Vikand - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate 35.2 mg / 140.8 mg, silicon colloidal dioxide (aerosil) 3.6 mg / 14.4 mg, microcrystalline cellulose 33.0 mg / 132.0 mg, corn starch 27.0 mg / 108.0 mg, povidone 4.4 mg / 17.6 mg, macrogol 6000 (polyethylene glycol 6000) 8.8 mg / 35.2 mg, crospovidone 12.6 mg / 50.4 mg, talc 3.6 mg / 14.4 mg , magnesium stearate 1.8 mg / 7.2 mg;

excipients for the shell: giprolose (hydroxypropylcellulose) 3.3 mg / 13.2 mg, macrogol 6000 (polyethylene glycol 6000) 0.7 mg / 2.8 mg, titanium dioxide 1.0 mg / 4.0 mg.

Description:

Dosage of 50 mg. Round biconvex tablets covered with a film coat of white or almost white color. On the cross section, the nucleus is white or almost white in color.

Dosage of 200 mg. Oblong biconvex tablets with rounded ends, covered with a film coat of white or almost white, with a risk. On the cross section, the nucleus 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 demethylation of 14α-sterol mediated via fungal cytochrome R₄₅₀, which is a key stage in the biosynthesis of ergosterol. Accumulation of 14a-methylsterol correlates with 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.

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, C. glabrata, S. krusei, C. parapsilosis and C. tropicalis, as well as for a limited number of strains S. dubliniensis, S. 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. mameffei, Phialophora richardsiae, Scopulariopsis brevicaulis and Trichosporon spp., including T. beigelii.

Voriconazole activity was demonstrated in vitro in relation to clinical strains Acremonium spp., Alternaria spp., Bipolaris spp., Cladophialophora spp., Histoplasma 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., but the clinical significance of this effect is unknown.

Pharmacokinetics:

general characteristics

Pharmacokinetic parameters of voriconazole are characterized by significant interindividual variability.

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

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 sixth day in most patients.

Suction and distribution

Voriconazole quickly and almost completely absorbed after oral administration: the maximum concentration in the blood plasma (C_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 C_max and AUC_τ 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, 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 in vitro studies 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 inside or intravenous injection in urine, about 83 % and 80 % of the dose, 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_1/2 does not allow to predict the cumulation or excretion of voriconazole. Pharmacokinetics in special groups

Floor

With multiple administration of voriconazole inside C_max and AUC_τ in healthy young women were 83% and 113%, respectively, higher than in healthy young men (18-45 years).Significant differences C_max and AUC_τ in healthy elderly men and healthy elderly women (≥65 years) do not. The equilibrium concentration of voriconazole in blood plasma in women was 100% higher than that of men. There is no need 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_max and AUC_τ in healthy elderly men (≥65 years) by 61% and 86%, respectively, higher than in healthy young men (18-45 years). Significant differences C_max and AUC_τ in healthy elderly women (≥65 years of age) and healthy young women (18-45 years) do not.

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

Children

The estimated total concentration of voriconazole in children with oral administration of a maintenance dose of 9 mg / kg (maximum 350 mg) twice a day is comparable to that of adults 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 in thisage, and in this case intravenous administration may be indicated.

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

Impaired renal function

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

Impaired liver function

After a single intake of the drug in a dose of 200 mg AUC_τ voriconazole in patients with mild or moderate severity of liver function disorder (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 the AUC_τ voriconazole is comparable in patients with moderate hepatic cirrhosis (Child-Pugh class B) who received the drug at a maintenance dose of 100 mg twice daily 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:

Invasive aspergillosis.
Candidemia in patients without neutropenia.
Severe invasive candidiasis infections (including S. 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:

Hypersensitivity to voriconazole or any other component of the drug.
Simultaneous use with the following drugs: isoenzymatic substrates 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 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 cytochrome P inducer₄₅₀ and P-glycoprotein) (see section "Interaction with other drugs").
Children under 3 years.
Deficiency of lactase, 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 acquired increase in the OT interval, cardiomyopathy, especially with heart failure, sinus bradycardia, the presence of symptomatic arrhythmia, simultaneous use of drugs that elongate the interval QT.
Care should also be taken when using voriconazole in patients with electrolyte disorders, such as: hypokalemia, hypomagnesemia and hypocalcemia.

