Voriconazole-Acry - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate - 72.00 mg, pregelatinized starch - 15.00 mg, croscarmellose sodium - 9.75 mg, povidone K-25 - 2.50 mg, magnesium stearate - 0.75 mg.

Composition of the film shell: Opadrai II 85F18422 (white) - 6.00 mg (polyvinyl alcohol - 2.40 mg, titanium dioxide (E171) - 1.50 mg, macrogol 3350 - 1.21 mg, talc - 0.89 mg.

One tablet (200 mg) contains:

Active substance: voriconazole - 200.00 mg;

Excipients: lactose monohydrate 288.00 mg, pregelatinized starch 60.00 mg, croscarmellose sodium 39.00 mg, povidone K-25 10.00 mg, magnesium stearate 3.00 mg.

Composition of the film shell: Opadrai II 85F18422 (white) - 24.00 mg (polyvinyl alcohol - 9.60 mg, titanium dioxide (E171) - 6.00 mg, macrogol 3350 - 4.84 mg, talc - 3.56 mg.

Description:

Dosage 50 mg: round, biconvex tablets, film-coated, white or almost white. On the cross section, the core of the tablet is white or almost white in color.

Dosage of 200 mg: oblong, biconvex tablets, film-coated, white or almost white. On the cross section, the core of the tablet 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 14α-methylsterol correlates with the subsequent loss of ergosterol in fungal cell membranes,which determines the antifungal activity of voriconazole. It was found that voriconazole more active with respect to cytochrome P isoenzymes₄₅₀ fungi than with respect to various enzyme systems of cytochrome P₄₅₀ mammals.

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

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

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

The activity of voriconazole in vitro in relation to clinical strains Acremonium spp., Alternaria spp., Bipolaris spp., Cladophialophora spp., Histoplasma capsulatum.

The growth of most strains was suppressed at voriconazole concentrations from 0.05 μg / ml to 2 μg / ml.

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

Pharmacokinetics:

general characteristics

Pharmacokinetic parameters of voriconazole are characterized by significant interindividual variability.

The pharmacokinetics of voriconazole is nonlinear due to the saturation of its metabolism. When the dose is increased, a disproportionate (more pronounced) increase in the area under the concentration-time curve (AUC_τ). An increase in the oral dose from 200 mg twice a day to 300 mg twice daily leads to an increase 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.

With intravenous administration or ingestion of saturating doses of voriconazole, the equilibrium concentration is reached within the first 24 hours. If the drug is administered twice a day in the average therapeutic dose (but not in saturating), 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_mOh) 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_mOh 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 research data in vitro voriconazole is metabolized by isozymes CYP2C19, CYP2C9, CYP3A4. An important role in the metabolism of voriconazole is played by isoenzyme CYP2C19, showing a pronounced genetic polymorphism, and therefore a reduced metabolism of voriconazole is possible in 15-20% of representatives of Asian descent and 3-5% of representatives of Caucasoid and Negroid races.

It was found that in patients with a reduced metabolism AUC_τ voriconazole is on average 4 times higher than in homozygous patients with high metabolism. In heterozygous patients with high metabolism AUC_τ voriconazole on average is 2 times higher than in homozygous.

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 or intravenous administration in urine, about 83% and 80% of the dose of the drug are detected, respectively. Most (> 94%) of the total dose is excreted within the first 96 hours after ingestion and intravenously.

The half-life (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 quantity T_1/2does not allow to assume the presence or absence of cumulation, and also to judge the parameters of voriconazole excretion.

Pharmacokinetics in special groups

Floor

With multiple administration of voriconazole inside C_mOh and AUC_τ in healthy young women were 83% and 113%, respectively, higher than in healthy young men (18-45 years). Significant differences FROM_m_Oh 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_mOh 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_mOh 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

Children have a higher intra-individual variability than adults. Comparison of child and adult populations showed that the estimated AUC_τ in children after administration of a saturating dose of 9 mg / kg was comparable to that in adults after administration of a saturating dose of 6 mg / kg. The estimated total concentration in children after administration of a maintenance dose of 4 mg / kg and 8 mg / kg twice daily was also comparable to that in adults after administration of a maintenance dose of 3 mg / kg and 4 mg / kg twice daily. 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 with impaired suction and low body weight for their age can be reduced; In this case, intravenous administration may be indicated.

