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

Excipients: lactose monohydrate (Pharmatosis 200M) 63.250 mg, pregelatinized starch (corn starch 1500) 24.250 mg, croscarmellose sodium (Ac-di-sol) 6.250 mg, povidone (Kollidon K 30) 5,000 mg, magnesium stearate 1,250 mg;

tablet coating composition: fall off II white ZZK58715 (HPC2910 / hypromellose 6sP (E464) 1,500 mg, lactose monohydrate 1,012 mg, titanium dioxide (E171) 0.900 mg, triacetin 0.337 mg) 3.750 mg.

1 tablet, film-coated, 200 mg, contains:

active substance: voriconazole 200,000 mg;

Excipients: lactose monohydrate (Pharmacosis 200M) 253,000 mg, pregelatinized starch (corn starch 1500) 97,000 mg, croscarmellose sodium (Ac-di-sol) 25,000 mg, povidone (Kollidon K 30) 20,000 mg, magnesium stearate 5,000 mg;

tablet coating composition: fall off II White ZZK58715 (HPC2910 / hypromellose 6sP (E464) 6,000 mg, lactose monohydrate 4,050 mg, titanium dioxide (E171) 3,600 mg, triacetin 1,350 mg) 15,000 mg.

Description:

Tablets 50 mg: white or almost white, round biconvex tablets covered with a film sheath, engraved "50" on one side and smooth on the other side.

Tablets 200 mg: white or almost white, oblong biconvex tablets covered with a film sheath, engraved "200" on one side and smooth on the other side.

Pharmacotherapeutic group:Antifungal agent

ATX: & nbsp

J.02.A. C.03 Voriconazole

Pharmacodynamics:

Mechanism of action

Voriconazole is a broad-spectrum antifungal agent from the group of triazoles. The mechanism of action of voriconazole is associated with the inhibition of demethylation of 14α-sterol, mediated via fungal cytochrome P450, which is a key stage in the biosynthesis of ergosterol.The accumulation of 14α-methylsterol correlates with the subsequent loss of ergosterol in fungal cell membranes, which determines the antifungal activity of voriconazole. It was found that voriconazole more selective for cytochrome P450 isoenzymes of fungi than for various enzyme systems of mammalian cytochrome P450.

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

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

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

The clinical efficacy of voriconazole (with partial or complete response) was demonstrated in infections caused by Aspergillus spp., including A. flavus, A. fumigatus, A. terreus, A. niger, A. nidulans; Candida spp., including FROM. albicans, FROM. glabrata, FROM. krusei, FROM. parapsilosis, FROM. tropicalis, as well as for a limited number of strains FROM. dubliniensis, FROM. inconspicua and FROM. guilliermondii; Scedosporium spp., including S. apiospermum, S. prolificans; 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 marneffei, Phialophora richardsiae, Scopulariopsis brevicaulis and Trichosporon spp., including infections T. beigelii.

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

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

Pharmacokinetics:

general characteristics

Pharmacokinetic parameters of voriconazole are characterized by significant interindividual variability.

The pharmacokinetics of voriconazole is nonlinear due to the saturation of its metabolism. With an increase in the dose of voriconazole, 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.

When taking saturating doses of voriconazole, the equilibrium concentration is reached within the first 24 hours. If the drug is administered twice a day in medium (but not in saturating) doses, then voriconazole is cumulated, and equilibrium concentrations are reached by the 6th day in most patients.

Suction and distribution

Voriconazole quickly and almost completely absorbed after oral administration: the maximum concentration in the blood plasma (C_mOh) is achieved 1-2 hours after admission. Bioavailability of voriconazole after oral administration is 96%. With repeated use of voriconazole with food with a high content of fat C_mOhand AUC_τ decrease by 34% and 24% respectively. Absorption of voriconazole is independent of pH of 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 tissues. Binding to plasma proteins is 58%. Voriconazole penetrates the blood-brain barrier and is determined in the cerebrospinal fluid.