Pregnancy and lactation:

There is no sufficient information about the use of voriconazole in pregnant women.

In animal studies, it has been established that the drug has a toxic effect on reproductive function. The possible risk to man is unknown. Voriconazole should not be used in pregnant women, 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. For the duration of the drug, breastfeeding should be discontinued.

Women of reproductive age should use reliable contraceptive methods when using the drug.

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

Therapy should begin with the intravenous introduction of voriconazole in 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 voriconazole in oral administration, 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 adjustment.

The table provides detailed information on the dosage of voriconazole:

	Intravenously	Inside
		Patients with a body weight of 40 kg and more	Patients weighing less than 40 mg
Saturated dose - all indications (first 24 h)	6 mg / kg every 12 hours
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 hours	200 mg every 12 hours		100 mg every 12 hours
Invasive aspergillosis / infections caused by Scedosporium spp. and Fusarium spp. / other severe invasive fungal infections.	4 mg / kg every 12 hours	200 mg every 12 hours		100 mg every 12 hours
Candidemia in patients without neutropenia	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, the maintenance dose of voriconazole 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 depends on the clinical effect and the results of laboratory studies.

Impaired renal function

Correction of the dose of voriconazole for oral administration in patients with mild or severe renal dysfunction 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, but it is recommended to continue monitoring liver function.

Patients with mild or moderate hepatic impairment (Child-Pugh class A and B classes) should be prescribed a standard saturating dose of voriconazole, and the maintenance dose should be reduced by a factor of 2. Patients with severe hepatic impairment (Child-Pugh class C) should be prescribed voriconazole only in those cases when the expected benefit exceeds the possible risk, and under constant monitoring to identify 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 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 voriconazole, and the possibility of oral administration of the drug should be considered only after the clinical improvement and the patient's ability to take oral medications.

It should be taken into account that the effect of 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. If the child can swallow the pill, then the dose is rounded to the nearest dose in mg / kg, a multiple of 50 mg, and is given as whole tablets, i.e. tablets can not be divided. 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 voriconazole in the form of a powder for the preparation of a suspension for ingestion and tablets when used in children has not been studied. Given that children have slowed down the passage of food through the gastrointestinal tract, it is likely that the absorption of voriconazole when taken in the form of tablets will be different than in adults.

The use of voriconazole in children aged 3 to 12 years with impaired liver or kidney function has not been studied.

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

Correction of dose

In case of inadequate clinical response of the patient, the dose may be increased in steps of 1 mg / kg (or 50 mg if a maximum dose of 350 mg was initially administered).

Side effects:

The data on the safety of voriconazole are based on the results of a study of more than 2000 people 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 healthy volunteers). In addition, the safety of voriconazole has been studied in studies involving patients receiving voriconazole treatment for prophylactic purposes. The profile of the side effect of voriconazole in these studies was the same as in the 2000 study.

The following are undesirable events that were observed with the use of voriconazole and, possibly, were associated with treatment. The most common adverse reactions are visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, peripheral edema and abdominal pain. 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 assessment: very frequent (≥ 10%), frequent (≥1% and <10%), infrequent (≥ 0,1 % and <1%), rare (≥ 0.01% and <OD%), very rare (<0.01%).

Laboratory indicators: frequent - a violation of liver function (including increased activity ACT, ALT, alkaline phosphatase, gammaglutamintransferase, lactate dehydrogenase, bilirubin concentration), increased creatinine concentration in the blood plasma; infrequent - increasing residual urea nitrogen, hypercholesterolemia.

From the cardiovascular system: very frequent - peripheral edema; frequent - lowering blood pressure, thrombophlebitis, phlebitis; infrequent - ventricular fibrillation, ventricular arrhythmia, syncope, atrial arrhythmia, supraventricular arrhythmia, supraventricular tachycardia, bradycardia, tachycardia, lengthening of the interval QT; rare - ventricular tachycardia of the "pirouette" type; complete atrioventricular block, blockade of the bundle branch, nodular arrhythmias, lymphangitis.

From the hemopoietic system and lymphatic system: frequent - pancytopenia, thrombocytopenia, leukopenia, purpura, anemia (including macrocytic, microcytic, normocytic, megaloblastic, aplastic), bone marrow depression; infrequent - a syndrome of disseminated intravascular coagulation, lymphadenopathy, agranulocytosis, eosinophilia.