The findings suggest a higher elimination of voriconazole in children compared with adults due to the large ratio of liver weight and body weight. In most adolescents, the concentration of voriconazole in the blood plasma corresponds to this parameter in adult patients. However, fewer voriconazole concentrations were observed in plasma 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 children.

Impaired renal function

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(SC) - 41-60 ml / min) to severe (KC <20 ml / min) degree of pharmacokinetics of voriconazole is not significantly affected by the degree of renal dysfunction. The binding of voriconazole to plasma proteins is approximately the same in patients with varying degrees of renal insufficiency.

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 cirrhosis (classes A and B on the Child-Pugh scale) was 223% higher than in patients with normal liver function. Dysfunction of the liver does not affect the binding of voriconazole with plasma proteins.

With repeated intake of the drug inside AUC_τ voriconazole is comparable in patients with cirrhotic liver of moderate severity (class B on the Child-Pugh scale) who received the drug in a maintenance dose of 100 mg twice a day, and in patients with normal liver function receiving voriconazole in a dose of 200 mg twice a day. There is no information on the pharmacokinetics of voriconazole in patients with severe liver cirrhosis (grade C on the Child-Pugh scale). For recommendations on how to dose the drug, see "How to use".

Indications:

Invasive aspergillosis.

Candidemia in patients without neutropenia.

Severe invasive candidiasis infections (including FROM. krusei).

Candidiasis of the esophagus.

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

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

Prevention of "breakthrough" fungal infections in patients with reduced immune system function, fever and neutropenia, from high-risk groups (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 of the drug Voriconazole-Acry and the following 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; 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);

- Lactase deficiency, lactose intolerance, glucose-galactose malabsorption;

- Children's age is less than 3 years (for this dosage form).

Carefully:

- Hypersensitivity to other drugs - derivatives of azoles;

- severe degree of insufficiency of liver function, severe degree of kidney failure;

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

- also care should be taken when using the drug Voriconazole-Acry in patients with electrolyte imbalance, 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 when using the drug Vorikonazol-Akri should use reliable methods of contraception.

Dosing and Administration:

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

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

Adult patients

Treatment with the drug Voriconazole-Acry should be started with intravenous administration at the recommended saturating dose, so that on the first day of treatment, an adequate concentration in the blood plasma can be achieved.Intravenous infusions 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 the drugs inside.

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 infusions to oral administration of the drug without dose correction.

The table gives details of the dosage of the drug Voriconazole-Acry:

	Intravenous infusion	Inside
	Intravenous infusion	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 infections in patients (adults and children over 12 years) high risk groups, 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

With insufficient effectiveness of treatment, the maintenance dose of Voriconazole-Acry for oral administration can 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.

Prevention in adults and children

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

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

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

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 function impairment, manifested by an increase in the activity of "hepatic" 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 to moderate liver failure (class A and B on the Child-Pugh scale) should be given a standard saturating dose of the drug Voriconazole-Acrya, and the maintenance dose should be reduced by a factor of 2. Patients with severe liver function disorder (class C on the Child-Pugh scale) drug Voriconazole-Acry should be prescribed only in cases where the expected benefit exceeds the possible risk, and under constant monitoring to identify signs of toxic effects of the drug.

Patients of the older age group

Correction of the dose is not required.

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:

Intravenous infusion

Inside

The saturation dose

(first 24 hours)

9 mg / kg every 12 hours

Not recommended

Maintenance dose

(after the first 24 hours)

8 mg / kg 2 times a day

9 mg / kg twice daily (maximum dose of 350 mg twice daily)

It is recommended to start therapy with intravenous administration of the drug, and the possibility of taking oral forms of the drug voriconazole should be considered only after clinical improvement and if the patient has the opportunity to take oral forms.

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 pronounced 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 2 to 12 years with impaired liver or kidney function has not been studied.

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

Correction of dose

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

If the child does not tolerate therapy at the prescribed dose, it should be reduced in steps of 1 mg / kg (or 50 mg if a maximum dose of 350 mg was initially administered).

Side effects:

The most common adverse reactions are visual disturbances, abnormal results of functional liver tests, fever, rash, vomiting, nausea, diarrhea, headache, peripheral edema, abdominal pain and respiratory depression. Undesirable reactions were usually easily or moderately expressed. Clinically significant dependence of drug safety on age, race or sex was not revealed.