Metabolism

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

Excretion

Voriconazole is excreted in the form of metabolites after biotransformation in the liver, in unchanged form, less than 2% of the applied dose of the drug is excreted by the kidneys.

After repeated administration of voriconazole inside or intravenous administration in urine, about 83% and 8% of the dose of the drug are detected, respectively. Most (> 94%) of the total dose of voriconazole is excreted within the first 96 hours after ingestion or 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 predict the cumulation or excretion of voriconazole.

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 C_mOh 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 repeated use 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

The estimated total concentration of voriconazole in children with oral administration of a maintenance dose of 9 mg / kg (maximum 350 mg) 2 times a day is comparable to that of adults when taking voriconazole by mouth at a dose of 200 mg 2 times a day. The concentration of voriconazole with an intravenous dose of 8 mg / kg is twice that of oral administration at a dose of 9 mg / kg. Bioavailability of voriconazole for oral administration in children may be limited by a malabsorption and a sufficiently low body weight at this age, and in this case intravenous administration may be indicated.

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

Impaired renal function

When taking voriconazole once in a dose of 200 mg by patients with normal renal function or with impaired renal function from mild (creatinine clearance 41-60 ml / min) to severe (CF <20 ml / min), the degree of pharmacokinetics of voriconazole does not depend significantly from the degree of impaired renal function. The binding of voriconazole with plasma proteins is approximately the same in patients with varying degrees of renal failure (see "Dosing and Administrationand "Special instructions").

Impaired liver function

After a single intake of the drug in a dose of 200 mg AUC_τvoriconazole in patients with mild to moderate severity of liver cirrhosis (classes A and B according to the classification Child-Pugh) was 233% higher than in patients with normal liver function. 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 cirrhosis of the liver of moderate severity (class B according to the Child-Pugh classification) who receive the drug in a maintenance dose of 100 mg twice a day, and in patients with normal liver function who receive the drug at a dose of 200 mg twice a day . There is no information about the pharmacokinetics of voriconazole in patients with severe liver cirrhosis (class C according to the Child-Pugh classification). For recommendations on dosing, see "Mode of administration and dose."

Indications:

- Invasive aspergillosis;

- Candida in patients without neutropenia;

- Candidiasis of the esophagus;

- severe invasive candidiasis infections (including Candida krusei);

- severe fungal infections caused by Scedosporium spp. and Fusarium spp.;

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

- prophylaxis of breakthrough fungal infections in patients with reduced immune system function, fever, neutropenia, high-risk group (recipients of hematopoietic stem cell transplantation (HSC), patients with relapse of leukemia);

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

Contraindications:

- Hypersensitivity to voriconazole or another component of the drug;

- simultaneous use with the following drugs metabolized with the help of the isoenzyme CYP3A4 (see the section "Interaction with other drugs"): terfenadine, astemizole, cisapride, pimozide, quinidine, rifampicin, carbamazepine, long-acting barbiturates (phenobarbital), efavirenz (in a dose of 400 mg and higher once a day), ritonavir (in a dose of 400 mg and more 2 times a day), ergot alkaloids (ergotamine, dihydroergotamine), sirolimus, rifabutin, preparations of St. John's wort perfumed;

- Children under 3 years old (for this dosage form);

- deficiency of lactase, lactose intolerance, glucose-galactose malabsorption.

Carefully:

Hypersensitivity to other drugs - azoles, hepatic insufficiency, severe renal failure, potentially proaritmogenic conditions in patients with multiple risk factors (congenital or acquired increase in the interval QT, cardiomyopathy, especially with heart failure, sinus bradycardia, the presence of symptomatic arrhythmia, simultaneous use of drugs that increase the interval QT), electrolyte imbalance, such as hypokalemia, hypomagnesemia, 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 voriconazole should use reliable methods of contraception.

Dosing and Administration:

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

Before the start of therapy, such electrolyte disorders as hypokalemia, hypomagnesemia, hypocalcemia should be corrected.

