Bethend, lyophilizate 200 mg

Voriconazole is a broad-spectrum antifungal drug that belongs to the group of triazole antibiotics.

The mechanism of action of voriconazole is associated with inhibition of 14α-sterol demethylation mediated by fungal cytochrome P450; this reaction is a key step in ergosterol biosynthesis.

In vitro voriconazole has a broad spectrum of antifungal activity and is active against Candida spp. (including fluconazole-resistant strains of C. krusei and resistant strains of C. glabrata and C. albicans), and has a fungicidal effect against all Aspergillus sp. strains studied as well as pathogenic fungi of recent relevance, including Scedosporium or Fusarium, which have limited sensitivity to existing antifungal agents.

The clinical efficacy has been demonstrated in infections caused by Aspergillus spp. including A. flavus, A. fumigatus, A. terreus, A. niger, A. nidulans, Candida spp. including C. albicans, C. dubliniensis, C. glabrata, C. inconspicua, C. krusei, C. parapsilosis, C. tropicalis and C. guilliermondii, Scedosporium spp. including S. apiospermum, S. prolificans and Fusarium spp.

Other fungal infections for which the drug was used (often with partial or complete response) included isolated infections caused by Alternaria spp., Blastomyces dermatitidis, Blastoschizomyces capitatus, Cladosporium spp, Coccidioides immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum, Exophiala spinifera, Fonsecaea pedrosoi, Madurella mycetomatis, Paecilomyces lilacinus, Penicillium spp. including P. marneffei, Phialophora richardsiae, Scopulariopsis brevicaulis and Trichosporon spp. including T. beigelii.

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

In vitro activity of voriconazole against Curvularia spp. and Sporothrix spp. was detected, but its clinical significance is unknown.

Pharmacokinetics

The pharmacokinetics of voriconazole were studied in healthy subjects, special groups and patients.
The pharmacokinetics of voriconazole is nonlinear due to its metabolic saturation. A disproportionate (more pronounced) increase in AUC (area under the curve “concentration-time”) is observed with increasing dose. It has been calculated that increasing the oral dose from 200 mg 2 times a day to 300 mg 2 times a day leads to an average 2.5-fold increase in AUCτ. With intravenous or oral shock doses, plasma concentrations approach equilibrium within the first 24 hours. If a patient does not receive a shock dose, repeated administration of voriconazole 2 times daily causes cumulation of the drug, and equilibrium plasma concentrations are reached by day 6 in most patients.

Voriconazole is rapidly and almost completely absorbed after oral administration; maximum plasma concentrations (Cmax) are reached 1-2 hours after administration. Bioavailability of voriconazole when taken orally is 96%. When voriconazole is repeatedly taken with a fatty food Cmax and AUCτ are decreased by 34% and 24% respectively.

The absorption of voriconazole is independent of the pH of gastric juice.

The calculated volume of distribution of voriconazole in equilibrium is 4.6 l/kg, indicating active distribution of the drug in the tissue. Binding to plasma proteins is 58%.

Voriconazole is determined in the cerebrospinal fluid.

Pharmacokinetics of voriconazole is characterized by high interindividual variability.
In vitro studies showed that voriconazole is metabolized under the influence of hepatic cytochrome P450 isoenzymes – CYP2C19, CYP2C9 and CYP3A4.

In vivo studies also suggest that CYP2C19 plays an important role in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism. For example, reduced metabolism of voriconazole can be expected in 15-20% of Asians and 3-5% of whites and blacks. Studies in white and Japanese patients have shown that the AUCτ of voriconazole is, on average, 4 times higher in patients with low metabolism than in homozygous patients with high metabolism. In heterozygous patients with active metabolism, the AUCτ of voriconazole was, on average, 2 times higher than in homozygous patients.

The main metabolite of voriconazole is N-oxide, which accounts for 72% of the circulating labeled metabolites in plasma. This metabolite has minimal antifungal activity and does not contribute to the effect of voriconazole.
Less than 2% of the drug dose is excreted unchanged in the urine.