The following undesirable effects are given in accordance with the following gradations of their frequency: very often (≥10%); often (≥ 1%, <10%); infrequently (≥0.1%, <1%); rarely (≥0.01%, <0.1%); very rarely (<0.01%); frequency is unknown (according to available data, it is not possible to establish the frequency of occurrence).

Infectious and parasitic diseases: often - sinusitis, gastroenteritis, gingivitis; infrequently - pseudomembranous colitis, lymphangitis, peritonitis.

Violations 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, disseminated intravascular coagulation syndrome, lymphadenopathy.

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

Disorders from the endocrine system: infrequently - insufficiency of the adrenal cortex; rarely - hyperthyroidism.

Disorders from the metabolism and nutrition: very often peripheral edema; often - hypokalemia, hypoglycemia, hyponatremia (identified in post-marketing studies).

Disorders of the psyche: often - depression, hallucinations, anxiety, insomnia, agitation, confusion.

Impaired nervous system: very often - headache; often - syncope, tremor, paresthesia, drowsiness, dizziness, convulsions, nystagmus; infrequently - cerebral edema, encephalopathy, extrapyramidal disorders, peripheral neuropathy, ataxia, hypoesthesia, dysgeusia (taste dysfunction); rarely - hepatic encephalopathy, Guillain-Barre syndrome.

Disturbances on the part of the organ of sight: Very often - visual disturbances (including blurred vision, blurred vision, photophobia, chloropia, hromatopsiya, photophobia, color blindness, tsianopsiya, the presence in the field of view of bright circles around lights, night blindness, oscillopsia, photopsia, scintillating scotoma ,decrease in visual acuity, visual brightness, defect of visual fields, floating opacities of the vitreous body and xantopsy); often - hemorrhage at the retina of the eye; infrequently - optic neuritis, edema of the nipple of the optic nerve, oculogic crisis, scleritis, diplopia, blepharitis; rarely - atrophy of the optic nerve, corneal opacity.

Violations from the side of the hearing organ and labyrinthine disorders: infrequently - vertigo, hypoacusia, tinnitus.

Heart Disease: often - supraventricular arrhythmia, tachycardia, bradycardia; infrequently - ventricular fibrillation, ventricular extrasystole, ventricular tachycardia, supraventricular tachycardia; rarely - an arrhythmia of the type "pirouette"; complete atrioventricular block, blockade of the bundle branch, nodular arrhythmias.

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

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

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

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

Disturbances from the musculoskeletal system and connective tissue: often - pain in the back; infrequently - arthritis; frequency is unknown - periostitis.

Disorders from the kidneys and urinary tract: often acute renal failure, hematuria; infrequently - necrosis of the renal tubules, proteinuria, nephritis.

General disorders and disorders at the site of administration: very often - fever; often - chills, asthenia, chest pain, flu-like illness, facial swelling (including periorbital edema, swelling of the lips and swelling of the mouth).

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

Laboratory and instrumental data: often - increasing the concentration of creatinine in the blood; infrequent - lengthening of the interval QT on an electrocardiogram, an increase in the concentration of urea in the blood, an increase in the concentration of cholesterol in the blood.

Side effect when applied the children

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

Overdose:

There are three cases of unintentional overdose. All of these cases occurred in children who received a dose of voriconazole intravenously, five times the recommended dose.In this case, the only case of an undesirable reaction in the form of photophobia was registered, 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 P isoenzymes₄₅₀ (CYP2C19, CYP2C9 and CYP3A4) can cause, respectively, an increase or decrease in the concentration of voriconazole in the blood plasma.

Voriconazole inhibits the activity of cytochrome isoenzymes R₄₅₀ - CYP2C19, CYP2C9 and CYP3A4, - and can increase plasma concentrations of substances that are metabolized with the participation of cytochrome isoenzymes R₄₅₀.

