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.

– Candidaemia in patients without neutropenia.

– Severe invasive candidiasis infections (including C. krusei).

– Esophageal candidiasis.

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

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

– Prevention of “breakthrough” fungal infections in patients with reduced immune system function with fever and neutropenia in 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 high-risk groups such as hematopoietic stem cell transplant recipients.

Active ingredient

Voriconazole

Composition

1 vial of lyophilisate for preparation of solution for infusion contains:

the active ingredient:

voriconazole 200 mg,

excipients:

sodium salt of sulfobutyl ester of beta-cyclodextrin (SBECD).

How to take, the dosage

Vifend® is not recommended as a bolus (jet) injection. The infusion rate should not exceed 3 mg/kg/h for 1-3 hours.

Electrolyte disorders such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected before initiating therapy (see section “Side effects”).

The administration of Bethend® should start with intravenous administration at the recommended saturation dose to achieve adequate plasma concentrations on the first day. Intravenous administration should be continued for at least 7 days after which the drug can be taken orally if the patient is able to take oral medicinal products. Taking into account high bioavailability of the drug in per oral administration of 96% (see section “Pharmacokinetics”) it is possible to switch from intravenous to oral administration of the drug without dosage adjustment in case of clinical indications.

The table gives detailed information about the dosing of Bethend®:

Intravenous Dose Selection

If treatment is not effective, the maintenance dose of Vifend® for intravenous administration may be increased to 4 mg/kg every 12 hours. If a patient cannot tolerate the preparation in high dose it should be reduced up to 3 mg/kg every 12 hours.

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

Prophylaxis in adults and children

The prophylactic use of the drug should be started on the day of transplant and can be continued for up to 100 days. Prophylaxis can be extended up to 180 days after transplantation only if immunosuppressive therapy is continued or if a graft vs. host reaction (GTP) develops. The safety and efficacy of voriconazole over 180 days has not been adequately studied in clinical trials. The dosing regimen for prophylaxis is the same as that for treatment in appropriate age groups.

Patients with moderate to severe renal impairment (creatinine clearance < 50 ml/min) have cumulation of the excipient of the drug betadex sulfobutylate sodium. In such patients Vifend® should be administered orally unless the expected benefits of intravenous administration exceed the potential risk. In such situations creatinine concentration should be monitored regularly and in case of its increase the possibility of switching to oral voriconazole administration should be discussed.

Voriconazole is excreted during hemodialysis with a clearance of 121 ml/min. A 4-hour session of hemodialysis does not remove a significant portion of the voriconazole dose and does not require correction. Betadex sulfobutylate sodium is excreted during hemodialysis with a clearance of 55 mL/min.

Hepatic impairment

In acute hepatic impairment manifested by increased “hepatic” transaminases: alanine aminotransferase (ALT) and aspartate aminotransferase (ACT), dosage adjustment is not required but continued monitoring of liver function is recommended. Patients with mild or moderate liver function abnormalities (classes A and B according to Child-Pugh classification) should take standard saturation dose of Vifend® and maintenance dose should be reduced by half. In patients with severe hepatic impairment (Child-Pugh class C), Vifend® should be used only when the expected benefit exceeds the possible risk and under continuous monitoring for signs of drug toxicity.

Elderly patients

There is no need for dose adjustment in the elderly.

Use in children

The safety and effectiveness of voriconazole in children younger than 2 years old has not been established.

The dosing regimen of voriconazole in children (ages 2 to 12 years) and adolescents ages 12 to 14 years and body weight less than 50 kg:

The therapy should be initiated with intravenous infusion of the drug and the possibility of taking Vifend® orally should be considered only after clinical improvement and the patient’s ability to take oral medications.

We should note that the effect of intravenous administration of 8 mg/kg is approximately double that of oral administration of 9 mg/kg. The use of voriconazole in children aged from 2 to 12 years with hepatic or renal impairment has not been studied.

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

Dose adjustment

If the patient’s clinical response is inadequate, the dose may be increased in 1 mg/kg increments (or 50 mg if the maximum oral dose of 350 mg was initially used). If the child is intolerant, the dose of voriconazole may be reduced in 1 mg/kg increments (or 50 mg if the maximum oral dose of 350 mg was initially used).