From the nervous system: very frequent - headache; frequent - dizziness, confusion, agitation, tremor, paresthesia; infrequent - cerebral edema, ataxia, diplopia, vertigo, hypoesthesia; rare - convulsions, encephalopathy, Hyenna-Barre syndrome, extrapyramidal disorders, drowsiness during infusion, peripheral neuropathy.

From the side of the organ of vision: very frequent - visual disturbances (including impaired / increased visual perception, the appearance of "shrouds" before the eyes, change in color perception, photophobia); infrequent - edema of the nipple of the optic nerve, scleritis, blepharitis, optic neuritis, nystagmus; rare - hemorrhage in the retina of the eye, atrophy of the optic nerve, corneal opacity, oculogic crisis.

From the organ of hearing and the vestibular apparatus: infrequent - hypoacusia, tinnitus.

From the respiratory system, thoracic and mediastinal: frequent - respiratory distress syndrome, pulmonary edema, respiratory failure, chest pain.

From the gastrointestinal tract: very frequent - nausea, vomiting, diarrhea, abdominal pain; infrequent - constipation, duodenitis, indigestion, gingivitis, glossitis, pancreatitis, edema of the tongue, peritonitis; rare - a violation of taste perception.

From the genitourinary system: frequent - acute renal failure, hematuria; infrequent - albuminuria, nephritis; rare - necrosis of renal tubules.

From the skin and subcutaneous tissues: very frequent - rash; frequent - edema of the face, pruritus, maculopapular rash, macular rash, papular rash, photosensitivity, alopecia, exfoliative dermatitis, cheilitis, erythema; infrequent - Stevens-Johnson syndrome, angioedema, drug-induced erythema, eczema, psoriasis, urticaria; rare - discoid lupus erythematosus, erythema multiforme, toxic epidermal necrolysis, pseudoporphyria.

From the side of the musculoskeletal system and connective tissue: frequent - back pain; infrequent - arthritis; rare - hypertension.

From the endocrine system: infrequent - insufficiency of the adrenal cortex; rare - hyperthyroidism, hypothyroidism.

Metabolic and nutritional disorders: frequent - hypokalemia, hypoglycemia.

Infections and infestations: frequent - gastroenteritis, flu-like syndrome; rare - pseudomembranous colitis.

General and local reactions: very frequent fever; frequent - chills, asthenia.

From the immune system: frequent - sinusitis; infrequent - allergic reactions, anaphylactoid reactions.

From the hepatobiliary system: frequent - jaundice, cholestatic jaundice; infrequent - cholecystitis, cholelithiasis, liver enlargement, hepatitis, liver failure; rare - hepatic coma.

Mental disorders: frequent - hallucinations, depression, anxiety; rare - insomnia.

Side effect when applied the children

It was found that the undesirable effects with voriconazole in children aged 3 to 12 years are similar to those in adults. In the course of postmarketing studies, the development of pancreatitis in children with voriconazole therapy was revealed, as well as the more frequent occurrence of skin reactions.

If any of the unwanted reactions listed in the manual is aggravated, or you notice other unwanted reactions not listed in the instructions, report it the doctor.