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

Drug (mechanism of interaction)	Interaction: changes pharmacokinetic parameters (%)	Recommendations for simultaneous application
Astemizole, cisapride, pimozide, quinidine and terfenadine [substrates of the isoenzyme 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 QT_C 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 and long-acting barbiturates are likely to significantly reduce plasma concentrations of voriconazole	Contraindicated
Efavirenz (non-nucleoside reverse transcriptase inhibitor) [cytochrome inducer R₄₅₀; inhibitor and substrate of the isoenzyme CYP3A4]
Simultaneous use of efavirenz in a dose of 400 mg once a day and voriconazole at a dose of 200 mg twice a day *	FROM_mOh efavirenz ↑ 38% AUC_τ efavirenz ↑ 44% FROM_mOh voriconazole ↓ 61% AUC_τ voriconazole ↓ 77%	The use of standard doses of voriconazole and efavirenz 400 mg once a day is contraindicated.
Simultaneous application of 300 mg of efavirenz once a day and voriconazole 400 mg twice a day *	In comparison with efavirenz 600 mg once a day: FROM_mOhefavirenz ↔ AUC_τ efavirenz ↑ 17%	Simultaneous application is possible if a maintenance dose of voriconazole is increased to 400 mg two once a day, and the dose of efavirenz is reduced to 300 mg once a day. With the withdrawal of voriconazole therapy, the initial dose of efavirenz should be restored.
	In comparison with voriconazole 200 mg twice a day: FROM_mOhvoriconazole ↑ 23% AUC_τ voriconazole ↓ 7%
Ergot alkaloids (eg, ergotamine and dihydroergotamine) [substrates of the isoenzyme CYP3A4]	The interaction of voriconazole with ergot alkaloids (ergotamine and dihydroergotamine) has not been studied, but there is a high probability that voriconazole can cause an increase in the concentrations of these drugs in the blood plasma and lead to ergotism.	Contraindicated
Rifabutin [powerful cytochrome inducer R₄₅₀] 300 mg once daily	FROM_mOh voriconazole ↓69% AUC_τ voriconazole ↓ 78% FROM_mOh rifabutin ↑ 195% AUC_τ rifabutin ↑ 331%	Contraindicated
300 mg once a day (with simultaneous application with voriconazole 400 mg twice daily) *	In comparison with voriconazole 200 mg twice a day: FROM_mOh voriconazole ↑ 104% AUC_τ voriconazole ↑ 87%	Contraindicated
Rifampicin (600 mg once daily) [powerful cytochrome P450 inducer]	FROM_mOh voriconazole ↓ 93% AUC_τ voriconazole ↓ 96%	Contraindicated
Ritonavir (protease inhibitor) [powerful cytochrome P450 inducer; inhibitor and substrate of the isoenzyme CYP3A4]
High doses (400 mg twice daily)	FROM_mOh and AUC_τ ritonavir ↔ FROM_mOh voriconazole ↓ 66% AUC_τ voriconazole ↓ 82%	Simultaneous use of voriconazole and high doses of ritonavir (400 mg and higher twice a day is contraindicated.
Low doses (100 mg twice daily) *	FROM_mOh ritonavir ↓ 25% AUC_τ ritonavir ↓ 13% FROM_mOh voriconazole ↓ 24% AUC_τ voriconazole ↓ 39%	Apply simultaneously voriconazole and ritonavir in low doses (100 mg twice a day) should be given only if the expected benefit from taking voriconazole significantly exceeds the risk of their combined use.
St. John's wort perforated [cytochrome P inducer₄₅₀ and P-glycoprotein] 300 mg three times a day (simultaneous application with a single dose of voriconazole 400 mg)	According to an independent study: AUC_0-∞ voriconazole ↓ 59%	Contraindicated
Everolimus [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, CYP2CJ9 and CYP3A4]	FROM_mOh voriconazole ↑ 57% AUC_τ voriconazole ↑ 79% Changes in C_mOh and AUC_τ, fluconazole not established	A suitable regimen for dose adjustment and / or reception frequency of voriconazole and fluconazole is not established. In case if voriconazole is used after fluconazole, it is recommended that careful monitoring of unwanted reactions associated with the use of voriconazole is recommended.
Phenytoin [substrate of the isoenzyme CYP2C9 and a powerful inducer of cytochrome P₄₅₀]
300 mg once daily	FROM_mOh voriconazole ↓ 49% AUC_τ voriconazole ↓ 69%	Avoid simultaneous administration of voriconazole and phenytoin, unless the patient's benefit exceeds the risk. It is recommended to monitor plasma concentrations of phenytoin.
300 mg once a day (simultaneous application with voriconazole at a dose of 400 mg twice a day) *	FROM_mOh phenytoin ↑ 67% AUC_τ phenytoin ↑ 81% In comparison with voriconazole 200 mg twice a day, FROM_mOh voriconazole ↑ 34% AUC_τ voriconazole ↑ 39%	Simultaneous application is possible only in the case,if the maintenance dose of voriconazole is increased to 5 mg / kg intravenously or 200 mg to 400 mg orally twice a day (in patients with a body weight of less than 40 kg from 100 mg to 200 mg orally twice a day).