After repeated intravenous and oral administration of labeled voriconazole, approximately 80% and 83% of the radioactive dose, respectively, are detected in the urine. Most (>94%) of the total dose is excreted within the first 96 h after oral and intravenous administration.

The terminal elimination half-life of voriconazole is dose-dependent and is approximately 6 h when administered orally at a dose of 200 mg. Due to the non-linearity of pharmacokinetics, the terminal elimination half-life does not predict the cumulation or excretion of voriconazole.

Pharmacokinetics in Special Groups
Gender
On oral repeated administration, Cmax and AUCτ in healthy young women were 83% and 113% higher, respectively, than in young healthy men (18-45 years). There were no significant differences in Cmax and AUCτ in healthy older men and healthy older women (>65 years).

There is no need for dose adjustment depending on sex. Plasma concentrations in men and women are similar.

Age
On repeated oral administration, Cmax and AUCτ in healthy elderly men (>65 years) are 61%) and 86%o higher, respectively, than in healthy young men (18-45 years). There are no significant differences in Cmax and AUCτ in healthy elderly women (>65 years old) and healthy young women (18-45 years old). Safety of voriconazole in young and elderly patients is the same, in connection with that the dose adjustment in elderly age is not required.

Kidney dysfunction
A single oral dose of voriconazole 200 mg in patients with normal renal function and patients from mild (creatinine clearance 41-60 ml/min) to severe (creatinine clearance In patients with moderate to severe renal function impairment (serum creatinine levels >220 μmol/l, or 2.5 mg/dL), there is a cumulation of the excipient in SBECD lyophilisate for preparation of solution for injection.

Hepatic impairment
After a single oral dose (200 mg), the AUC of voriconazole in patients with mild to moderately severe cirrhosis (Child-Pugh A and B) is 233% higher than in patients with normal liver function. Impaired liver function does not affect the binding of voriconazole to plasma proteins.

Indications

– Invasive aspergillosis.

– Candidemia in patients without neutropenia.

– Severe invasive candidal infections (including S. krusei).

– Candidiasis of the esophagus.

– Severe fungal infections caused by Scedosporium spp. and Fusarium spp.

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

– Prevention of “breakthrough” fungal infections in patients with reduced immune system function, fever and neutropenia from high-risk groups (hematopoietic stem cell transplant recipients, patients with relapsed leukemia).

– Prevention of invasive fungal infections in patients (adults and children over 12 years of age) at high risk such as hematopoietic stem cell transplant recipients.

Pharmacological effect

Voriconazole is a broad-spectrum antifungal drug that belongs to the group of antibiotics with a triazole structure.

The mechanism of action of voriconazole is associated with inhibition of 14α-sterol demethylation mediated by fungal cytochrome P450; this reaction is a key step in the biosynthesis of ergosterol.

In vitro, voriconazole has a broad spectrum of antifungal activity and is active against Candida spp. (including strains of C. krusei resistant to fluconazole, and resistant strains of C. glabrata and C. albicans), and has a fungicidal effect against all studied strains of Aspergillus sp. as well as pathogenic fungi that have become relevant recently, including Scedosporium or Fusarium, which have limited sensitivity to existing antifungal agents.

Clinical efficacy has been demonstrated in infections caused by Aspergillus spp., including A. flavus, A. fumigatus, A. terreus, A. niger, A. nidulans, Candida spp., including C. albicans, C. dubliniensis, C. glabrata, C. inconspicua, C. krusei, C. parapsilosis, C. tropicalis and C. guilliermondii, Scedosporium spp., including S. apiospermum, S. prolificans and Fusarium spp.

Other fungal infections for which the drug has been used (often with partial or complete response) have included isolated cases of infections caused by Alternaria spp., Blastomyces dermatitidis, Blastoschizomyces capitatus, Cladosporium spp., Coccidioides immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum, Exophiala spinifera, Fonsecaea pedrosoi, Madurella mycetomatis, Paecilomyces lilacinus, Penicillium spp., including P. marneffei, Phialophora richardsiae, Scopulariopsis brevicaulis and Trichosporon spp., including T. beigelii.