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 isoenzymes R₄₅₀ (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 isoenzymes R₄₅₀ - 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 can lead toto lengthen the interval QTc and in rare cases, the occurrence of ventricular tachycardia as pirouette.	Contraindicated
Carbamazepine and long-acting barbiturates (for example, phenobarbital, mefobarbital) [powerful cytochrome P inducers₄₅₀]	Interaction has not been studied, however carbamazepine and long-acting barbiturates are likely to significantly reduce plasma concentrations of voriconazole.	Contraindicated
Efavirenz (non-nucleoside reverse transcriptase inhibitor) [inducer of cytochrome P₄₅₀; inhibitor and substrate isoenzymes CYP3A4]
High doses (400 mg once daily) *	FROM_m_Oh efavirenz ↑ 38% AUC_τ efavirenz ↑44% FROM_m_Oh voriconazole ↓ 61% AUC_τ voriconazole ↓77 %	Standard doses of voriconazole and efavirenz (400 mg once daily) are contraindicated
Low doses (with the simultaneous use of 300 mg efavirenz once a day and voriconazole 400 mg twice daily)	In comparison with efavirenz 600 mg once a day: FROM_m_Ohefavirenz ↔ AUC_τ efavirenz ↑ 17 % In comparison with voriconazole 200 mg twice a day: FROM_m_Oh voriconazole ↑ 23 % AUC_τ voriconazole ↓7 %	Simultaneous application is possible if the maintenance dose of voriconazole is increased to 400 mg twice a day, and the dose of efavirenz is reduced to 300 mg once a day.With the withdrawal of voriconazole therapy, the initial dose of efavirenz should be restored.
Ergot alkaloids (eg, ergotamine and dihydroergotamine) [isoenzymatic substrates CYP3A4]	The interaction of voriconazole with ergot alkaloids (ergotamine and dihydroergotamine) has not been studied, but there is a high probability that voriconazole can cause an increase in the concentrations of these drugs in the blood plasma and lead to ergotism.	Contraindicated
Rifabutin [powerful cytochrome inducer R₄₅₀] 300 mg once daily 300 mg once a day (with simultaneous application with voriconazole 400 mg twice daily) *	FROM_m_Ohvoriconazole ↓ 69 % AUC_Ʈ voriconazole ↓ 78 % FROM_m_Oh rifabutin # 195 % AUC_Ʈ rifabutin # 331 % In comparison with voriconazole 200 mg twice a day: FROM_m_Oh voriconazole # 104 % AUC_Ʈ voriconazole # 87 %	Contraindicated
Rifampicin (600 mg once daily) [powerful cytochrome inducer R _45o]	FROM_m_Ohvoriconazole ↓ 93 % AUC_Ʈ voriconazole ↓ 96 %	Contraindicated
Ritonavir (protease inhibitor) [powerful cytochrome inducer P₄₅₀ inhibitor and isoenzyme substrate CYP3A4] High doses (400 mg twice daily)	FROM_m_Oh and AUC_Ʈ ritonavir ↔ FROM_m_Oh voriconazole ↓ 66 % AUC_Ʈ voriconazole ↓ 82 %	Simultaneous use of voriconazole and high doses of ritonavir (400 mg and more twice a day) is contraindicated.
Low doses (100 mg twice daily) *	FROM_m_Oh ritonavir ↓ 25 % AUC_Ʈ ritonavir ↓13 % FROM_m_Oh voriconazole ↓ 24 % AUC_Ʈ voriconazole ↓ 39 %	Apply simultaneously voriconazole and ritonavir in low doses (100 mg twice a day) should be given only if the expected benefit from taking voriconazole significantly exceeds the risk of their combined use.
Rifabutin [powerful cytochrome inducer R₄₅₀] 300 mg once daily 300 mg once a day (with simultaneous application with voriconazole 400 mg twice daily) *	FROM_m_Ohvoriconazole ↓ 69 % AUC_Ʈ voriconazole ↓ 78 % FROM_m_Oh rifabutin # 195 % AUC_Ʈ rifabutin # 331 % In comparison with voriconazole 200 mg twice a day: FROM_m_Oh voriconazole # 104 % AUC_Ʈ voriconazole # 87 %	Contraindicated
Rifampicin (600 mg once daily) [powerful cytochrome inducer R _45o]	FROM_m_Ohvoriconazole ↓ 93 % AUC_Ʈ voriconazole ↓ 96 %	Contraindicated
Ritonavir (protease inhibitor) [powerful cytochrome inducer P₄₅₀ inhibitor and isoenzyme substrate CYP3A4] High doses (400 mg twice daily)	FROM_m_Oh and AUC_Ʈ ritonavir ↔ FROM_m_Oh voriconazole ↓ 66 % AUC_Ʈ voriconazole ↓ 82 %	Simultaneous use of voriconazole and high doses of ritonavir (400 mg and more twice a day) is contraindicated.
Low doses (100 mg twice daily) *	FROM_m_Oh ritonavir ↓ 25 % AUC_Ʈ ritonavir ↓13 % FROM_m_Oh voriconazole ↓ 24 % AUC_Ʈ voriconazole ↓ 39 %	Apply simultaneously voriconazole and ritonavir in low doses (100 mg twice a day) should be given only if the expected benefit from taking voriconazole significantly exceeds the risk of their combined use.
Phenytoin [isoenzymatic substrate CYP2C9 and a powerful inducer of cytochrome P₄₅₀] 300 mg once daily	FROM_m_Ohvoriconazole ↓ 49 % AUC_Ʈ voriconazole ↓ 69 %	It should avoid simultaneous reception of voriconazole and phenytoin, except when 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_m_Oh phenytoin # 67 % AUC_Ʈ phenytoin # 81 % In comparison with voriconazole 200 mg twice a day, FROM_m_Oh voriconazole # 34 % AUC_Ʈ voriconazole # 39 %	Simultaneous application is possible only if the maintenance dose of voriconazole is increased to 5 mg / kg intravenouslyor 200 mg to 400 mg orally twice a day (in patients with a body weight of less than 40 kg with 100 mg to 200 mg orally twice a day).
