Bethend, 40 mg/ml 45 g

1. invasive aspergillosis
2. severe invasive candidiasis infections (including C. krusei) resistant to fluconazole.
3. esophageal candidiasis caused by C. albicans in immunodeficient patients.
4. severe fungal infections caused by Scedosporium spp. and Fusarium spp.
5. severe fungal infections with intolerance or refractoriness to other medications.
6. Prevention of “breakthrough” fungal infections in febrile high-risk patients (allogeneic bone marrow recipients, patients with relapsed leukemia).
   

Active ingredient

Composition

The composition of 1 ml of the ready-to-use suspension: active ingredient: voriconazole – 40 mg; excipients: colloidal silicon dioxide – 1 mg; sucrose – 542.4 mg; titanium dioxide – 1 mg; sodium benzoate – 2.4 mg; xanthan gum – 2 mg; orange flavoring – 4 mg; sodium citrate dihydrate – 3 mg; citric acid – 4.2 mg.

How to take, the dosage

It is administered orally or parenterally as an infusion.

The dose is set individually, depending on the indication, the age and weight of the patient, the treatment regimen.

Interaction

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

Concomitant use with rifampicin (CYP isoenzyme inducer) at a dose of 600 mg/day decreases Cmax and AUC of voriconazole by 93% and 96% respectively (the combination is contraindicated).

When used concomitantly with voriconazole, ritonavir (a CYP isoenzyme inducer, inhibitor and substrate of CYP3A4) at a dose of 400 mg every 12 h reduced the equilibrium 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 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 inducers of CYP isoenzymes 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 isoenzymes) 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 voriconazole is required).

Voriconazole inhibits the activity of CYP2C19, CYP2C9, CYP3A4, therefore there may be increased plasma concentrations of drugs that are metabolized by these isoenzymes.

Special Instructions

Cautiously use in patients with severe hepatic insufficiency, with severe renal insufficiency (when parenteral administration), as well as with hypersensitivity to other azole derivatives.

Pre-treatment of electrolyte disturbances (hypokalemia, hypomagnesemia and hypocalcaemia) should be corrected.

Sampling for culture and other laboratory tests (serological, histopathological) in order to isolate and identify pathogens should be carried out before the start of treatment. Therapy can be started before the results of laboratory tests are available, and then adjusted if necessary.

The use of voriconazole may lead to prolongation of the QT interval on ECG, which is accompanied by rare cases of ventricular fibrillation-truncation in patients with multiple risk factors (cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant therapy that may have contributed to cardiovascular adverse events). In patients with these potentially proarrhythmic conditions voriconazole should be used with caution.

When treating it it is necessary to monitor liver function regularly (in case of clinical signs of liver disease the expediency of discontinuation of therapy should be discussed), renal function (including creatinine level in serum).

The drug should be discontinued if dermatologic reactions have progressed.

Patients receiving voriconazole should avoid sun exposure and UV exposure during treatment.

The concomitant use of voriconazole in patients receiving cyclosporine and tacrolimus should adjust the dose of the latter and monitor their plasma concentrations. After cancellation of voriconazole, plasma concentrations of cyclosporine and tacrolimus should be assessed and, if necessary, their doses should be increased.

If it is necessary to combine voriconazole and phenytoin, the estimated benefits and potential risks of combined therapy should be carefully evaluated and phenytoin levels should be continuously monitored.

If voriconazole and rifabutin are to be used together, the anticipated benefits and potential risks of combination therapy should be carefully evaluated and the peripheral blood count should be monitored, as well as other possible adverse effects of rifabutin.

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

Impact on driving and operating machinery

Since voriconazole may cause transient visual impairment, including blurred vision, impaired/enhanced visual perception and/or photophobia, patients should not engage in potentially dangerous activities, such as driving or operating complex machinery, if these reactions occur. During the use of voriconazole patients should not drive a car in the dark time of the day.