Adult patients

The appointment of voriconazole should begin with intravenous administration of the recommended saturating dose, in order to achieve an adequate concentration in the blood plasma on the first day. Intravenous administration should be continued for at least 7 days, after which it is possible to switch to oral intake of the drug, provided that the patient is able to take medication for oral administration. Given the high bioavailability of the drug with oral intake, reaching 96% (see 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
	Intravenously	Patients with a body weight of 40 kg and more	Patients weighing less than 40 kg
Saturated dose - all indications (first 24 h)	6 mg / kg every 12 hours	Not recommended	Not recommended
The maintenance dose (after the first 24 hours)
Prophylaxis of invasive fungal infections in patients (adults and children over 12 years), high-risk groups, such as transplant recipients of hematopoietic stem cell / prevention of "breakthrough" of 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 is established	200 mg every 12 hours	100 mg every 12 hours

Selection of dose for oral administration

In case of insufficient effectiveness of treatment voriconazole maintenance dose for oral administration can be increased by 200 mg every 12 hours to 300 mg every 12 hours. In patients weighing 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).

Duration of treatment

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

Prevention in adults and children

Prophylactic use of the drug should be started on the day of transplantation and can be continued up to 100 days. To prolong prophylaxis up to 180 days after transplantation it is possible only in case of continuation of immunosuppressive therapy or development of the "transplant versus host" reaction.

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

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

Impaired renal function

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

Impaired liver function

In acute liver damage, manifested by increased activity of "liver" transaminases: alanine 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 given a standard saturating dose of the drug, and the maintenance dose should be reduced by a factor of 2.

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

Elderly patients

Correction of dose in elderly patients is not required.

Use in children

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

The dosage regimen of voriconazole in children (aged 3 (for a given dosage form) to 12 years) and adolescents aged 12 to 14 years with a body weight of 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 2 times a day (maximum dose of 350 mg twice a day)

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

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

Recommendations for the use of voriconazole in children are given on the basis of studies of its use in the form of a powder for the preparation of a suspension for oral administration. The bioequivalence of 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) voriconazole is dosed as well as for adults.

Correction of dose

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

Side effects:

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

The most common adverse reactions are abnormalities in the body of the eye, deviations from the norms of the results of functional liver tests, fever, rash, nausea, vomiting, 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.

According to the World Health Organization (WHO), unwanted effects are classified according to their frequency of development as follows: very often (≥1/10), often (from ≥1/100 before <1/10), infrequently ≥1/1000 to <1/100), rarely (from ≥1 / 10000 to <1/1000), very rarely (<1/10000); frequency is unknown - according to available data, it was not possible to establish the frequency of occurrence.

Heart Disease

often: supraventricular arrhythmia, tachycardia, bradycardia;

infrequently: ventricular fibrillation, ventricular extrasystole, supraventricular and ventricular tachycardia;

rarely: arrhythmia of the type "pirouette", complete atrioventricular block, blockade of the legs of the bundle of the Guiss, nodular arrhythmias.

Vascular disorders

often: arterial hypotension, phlebitis;

infrequently: thrombophlebitis.

Violations of the blood and lymphatic system

often: agranulocytosis (including febrile neutropenia and neutropenia), pancytopenia, thrombocytopenia (including immune thrombocytopenic purpura), anemia;

infrequently: bone marrow depression, leukopenia, lymphadenopathy, eosinophilia,syndrome of disseminated intravascular coagulation.

Disturbances from the nervous system

Often: headache;

often: syncope, tremor, paresthesia, drowsiness, dizziness, convulsions, nystagmus;

infrequently: cerebral edema, encephalopathy, extrapyramidal disorder, peripheral neuropathy, ataxia, hypoesthesia, dysgeusia (a violation of taste perception);

rarely: hepatic encephalopathy, Guillain-Barre syndrome.