Anticoagulants Warfarin (30 mg once with voriconazole 300 mg twice daily) [substrate of the isoenzyme CYP2C9]	The increase in the maximum prothrombin time was approximately two-fold.	If patients receiving coumarin preparations are prescribed voriconazole, it is necessary to monitor prothrombin time at short intervals and appropriately select doses of anticoagulants.
Other oral anticoagulants, for example, fenprokumone, acenocoumarol [substrates of isoenzymes CYP2C9 and CYP3A4]	It is assumed that voriconazole can increase plasma concentrations of coumarins, which can lead to an increase in prothrombin time.
Benzodiazepines (e.g., midazolam, triazolam, alprazolam) [substrates of the isoenzyme CYP3A4]	In vitro voriconazole may cause an increase in plasma concentrations of benzodiazepines that are metabolized by isoenzyme CYP3A4, and cause the development of prolonged sedation.	It is recommended to evaluate the appropriateness of dose adjustment for benzodiazepines.
Immunosuppressants [substrates of the isoenzyme CYP3A4]
Sirolimus (2 mg once)	According to an independent study: FROM_mOh sirolimus ↑ 6,6 times AUC_0-∞ sirolimus ↑ 11 times	The simultaneous use of voriconazole and sirolimus is contraindicated.
Cyclosporin (in patients who underwent kidney transplantation and are in a stable state)	FROM_mOh cyclosporine ↑ 13% AUC_τ cyclosporine ↑ 70%	When prescribing voriconazole, patients receiving ciclosporin, it is recommended to reduce the dose of cyclosporine by half and monitor its concentration in the blood plasma. An increase in the concentration of cyclosporine is accompanied by nephrotoxicity. After voriconazole cancellation, it is necessary to control the concentration of cyclosporine and, if necessary, increase its dose.
Tacrolimus (0.1 mg / kg once)	FROM_mOh tacrolimus ↑ 117% AUC_t tacrolimus ↑ 221%	When prescribing voriconazole, patients receiving tacrolimus, it is recommended to reduce the dose of the latter to one third and monitor its concentration in the blood plasma. Increased concentration of tacrolimus is accompanied by nephrotoxicity. After voriconazole cancellation, it is necessary to monitor the concentration of tacrolimus and, if necessary, increase its dose.
Long-acting opiates [substrates of the isoenzyme CYP3A4]
Oxycodone (10 mg once)	According to an independent study: FROM_mOh oxycodone ↑ 1.7 times AUC_0-∞ oxycodone ↑ 3,6 times	The possibility of reducing the dose of oxycodone and other long-acting opiates metabolized by the CYP3A4 isoenzyme (eg, hydrocodone) should be evaluated. It may be necessary to monitor the patient's condition at short intervals for the development of unwanted reactions. associated with opiates.
Methadone (32-100 mg once daily) [substrate of the isoenzyme CYP3A4]	FROM_mOh R-metadone (active metabolite) ↑ 31% AUC_τ R-metadone (active metabolite) ↑ 47% FROM_mOh S-methanone ↑ 65% AUC_τ Smethadone ↑ 103%	An increase in the concentration of methadone in the blood plasma leads to the appearance of toxic effects, including lengthening of the interval QT. It is recommended that frequent monitoring of the patient's condition for the development of unwanted reactions and toxicity (including lengthening of the interval QT) associated with methadone. You may need to reduce the dose of methadone.
Non-steroidal anti-inflammatory drugs (NSAIDs) [substrates of the isoenzyme CYP2C9]		Patients should be monitored to identify possible toxic effects and, if necessary, adjust the dose of NSAIDs.
Ibuprofen (400 mg once)	FROM_mOh S-ibuprofen ↑ 20% AUC_0-∞ ibuprofen ↑ 100%
Diclofenac (50 mg once)	FROM_mOh diclofenac ↑ 114% AUC_0-∞ diclofenac ↑ 78%
Omeprazole (40 mg once daily) * [inhibitor of the isoenzyme CYP2C19; substrate of isoenzymes CYP2C19 and CYP3A4]	FROM_mOh omeprazole ↑ 116% AUC_τ omeprazole ↑ 280% FROM_mOh voriconazole ↑15% AUC_τ voriconazole ↑ 41% Voriconazole can also inhibit the action of other proton pump inhibitors, which are substrates of the isoenzyme CYP2C19, which can lead to an increase in the plasma concentrations of these drugs.	Correction of the dose of voriconazole is not required. When starting voriconazole in patients who are already receiving omeprazole therapy at doses of 40 mg or higher, a dose reduction of omeprazole is recommended in half.
