole ↑ 49%

AUCτ voriconazole ↑ 69%

Cmax phenytoin ↑ 67%

AUCτ of phenytoin ↑ 81%

In comparison with voriconazole

200 mg twice daily,

Cmax voriconazole ↑ 34%

AUCt of voriconazole ↑ 39%

Avoid

simultaneous reception

voriconazole and phenytoin, for

except when

benefit for the patient

exceeds the risk.

Recommended

controlled, plasma

concentration of phenytoin.

Simultaneous application

is possible only in the case,

if the maintenance dose

voriconazole will be

increased to 5 mg / kg

intravenously or with 200 mg to

400 mg orally twice a day

day (in patients with weight

body less than 40 kg with 100 mg to

200 mg orally twice a day

day).

Anticoagulant

Warfarin (30 mg once

concomitantly with voriconazole

300 mg twice daily)

[isoenzymatic substrate

CYP2C9]

Increase the maximum

prothrombin time was

approximately twice.

If the patient receiving

preparations of coumarin.

appoint voriconazole.

necessary with short

intervals

prothrombin time and

Other oral

anticoagulants, for example,

fenprokumone, acenocoumarol

[substrates of isoenzymes

CYP2C9 and CYP3A4]

Benzodiazepines (e.g.,

midazolam, triazolam,

alprazolam)

[isoenzymatic substrates

CYP3A4]

It is suggested that voriconazole

can increase plasma

concentration of kumarnns that

may lead to an increase

prothrombin time.

1n vitro voriconazole can

cause an increase

plasma concentrations

benzodiazepines, which

metabolized under

isoenzyme

CYP3A4, and cause development

prolonged sedation

effect.

accordingly

titrate

anticoagulants.

It is recommended that

expediency of correction

doses of benzodiazepines.

Immunosuppressants

[isoenzymatic substrates

CYP3A4]

Sirolimus (2 mg once)

Cyclosporine (in patients,

after transplantation

kidney and being in

stable state)

According to independent

Research:

Cmax sirolimus ↑ 6,6 times

AUC0-∞ sirolimus ↑ 11 times

Cmax cyclosporine ↑ 13%

AUCτ cyclosporine ↑ 70%

Simultaneous application

voriconazole and sirolimus

it is contraindicated.

When appointing

voriconazole patients,

receiving ciclosporin,

it is recommended that

The dose of cyclosporine is doubled and

control it

concentration in

blood plasma. Increase

concentrations of cyclosporine

is accompanied by nephrotoxicity. After voriconazole withdrawal, it is necessary to monitor the concentration of cyclosporine and, if necessary, increase the dose.

Tacrolimus (0.1 mg / kg

once)

Cmax tacrolimus ↑ 117%

AUCT tacrolimus ↑ 221%

When appointing

voriconazole patients,

receiving tacrolimus,

it is recommended that

the dose of the latter to one

third and control it

concentration in plasma

blood. Increase

concentration of tacrolimus

accompanied by

nephrotoxicity. After

withdrawal of voriconazole

need to monitor

concentration of tacrolimus and

if necessary

increase its dose.

Long-acting opiates

[isoenzymatic substrates

CYP3A4]

Oxycodone (10 mg once)

According to independent

Research:

Cmax oxycodone ↑ 1.7 times

AUC0-

∞ oxycodone ↑ 3.6 times

It should be assessed

possibility of dose reduction

oxycodone and other

long-term

opioids metabolized by

isoenzyme CYP3A4

(e.g., hydrocodone).

It may be necessary

monitoring the patient's condition

with short intervals at

subject of development

undesirable reactions

associated with opiates.

Methadone (32-100 mg once a day

day)

[isoenzymatic substrate

SUR FOR 4]

Cmax R-methadone (active

metabolite) ↑ 31%

AUCτ R-methadone (active

metabolite) ↑ 47%

Cmax S-methadone ↑ 65%

AUCτ S-methadone ↑ 103%

Increase in concentration

of methadone in blood plasma

leads to the manifestation

toxic effects.

including interval lengthening

FROM. Recommended frequent

monitoring of the patient's condition

for development

unwanted reactions and

toxicity (including,

elongation interval QT),

associated with methadone.

It may be necessary

reduction in the dose of methadone.