In vitro activity of voriconazole has been demonstrated against clinical strains of Acremonium spp., Alternaria spp., Bipolaris spp., Cladophialophora spp., Histoplasma capsulatum. The growth of most strains was inhibited at voriconazole concentrations ranging from 0.05 to 2 μg/ml.

In vitro activity of voriconazole against Curvularia spp. and Sporothrix spp., but its clinical significance is unknown.

Pharmacokinetics

The pharmacokinetics of voriconazole were studied in healthy people, representatives of special groups and patients.
The pharmacokinetics of voriconazole is nonlinear due to the saturation of its metabolism. As the dose increases, a disproportionate (more pronounced) increase in AUC (area under the concentration-time curve) is observed. It is estimated that increasing the oral dose from 200 mg twice daily to 300 mg twice daily results in an average 2.5-fold increase in AUCτ. With intravenous or oral administration of loading doses, plasma concentrations approach equilibrium within the first 24 hours. If the patient does not receive a loading dose, then with repeated use of voriconazole 2 times a day, the drug cumulates, and equilibrium plasma concentrations are achieved by the 6th day in most patients.

Voriconazole is rapidly and almost completely absorbed after oral administration; Maximum plasma concentrations (Cmax) are achieved 1-2 hours after administration. The bioavailability of voriconazole when taken orally is 96%. When voriconazole is repeated with a fatty meal, Cmax and AUCτ are reduced by 34% and 24%, respectively.

The absorption of voriconazole is independent of gastric pH.

The estimated volume of distribution of voriconazole at steady state is 4.6 L/kg, indicating active distribution of the drug into tissue. Plasma protein binding is 58%.

Voriconazole is detected in the cerebrospinal fluid.

The pharmacokinetics of voriconazole is characterized by high interindividual variability.
In vitro studies have shown that voriconazole is metabolized by the hepatic isoenzymes of cytochrome P450 – CYP2C19, CYP2C9 and CYP3A4.

In vivo studies also suggest that CYP2C19 plays an important role in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism. For example, decreased metabolism of voriconazole can be expected in 15-20% of Asians and 3-5% of whites and blacks. Studies in Caucasians and Japanese subjects have shown that in poor metabolizers, the voriconazole AUCτ is on average 4 times higher than in homozygous high metabolizers. In heterozygous patients with active metabolism, the AUCτ of voriconazole is on average 2 times higher than in homozygous patients.

The main metabolite of voriconazole is N-oxide, which accounts for 72% of circulating labeled metabolites in plasma. This metabolite has minimal antifungal activity and does not contribute to the effect of voriconazole.
Less than 2% of the drug dose is excreted unchanged in the urine.

After repeated intravenous and oral administration of labeled voriconazole, approximately 80% and 83% of the radioactive dose, respectively, are found in the urine. The majority (>94%) of the total dose is eliminated within the first 96 hours after oral and intravenous administration.

The terminal half-life of voriconazole is dose dependent and is approximately 6 hours when the drug is taken orally at a dose of 200 mg. Due to the non-linearity of pharmacokinetics, the terminal half-life does not predict the accumulation or elimination of voriconazole.

Pharmacokinetics in special groups
Gender
With repeated oral administration, Cmax and AUCτ in healthy young women were 83% and 113% higher, respectively, than in young healthy men (18-45 years). There are no significant differences in Cmax and AUCτ between healthy elderly men and healthy elderly women (>65 years).

There is no need for dose adjustment depending on gender. Plasma concentrations are similar in men and women.

Age
With repeated oral administration, Cmax and AUCτ in healthy elderly men (>65 years) are 61%) and 86% higher, respectively, than in healthy young men (18-45 years). There are no significant differences in Cmax and AUCτ in healthy elderly women (>65 years) and healthy young women (18-45 years). The safety of voriconazole is similar in young and elderly patients, and therefore no dosage adjustment is required in the elderly.

