Vifend, 200 mg 14 pcs

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

Pharmacokinetics of voriconazole were studied in healthy subjects, special groups and patients.

The pharmacokinetics of voriconazole are nonlinear due to saturation of its metabolism. 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.

The pharmacokinetics of voriconazole is characterized by high interindividual variability.

In vitro studies showed that voriconazole is metabolized under the action 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 nonlinearity of pharmacokinetics, the terminal elimination half-life does not predict the cumulation or excretion of voriconazole.

Pharmacokinetics in special groups

Gender
When administered orally repeatedly, Cmax and AUCτ were 83% and 113% higher, respectively, in healthy young women 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.

Renal dysfunction

. A single oral dose of 200 mg of 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 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
• severe invasive candidiasis infections (including C. krusei) resistant to fluconazole.
• esophageal candidiasis caused by C. albicans in immunodeficient patients.
• severe fungal infections caused by Scedosporium spp. and Fusarium spp.
• severe fungal infections with intolerance or refractoriness to other medications.
• Prevention of “breakthrough” fungal infections in febrile high-risk patients (allogeneic bone marrow recipients, patients with relapsed leukemia).

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Active ingredient

Voriconazole

Composition

1 film-coated tablet contains:

the active ingredient:

voriconazole 200 mg,

excipients:

Lactose monohydrate;

Pregelatinized starch;

Croscarmellose sodium;

povidone;

Magnesium stearate

coating:

Opadry white (hypromellose; titanium dioxide; lactose monohydrate; glycerol triacetate)

How to take, the dosage

Voriconazole in coated tablets should be taken orally at least 1 hour before or 1 hour after meals.

Application in adults

The intravenous or oral administration of voriconazole should be started at the recommended saturation dose in order to achieve serum concentrations close to equilibrium on the first day.

With regard to high bioavailability when oral administration (96%, see section Pharmacokinetics), the drug can be switched from intravenous to oral administration if clinically indicated.
The table contains detailed information about the dosing of the drug:

IntravenousIntravenousPatients with a body weight
of 40 kg or morePatients with a body weight
of less than 40 kgThe saturation dose
– all indications
(first 24 h)6 mg/kg every 12 h
(during the first 24 h)400 mg every 12 h
(during the first 24 h) 200 mg every 12 h
(during the first 24 h)Maintenance dose
(after the first 24 h)Prevention
breakthrough infections3 mg/kg every 12 h200 mg every 12 h100 mg every 12 hSevere invasive candidiasis infections resistant to fluconazole/invasive aspergillosis/infections caused by Scedosporium and Fusarium/Other serious mold infections4 mg/kg every 12 h200 mg every 12 h100 mg every 12 hEoesophageal candidiasis caused by C. albicans,in patients with immunodeficiency

No recommendations200 mg every 12 h100 mg every 12 h

Dose selection
If treatment is not effective, the maintenance dose may be increased to 300 mg every 12 hours orally. In patients with body weight less than 40 kg the dose may be increased to 150 mg every 12 hours orally.
If a patient cannot tolerate the drug in a high dose, it is reduced in steps of 50 mg every 12 hours to 200 mg orally (or 100 mg every 12 hours in patients with body weight less than 40 kg).

Phenytoin can be used with voriconazole if the maintenance dose of the latter is increased from 200 to 400 mg every 12 hours orally (from 100 to 200 mg every 12 hours orally in patients weighing less than 40 kg).

Rifabutin can be used with voriconazole if the maintenance dose of the latter is increased from 200 to 350 mg every 12 hours orally (from 100 to 200 mg every 12 hours orally in patients with body weight less than 40 kg).
The duration of treatment depends on the clinical effect and results of mycological analysis.

Periatric use

Dose adjustment in the elderly is not required.
Use in patients with impaired renal function
Coated tablets:
Impaired renal function does not affect the pharmacokinetics of voriconazole when taken orally. In this regard the adjustment of oral voriconazole dose in patients with mild, moderate or expressed renal dysfunction is not required.