Anticoagulant		If patients receiving
Warfarin (30 mg once	Increase the maximum	preparations of coumarin,
concomitantly with voriconazole	prothrombin time was	appoint voriconazole,
300 mg twice daily)	approximately twice.	necessary with short
[isoenzymatic substrate		intervals
CYP2C9]		prothrombin time and
Other oral	It is assumed that	accordingly
anticoagulants, for example,	voriconazole may increase	titrate
fenprokumone, acenocoumarol	plasma concentrations	anticoagulants.
[substrates of isoenzymes	coumarins, which can lead to
CYP2C9 and CYP3A4]	to increase prothrombin time.
Benzodiazepines (e.g.,	In vitro voriconazole may	It is recommended that
midazolam, triazolam,	cause an increase	expediency of correction
alprazolam)	plasma concentrations	doses of benzodiazepines.
[isoenzymatic substrates	benzodiazepines, which
CYP3A4]	metabolized by isoenzyme CYP3A4, and cause the development of prolonged sedation.
Immunosuppressants [isoenzymatic substrates CYP3A4] Sirolimus (2 mg once) Cyclosporin (in patients who underwent kidney transplantation and are in a stable state)	According to an independent study: Stam sirolimus # in 6,6 times AUC_o-∞ sirolimus # 11 times FROM_max cyclosporine # 13 % AUC_Ʈ cyclosporine # 70 %	The simultaneous use of voriconazole and sirolimus is contraindicated. When prescribing voriconazole, patients receiving ciclosporin, it is recommended to reduce the dose of cyclosporine by half and monitor its concentration in the blood plasma. An increase in the concentration of cyclosporine is accompanied by nephrotoxicity. After voriconazole cancellation, it is necessary to control the concentration of cyclosporine and, if necessary, increase its dose.
Tacrolimus (0.1 mg / kg once)	FROM_max tacrolimus # 117 % AUCt tacrolimus # 221%	When prescribing voriconazole, patients receiving tacrolimus, it is recommended to reduce the dose of the latter to one third and monitor its concentration in the blood plasma. Increased concentration of tacrolimus is accompanied by nephrotoxicity. After voriconazole cancellation, it is necessary to monitor the concentration of tacrolimus and, if necessary, increase its dose.
Long-acting opiates [isoenzymatic substrates CYP3A4] Oxycodone (10 mg once)	According to independent	The opportunity should be assessed
	Research:	reduce the dose of oxycodone and
	FROM_m_Oh oxycodone # in 1,7 times	others for a long time
	AUC_o_-∞ oxycodone # in 3,6 times	existing opiates,
Methadone (32-100 mg once a day	Сmах R(active	metabolized by isoenzyme CYP3A4 (e.g., hydrocodone). It may be necessary to monitor the patient's condition at short intervals for the development of unwanted reactions associated with opiates. Increase in concentration
crochets)	metabolite)# 31 %	of methadone in blood plasma
[isoenzymatic substrate	AUCt R(active	leads to the manifestation
CYP3A4]	metabolite)# 47 %	toxic effects,
	Сmах S-methadone #65 %	including interval lengthening
	AUCt S-methadone # 103 %	QT. Recommended frequent
		monitoring of the patient's condition for the development of unwanted reactions and toxicity (including lengthening of the interval QT), associated with methadone. You may need to reduce the dose of methadone.
Non-steroidal anti-inflammatory drugs (NSAIDs) [isoenzymatic substrates CYP2C9] Ibuprofen (400 mg once) Diclofenac (50 mg once)	FROM_m_Oh S-Ibuprofen # 20 % AUC_o_-∞ S-Ibuprofen #100 % FROM_m_Oh diclofenac # 114 % AUCo-∞ of diclofenac # 78 %	Patients should be monitored to identify possible toxic effects and, if necessary, adjust the dose of NSAIDs.
Omeprazole (40 mg once a day	FROM_m_Oh omeprazole # 116 %	Correction of the dose of voriconazole
day)*	AUC_Ʈ omeprazole # 280 %	not required.
[inhibitor of isoenzyme	FROM_m_Oh voriconazole # 15 %	At the beginning of admission
CYP2C19; substratum	AUC_Ʈ voriconazole # 41 %	voriconazole in patients already
isozymes CYP2C19 and	Voriconazole can also	receiving therapy.
CYP3A4]	oppress the action of other proton pump inhibitors, which are substrates of the isoenzyme CYP2C19, which can lead to an increase in the plasma concentrations of these drugs.	omeprazole in doses of 40 mg or higher, it is recommended that the dose of omeprazole be reduced by half.
Oral contraceptives *	FROM_m_Oh ethinyl estradiol # 36 %	Control is recommended
[isoenzymatic substrates	AUC_Ʈ ethinyl estradiol #61 %	patient's condition for
CYP3A4; inhibitors	FROM_m_Oh norethisterone # 15 %	development of undesirable