The mean steady-state plasma concentrations of the drug in children receiving the drug at a dose of 4 mg/kg every 12 hours are comparable to those in adults receiving voriconazole at a dose of 3 mg/kg every 12 hours. The mean concentration was 1186 ng/ml in children and 1155 ng/ml in adults. In this regard, the recommended maintenance dose in children aged 2 to

Renal dysfunction
With a single oral dose of 200 mg voriconazole in patients with normal renal function and patients with mild (creatinine clearance 41-60 ml/min) to severe (creatinine clearance in patients with moderate or severe renal impairment (serum creatinine levels > 220 µmol/l, or 2.5 mg/dl) there is an accumulation of the excipient included in in the composition of the lyophilisate for the preparation of solution for injection – SBECD.

Liver dysfunction
After a single oral dose (200 mg), the AUC of voriconazole in patients with mild to moderately severe liver cirrhosis (Child-Pugh A and B) is 233% higher than in patients with normal liver function. Impaired liver function does not affect the binding of voriconazole to plasma proteins.

With repeated oral administration, the AUCX of voriconazole is comparable in patients with moderate liver cirrhosis (Child-Pugh B) receiving the drug at a maintenance dose of 100 mg twice daily and in patients with normal liver function receiving voriconazole at a dose of 200 mg twice daily. There is no information on pharmacokinetics in patients with severe liver cirrhosis (Child-Pugh C).

Special instructions

Sampling for culture and other laboratory tests (serology, histopathology) for the purpose of isolating and identifying pathogens should be done before treatment. Therapy may be initiated pending culture and other laboratory results, but if available, treatment should be adjusted accordingly.
Clinical strains with reduced sensitivity to voriconazole have been isolated.

However, elevated minimal inhibitory concentrations (MICs) do not always predict clinical failure; There are cases where voriconazole was effective in patients infected with microorganisms resistant to other azoles. Assessing the correlation between in vitro activity and clinical treatment outcomes is difficult given the complexity of the patients included in clinical studies; Breakpoint concentrations for voriconazole to assess sensitivity to this drug have not been established.
Hypersensitivity: Patients with hypersensitivity to other azoles should use voriconazole with caution.

Cardiovascular Adverse Events: The use of voriconazole is associated with prolongation of the QT interval on the electrocardiogram, which is accompanied by rare cases of ventricular fibrillation-flutter in patients receiving voriconazole therapy (in critically 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 administered with caution to patients with these potentially proarrhythmic conditions (see Dosage and Administration).
Hepatotoxicity: Infrequent (0.1-1%) cases of serious liver reactions (including clinically manifested hepatitis, cholestasis and hepatic cell failure, including death) have been observed during treatment with voriconazole. Adverse events from the liver are mainly observed in patients with serious diseases (mainly malignant blood tumors). In patients without any risk factors, transient liver reactions, including hepatitis and jaundice, are observed. Liver dysfunction is usually reversible and disappears after cessation of treatment.

Monitoring liver function: During treatment with voriconazole, it is recommended to regularly monitor liver function, especially liver function tests and bilirubin. If clinical signs of liver disease that may be associated with voriconazole occur, the advisability of discontinuing therapy should be discussed.
Adverse events from the kidneys: Cases of acute renal failure have been observed in severely ill patients receiving voriconazole.

Renal function monitoring:
Patients should be monitored for signs of renal dysfunction. To do this, it is necessary to conduct laboratory tests, in particular, determine the serum creatinine level.
Infusion reactions: When voriconazole is administered intravenously, infusion reactions are observed, mainly “flushing” and nausea. If these symptoms are severe, the advisability of stopping treatment should be discussed (see section Side effects).
Skin reactions: In rare cases, patients treated with voriconazole have developed exfoliative skin reactions such as Stevens-Johnson syndrome. Patients should be observed if a rash appears. If skin lesions progress, it is advisable to discontinue voriconazole.
In addition, the use of voriconazole was accompanied by photosensitivity skin reactions, especially with long-term treatment. During treatment, patients are advised to avoid intense or prolonged exposure to direct sunlight.