Oral contraceptives * [substrates of the isoenzyme CYP3A4; inhibitors of the isoenzyme CYP2C19] Norethisterone / ethinyl estradiol (1 mg / 0.35 mg once daily)	FROM_mOh ethinylestradiol ↑ 36% AUC_τethinyl estradiol ↑ 61% FROM_mOh norethisterone ↑ 15% AUC_τ norethisterone ↑ 53% FROM_mOh voriconazole ↑ 14% AUC_τ voriconazole ↑ 46%	It is recommended to monitor the patient's condition for the development of unwanted reactions associated with the use of oral contraceptives and voriconazole.
Narcotic analgesics of short action [isoenzymatic substrates CYP3A4]		It should evaluate the possibility of reducing the dose of alfentanil, fentanyl and other narcotic analgesics short-acting, having a similar chemical structure with alfentanilom and metabolizable isoenzyme CYP3A4 (e.g., sufentanil). Patients should be under constant surveillance to prevent respiratory depression or other side effects associated with the use of short-acting narcotic analgesics and, if necessary, their dose should be reduced.
Alfentanil (a single dose of 20 mcg / kg with the simultaneous use of naloxone)	According to an independent study: AUC_0-∞ alfentanil ↑ 6 times
Fentanyl (a single dose of 5 μg / kg)	According to an independent study: AUC_0-∞ fentanyl ↑ 1,34 times
Statins (for example, lovastatin) [substrates of the CYP3A 4 isoenzyme]	The interaction was not studied, however, voriconazole can increase plasma concentrations of statins that are metabolized by an isoenzyme CYP3A4 and can lead to rhabdomyolysis.	It should be assessed the possibility of reducing the dose of statins.
Derivatives of sulfonylureas (for example, tolbutamide, glipizide, glibenclamide) [isoenzymatic substrates CYP2C9]	The interaction was not studied, however, voriconazole can increase plasma concentrations of sulfonylureas and cause hypoglycemia.	It is necessary to carefully monitor the concentration of glucose in the blood plasma.
Vinca alkaloids (for example, vincristine and vinblastine) [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 nelfinavir) * [inhibitors and substrates of the isoenzyme CYP3A4]	Research in vitro evidence that voriconazole can inhibit the metabolism of HIV protease inhibitors: saquinavir, amprenavir and nelfinavir. In turn, HIV protease inhibitors can suppress the metabolism of voriconazole.	It is recommended that the patient be carefully monitored for any manifestation of drug toxicity and / or lack of action. Probably, correction of a dose of preparations is required.
Other non-nucleoside reverse transcriptase inhibitors (NNRTIs) (eg, delavirdine, nevirapine) * [inhibitors or inducers of cytochrome P450 and substrates of the isoenzyme CYP3A4]	Research in vitro showed that voriconazole metabolism may be inhibited by NNRTI, and voriconazole in turn, can inhibit the metabolism of the NNRTI. Based on the results of the study of the effect of efavirenz on voriconazole, it can be assumed that NNRTIs can enhance the metabolism of voriconazole.	It is recommended to carefully monitor the patient's condition for the development of drug toxicity and / or lack of action. You may need to adjust the dose of drugs.
Cimetidine (400 mg twice daily) [nonspecifically inhibits cytochrome P₄₅₀and increases the pH of the gastric juice]	FROM_mOh voriconazole ↑ 18% AUC_τ voriconazole ↑ 23%	Correction of the dose is not required.
Digoxin (0.25 mg once daily) [P-glycoprotein substrate]	FROM_mOh digoxin ↔ AUC_τ digoxin ↔	Correction of the dose is not required.
Indinavir (800 mg three times daily) [inhibitor and substrate of the isoenzyme CYP3A4]	FROM_max indinavir ↔ AUC_τ indinavir ↔ FROM_max voriconazole ↔ AUC_τ voriconazole ↔	Correction of the dose is not required.
Antibiotics of the macrolide group		Correction of the dose is not required.
Erythromycin (1 g twice daily) [inhibitor of the isoenzyme CYP3A4]	FROM_mOh and AUC_τ voriconazole ↔
Azithromycin (500 mg once daily)	FROM_mOh and AUC_τ voriconazole ↔ The effect of voriconazole on the metabolism of erythromycin or azithromycin is unknown.
Mycophenolic acid (1 g once) [uridine-5 diphosphate-glucuronyltransferase substrate]	FROM_mOh mycophenolic acid ↔ AUC_t mycophenolic acid ↔	Correction of the dose is not required.
Prednisolone (60 mg once) [isoenzymatic substrate CYP3A4]	FROM_mOh prednisolone ↑ 11% AUC_0-∞ prednisolone ↑ 34%	Correction of the dose is not required.
Ranitidine (150 mg twice daily) [increases the pH of gastric juice]	FROM_max and AUC_τ voriconazole ↔	Correction of the dose is not required.

