Vifend pills 200mg, 14pcs

Composition

1 coated tablet contains:

Active ingredient:

voriconazole 200 mg,

excipients:

lactose monohydrate;

pregelatinized starch;

sodium croscarmellose;

povidone;

magnesium stearate

shell:

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

Pharmacological action

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

The mechanism of action of voriconazole is related to the inhibition of 14α-sterol demethylation mediated by fungal cytochrome P 450; 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 C. krusei strains 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 recently become relevant, including Scedosporium or Fusarium, which are only slightly sensitive 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 that used the drug (often with partial or complete response) 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 studies demonstrated the activity of voriconazole against clinical strains of 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 micrograms / 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 people, representatives of special groups, and patients.

The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. When the dose is increased, a disproportionate (more pronounced) increase in AUC (area under the concentration-time curve) is observed. It is estimated that an increase in the oral dose from 200 mg 2 times a day to 300 mg 2 times a day leads to an increase in AUCt by an average of 2.5 times. With intravenous or oral shock doses, plasma concentrations approach equilibrium within the first 24 hours. If the patient does not receive a shock dose, then with repeated use of voriconazole 2 times a day, the drug accumulates, and equilibrium plasma concentrations are reached by day 6 in most patients.

Voriconazole is rapidly and almost completely absorbed after oral use; maximum plasma concentrations (Cmax) are reached 1-2 hours after use. The oral bioavailability of voriconazole is 96%. When voriconazole is re-administered with fatty foods, Cmax and AUCt decrease by 34% and 24%, respectively.

The absorption of voriconazole does not depend on the pH of gastric juice.

The estimated volume of distribution of voriconazole at steady state is 4.6 l/kg, which indicates an active distribution of the drug in the tissue. Binding to plasma proteins is 58%.

Voriconazole is detected in the spinal fluid.

The pharmacokinetics of voriconazole are characterized by high interindividual variability.

In vitro studies have shown that voriconazole is metabolized by hepatic cytochrome P 450 isoenzymes-CYP2C19, CYP2C9, and CYP3A4.

In vivo studies also suggest that CYP2C19 plays an important role in voriconazole metabolism. This enzyme exhibits a genetic polymorphism. For example, reduced voriconazole metabolism can be expected in 15-20% of Asians and 3-5% of whites and blacks. Studies in white and Japanese people have shown that patients with reduced metabolism have an average AUCt of voriconazole 4 times higher than in homozygous patients with high metabolism. In heterozygous patients with active metabolism, the AUCt 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 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 use of labeled voriconazole, approximately 80% and 83% of the radioactive dose, respectively, are detected in the urine. Most (>94%) of the total dose is eliminated within the first 96 hours after oral and intravenous use.

The terminal half-life of voriconazole depends on the dose 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 allow predicting the accumulation or elimination of voriconazole.

Pharmacokinetics in special groups

After oral repeated use, Cmax and AUCt 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 AUCt in healthy elderly men and healthy elderly women (>65 years).

There is no need to adjust the dose depending on gender. Plasma concentrations in men and women are similar.

Age at repeated oral use of Cmax and AUCt in healthy elderly men (>65 years) is 61% and 86% o, respectively, higher than in healthy young men (18-45 years). There were no significant differences in Cmax and AUCt in healthy elderly women (>65 years) and healthy young women (18-45 years). The safety of voriconazole in young and elderly patients is the same, and therefore no dose adjustment is required in the elderly.

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 average concentration was 1186 ng / ml in children and 1155 ng / ml in adults. Therefore, the recommended maintenance dose in children aged 2 to

Impaired renal function

In single dose of voriconazole oral dose of 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 or severe impairment of renal function (serum creatinine >220 µmol/l, or 2.5 mg/DL) was observed accumulation auxiliary substances included in the composition of the lyophilisate for preparation of solution for injection – SBECD.

Impaired liver function

After a single oral dose (200 mg), the AUC of voriconazole in patients with mild to moderate cirrhosis of the liver (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 use, the AUCX of voriconazole is comparable in patients with moderate cirrhosis of the liver (Child-Pugh B), who received the drug at a maintenance dose of 100 mg 2 times a day, and patients with normal liver function receiving voriconazole at a dose of 200 mg 2 times a day. There are no data on pharmacokinetics in patients with severe cirrhosis of the liver (Child-Pugh C).

Indications

• invasive aspergillosis
• severe invasive forms of candida infections (including C. krusei) that are resistant to fluconazole.
• candidiasis of the esophagus caused by C. albicans in patients with immunodeficiency.
• severe fungal infections caused by Scedosporium spp and Fusarium spp.
• severe fungal infections caused by intolerance or refractoriness to other medications.
• Prevention of “breakthrough” fungal infections in high-risk febrile patients (recipients of allogeneic bone marrow, patients with recurrent leukemia).

Use during pregnancy and lactation

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 elimination of voriconazole in breast milk has not been studied. Voriconazole should not be used in breast-feeding women unless the expected benefit clearly outweighs the risk.