Non-steroidal

anti-inflammatory

preparations (IIVB)

[isoenzymatic substrates

CYP2C9]

Ibuprofen (400 mg once)

Diclofenac (50 mg once)

Cmax S-ibunrofen ↑ 20%

AUC0-∞ S-ibuprofepa ↑ 100%

Cmax of dlclofenac ↑ 114%

AUC0-

∞ diclofenac ↑ 78%

Patients should be observed with

the purpose of identifying possible

toxic effects and

need

adjust the dose of NSAIDs.

Omeprazole (40 mg once a day

day)*

[inhibitor of isoenzyme

CYP2C19; substratum

isoenzymes CYP2C19 and

CYP3A4]

Cmax of omeprazole ↑ 116%

AUCT of omeprazole ↑ 280%

Cmax voriconazole ↑ 15%

AUCτ voriconazole ↑ 41%

Voriconazole can also

oppress the action of others

proton pump injectors.

which are substrates

isoenzyme CYP2C19, which

can lead to an increase

plasma concentrations of these

medicines.

Correction of dose

voriconazole is not required.

At the beginning of admission

voriconazole patients.

already receiving therapy

omeprazole in doses of 40 mg

or higher, it is recommended

reduction in the dose of omeprazole in

twice.

Oral contraceptives *

[isoenzymatic substrates

CYPZA4; inhibitors

isoenzyme CYP2C19]

Norethisterone / ethinylestradiol

(1 mg / 0.35 mg once daily)

Cmax ethinylestradiol ↑ 36%

AUCτ ethinylestradiol ↑ 61%

Cmax of norethisterone ↑ 15%

AUCτ of norethisterone ↑ 53%

Cmax voriconazole ↑ 14%

AUCτ voriconazole ↑ 46%

Control is recommended

patient's condition at

subject of development

undesirable reactions.

related to the application

oral contraceptives

and voriconazole.

Narcotic analgesics

short-acting [substrates

isoenzyme C YP3A4]

Alfentanil (a single dose of 20

mkg / kg with simultaneous

application of naloxone)

Fentanyl (single dose

5 μg / kg)

According to independent

Research:

AUC0-∞ of alfentanil ↑ 6 times

According to independent

Research:

AUC0-∞ fentanyl ↑ 1.34 times

It should be assessed

possibility of dose reduction

alfentanil, fentanyl and

other narcotic drugs

analgesics short

actions that are similar to

alfentanil chemical

structure and

metabolized

isoenzyme CYP3A4

(e.g. sufentanil).

Patients should

be under constant observation 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.

Statins (for example, lovastatin) [substrates of the isoenzyme 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, glinizide, glibenclamide)

[substrates of the 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 of the 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 nelfipavir) * [inhibitors and substrates of the isoenzyme C YP3A4]

In vitro studies indicate 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 insufficiency 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 substrates of the isoenzyme CYP3A4]

In vitro studies have shown that the metabolism of voriconazole can 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 gastric juice]

Cmax voriconazole ↑ 18% AUCτ voriconazole ↑ 23%

Dose correction is not required

Digoxin (0.25 mg once daily)

[P-glycoprotein substrate]

Cmax digoxin ↔

AUCτ digoxin ↔

Dose correction is not required

Indinavir (800 mg three times a day)

[inhibitor and substrate of the isoenzyme CYP3A4]

Cmax indinavir↔

AUCT of indinavir ↔

Cmax voriconazole ↔

AUCτ Voriconazole ↔

Dose correction is not required

Antibiotics of the macrolide group

Erythromycin (1 g twice daily)

[inhibitor of isoenzyme CYP3A4]

Azithromycin (500 mg once daily)

Cmax and AUCτ of voriconazole ↔

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

Dose correction is not required

Mycophenolic acid (1 g once)

[uridine-5 '-diphosphate-glucuronyltransferase substrate]

FROMmax mycophenolic acid ↔

AUCt mycophenolic acid ↔

Dose correction is not required

Prednisolone (60 mg once) [isoenzymatic substrate CYP3A4]

FROMmax prednisolone ↑ 11% AUC_0- _∞prednisolone ↑ 34%

Dose adjustments will be required

Ranitidine (150 mg twice daily)

[increases the pH of gastric juice]

FROMmax and AUCτ 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 (↓) of the interval

80 % - 125 %.