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

* Mutual effect.

AUC_τ, AUC_t, AUC_0-∞ - area under the curve "concentration-time" during the dosing period, from the moment of administration of the drug to the visible concentration in the blood plasma, from the moment of drug administration to infinity, respectively.

Special instructions:

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

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

Undesirable effects from the cardiovascular system

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

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

- congenital and acquired lengthening interval QT;

- Cardiomyopathy, especially in combination with heart failure;

- sinus bradycardia;

- existing arrhythmias with clinical manifestations;

- simultaneous use of drugs that extend the interval QT (see interaction with other drugs). Electrolyte disorders, for example, hypokalemia, hypomagnesemia, and hypocalcemia, if necessary, should be monitored and eliminated before and during therapy with voriconazole.

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

Hepatocellularcvernacular

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

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

Monitoring of liver function

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

Visual disturbances

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 paracoccidioidosishas a clinically significant effect on visual function, which is 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 of the kidneys

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

Monitoring of kidney function

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

Monitoring of pancreatic function

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

Undesirable skin effects

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

During treatment with voriconazole, patients experienced cases of exfoliative skin reactions, such as Stevens-Johnson syndrome. If the patient develops exfoliative skin reactions, then voriconazole should be canceled.

Since during the therapy with voriconazole the development of photosensitization is possible, during the treatment it is recommended that patients avoid intense or prolonged exposure to direct sunlight and take protective measures such as wearing clothes and applying sunscreens with a high UV-protection factorSPF).

Long-term treatment

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

Noninfectious periostitis

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

Use in children

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

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

Narcotic analgesics of short action (substrates of isoenzyme CYP3A4)

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

Long-acting narcotic analgesics (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 carefully monitor undesirable phenomena associated with the use of narcotic analgesics (see section "Interaction with other drugs").

Phenytoin (a powerful inducer of cytochrome P₄₅₀ and the substrate of the isoenzyme CYP2C9)

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

Efavirenz (non-nucleoside reverse transcriptase inhibitor, cytochrome P inductor₄₅₀, inhibitor and substrate of the 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 cytochrome P₄₅₀, inhibitor and substrate of the isoenzyme CYP3A4)

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

Everolimus (isoenzymatic substrate CYP3A4 and P-glycoprotein)

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

Methadone (isoenzymatic substrate CYP3A4)

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

Fluconazole (inhibitor of isoenzymes CYP2C9, CYP2C19, CYP3A4)

Simultaneous use of voriconazole and fluconazole inside of healthy volunteers leads to a significant increase in C_mOh and AUC_τ voriconazole. A suitable regimen for dose adjustment and / or reception frequency of voriconazole and fluconazole is not established. In case if voriconazole is used after fluconazole, it is recommended that careful monitoring of unwanted reactions associated with the use of voriconazole is recommended.

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 car or using sophisticated technology. 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:

14 tablets in a blister of aluminum foil and PVC film.

1 blister together with instructions for use in a pack of cardboard.

Storage conditions:

At a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004050

Date of registration:27.12.2016

Expiration Date:27.12.2021

The owner of the registration certificate:AKRIKHIN HFK, JSC AKRIKHIN HFK, JSC Russia

Manufacturer: & nbsp

POLPHARMA PHARMACEUTICAL WORKS, S.A. Poland

Representation: & nbspAKRIKHIN OJSC AKRIKHIN OJSC Russia

Information update date: & nbsp10.03.2017

Illustrated instructions

Instructions

Voriconazole Acry (Voriconazole-Akri)