Instructions for preparing the infusion solution

The drug Vifend® is available in single-use vials. The content of the vial is reconstituted by dissolving in 19 ml of water for injection to produce 20 ml of clear concentrate with voriconazole concentration 10 mg/ml. If the solvent does not enter the vial under vacuum, the vial cannot be used. Before use, the required volume of concentrate (see table) is added to the recommended compatible infusion solution (see below) to produce a solution containing voriconazole at concentrations ranging from 05 mg/ml to 5 mg/ml.

Volumes of Vifend® 10 mg/ml concentrate are required:

Vifend® lyophilisate for preparation of solution for infusion is a sterile lyophilisate without preservative for single use. Microbiologically, the drug should be administered immediately. The reconstituted solution (concentrate) can be stored up to 24 hours at 2 to 8 °С if it was prepared under controlled aseptic conditions.

The concentrate can be further diluted with the following solutions:

– 09% sodium chloride solution for intravenous administration;

– Ringer’s lactate solution for intravenous administration;

– 5% dextrose solution and Ringer’s lactate solution for intravenous injection;

– 5% dextrose solution and 045% sodium chloride solution for intravenous injection;

– 5% dextrose solution for intravenous injection;

– 5% dextrose solution and 015% potassium chloride solution for intravenous injection;

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– 045% sodium chloride solution for intravenous injection;

– 5% dextrose solution and 09% sodium chloride solution for intravenous injection.

The compatibility of voriconazole with solutions other than those listed above is unknown.

Interaction

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

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

When used concomitantly with Bethend, ritonavir (a CYP P450 inducer, inhibitor and substrate of CYP3A4) at a dose of 400 mg every 12 hours reduced the Cmax at equilibrium and AUC of oral voriconazole by 66% and 82%, respectively on average. The effect of lower doses of ritonavir on voriconazole concentrations is not yet known. It was found that repeated oral use of voriconazole had no significant effect on the Cmax at equilibrium and AUC of ritonavir, also taken repeatedly (concomitant use of voriconazole and ritonavir at a dose of 400 mg every 12 hours is contraindicated).

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

When used together with cimetidine (nonspecific inhibitor of CYP P450) in dose 400 mg 2 times per day the Cmax and AUC of voriconazole are increased by 18% and 23% respectively (no dose adjustment of Bethend is required).

Ranitidine in dose 150 mg 2 times/day when used together has no significant effect on Cmax and AUC of voriconazole.

Eritromycin (CYP3A4 inhibitor) in dose 1 g 2 times per day and azithromycin in dose 500 mg once daily have no significant effect on Cmax and AUC of voriconazole.

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

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

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

When co-administered in patients with stable kidney transplantation, voriconazole increases Cmax and AUC of cyclosporine by at least 13% and 70%, respectively, with an increased risk of nephrotoxic reactions. When voriconazole is administered to patients receiving cyclosporine, it is recommended to reduce the dose of cyclosporine by half and monitor its plasma levels. After voriconazole withdrawal it is necessary to control cyclosporine levels and increase the dose if necessary.

When used together voriconazole increases Cmax and AUC of tacrolimus (used in 0.1 mg/kg single dose) 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 voriconazole withdrawal the concentration of tacrolimus should be controlled and the dose should be increased if necessary.

Voriconazole when used together may increase plasma concentrations of phenprocoumon, acenocoumarol (CYP2C9, CYP3A4 substrates) and prothrombin time. If voriconazole is administered to patients receiving coumarin preparations, prothrombin time should be monitored at short intervals and the doses of anticoagulants should be adjusted accordingly.

When used concomitantly voriconazole may increase plasma concentrations of sulfonylurea derivatives (CYP2C9 substrates) – tolbutamide, glipizide and glibenclamide and cause hypoglycemia. If they are used concomitantly, blood glucose levels should be monitored carefully.