Cyclosporine and tacrolimus (CYP3A4 substrates): Patients receiving cyclosporine or tacrolimus may experience clinically significant interactions with voriconazole (see Section Interactions with other drugs and other forms of interaction).
Phenytoin (CYP2C9 substrate and strong CYP450 inducer): Close monitoring of phenytoin levels is recommended when phenytoin is used concomitantly with voriconazole. If possible, the simultaneous use of voriconazole and phenytoin should be avoided unless the expected benefit outweighs the possible risk (see Interactions with other drugs and other forms of interaction).

Rifabutin (CYP450 inducer): When coadministering rifabutin with voriconazole, it is recommended to perform a complete blood count and monitor for adverse effects of rifabutin (e.g., uveitis). Concomitant use of voriconazole and rifabutin should be avoided unless the expected benefit outweighs the possible risk (see Interactions with other drugs and other forms of interaction).
Women of reproductive age
Women of reproductive age should always use effective methods of contraception during treatment.

Impact on the ability to drive a car and use equipment
Voriconazole may cause transient and reversible visual disturbances, including blurred vision, blurred/increased visual perception and/or photophobia. If these symptoms occur, patients should avoid performing potentially dangerous activities such as driving or using complex machinery. While taking voriconazole, patients should not drive at night.

Active ingredient

Voriconazole

Composition

1 bottle of lyophilisate for preparing a solution for infusion contains:

active ingredient:

voriconazole 200 mg,

excipients:

Sodium beta-cyclodextrin sulfobutyl ether (SBECD).

Pregnancy

There is no adequate information on the use of voriconazole in pregnant women.

Animal studies have shown that the drug in high doses has a toxic effect on reproductive function. The possible risk to humans is unknown.

Voriconazole should not be used in pregnant women unless the expected benefit to the mother clearly outweighs the possible risk to the fetus.

The excretion of voriconazole into breast milk has not been studied. Voriconazole should not be used in women who are breastfeeding unless the expected benefit clearly outweighs the risk.

Contraindications

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

– The simultaneous use of Vfend® and the following drugs is contraindicated (see section “Interaction with other drugs”): substrates of the CYP3A4 isoenzyme – terfenadine astemizole cisapride pimozide or quinidine; sirolimus; rifamycin carbamazepine and long-acting barbiturates (phenobarbital); rifabutin; efavirenz in doses of 400 mg or higher once daily (with voriconazole in standard doses); ritonavir in high doses (400 mg or more twice a day); ergot alkaloids (ergotamine dihydroergotamine) which are substrates of the CYP3A4 isoenzyme; St. John’s wort (inducer of cytochrome P450 and P-glycoprotein).

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

With caution:

– Hypersensitivity to other drugs – azole derivatives.

– Severe degree of liver failure; severe degree of kidney failure.

– Voriconazole should be used with caution in patients with proarrhythmic conditions: congenital or acquired increase in the QT interval, cardiomyopathy, especially with heart failure, sinus bradycardia, the presence of symptomatic arrhythmia, concomitant use of drugs that cause prolongation of the QT interval (see section “Special Instructions”).

– Caution should also be exercised when using Vfend® in patients with electrolyte disturbances such as hypokalemia, hyiomagnesemia and hypocalcemia.

Side Effects

The most common adverse reactions are visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, peripheral edema and abdominal pain. Adverse reactions were usually mild or moderate.

General: fever, peripheral edema (very common); chills, asthenia, chest pain, injection site reactions/inflammation, flu-like syndrome (common).

Cardiovascular system: decreased blood pressure, thrombophlebitis, phlebitis (often); atrial arrhythmias, bradycardia, tachycardia, ventricular arrhythmia, supraventricular tachycardia, QT interval prolongation, ventricular fibrillation (rare); complete atrioventricular block, bundle branch block, nodal arrhythmias, ventricular tachycardia (including ventricular flutter) (very rare).

Digestive system: nausea, vomiting, diarrhea, abdominal pain (very common); increased liver function tests (including AST, ALT, alkaline phosphatase, gamma-GT, LDH, bilirubin), jaundice, cheilitis, gastroenteritis, cholestatic jaundice (often); cholecystitis, cholelithiasis, constipation, duodenitis, dyspepsia, liver enlargement, gingivitis, glossitis, hepatitis, liver failure, pancreatitis, swelling of the tongue, peritonitis (rare); pseudomembranous colitis, hepatic coma (very rare).