Application in patients with hepatic impairment
In acute liver injury manifested by increased liver transaminases activity (AJIT, ACT) the dose adjustment is not required. In such cases it is recommended to continue monitoring of liver function parameters in order to detect further increase.

In patients with mild to moderate cirrhosis of the liver (Child-Pugh A and B) it is recommended to administer a standard shock dose of voriconazole, and the maintenance dose should be reduced by half.

Patients with severe liver dysfunction should only be prescribed voriconazole when the expected benefits outweigh the possible risks.
In patients with severe liver dysfunction, treatment should be monitored continuously to detect signs of toxicity of the drug.

Periatric use
The safety and efficacy of voriconazole in children less than 2 years of age has not been established, Therefore, voriconazole is not recommended for administration in children younger than 2 years of age.

The experience of use in children is limited, making it difficult to choose the optimal dosage. However, in pharmacokinetic studies in children, voriconazole has been used according to the following regimens.
Children aged 2 to :

IntravenouslyIntravenousThe saturation dose
(first 24 h)6 mg/kg every 12 h
(during the first 24 h)6 mg/kg every 12 h
(during the first 24 h)The maintenance dose
(After the first 24 h)4 mg/kg every 12 h4 mg/kg every 12 h

If the child can swallow the tablets, the dose is rounded to the nearest mg/kg multiple of 50 mg and administered as whole tablets.
Pharmacokinetics and tolerability of higher doses in children have not been studied.”
Adolescents aged 12 to 16 years: the drug is dosed the same as in adults.

Interaction

Influence of other drugs on pharmacokinetics of voriconazole

Voriconazole is metabolized under the action of 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.
Plasma levels of voriconazole are significantly reduced when used simultaneously with the following drugs:
Rifampicin (CYP450 inducer): Rifampicin (600 mg once daily) decreases Cmax (maximum plasma concentration) and AUCτ of voriconazole by 93% and 96%, respectively.

The concomitant use of voriconazole and rifampicin is contraindicated (see Contraindications).

Carbamazepine and long-acting barbiturates (potent CYP450 inducers):
Carbamazepine and long-acting barbiturates (such as phenobarbital) are likely to significantly decrease plasma concentrations of voriconazole, although their interaction has not been studied.

The concomitant use of voriconazole with carbamazepine and long-acting barbiturates is contraindicated (see Contraindications).

Given little or no significant pharmacokinetic interaction, dosage adjustment of the following drugs is not required:

Cimetidine (non-specific CYP450 inhibitor, and also increases the pH of gastric juice): Cimetidine (400 mg 2 times daily) causes an 18% and 23% increase in Cmax and AUCX of voriconazole, respectively. No dose adjustment for voriconazole is recommended.
Ranitidine (increases gastric juice pH): Ranitidine (150 mg 2 times daily) has no significant effect on Cmax and AUCτ of voriconazole.

Macrolide group antibiotics : Erythromycin (CYP3A4 inhibitor; 1 g 2 times daily) and azithromycin (500 mg once daily) have no significant effect on Cmax and AUCτ of voriconazole.

The effect of voriconazole on other drugs

Voriconazole inhibits the activity of cytochrome P450 isoenzymes – CYP2C19, CYP2C9 and CYP3A4. In this regard, voriconazole may increase plasma concentrations of substances that are metabolized by these CYP450 isoenzymes.

The concomitant use of voriconazole with the following drugs is contraindicated:
Terfenadine, astemizole, cisapride, pimozide and quinidine (CYP3A4 substrates): Although interactions with these drugs have not been studied, however, concomitant use of voriconazole with terfenadine, astemizole, cisapride, pimozide or quinidine is contraindicated because an increase in their plasma concentrations may lead to prolonged QT interval and in rare cases to the development of ventricular fibrillation/tripping.