Disturbances on the part of the organ of sight

Often: visual impairment (including blurred vision, blurred vision, photophobia, chloropsy, chromatopsy, color blindness, cyanopsy, presence of iridescent circles around the light sources in the field of vision, night blindness, oscilloscopy, photopsy, scintillation scotoma, visual acuity, visual brightness, defect of visual fields, floating opacities of the vitreous body and xantopsy);

often: hemorrhage into the retina of the eye;

infrequently: neuritis of the optic nerve, edema of the nipple of the optic nerve, oculogic crisis, scleritis, diplopia, blepharitis;

rarely: atrophy of the optic nerve, corneal opacity.

Violations of the hearing and vestibular organs

infrequently: vertigo, hypoacusia, tinnitus.

Disturbances from the respiratory system, chest and mediastinal organs

Often: respiratory depression;

often: pulmonary edema, acute respiratory distress syndrome.

Disorders from the gastrointestinal tract

Often: nausea, vomiting, diarrhea, abdominal pain;

often: dyspepsia, constipation, cheilitis;

infrequently: duodenitis, glossitis, pancreatitis, edema of the tongue.

Disorders from the kidneys and urinary tract

often: acute renal failure, hematuria;

infrequently: necrosis of the kidneys, proteinuria, nephritis.

Disturbances from the skin and subcutaneous tissues

Often: rash;

often: exfoliative dermatitis, alopecia, 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: cutaneous systemic lupus erythematosus.

Disorders from the musculoskeletal system and connective tissue

often: backache;

infrequently: arthritis;

frequency unknown: periostitis.

Disorders from the endocrine system

infrequently: insufficiency of the adrenal cortex, hypothyroidism;

rarely: hyperthyroidism.

Disorders from the metabolism and nutrition

Often: peripheral edema;

often: hypokalemia, hypoglycemia, hyponatremia (identified in post-registration studies).

Infectious and parasitic diseases

often: sinusitis, gastroenteritis, gingivitis;

infrequently: pseudomembranous colitis, lymphangitis, peritonitis.

General disorders and disorders at the site of administration

Often: fever;

often: chills, asthenia, chest pain, flu-like illness, facial edema (including periorbital edema, edema of the lips and swelling of the mouth).

Immune system disorders

infrequently: allergic reactions;

rarely: anaphylactoid reactions.

Disturbances from the liver and bile ducts

Often: deviation 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.

Disorders of the psyche

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

Benign, malignant and unspecified neoplasms (including cysts and polyps)

frequency is unknown: squamous cell carcinoma of the skin.

Laboratory and instrumental data

often: increased serum creatinine concentration;

infrequently: interval lengthening QT on an electrocardiogram, an increase in the concentration of urea in the blood serum, an increase in the concentration of cholesterol in the blood serum.

Side effect when used in children

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

Overdose:

There are three cases of overdose. All of these cases occurred in children who received a dose of voriconazole intravenously,five times the recommended one. There is a report of a single case of photophobia lasting 10 minutes.

Treatment

The antidote is unknown. In case of an overdose, symptomatic and supportive therapy is indicated.

Interaction:

Inhibitors or inducers of cytochrome P450 isoenzymes (CYP2C19, CYP2C9 and CYP3A4) can cause, respectively, an increase or decrease in the concentration of voriconazole in the blood plasma.

Voriconazole inhibits the activity of cytochrome P450 isoenzymes - CYP2C19, CYP2C9 and CYP3A4 - and can increase plasma concentrations of substances that are metabolized with the participation of cytochrome P450 isoenzymes. The interaction of voriconazole with other drugs and recommendations for simultaneous use are presented in the table below:

Medicine [interaction mechanism]	Interaction: change in 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 in the blood plasma can lead to an extension of the QTc interval and, in rare cases, the occurrence of ventricular pirouette tachycardia.	Contraindicated
Carbamazepine and long-acting barbiturates (for example, phenobarbital, mefobarbital) [powerful inductors CYP450]	Interaction has not been studied, potentially can significantly reduce the concentration of voriconazole in blood plasma.	Contraindicated
Efavirenz (non-nucleoside reverse transcriptase inhibitor) [CYP450 inducer; 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_maxefavirenz ↑ 38% AUC_τ efavirenz ↑ 44% FROM_maxvoriconazole ↓ 61% AUC_τ voriconazole ↓ 77%	The use of standard doses of voriconazole and efavirenz 400 mg once a day is contraindicated.
Simultaneous use of efavirenz in a dose of 300 mg once a day and voriconazole at a dose of 400 mg 2 times a day *	In comparison with efavirenz in a dose of 600 mg once a day, FROM_maxefavirenz ↔ AUC_τ efavirenz ↑ 17%. In comparison with voriconazole in a dose of 200 mg 2 times a day, FROM_max voriconazole ↑ 23% AUC_τ voriconazole ↓ 7%	Simultaneous use of voriconazole and efavirenz is possible if the maintenance dose of voriconazole is increased to 400 mg 2 times a day, and the dose of efavirenz is reduced to 300 mg once a day. After cessation of therapy with voriconazole, the initial dose of efavirenz should be restored.
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 [a powerful inducer of CYP450]
300 mg once a day	FROM_max voriconazole ↓ 69% AUC_τ voriconazole ↓ 78% FROM_max rifabutin ↑ 195% AUC_τ rifabutin ↑ 331%
300 mg once a day with simultaneous application with voriconazole at a dose of 400 mg 2 times a day *	In comparison with voriconazole in a dose of 200 mg 2 times a day: FROM_max voriconazole ↑ 104% AUC_τ voriconazole ↑ 87%	Contraindicated
Rifampicin (600 mg once daily) [powerful CYP450 inducer]	FROM_max voriconazole ↓ 93% AUC_τ voriconazole ↓ 96%	Contraindicated
Ritonavir (protease inhibitor) [potent inducer of cytochrome P450 isoenzymes inhibitor and substrate of isoenzyme CYP3A4]
High doses (400 mg twice a day)	FROM_max and AUC_τ ritonavir ↔ FROM_maxvoriconazole ↓ 66% AUC_τ voriconazole ↓ 82%	The simultaneous use of voriconazole and high doses of ritonavir (400 mg and above 2 times a day) is contraindicated.
Low doses (100 mg twice a day) *	FROM_max ritonavir ↓ 25% AUC_τ ritonavir ↓ 13% FROM_max 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 exceeds the risk of their combined use.
St. John's wort perforated [cytochrome P450 isoenzyme inducer; inducer of P-glycoprotein] 300 mg 3 times a day (simultaneous application with a single dose of voriconazole 400 mg)	According to independent research: 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, CYP2C19 and CYP3A4]	FROM_maxvoriconazole ↑ 57% AUC_τ voriconazole ↑ 79% Changes in C_max and AUC_τfluconazole are not established.	A suitable dosing regimen and / or frequency of administration of voriconazole and fluconazole are 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 [CYP2C9 substrate and powerful CYP450 inducer]
300 mg once a day	FROM_max voriconazole ↓ 49% AUC_τ voriconazole ↓ 69%	It should avoid simultaneous reception of voriconazole and phenytoin, except when the expected benefit exceeds the risk. It is recommended to monitor plasma concentrations of phenytoin.