Endocrine system: adrenal insufficiency (rare); hyperthyroidism, hypothyroidism (very rare). Immune system: allergic reactions, anaphylactoid reactions (rare).

Blood and lymphatic system: thrombocytopenia, anemia (including macrocytic, microcytic, normocytic, megaloblastic, aplastic), leukopenia, pancytopenia (often); lymphadenopathy, agranulocytosis, eosinophilia, disseminated intravascular coagulation syndrome, suppression of bone marrow hematopoiesis (rare); lymphangitis (very rare).

Metabolism and nutrition: hypokalemia, hypoglycemia (often); hypercholesterolemia (rare).

Musculoskeletal system: back pain (common); arthritis (rare).

Nervous system: headache (very common); dizziness, hallucinations, confusion, depression, anxiety, tremor, agitation, paresthesia (common); Ataxia, cerebral edema, hypertension, hyposthesia, nystagmus, syncope (rare); Guienne-Barré syndrome, oculomotor crisis, extrapyramidal syndrome, insomnia, encephalopathy, drowsiness during infusion (very rare).

Respiratory system: respiratory distress syndrome, pulmonary edema, sinusitis (often).

Skin and subcutaneous tissues: rash (very common); itching, maculopapular rash, photosensitivity skin reactions, alopecia, exfoliative dermatitis, facial edema, purpura (common); fixed drug rash, eczema, psoriasis, Stevens-Johnson syndrome, urticaria (rare); angioedema, discoid lupus erythematosus, erythema multiforme, toxic epidermal necrolysis (very rare).

Sense organs: visual disturbances (including impaired/increased visual perception, blurred vision, changes in color vision, photophobia) (very common); blepharitis, optic neuritis, papilledema, scleritis, impaired taste perception, diplopia (rare); retinal hemorrhage, corneal opacities, optic atrophy, hypoacusis, tinnitus (very rare).

Genitourinary system: increased creatinine, acute renal failure, hematuria (often); increased residual urea nitrogen, albuminuria, nephritis (rare); necrosis of renal tubules (very rare).

Interaction

Voriconazole is metabolized by the action of cytochrome P450 isoenzymes – CYP2C19, CYP2C9 and CYP3A4. Inhibitors or inducers of these isoenzymes may cause an increase or decrease in voriconazole plasma concentrations, respectively.

When used simultaneously with rifampicin (CYP P450 inducer) at a dose of 600 mg/day, the Cmax and AUC of voriconazole are reduced by 93% and 96%, respectively (this combination is contraindicated).

When used concomitantly with Vfend, ritonavir (CYP P450 inducer, CYP3A4 inhibitor and substrate) at a dose of 400 mg every 12 hours reduced the steady-state Cmax and AUC of oral voriconazole by an average of 66% and 82%, respectively. The effect of lower doses of ritonavir on voriconazole concentrations is not yet known. It has been established that repeated oral use of voriconazole does not have a significant effect on Cmax at steady state and AUC of ritonavir, also taken repeatedly (simultaneous use of voriconazole and ritonavir at a dose of 400 mg every 12 hours is contraindicated).

When used concomitantly with the strong CYP P450 inducers carbamazepine or long-acting barbiturates (phenobarbital), a significant decrease in the plasma Cmax of voriconazole is possible, although their interaction has not been studied. This combination is contraindicated.

When used together with cimetidine (a nonspecific CYP P450 inhibitor) at a dose of 400 mg 2 times / day, the Cmax and AUC of voriconazole increase by 18% and 23%, respectively (no dose adjustment of Vfend is required).

Ranitidine at a dose of 150 mg 2 times a day when used together does not have a significant effect on the Cmax and AUC of voriconazole.

Erythromycin (CYP3A4 inhibitor) when used at a dose of 1 g 2 times / day and azithromycin at a dose of 500 mg 1 time / day do not have a significant effect on the Cmax and AUC of voriconazole.