* Mutual effect.

AUCτ, AUCt, 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 species that most often cause infection in humans include S. albicans, C. parapsilosis, C.tropicalis, C. glabrata and C. krusei, while for all of them the minimal suppressive concentration (MIC) of voriconazole is usually less than 1 mg / ml.

However, in vitro, the activity of voriconazole against fungi of different species of Candida is not the same. In particular, the MIC of voriconazole for fluconazole-resistant isolates of S. glabrata is proportionally higher than the MIC for fluconazole-sensitive isolates. In this regard, fungi of the genus Candida should be identified in all possible cases to the species level. If it is possible to determine the sensitivity of fungi to antifungal agents, the values of the MIC should be interpreted using threshold criteria.

Undesirable effects from the cardiovascular system.

The use of voriconazole is associated with the prolongation of the QT interval on an electrocardiogram, which is accompanied by rare cases of fibrillation / flutter of the ventricles in seriously 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 of the QT interval;

- cardiomyopathy, especially in combination with heart failure;

- sinus bradycardia;

- existing arrhythmias with clinical manifestations;

- simultaneous use of drugs that extend the QT interval (see the 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.

In a study on healthy volunteers of the effect of voriconazole on the QT interval on the ECG when single doses were used,exceeding the usual daily dose by no more than 4 times, it was found that none of the subjects observed an increase in the QT interval by 60 or more ms 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 liver-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 both children and adults. Clinical management of such patients should include a laboratory assessment of liver function (in particular, ACT and ALT activity) 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 the laboratory examination 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 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 from 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, transplantation hematopoietic stem cells) should be screened (determination of the activity of amylase and lipase in the blood serum) to address the issue of therapy with voriconazole.

Undesirable skin side 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, photosensitization may develop, during treatment, patients (including children) are advised to avoid exposure to direct sunlight and take protective measures such as wearing clothing and using sunscreens with a high protection factor from ultraviolet radiation (SPF).

Long-term treatment

In patients with skin photosensitivity reactions and additional risk factors are reported about development of squamous cell carcinoma of skin and melanoma on the background of prolonged therapy. When the patient phototoxic reactions, he should be consulted by appropriate specialists and sent to a dermatologist. Voriconazole should be considered. With continued 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, who receive 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 constant 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, it is recommended to avoid the sun and be examined by a dermatologist even after discontinuation of treatment.

Narcotic analgesics of short action (substrates of isoenzyme CYP3A4). Because the the half-life of alfentanil with its simultaneous application with voriconazole increases 4-fold, careful monitoring of undesirable phenomena associated with the use narcotic analgesics, including more

continuous monitoring of respiratory function.

Narcotic drugs analgesics long-acting (substrates of 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 carry out careful monitoring of undesirable phenomena,related to the use of narcotic analgesics (see section "Interaction with other drugs").

Phenytoin (powerful inductor cytochrome P₄₅₀and 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 cytochrome P450, inhibitor and substrate 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 reduces the concentration of voriconazole in blood plasma.

Ritonavir (a powerful inducer of isochrome R₄₅₀, 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 of taking voriconazole significantly exceeds the risk of their combined use (see the sections "Contraindications" and "Interactions with other drugs").

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 inwards in healthy volunteers leads to a significant increase FROM_m_Oh 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.

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, a disruption / enhancement 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:

Tablets, film-coated 50 mg and 200 mg.

Packaging:

2, 7 or 10 tablets in a blister of polyvinyl chloride and aluminum foil 1 blister for 2, 7 or 10 tablets; 2, 4 or 8 blisters for 7 tablets;

3, 5 or 10 blisters of 10 tablets in a cardboard box, along with instructions for use.

Storage conditions:

Store at temperatures not higher than 30 ° C. Keep out of the reach of children.

Shelf life:

3 years. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N015540 / 01

Date of registration:10.04.2009 / 05.05.2015

Expiration Date:Unlimited

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

Manufacturer: & nbsp

PFIZER MANUFACTURING DEUTSCHLAND, GmbH Germany

PFIZER ITALIA, S.r.L. Italy

Representation: & nbspPfizer LtdPfizer LtdUSA

Information update date: & nbsp28.02.2017

Illustrated instructions

Instructions

Vfend® (Vifend®)