300 mg once a day with the simultaneous use of voriconazole at a dose of 400 mg 2 times a day *	FROM_max phenytoin ↑ 67% AUC_τ phenytoin ↑ 81% In comparison with voriconazole in a dose of 200 mg 2 times a day, FROM_max voriconazole ↑ 34% AUC_τ voriconazole ↑ 39%	Simultaneous application is possible if the maintenance dose of voriconazole is increased to 5 mg / kg intravenously or 200 mg to 400 mg orally twice a day (or from 100 mg to 200 mg orally twice a day in patients with body weight less than 40 kg).
Anticoagulants Warfarin (30 mg once with voriconazole 300 mg twice a day) [substrate of the isoenzyme CYP2C9]	The maximum increase in prothrombin time is approximately 2-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 coumarins (eg, 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 can cause an increase in plasma concentrations of benzodiazepines, which are metabolized by the isozyme CYP3A4, and cause the development of a 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_max 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_max cyclosporine ↑ 13% AUC_τ cyclosporine ↑ 70%	When prescribing voriconazole, patients receiving ciclosporin, it is recommended to reduce the dose of cyclosporine by 2 times and carefully monitor its concentration in the blood plasma. There was a correlation between an increase in the concentration of cyclosporine and nephrotoxicity. After voriconazole cancellation, the concentration of cyclosporine in the blood plasma should be carefully monitored and, if necessary, increased its dose.
Tacrolimus (a single dose of 0.1 mg / kg)	FROM_max tacrolimus ↑ 117% AUC_t tacrolimus ↑ 221%	When prescribing voriconazole, patients receiving tacrolimus, it is recommended to reduce the dose of tacrolimus to 1/3 of the initial dose and carefully monitor its concentration in the blood plasma. There was a correlation between increased tacrolimus concentration and nephrotoxicity. After voriconazole withdrawal, the concentration of tacrolimus in the blood plasma should be carefully monitored and, if necessary, increased its dose.
Long-acting opiates [substrates of the isoenzyme CYP3A4]
Oxycodone (10 mg once)	According to an independent study: FROM_max oxycodone ↑ 1.7 times AUC_0-∞ oxycodone ↑ in 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 with short intervals for the development of unwanted reactions associated with opiates.
Methadone (32-100 mg once a day) [substrate of the isoenzyme CYP3A4]	FROM_max R-methadone (active) ↑ 31% AUC_τ R-methadone (active) ↑ 47% FROM_max S-methadone ↑ 65% AUC_τ S-methadone ↑ 103%	An increase in the concentration of methadone in the blood plasma leads to the appearance of toxic effects, including the prolongation of the QT interval. It is recommended that the patient be frequently monitored for the development of unwanted reactions and toxicity (including prolongation of the QT interval) associated with methadone. You may need to reduce the dose of methadone.
Non-steroidal anti-inflammatory drugs (NSAIDs) [substrates of the isoenzyme CYP2C9]		Patients should be observed to identify possible toxic effects and, if necessary, adjust the dose of NSAIDs.
Ibuprofen (400 mg once)	FROM_max S-ibuprofen ↑ 20% AUC_0-∞ S-ibuprofen ↑ 100%
Diclofenac (50 mg once)	FROM_max diclofenac ↑ 114% AUC_0-∞ diclofenac ↑ 78%
Omeprazole (1 40 mg once a day) * [isoenzyme inhibitor CYP2C19; substrate of isoenzymes CYP2C19 and CYP3A4]	FROM_maxomeprazole ↑ 116% AUC_τ omeprazole ↑ 280% FROM_maxvoriconazole ↑ 15% AUC_τ voriconazole ↑ 41%	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, it is recommended that the dose of omeprazole be reduced by a factor of 2.
	Voriconazole can inhibit other proton pump inhibitors (PPIs), which are substrates of the CYP2C19 isoenzyme, which can lead to an increase in their concentrations in the blood plasma.