Sirolimus (CYP3A4 substrate): Voriconazole increases Cmax and AUCT of sirolimus (2 mg once) by 556% and 1014%, respectively. Simultaneous use of voriconazole and sirolimus is contraindicated.

The use of ergot alkaloids (CYP3A4 substrates): Although interactions with these drugs have not been studied, however, voriconazole may cause an increase in plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) and the development of ergotism. Concomitant use of ergot alkaloids with voriconazole is contraindicated,

Interaction with voriconazole may lead to increased blood concentrations of the following drugs listed below. Therefore, continuous monitoring and/or dose adjustments are necessary when using them concomitantly.

Cyclosporine (CYP3A4 substrate): In kidney transplant patients who are stable, voriconazole increases Cmax and AUCτ of cyclosporine by at least 13% and 70%, respectively). When voriconazole is administered to patients receiving cyclosporine, it is recommended to reduce the dose of cyclosporine by half and monitor its plasma levels. Increased concentration of cyclosporine is accompanied by nephrotoxicity. After voriconazole withdrawal it is necessary to control cyclosporine levels and increase the dose if necessary.

Tacrolimus (CYP3A4 substrate): Voriconazole increases Cmax and AUCτ (area under the concentration-time curve to last quantitative measurement) of tacrolimus (0.1 mg/kg once) by 117% and 221%, respectively. When prescribing voriconazole to patients receiving tacrolimus, it is recommended to reduce the dose of the latter to one-third and monitor its plasma levels. Increased levels of tacrolimus are accompanied by nephrotoxicity. After voriconazole withdrawal, tacrolimus concentrations should be monitored and the dose should be increased if necessary.

Warfarin (CYP2C9 substrate): Concomitant use of voriconazole (300 mg twice daily) with warfarin (30 mg once daily) was accompanied by an increase in maximum prothrombin time up to 93%>. When concomitant administration of warfarin and voriconazole, it is recommended to monitor prothrombin time.

Other oral anticoagulants such as phenprocoumon, acenocoumarol (CYP2C9, CYP3A4 substrates): Voriconazole may cause increased plasma coumarin concentrations 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.

Sulfonylurea derivatives (CYP2C9 substrates): Voriconazole may increase plasma concentrations of sulfonylurea derivatives (e.g., tolbutamide, glipizide, and glibenclamide) and cause hypoglycemia. Blood glucose levels should be monitored carefully if they are used concomitantly.

Statins (CYP3A4 substrates): in vitro voriconazole inhibits the metabolism of lovastatin (in human liver microsomes). In this regard, voriconazole may cause increased plasma concentrations of statins metabolized by CYP3A4. If they are used concomitantly, it is recommended to evaluate the appropriateness of statin dose adjustment. Increased levels of statins have sometimes been accompanied by the development of rhabdomyolysis.

Benzodiazepines (CYP3A4 substrates): Although no interaction has been studied in clinical studies, voriconazole inhibits the metabolism of midazolam in vitro (human liver microsomes). In this regard, voriconazole may cause increased plasma levels of benzodiazepines that are metabolized by CYP3A4 (midazolam, triazolam, alprazolam) and development of prolonged sedative effects. If these drugs are used concomitantly, it is recommended to discuss the appropriateness of benzodiazepine dose adjustment.

The periwinkle alkaloids (CYP3A4 substrates): Voriconazole may increase plasma levels of barvinac alkaloids (e.g., vincristine and vinblastine) and cause neurotoxicity.

We recommend discussing the appropriateness of adjusting the dose of vinca alkaloids.

When using voriconazole concomitantly with the following drugs, no significant pharmacokinetic interaction has been identified, so no dose adjustment is required:

Prednisolone (a CYP3A4 substrate): Voriconazole increases Cmax and AUCτ of prednisolone (60 mg once) by 11% and 34%, respectively. Dose adjustment is not recommended.

Digoxin (P-glycoprotein-mediated transport): Voriconazole has no significant effect on Cmax and AUCτ of digoxin (0.25 mg once daily).