Voriconazole inhibits the activity of cytochrome P450 isoenzymes – CYP2C19, CYP2C9, CYP3A4, so it is possible to increase plasma concentrations of drugs that are metabolized by these isoenzymes.

With the simultaneous use of voriconazole with terfenadine, astemizole, cisapride, pimozide and quinidine, a significant increase in their plasma concentrations is possible, which can lead to prolongation of the QT interval and in rare cases to the development of ventricular fibrillation/flutter (this combination is contraindicated).

When used together, voriconazole increases the Cmax and AUC of sirolimus (2 mg once) by 556% and 1014%, respectively (this combination is contraindicated).

When used concomitantly, voriconazole may cause an increase in plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) and the development of ergotism (this combination is contraindicated).

When used together in stable renal transplant patients, voriconazole increases the Cmax and AUC of cyclosporine by at least 13% and 70%, respectively, which is accompanied by an increased risk of nephrotoxic reactions. When prescribing voriconazole to patients receiving cyclosporine, it is recommended to reduce the dose of cyclosporine by half and monitor its plasma levels. After discontinuation of voriconazole, cyclosporine levels should be monitored and the dose increased if necessary.

When used together, voriconazole increases the Cmax and AUC of tacrolimus (used at a dose of 0.1 mg/kg once) by 117% and 221%, respectively, which may be accompanied by nephrotoxic reactions. When prescribing voriconazole to patients receiving tacrolimus, it is recommended to reduce the dose of the latter to 1/3 and monitor its plasma levels. After discontinuation of voriconazole, it is necessary to monitor the concentration of tacrolimus and, if necessary, increase its dose.

The simultaneous use of voriconazole (at a dose of 300 mg 2 times / day) and warfarin (30 mg 1 time / day) was accompanied by an increase in the maximum prothrombin time to 93%. When prescribing warfarin and voriconazole simultaneously, it is recommended to monitor prothrombin time.

Voriconazole, when used together, may cause an increase in plasma concentrations of phenprocoumon, acenocoumarol (CYP2C9, CYP3A4 substrates) and prothrombin time. If voriconazole is prescribed to patients receiving coumarin drugs, the prothrombin time should be monitored at frequent intervals and the dosage of anticoagulants should be adjusted accordingly.

When used together, voriconazole may cause an increase in plasma concentrations of sulfonylurea derivatives (CYP2C9 substrates) tolbutamide, glipizide and glibenclamide and cause hypoglycemia. If they are used concomitantly, carefully monitor blood glucose levels.

In vitro, voriconazole inhibits the metabolism of lovastatin (a CYP3A4 substrate). When used together, it is possible to increase the plasma concentration of statins metabolized by CYP3A4, which may increase the risk of developing rhabdomyolysis. When using them simultaneously, it is recommended to evaluate the feasibility of adjusting the statin dose.

In vitro, voriconazole inhibits the metabolism of midazolam (a CYP3A4 substrate). When used together, it is possible to increase the plasma concentration of benzodiazepines metabolized under the influence of CYP3A4 (midazolam, triazolam, alprazolam) and the development of a prolonged sedative effect. If these drugs are used concomitantly, it is recommended to discuss the advisability of adjusting the benzodiazepine dose.

When used together, voriconazole may increase the content of vinca alkaloids (CYP3A4 substrates) – vincristine, vinblastine in plasma and lead to the development of neurotoxic reactions. It is recommended to discuss the appropriateness of dosage adjustments of vinca alkaloids.

Voriconazole increases the Cmax and AUC of prednisolone (CYP3A4 substrate) administered at a dose of 60 mg once by 11% and 34%, respectively. Dose adjustment is not recommended.

With simultaneous use, voriconazole does not have a significant effect on the Cmax and AUC of digoxin prescribed at a dose of 0.25 mg 1 time / day.

When used together, voriconazole does not affect the Cmax and AUC of mycophenolic acid administered in a dose of 1 g.