Oral contraceptives * [substrates of the isoenzyme CYP3A4; inhibitors of the isoenzyme CYP2C19] Norethisterone / ethinylestradiol (1 mg / 0.035 mg once daily)	FROM_max ethinylestradiol ↑ 36% AUC_τethinyl estradiol ↑ 61% FROM_max norethisterone ↑ 15% AUC_τ norethisterone ↑ 53% FROM_max voriconazole ↑ 14% AUC_τ voriconazole ↑ 46%	It is recommended to monitor the patient's condition for the development of unwanted reactions associated with the use of oral contraceptives and voriconazole.
Narcotic analgesics of short action [substrates of isoenzyme CYP3A4]		The possibility of reducing the dose of alfentanil and other narcotic short-acting analgesics having a chemical structure similar to alfentanil and metabolized by the CYP3A4 isoenzyme (eg, sufentanil). Patients should be under constant supervision to prevent oppression of respiratory function or other side effects,associated with the use of short-acting narcotic analgesics, if necessary, their dose should be reduced.
Alfentanil (a single dose of 20 mcg / kg, with the concomitant administration of naloxone)	According to an independent study: AUC_0-∞ alfentanil ↑ 6 times
Fentanyl (5 μg / kg single dose)	According to an independent study: AUC_0-∞ fentanyl ↑ 1,34 times
Statins (for example, lovastatin) [substrates of the isoenzyme CYP3A4]	The interaction was not studied, however, voriconazole can increase plasma concentrations of statins that are metabolized by the CYP3A4 isoenzyme, which can lead to rhabdomyolysis.	It should be assessed the possibility of reducing the dose of statins.
Derivatives of sulfonylureas (for example, tolbutamide, glipizide, glibenclamide) [substrates of the isoenzyme CYP2C9]	The interaction was not studied, however, voriconazole can increase plasma concentrations of sulfonylureas and cause hypoglycemia.	It is necessary to carefully monitor the concentration of glucose in the blood plasma.
Vinca alkaloids (for example, vincristine and vinblastine) [substrates of the isoenzyme CYP3A4]	Voriconazole can increase the vinca alkaloids (vincristine and vinblastine) in the blood plasma and cause neurotoxicity.	It is recommended to evaluate the feasibility of correcting the dose of vinca alkaloids.
Other HIV protease inhibitors (eg, saquinavir, amprenavir and nelfinavir) [substrates and inhibitors 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) * [substrates of the CYP3A 4 isoenzyme, inhibitors or inducers of CYP450]	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 a day) [non-specifically inhibits CYP450, increases the pH of gastric juice]	FROM_max voriconazole ↑ 18% AUC_τ voriconazole ↑ 23%	Correction of dose is not required
Digoxin (0.25 mg once daily) [P-glycoprotein substrate]	FROM_max digoxin ↔ AUC_τ digoxin ↔	Correction of dose is not required
Indinavir (800 mg 3 times daily) [inhibitor and substrate of the isoenzyme CYP3A4]	FROM_max indinavir ↔ AUC_T indinavir ↔ FROM_max voriconazole ↔ AUC_τ voriconazole ↔	Correction of dose is not required
Antibiotics of the macrolide group		Correction of dose is not required
Erythromycin (1 g 2 times per day) [inhibitor of the isoenzyme CYP3A4]	FROM_max and AUC_τ voriconazole ↔
Azithromycin (500 mg once daily)	FROM_max and AUC_τ voriconazole ↔ Effect of voriconazole on erythromycin or azithromycin is unknown.
Mycophenolic acid (1 g once) [uridine-5-diphosphate-glucuronyltransferase substrate]	FROM_max mycophenolic acid ↔ AUC_t mycophenolic acid	Correction of dose is not required
Prednisolone (60 mg once) [substrate of the isoenzyme CYP3A4]	FROM_max prednisolone ↑ 11% AUC_0-∞ prednisolone ↑ 34%	Correction of dose is not required
Ranitidine (150 mg twice daily) [increases the pH of gastric juice]	FROM_max and AUC_τ voriconazole ↔	Correction of dose is not required