Mycophenolic acid (UDF-glucuronyltransferase substrate): Voriconazole has no effect on the Cmax and AUCτ of mycophenolic acid (1 g once daily).

Phenytoin (CYP2C9 substrate and potent inducer of CYP450): Concomitant use of voriconazole and phenytoin should be avoided unless the expected benefits outweigh the possible risks.

Phenytoin (300 mg once daily) decreases Cmax and AUCτ of voriconazole by 49% and 69%, respectively. Voriconazole (400 mg twice daily, see section 4.2) increases Cmax and AUCτ of phenytoin (300 mg once daily) by 67% and 81%, respectively. When phenytoin is used concomitantly with voriconazole, close monitoring of plasma levels of phenytoin is recommended.
Phenytoin can be used concomitantly with voriconazole if the maintenance dose of the latter is increased to 5 mg/kg every 12 h intravenously or from 200 to 400 mg every 12 h orally (from 100 to 200 mg every 12 h orally in patients with a body weight less than 40 kg; see Dosage and administration section).

Rifabutin (CYP450 inducer): Rifabutin (300 mg once daily) reduces Cmax and AUCτ of voriconazole (200 mg twice daily) by 69% and 78%, respectively. During concomitant administration of rifabutin Cmax and AUCτ of voriconazole in dose 350 mg twice daily are 96% and 68% from those during usage of voriconazole separately in dose 200 mg twice daily. Cmax and AUCτ were 104% and 87% higher, respectively, when using voriconazole at a dose of 400 mg twice daily than when using voriconazole monotherapy at a dose of 200 mg twice daily. Voriconazole at a dose of 400 mg twice daily increases Cmax and AUCτ of rifabutin by 195% and 331%, respectively.

If the expected benefits of treatment outweigh the risks, rifabutin can be used concomitantly with voriconazole. In this case, the maintenance dose of voriconazole should be increased to 5 mg/kg every 12 hours intravenously or from 200 to 350 mg every 12 hours orally (from 100 to 200 mg every 12 hours orally in patients with body weight less than 40 kg) (see section Dosage and administration). In concomitant treatment with rifabutin and voriconazole it is recommended to perform regular detailed blood tests and control undesirable effects of rifabutin (e.g., uveitis).

Omeprazole (CYP2C19 inhibitor; substrate of CYP2C19 and CYP3A4): Omeprazole (40 mg once daily) increases Cmax and AUCτ of voriconazole by 15% and 41%, respectively. No dose adjustment for voriconazole is recommended.

Voriconazole increases Cmax and AUCτ of omeprazole by 116% and 280%, respectively. When voriconazole is administered to patients receiving omeprazole, it is recommended to reduce the dose of the latter by half.

Voriconazole may also inhibit the metabolism of other proton pump blockers that are CYP2C19 substrates.
Indinavir (CYP3A4 inhibitor and substrate): Indinavir (800 mg three times daily) has no significant effect on the Cmax and AUCτ of voriconazole.

Voriconazole has no significant effect on the Cmax, Cmin and AUCτ of indinavir (800 mg three times daily).

Other HIV protease inhibitors (CYP3A4 substrates and inhibitors): In vitro studies suggest that voriconazole can inhibit the metabolism of HIV protease inhibitors (e.g., saquinavir, amprenavir, and nelfinavir). In vitro studies have also shown that HIV protease inhibitors can inhibit the metabolism of voriconazole. If voriconazole is used concomitantly with HIV protease inhibitors, patients should be monitored for possible toxic effects.

Non-nucleoside reverse transcriptase inhibitors (CYP3A4 substrates, inhibitors or inducers of CYP450): In vitro studies show that delaverdine and efavirenz can inhibit the metabolism of voriconazole. Efavirenz and nevirapine may induce metabolism of voriconazole, although this effect has not been studied. Voriconazole may inhibit the metabolism of non-nucleoside reverse transcriptase inhibitors. If voriconazole is used concomitantly with non-nucleoside reverse transcriptase inhibitors, patients should be monitored to identify possible toxic effects.