Features

Pharmacodynamics
Mechanism of action:
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 studied strains of Aspergillus sp. as well as pathogenic fungi of recent relevance, including Scedosporium or Fusarium, which are limited sensitive to existing antifungal agents.
Clinical efficacy has been demonstrated in infections caused byAspergillus 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 was demonstrated against clinical strains Acremonium spp., Alternaria spp., Bipolaris spp., Cladophialophora spp., Histoplasma capsulatum. The growth of most strains was suppressed at voriconazole concentrations from 0.05 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 was studied in healthy people, 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 quickly and almost completely absorbed after oral administration; maximum plasma concentrations (Cmax) are reached 1-2 hours after administration. Bioavailability of voriconazole during oral administration is 96%. When voriconazole is repeatedly taken with a fatty food Cmax and AUCτ are decreased by 34% and 24% respectively.
Absorption of voriconazole does not depend on the pH of gastric juice.
Calculated volume of distribution of voriconazole in equilibrium state is 4.6 l/kg, indicating active distribution of the drug in tissues. Binding to plasma proteins is 58%.
Voriconazole is determined in 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 indicate 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. Heterozygous patients with active metabolism have on average 2 times higher AUCτ of voriconazole than 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 depends on the dose and is approximately 6 hours 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
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 elderly men and healthy elderly women (>65 years).
There is no need for dose adjustment depending on sex. Plasma concentrations in men and women are similar.
Age
With 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). The safety of voriconazole in young and elderly patients is the same, therefore no dose adjustment is required in elderly patients.

Contraindications

Simultaneous use of CYP3A4 substrate drugs – terfenadine, astemizole, cisapride, pimozide and quinidine; simultaneous use of sirolimus; simultaneous use of rifampicin, carbamazepine and long-acting barbiturates; concomitant use of ritonavir; concomitant use of efavirenz; concomitant use of ergot alkaloids (ergotamine, dihydroergotamine); hypersensitivity to voriconazole.

Side effects

From the body in general: very often – fever, peripheral edema; often – chills, asthenia, chest pain, reactions and inflammation at the injection site, flu-like syndrome.

Cardiovascular system disorders: common – decreased BP, thrombophlebitis, phlebitis; rare – atrial arrhythmias, bradycardia, tachycardia, ventricular arrhythmias; very rare – supraventricular tachycardia, complete AV blockade, Gis bundle leg block, nodal arrhythmias, ventricular tachycardia (including ventricular flutter), prolonged QT interval, ventricular fibrillation.

Digestive system disorders: very common – nausea, vomiting, diarrhea, abdominal pain; common – increased activity of ALT, AST, ALF, LDH, GGT and plasma bilirubin levels, jaundice, cheilitis, cholestasis; rare – cholecystitis, cholelithiasis, constipation, duodenitis, dyspepsia, liver enlargement, gingivitis, glossitis, hepatitis, liver failure, pancreatitis, tongue edema, peritonitis; very rare – pseudomembranous colitis, liver coma. In patients with serious underlying diseases (malignant hematologic diseases) against the background of voriconazole use, severe hepatotoxicity (cases of jaundice, hepatitis, hepatocellular failure leading to death) were rarely observed.

Endocrine system: rare – insufficiency of the adrenal cortex; very rare – hyperthyroidism, hypothyroidism.

Allergic reactions: rare – toxic epidermal necrolysis, Stevens-Johnson syndrome, urticaria; very rare – angioedema, erythema multiforme. In intravenous infusion anaphylactoid reactions have been described, including hot flashes, fever, sweating, tachycardia, chest tightness, shortness of breath, fainting states, itching, rash.

Hematopoietic system: often – thrombocytopenia, anemia (incl. macrocytic, microcytic, normocytic, megaloblastic, aplastic), leukopenia, pancytopenia; rarely – lymphadenopathy, agranulocytosis, eosinophilia, disseminated intravascular coagulation syndrome, suppression of medullar hemopoiesis; very rarely – lymphangitis.

Metabolism: often – hypokalemia, hypoglycemia; rarely – hypocholesterolemia.

Muscular system: often – back pain; rarely – arthritis.

CNS and peripheral nervous system disorders: very common Рheadache; common Рdizziness, hallucinations, confusion, depression, anxiety, tremor, agitation, paresthesias; rare Рataxia, cerebral edema, intracranial hypertension, hyposthesia, nystagmus, dizziness, syncope; very rare РGuillain-Barr̩ syndrome, oculomotor crisis, ectrapyramid syndrome.

In the respiratory system: often – respiratory distress syndrome, pulmonary edema, sinusitis.

Dermatological reactions: very common – rash; common – itching, maculopapular rash, photosensitization, alopecia, exfoliative dermatitis, facial edema, purpura; rarely – psoriasis; very rare – discoid lupus erythematosus.

Sense organs: often – visual disorders (including disturbance/enhancement of visual perception, fog before eyes, altered color perception, photophobia); rarely – blepharitis, optic neuritis, papilledema, scleritis, disorders of taste perception, diplopia; very rarely – retinal hemorrhage, corneal clouding, optic atrophy.

Over urinary system: often – increased serum creatinine level, acute renal failure, hematuria; rarely – increased residual urea nitrogen, albuminuria, nephritis; very rarely – renal tubule necrosis.