When used concomitantly with Vfend, efavirenz (CYP P450 inducer, CYP3A4 inhibitor and substrate), used at a dose of 400 mg 1 time / day at steady state, reduces the Cmax and AUC of voriconazole by an average of 61% and 77%, respectively. Voriconazole at steady state (400 mg PO every 12 hours on day 1, then 200 mg PO every 12 hours for 8 days) increased the steady-state Cmax and AUC of efavirenz by an average of 38% and 44%, respectively (this combination is contraindicated).

When used together, phenytoin (a CYP2C9 substrate and a powerful inducer of cytochrome P450), used at a dose of 300 mg 1 time / day, reduces the Cmax and AUC of voriconazole by 49% and 69%, respectively; and voriconazole (400 mg 2 times / day) increases the Cmax and AUC of phenytoin by 67% and 81%, respectively (if coadministration is necessary, the ratio of the expected benefits and potential risks of combination therapy should be carefully assessed, and phenytoin plasma levels should be carefully monitored).

When used together, rifabutin (a cytochrome P450 inducer) used at a dose of 300 mg 1 time / day reduces the Cmax and AUC of voriconazole (200 mg 1 time / day) by 69% and 78%, respectively. When used together with rifabutin, the Cmax and AUC of voriconazole (350 mg 2 times/day) are, respectively, 96% and 68% of those with voriconazole monotherapy (200 mg 2 times/day). When using voriconazole at a dose of 400 mg 2 times / day, Cmax and AUC are, respectively, 104% and 87% higher than when using voriconazole monotherapy at a dose of 200 mg 2 times / day. Voriconazole at a dose of 400 mg 2 times / day increases the Cmax and AUC of rifabutin by 195% and 331%, respectively. During simultaneous treatment with rifabutin and voriconazole, it is recommended to regularly conduct a detailed analysis of the peripheral blood picture and monitor for undesirable effects of rifabutin (for example, uveitis).

When used together at a dose of 40 mg 1 time / day, omeprazole (inhibitor of CYP2C19; substrate of CYP2C19 and CYP3A4) increases the Cmax and AUC of voriconazole by 15% and 41%, respectively, and voriconazole increases the Cmax and AUC of omeprazole by 116% and 280%, respectively (hence, no dose adjustment of voriconazole is required, and the dose omeprazole should be halved). The possibility of drug interaction between voriconazole and other H+-K+-ATPase inhibitors that are substrates of CYP2C19 should be taken into account.

Indinavir (an inhibitor and substrate of CYP3A4), used at a dose of 800 mg 3 times / day, does not have a significant effect on the Cmax and AUC of voriconazole, and voriconazole does not affect the Cmax and AUC of indinavir.

When used concomitantly with other HIV protease inhibitors (substrates and inhibitors of CYP3A4), the patient’s condition should be carefully monitored for possible toxic effects, because In vitro studies have shown that voriconazole and HIV protease inhibitors (saquinavir, amprenavir, nelfinavir) may mutually inhibit each other’s metabolism.

When co-administering voriconazole with non-nucleoside reverse transcriptase inhibitors (CYP3A4 substrates, cytochrome P450 inhibitors or inducers), it should be taken into account that efavirenz and nevirapine can induce the metabolism of voriconazole, and delaverdine and efavirenz can inhibit it; Voriconazole, in turn, may inhibit the metabolism of reverse transcriptase inhibitors. When voriconazole is used concomitantly with non-nucleoside reverse transcriptase inhibitors, patients should be monitored for possible toxic effects.

Overdose

Three cases of accidental overdose are known. All of the cases mentioned occurred in children who were given an intravenous dose of voriconazole five times the recommended dose.

There is a report of a single case of photophobia lasting 10 minutes.

There is no known antidote for voriconazole. In case of overdose, symptomatic and supportive therapy is indicated.

Voriconazole is eliminated during hemodialysis with a clearance of 121 ml/min. betadex sodium sulfobutylate – with a clearance of 55 ml/min. In cases of overdose, hemodialysis may help eliminate voriconazole and betadex sodium sulfobutylate from the body.

Storage conditions

Lyophilisate for preparing solution for infusion: at a temperature not exceeding 30°C

Shelf life

2 years. Reconstituted solution – no more than 24 hours.

Manufacturer

Pharmacy and Upjohn Company LLC, USA