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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 is 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. Concomitant use of voriconazole and phenytoin should be avoided if possible, 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

• Wifend is contraindicated in patients with hypersensitivity to voriconazole or any component of the drug;
• Simultaneous use of Wifend and CYP3A4 substrates – terfenadine, astemizole, cisapride, pimozide or quinidine is contraindicated, as increased plasma concentrations of the latter may lead to prolongation of the QT interval and, rarely, the development of ventricular fibrillation.Increased plasma concentrations of the latter may prolong QT interval and, in rare cases, lead to ventricular flutter or fibrillation.
• Simultaneous use of Bethenda with rifampicin, carbamazepine and long-acting barbiturates (e.g. phenobarbital) is contraindicated because these drugs significantly decrease plasma concentrations of voriconazole.
• coincidental use of Bethenid with ritonavir (400 mg every 12 hours) is contraindicated because the latter significantly decreases voriconazole plasma concentrations in healthy subjects;
• coincidental use of Bethenid with efavirenz is contraindicated because the latter significantly decreases voriconazole plasma concentrations in healthy subjects. the latter significantly reduces plasma concentrations of voriconazole and voriconazole in turn increases plasma concentrations of efavirenz;
• co-administration of ergot alkaloids (ergotamine, dihydroergotamine) which are CYP3A4 substrates is contraindicated.Because increased plasma concentrations of these substances may lead to ergotism.

With caution – severe hepatic failure, severe renal failure (in parenteral administration). Safety and efficacy in children under the age of 2 years have not been established. Hypersensitivity to other drugs – azole derivatives.

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Side effects

The table lists the adverse events that have been observed when using the drug and may have been associated with treatment. The most common adverse reactions are visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, peripheral edema, and abdominal pain. The adverse reactions were usually mild to moderate in severity. There was no clinically significant dependence of drug safety on age, race, or gender

Body systems
Frequency*Unwanted drug reactions GeneralVery commonFever, peripheral edemaFrequentChills, asthenia, chest pain, injection site reactions/inflammation, flu-like syndromeCardiovascularFrequentDecrease in BP, thrombophlebitis, phlebitisRare rareRare atrial arrhythmias, bradycardia, tachycardia, ventricular arrhythmias.Very rareVentricular tachycardia, complete atrio-ventricular block, Gis bundle leg block, nodal arrhythmias, ventricular tachycardia (including ventricular flutter), prolonged QT interval, ventricular fibrillation.DigestionVery commonNausea, vomiting, diarrhea, abdominal painFrequentElevated liver function (including ACT, AJIT, alkaline phosphatase, gamma GT, LDH, bilirubin), jaundice, cheilitis, cholestasis.RareCholecystitis, cholelithiasis, constipation, duodenitis, dyspepsia, liver enlargement, gingivitis, glossitis, hepatitis, liver failure, pancreatitis, tongue swelling, peritonitisVery rarePseudomembranous colitis, hepatic comaEndocrineRarelyAdrenal cortical insufficiencyVery rareHyperthyroidism, HypothyroidismRarelyAllergic reactions, anaphylactoid reactionsBlood and lymphatic FrequentTrombocytopenia, anemia (including macrocytic, microcytic, normocytic, megaloblastic, aplastic), leukopenia, pancytopeniaRarelyLymphadenopathy, Agranulocytosis, eosinophilia, disseminated intravascular coagulation syndrome, suppression of medullary hematopoiesisVery rareLymphangitisMetabolism and nutritionFrequentHypokalemia, hypoglycemiaFrequentHypercholesterolemiaSkeletal and muscleFrequentBack painFrequentArtritisNervousVery frequentHeadacheFrequentDizziness, Hallucinations, confusion, depression, anxiety, tremor, agitation, paresthesiasRarelyAtaxia, cerebral edema, hypertension, hyposthesia, nystagmus, dizziness, syncopeVery rareGuienna-Barré syndrome, Oculomotor crisis, extrapyramidal syndrome RespiratoryFrequentDespiratory distress syndrome, pulmonary edema, sinusitisSkin and subcutaneous tissues Very commonFrequentItching, maculopapular rash, skin photosensitivity reactions, Alopecia, exfoliative dermatitis, facial edema, purpura RareToxic epidermal necrolysis, eczema, psoriasis, Stevens-Johnson syndrome, urticaria Very rareAngioneurotic edema, discoid lupus erythema multiforme, Toxic epidermal necrolysisSensory organsVery common Visual disturbances (including visual disturbances/enhancement, blurred vision, color vision changes, photophobia)RareBlepharitis, optic neuritis, optic nerve swelling, scleritis, impaired sense of taste, DiplopiaVery rareRare retinal hemorrhage, corneal opacity, optic atrophyRarelyCreatinine elevation, acute renal failure, hematuriaRarelyUrea residual nitrogen elevation, albuminuria, nephritisVery rareKidney tubular necrosis./p>