In vitro voriconazole inhibits the metabolism of lovastatin (CYP3A4 substrate). In concomitant use it is possible to increase plasma concentrations of statins metabolized by CYP3A4, which may increase the risk of rhabdomyolysis. If they are used concomitantly, it is recommended to evaluate the feasibility of statin dose adjustment.

In vitro voriconazole inhibits the metabolism of midazolam (CYP3A4 substrate). Co-administration may increase plasma concentrations of benzodiazepines (midazolam, triazolam, alprazolam) metabolized under the influence of CYP3A4 and develop prolonged sedative effect. If these drugs are used concomitantly, it is recommended to discuss the appropriateness of benzodiazepine dose adjustment.

When used concomitantly, voriconazole may increase plasma levels of barberry alkaloids (CYP3A4 substrates) – vincristine, vinblastine and lead to the development of neurotoxic reactions. It is recommended to discuss the feasibility of adjusting the dose of barvinac alkaloids.

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

When used concomitantly voriconazole has no significant effect on Cmax and AUC of digoxin, administered in a dose of 0.25 mg once daily.

When used concomitantly, voriconazole has no effect on the Cmax and AUC of mycophenolic acid administered in a dose of 1 g.

When used concomitantly with Vifend, efavirenz (CYP P450 inducer, inhibitor and substrate of CYP3A4) used at a dose of 400 mg 1 time/day in equilibrium reduces Cmax and AUC of voriconazole by 61% and 77% on average respectively. Voriconazole in equilibrium (400 mg orally every 12 h on the first day, then 200 mg orally every 12 h for 8 days) increases equilibrium Cmax and AUC of efavirenz by 38% and 44% on average, respectively (this combination is contraindicated).

When used together phenytoin (CYP2C9 substrate and potent inducer of cytochrome P450) administered in dose 300 mg once daily decreases Cmax and AUC of voriconazole by 49% and 69% respectively; and voriconazole (400 mg 2 times/day) increases Cmax and AUC of phenytoin by 67% and 81%, respectively (if co-administration is necessary, the ratio of perceived benefit to potential risk of combined therapy should be carefully evaluated, and plasma levels of phenytoin should be carefully monitored).

When co-administered, rifabutin (cytochrome P450 inducer) administered at a dose of 300 mg once daily reduces Cmax and AUC of voriconazole (200 mg once daily) by 69% and 78% respectively. When co-administration with rifabutin Cmax and AUC of voriconazole (350 mg 2 times/day) were 96% and 68% respectively from those of voriconazole monotherapy (200 mg 2 times/day). Cmax and AUC of voriconazole at a dose of 400 mg 2 times per day were 104% and 87% higher respectively than those of voriconazole monotherapy at a dose of 200 mg 2 times per day. Voriconazole at a dose of 400 mg 2 times/day increases Cmax and AUC of rifabutin by 195% and 331%, respectively. In concomitant treatment with rifabutin and voriconazole it is recommended to perform regular detailed analysis of peripheral blood picture and control undesirable effects of rifabutin (e.g. uveitis).

When co-administered at a dose of 40 mg once daily, omeprazole (CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate) increases Cmax and AUC of voriconazole by 15% and 41% respectively, and voriconazole increases Cmax and AUC of omeprazole by 116% and 280% respectively (consequently, it is not necessary to correct voriconazole dose, and the omeprazole dose should be reduced by half). The possibility of drug interaction of voriconazole with other H+-K+-ATPase inhibitors, which are CYP2C19 substrates, should be considered.

Indinavir (CYP3A4 inhibitor and substrate) administered in dose 800 mg 3 times per day has no significant effect on Cmax and AUC of voriconazole, and voriconazole has no effect on Cmax and AUC of indinavir.

When used concomitantly with other HIV protease inhibitors (CYP3A4 substrates and inhibitors), the patient should be closely monitored for possible toxic effects, because in vitro studies have shown that voriconazole and HIV protease inhibitors (saquinavir, amprenavir, nelfinavir) can 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 noted that efavirenz and nevirapine may induce voriconazole metabolism and delaverdine and efavirenz may inhibit it; voriconazole, in turn, can inhibit the metabolism of reverse transcriptase inhibitors. When using voriconazole concomitantly with non-nucleoside reverse transcriptase inhibitors, patients should be monitored for possible toxic effects.