isoenzyme CYP2C19]	AUC_Ʈ norethisterone # 53 %	reactions associated with
Norethisterone / ethinylestradiol	FROM_m_Oh voriconazole # 14 %	use of oral
(1 mg / 0.35 mg once daily)	AUC_Ʈ voriconazole # 46 %	contraceptives and voriconazole.
Narcotic analgesics		The opportunity should be assessed
short-acting		reduce the dose of alfentanil,
[isoenzymatic substrates		fentanyl and other
CYP3A4]		narcotic analgesics
Alfentanil (single dose	According to independent	short-acting
20 μg / kg with simultaneous	Research:	akin to alfentanil
application of naloxone)	AUCo-∞ alfentanil # 6 times	chemical structure and metabolizable
Fentanyl (single dose of 5	According to independent	isoenzyme CYP3A4
mkg / kg)	Research:	(e.g. sufentanil).
	AUCo-∞ fentanyl # in 1,34 times	Patients should be under constant supervision to prevent oppression of respiratory function or other side effects associated with the use of narcotic
		analgesics of short action, and if necessary their dose should be reduced.
Statins (for example,	the interaction was not studied,	should assess the possibility
lovastatin)	however, probably voriconazole	reduction in the dose of statins.
[isoenzymatic substrates	can increase plasma
cyp3a4]	the concentrations of statins that are metabolized by the isoenzyme cyp3a4 and can lead to rhabdomyolysis.
derivatives	the interaction was not studied,	must be carefully
sulfonylureas	however, probably voriconazole	control concentration
(e.g., tolbutamide,	can increase plasma	glucose in the blood plasma.
glipizide, glibenclamide)	concentration of derivatives
[isoenzymatic substrates	sulfonylureas and be
cyp2c9]	cause of hypoglycemia.
vinca alkaloids (eg, vincristine and vinblastine) [isoenzymatic substrates cyp3a4]	voriconazole may increase alkaloid content vinca (vincristine and vinblastine) in the blood plasma and cause neurotoxicity.	it is recommended that expediency of correction doses of vinca alkaloids.
other protease inhibitors (un) HIV (for example, saquinavir, amprenavir and nelfinavir) * [inhibitors and substrates isoenzyme cyp3a4]	research in vitro evidence that voriconazole may inhibit metabolism protease inhibitors HIV: saquinavir, amprenavir and nelfinavir. in turn, HIV protease inhibitors can suppress the metabolism of voriconazole.	careful monitoring of the patient's condition for the development of any manifestations of drug toxicity and / or insufficiency of action. you may need to adjust the dose of drugs.
other non-nucleoside reverse inhibitors transcriptase (nioth) (e.g., delavirdine, nevirapine) * [inhibitors or inducers cytochrome p₄₅₀ and Substrates isoenzyme cyp3a4]	research in vitro They showed, that the metabolism of voriconazole can be oppressed by the action of Nniot, and voriconazole in its turn can oppress metabolism of niottes. based on the results of the study of the effect of efavirenz on voriconazole, it can be assumed that the niote can enhance the metabolism of voriconazole.	careful monitoring of the patient's condition for development drug toxicity and / or insufficiency actions. perhaps, dose adjustment is required preparations.
cimetidine (400 mg twice daily)[nonspecifically inhibits cytochrome p450 and increases the ph of gastric juice]	from_maxvoriconazole # 18 % auc_Ʈ voriconazole # 23 %	dose adjustment is not required
digoxin (0.25 mg once daily day)[p-glycoprotein substrate]	from_m_Oh digoxin ↔ auc_t digoxin	dose adjustment is not required
indinavir (800 mg three times in day) [inhibitor and substrate isoenzyme cyp3a4]	from_m_Oh indinavir ↔ auc_Ʈindinavir ↔ from_m_Oh voriconazole ↔ auc_Ʈvoriconazole ↔	dose adjustment is not required
antibiotics of the macrolide group		dose adjustment is not required
erythromycin (1 g twice daily) [inhibitor of isoenzyme cyp3a4]	from_m_Oh and auc_Ʈ voriconazole ↔
azithromycin (500 mg once per day)	from_m_Oh and auc_Ʈ voriconazole ↔ the effect of voriconazole on the metabolism of erythromycin or azithromycin is unknown.
mycophenolic acid (1 g once) [uridine substrate -5 - diphosphate- glucuronyltransferase]	from_m_Oh mycophenolic acids auc_Ʈ mycophenolic acids ↔	dose adjustment is not required
prednisolone (60 mg once) [isoenzymatic substrate cyp3a4]	from_m_Oh prednisolone # 11 % auc _o_-∞, prednisolone # 34 %	dose adjustment is not required
ranitidine (150 mg twice daily) [increases ph of gastric juice]	from_m_Oh and auc_Ʈ voriconazole ↔	dose adjustment is not required
pharmacokinetic parameter,based on 90% confidence interval of the mean geometric value is inside (↔), higher (↑) or below (↓) of the interval 80% -125 %. * mutual impact. auc_τ, auc_t, auco-∞ - 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 administration drug 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.