*Frequency evaluation criteria were as follows: Very Frequent >10%; Frequent from >1% to>0.1% to

Visual disturbances
Visual disturbances are common with voriconazole treatment. Approximately 30% of patients have visual disturbances: blurred vision, altered color vision, or photophobia. Visual disturbances are transient and completely reversible; in most cases they disappear spontaneously within 60 minutes. On repeated use of voriconazole, a decrease in their severity is noted. Visual disturbances are usually easily expressed, rarely require discontinuation of treatment and do not lead to any consequences in the long-term period. Visual disturbances may be associated with higher plasma concentrations and/or doses of the drug.

The mechanism of their development is not known, although the drug most likely acts on the retina. In a study of the effects of voriconazole on retinal function in healthy volunteers, a decrease in the amplitude of the waves on the electroretinogram (ERG) was found. This method is used to measure the electrical current in the retina. The ERG changes did not increase with continuation of treatment for 29 days and completely disappeared after cancellation of voriconazole. The effect of longer therapy with voriconazole (more than 29 days) on visual function is not known.

Skin reactions

Skin reactions occur in 19% of patients taking voriconazole. In most cases, rashes are mild to moderate in severity. In rare cases severe skin reactions including Stevens-Johnson syndrome (infrequent), toxic epidermal necrolysis (rare) and erythema multiforme (rare) have developed during treatment with voriconazole.

In case of rash, the patient should be closely monitored, and if skin changes progress, voriconazole should be discontinued. Patients receiving long-term therapy with voriconazole may develop photosensitivity skin reactions.

Hepatic function parameters

The overall incidence of clinically significant increase in transaminase activity in patients receiving voriconazole is 13.4%. Liver function abnormalities may be associated with higher plasma concentrations and/or doses of the drug. In most cases, the liver function abnormalities disappear with continuation of treatment (without dose changes or after dose adjustment) or its discontinuation.

In the use of voriconazole, severe hepatotoxicity has rarely been observed in patients with serious underlying medical conditions. These cases may include jaundice, hepatitis and hepatic cell failure leading to death.

Reactions associated with infusion

In intravenous infusion of voriconazole, anaphylactoid reactions including flushes, fever, sweating, tachycardia, chest tightness, shortness of breath, fainting, nausea, itching, and rash may occur. These symptoms appear immediately after the start of the infusion.

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Overdose

The antidote for voriconazole is not known. In case of overdose symptomatic therapy is indicated. Possible gastric lavage.

Voriconazole is eliminated by hemodialysis with a clearance of 121 ml/min. SBECD (sulfobutyl ether of beta-cyclodextrin) is also dialyzed with a clearance of 55 ml/min. In case of overdose, hemodialysis may help to eliminate voriconazole and SBECD from the body.

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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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