Special Instructions

Sampling for culture and other laboratory studies (serology, histopathology) in order to isolate and identify pathogens should be performed before the start of treatment. Therapy can be initiated before the results of cultural and other laboratory tests are available, but if they are, treatment should be adjusted accordingly.
Clinical strains with reduced sensitivity to voriconazole have been identified.

But elevated minimum suppressive concentrations (MSCs) do not always predict clinical ineffectiveness; voriconazole has been known to be effective in patients infected with microorganisms resistant to other azoles. It is difficult to assess the correlation between in vitro activity and clinical results of treatment, given the complexity of patients who were included in clinical trials; values of borderline concentrations of voriconazole, which allow to assess sensitivity to this drug, have not been established.
Hypersensitivity: In patients with hypersensitivity to other azoles, voriconazole should be prescribed with caution

Adverse cardiovascular events: The use of voriconazole has been associated with prolongation of the QT interval on the electrocardiogram, with rare cases of ventricular fibrillation-tripping in patients receiving voriconazole therapy (in critically ill patients with multiple risk factors like cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant therapy that may have contributed to this complication). In patients with these potentially proarrhythmic conditions voriconazole should be administered with caution (see section Dosage and administration).
Hepatotoxicity: During treatment with voriconazole infrequent (0,1-1%) cases of serious liver reactions (including clinically manifested hepatitis, cholestasis and liver cell failure, including mortality) were observed. Undesirable liver events are mainly observed in patients with serious diseases (mainly malignant blood tumors). Transient liver reactions, including hepatitis and jaundice, have been seen in patients without any risk factors. The liver function abnormalities are usually reversible and go away after discontinuation of treatment.

Liver function monitoring: During treatment with voriconazole, it is recommended that liver function, especially liver function tests and bilirubin, be monitored regularly. If there are clinical signs of liver disease that may be associated with voriconazole, it is necessary to discuss the expediency of discontinuation of therapy.
Adverse renal events: In severe patients receiving voriconazole there are cases of acute renal failure.

Monitoring of renal function:
Patients should be monitored to detect signs of impaired renal function. For this purpose it is necessary to conduct laboratory tests, in particular to determine the serum level of creatinine.
Infusion reactions: When voriconazole is administered intravenously, infusion reactions are observed, mainly “flushes to the face” and nausea. If these symptoms are pronounced, the appropriateness of discontinuing treatment should be discussed (see side effects section).
Skin reactions: In rare cases during treatment with voriconazole patients develop exfoliative skin reactions, such as Stevens-Johnson syndrome. If the rash appears, patients should be monitored. In the progression of skin lesions it is advisable to cancel voriconazole.
In addition, the use of voriconazole was accompanied by photosensitivity skin reactions, especially during long-term treatment. During treatment, patients are advised to avoid intense or prolonged exposure to direct sunlight.

Cyclosporine and tacrolimus (CYP3A4 substrates): In patients receiving cyclosporine or tacrolimus, there may be clinically significant interactions between them and voriconazole (see Section Interaction with other drugs and other forms of interaction).
Phenytoin (CYP2C9 substrate and potent inducer of CYP450): Continuous monitoring of phenytoin levels is recommended when phenytoin and voriconazole are used concurrently. If possible, the concomitant use of voriconazole and phenytoin should be avoided, except in cases when the expected benefits outweigh the possible risks (see section Interaction with other drugs and other forms of interaction).

Rifabutin (CYP450 inducer): When concomitant use of rifabutin with voriconazole, it is recommended to perform clinical blood tests and monitor the unwanted effects of rifabutin (e.g., uveitis). Concomitant administration of voriconazole and rifabutin should be avoided unless the expected benefits outweigh the possible risks (see section Interaction with other drugs and other forms of interaction).
Women of reproductive age
Women of reproductive age should always use effective contraception methods during treatment.