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.

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

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

Monitoring of liver function. During treatment with voriconazole, it is recommended to constantly monitor liver function, in particular, to perform hepatic tests and determine bilirubin. When there are clinical signs of liver dysfunction that may be associated with voriconazole therapy, it is necessary to discuss the advisability of discontinuing treatment (see the section "Dosing and Administration"). Control of liver function should be carried out both in children and adults.

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

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

Long-term therapy with voriconazole (an average of 169 days) in patients with 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 nipple of the optic nerve.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, 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 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.

If the patient develops exfoliative skin reactions, then voriconazole should be canceled. Since during the therapy with voriconazole, photosensitization may develop, during treatment it is recommended that patients avoid intense or prolonged exposure to direct sunlight. 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 the patient develops skin lesions associated with squamous cell carcinoma of the skin or melanoma, consideration should be given to discontinuing voriconazole therapy.

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

Use in children. Voriconazole is indicated for use in children aged 3 years and older with continuous monitoring of liver function. Bioavailability of voriconazole for oral administration in children aged 3 to 12 years can be reduced by impaired absorption or decreased body weight. In such cases intravenous administration of voriconazole is indicated.

Narcotic analgesics of short action (substrates of isoenzyme CYP3A4). Since the half-life of alfentanil when it is used simultaneously with voriconazole is increased 4-fold, careful monitoring of undesirable phenomena associated with the use of narcotic analgesics, including longer monitoring of respiratory function, is necessary.

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

Form release / dosage:

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

Packaging:

By 2, 7, 10, 14 tablets in a contoured cell packaging made of polyvinylchloride film and aluminum foil printed lacquered.

According to 1, 2, 3, 4, 5, 7, 8, 10 contour cell packs together with instructions for use in a pack of cardboard.

Storage conditions:

In dry, dark place at a temperature of no higher than 25 ° 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:LP-002395

Date of registration:07.03.2014 / 14.04.2016

Expiration Date:Unlimited

The owner of the registration certificate:OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC Russia

Manufacturer: & nbsp

OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC Russia

Information update date: & nbsp14.02.2017

Illustrated instructions

Instructions

Wikand (VIKAND)