* Mutual effect.

The pharmacokinetic parameter based on a 90% confidence interval of the mean geometric value is within (↔), below (↓) or above (↑) of the 80% -125% interval.

AUC_τ, AUC_t and 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 and 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. paraprilosis, 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.

but in vitro voriconazole activity against fungi of different species Candida is not the same. In particular, the MIC of voriconazole for fluconazole-resistant isolates FROM. glabrata is proportionally higher than the MIC for isolates sensitive to fluconazole. In this regard, 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 (ECG), which is accompanied by rare cases of ventricular flicker / flutter in severely ill patients with multiple risk factors, such as cardiotoxic chemotherapy, cardiomyopathy, hypokalemia, concomitant therapy, which could contribute to the development of this complication.

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

- congenital or acquired lengthening interval QT;

- Cardiomyopathy, especially in combination with heart failure;

- sinus bradycardia;

- existing arrhythmias with clinical manifestations;

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

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

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

Hepatotoxicity

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

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

Monitoring of liver function

During treatment with voriconazole, it is recommended to constantly monitor liver function in both children and adults. Clinical management of such patients should include a laboratory assessment of liver function (in particular, activity determination ACT and ALT) at the beginning of treatment with voriconazole, and at least once a week during the first month of treatment. 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 correlation between the benefit and risk of therapy according to the medical evaluation does not justify its continued use (see the section "Dosing and Administration").

Visual disorders

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

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

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

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

Undesirable effects of the kidneys

In seriously ill patients, 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. For this, it is necessary to conduct laboratory tests, in particular, to determine the concentration of serum creatinine (see also the 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

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

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

Since during the therapy with voriconazole, photosensitization may develop, during treatment, patients (including children) are advised to avoid exposure to direct sunlight and take protective measures such as wearing clothes and applying sunscreens with a high UV-protection factor (SPF ).

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 transplant who receive voriconazole therapy. The therapy with voriconazole should be discontinued if the patient has bone pain and radiograph changes that are characteristic of periostitis.

Use in children

Voriconazole is indicated for use in children aged 3 years (for a given dosage form) and older with continuous monitoring of liver function. In children, an increase in the activity of liver enzymes is more common.

Bioavailability of voriconazole for oral administration in children aged 3 (for a given dosage form) to 12 years may be reduced due to impaired absorption or reduced 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, children should take strict measures to protect the skin from ultraviolet radiation. Children with signs of photoaging of the skin, such as lentigo or freckles, are advised to avoid the sun and be examined by a dermatologist even after discontinuation of treatment.

Narcotic analgesics of short action (substrates of isoenzyme CYP3A4)

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

Long-acting narcotic analgesics (substrates of isoenzyme CYP3A4)

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

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

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

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

In case of simultaneous use of voriconazole and efavirenz, a dose of voriconazole should be increased to 400 mg every 12 hours, and the dose of efavirenz should be reduced to 300 mg every 24 hours (see "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 isoenzymes, an inhibitor and isoenzyme substrate CYP3A4)

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

Everolimus (isoenzymatic substrate CYP3A4 and P-glycoprotein)

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

Methadone (isoenzymatic substrate CYP3A4)

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

Fluconazole (inhibitor of isoenzymes CYP2C9, CYP2C19 and CYP3A4)

Simultaneous use of voriconazole and fluconazole inwards in healthy volunteers leads to a significant increase in C_mOh and AUC_τvoriconazole. A suitable dosing regimen and / or frequency of administration 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. If such symptoms are present, 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:

For 10 or 14 tablets in PVC / PVDC / Al blister or 30, 100 or 1000 tablets in a bottle of high-density polyethylene with a polypropylene lid with protection from children.

For 1, 2 or 3 blisters or 1 bottle together with instructions for medical use are placed in a cardboard box.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

The preparation in vials after autopsy should be stored:

- dosage 50 mg - not more than 1 month;

- dosage 200 mg - not more than 2 months.

Do not use the drug after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004031

Date of registration:22.12.2016

Expiration Date:22.12.2021

The owner of the registration certificate:Sandoz d.Sandoz d. Slovenia

Manufacturer: & nbsp

SANDOZ PRIVATE, Limited India

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp21.01.2017

Illustrated instructions

Instructions

Voriconazole Sandoz® (Voriconazole Sandoz)