Impact on ability to drive and use machinery
Voriconazole may cause transient and reversible visual impairment, including fog in front of the eyes, impairment/enhancement of visual perception and/or photophobia. In the presence of these symptoms, patients should avoid potentially dangerous activities such as driving a car or using complex machinery. Patients should not drive at night while taking voriconazole.

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Contraindications

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

– Simultaneous use of Vifend® and the following drugs is contraindicated (see section “Interaction with other medicinal products”). concomitant use of Vifenda® is contraindicated (see section “Interaction with other medicinal products”): CYP3A4 isoenzyme substrates – 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 higher twice daily); ergot alkaloids (ergotamine dihydroergotamine) that are substrates of CYP3A4 isoenzyme; St. John’s wort (inducer of cytochrome P450 and P-glycoprotein).

The drug Vifend® is contraindicated in children under 2 years of age.

Cautions:

– Hypersensitivity to other azole derivatives.

– Severe hepatic function impairment Severe renal function impairment.

– Voriconazole should be used with caution in patients with proarrhythmic conditions: congenital or acquired prolongation of QT interval cardiomyopathy especially with cardiac insufficiency sinus bradycardia presence of symptomatic arrhythmia concurrent use of drugs causing prolongation of QT interval (see section “Indications”).

Patients with electrolyte disturbances, such as hypokalemia, hyomagnesemia, and hypocalcemia should also use Vifend® with caution.

Side effects

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

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

Cardiovascular: Decreased BP, thrombophlebitis, phlebitis (frequent); atrial arrhythmias, bradycardia, tachycardia, ventricular arrhythmias, supraventricular tachycardia, prolonged QT interval, ventricular fibrillation (rare); complete atrio-ventricular block, Gis bundle branch block, nodal arrhythmias, ventricular tachycardia (including ventricular flutter) (very rare).

The digestive system: Nausea, vomiting, diarrhea, abdominal pain (very common); increased liver function (including ACT, ALT, alkaline phosphatase, gamma GT, LDH, bilirubin), jaundice, cheilitis, gastroenteritis, cholestatic jaundice (common); cholecystitis, cholelithiasis, constipation, duodenitis, dyspepsia, liver enlargement, gingivitis, glossitis, hepatitis, liver failure, pancreatitis, tongue edema, peritonitis (rare); pseudomembranous colitis, liver coma (very rare).

Endocrine system: insufficiency of the adrenal cortex (rarely); hyperthyroidism, hypothyroidism (very rarely). 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, inhibition of bone marrow hematopoiesis (rare); lymphangitis (very rare).

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

Muscular system: back pain (often); arthritis (rarely).

Nervous system: Headache (very common); dizziness, hallucinations, confusion, depression, anxiety, tremor, agitation, paresthesias (common); Ataxia, cerebral edema, hypertension, hyposthesia, nystagmus, syncope (rare); Guienne-Barre 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, cutaneous photosensitivity reactions, alopecia, exfoliative dermatitis, facial edema, purpura (common); fixed drug rash, eczema, psoriasis, Stevens-Johnson syndrome, urticaria (rare); angioedema, discoid lupus erythematosus, multiform erythema, toxic epidermal necrolysis (very rare).

Sensory organs: Visual disturbances (including visual disturbance/enhancement, fog in front of eyes, altered color vision, photophobia) (very common); blepharitis, optic neuritis, optic nipple edema, scleritis, taste disturbance, diplopia (rare); retinal hemorrhage, corneal clouding, optic nerve atrophy, hypoacusis, tinnitus (very rare).

Mineral system: increased creatinine, acute renal failure, hematuria (frequent); increased residual urea nitrogen, albuminuria, nephritis (rare); renal tubular necrosis (very rare).

Overdose

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

A single case of photophobia has been reported that lasted 10 minutes.

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

Voriconazole is excreted during hemodialysis with a clearance of 121 ml/min. Betadex sulfobutylate sodium – with a clearance of 55 ml/min. In case of overdose hemodialysis can promote excretion of voriconazole and sodium betadex sulfobutylate.

Pregnancy use

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 not known.

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 with the breast milk has not been studied. Voriconazole should not be used in women who are breastfeeding, unless the expected benefits clearly outweigh the risks.

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