Contraindications

• Vfend is contraindicated in patients with hypersensitivity to voriconazole or any component of the drug;
• simultaneous use of Vfend and substrates of CYP3A4 — of terfenadine, astemizole, cisapride, pimozide or quinidine is contraindicated, since increased concentrations of the latter in plasma can lead to QT prolongation and in rare cases to the development flutter/ventricular fibrillation;
• the simultaneous use of Vfend and sirolimus is contraindicated becausevoriconazole significantly increased concentrations of sirolimus in the plasma of healthy people;
• the simultaneous use of Vfend with rifampin, carbamazepine and long-acting barbiturates (e. g. phenobarbital) is contraindicated because these drugs significantly reduce the concentration of voriconazole in plasma (see “Interaction”);
• concurrent use of Vfend with ritonavir (400 mg every 12 hours) is contraindicated as the latter significantly reduces the concentration of voriconazole in plasma of healthy people;
• the simultaneous use of Vfend with efavirenz contraindicated, since the latter greatly reduces the concentration of voriconazole in plasma voriconazole and, in turn, increases the plasma concentration of efavirenz;
• concurrent use of ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates, is contraindicated, since increased concentrations of these substances in the plasma may lead to ergotism.

With caution — severe hepatic insufficiency, severe renal insufficiency (with parenteral use). Safety and efficacy in children under 2 years of age have not been established. Hypersensitivity to other drugs-derivatives of azoles.

Side effects

The table lists the adverse events that were observed during the use of 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. Adverse reactions were usually mild to moderate. There was no clinically significant age, race, or gender-dependent relationship in the safety of the drug.

Body System Frequency*Adverse drug reactions Generally very frequent fever, peripheral edema, frequent chills, asthenia, chest pain, injection site reactions/inflammation, flu-like syndrome of cardiovasculature, frequent lowering of blood pressure, thrombophlebitis, phlebitis, atrial arrhythmias, bradycardia, tachycardia, ventricular arrhythmia. Very rare non-ventricular tachycardia, complete atrioventricular block, bundle branch block, nodal arrhythmias, ventricular tachycardia (including ventricular flutter), QT prolongation, ventricular fibrillation. Digestion Very often nausea, vomiting, diarrhea, abdominal pain, frequent increase in liver function indicators (including ACT, AJIT, alkaline phosphatase, gamma-HT, LDH, bilirubin), jaundice, cheilitis, cholestasis. Rare cholecystitis, cholelithiasis, constipation, duodenitis, dyspepsia, enlarged liver, gingivitis, glossitis, hepatitis, liver failure, pancreatitis, tongue edema, peritonitis Rare pseudomembranous colitis, hepatic comaendocrine infrequent adrenal insufficiency Very rare hyperthyroidism, Hypothyroidismimmune infrequently allergic reactions, anaphylactoid reactionsblood and lymphatic frequentstrombocytopenia, anemia (including macrocytic, microcytic, normocytic, megaloblastic, aplastic), leukopenia, pancytopenia infrequently lymphadenopathy, agranulocytosis, eosinophilia, disseminated intravascular coagulation syndrome, Inhibition of bone marrow hematopoiesis Very rareelymphangitis Metabolism and nutrition Frequent hypokalemia, hypoglycemia Rare hypercholesterolemia musculoskeletal pain Spinal pain Arthritic Nervous pain Very frequent headache Frequent dizziness, hallucinations, confusion, depression, anxiety, tremor, agitation, Paresthesia and rare ataxia, cerebral edema, hypertension, hyposthesia, nystagmus, dizziness, syncope very rare, Hyenne-Barre syndrome, oculomotor crisis, extrapyramidal syndrome of respiratory distress, pulmonary edema, sinusitis of the skin and subcutaneous tissues Very frequentscypes of pruritus, maculopapular rash, photosensitivity skin reactions, alopecia, exfoliative dermatitis, facial edema, purpurea, Toxic epidermal necrolysis, eczema, psoriasis, Stevens-Johnson syndrome, urticaria, Very rare angioedema, discoid lupus erythematosus, erythema multiforme, toxic epidermal necrolysis Sensitive organs Frequent visual disturbances (including impaired/enhanced visual perception, blurred vision, color vision changes, photophobia)Rare blepharitis, optic neuritis, edema of the nipple of the optic nerve, scleritis, impaired taste perception, diplopia very rare retinal hemorrhage, corneal opacities, atrophy of the optic nerve of the genitourinary tract, increased creatinine, acute renal failure, hematuria rarely increased residual urea nitrogen, albuminuria, nephritis very rare necrosis kidney tubules

*The frequency assessment 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 impairment: blurred vision, color vision changes, or photophobia. Visual disturbances are transient and completely reversible; in most cases, they disappear spontaneously within 60 minutes. With repeated use of voriconazole, a weakening of their severity is noted. Visual disturbances are usually mild, rarely require discontinuation of treatment, and do not lead to any long-term consequences. 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. When studying the effect of voriconazole on retinal function in healthy volunteers, a decrease in the amplitude of waves on the electroretinogram (ERG) was revealed. This method is used to measure the electric current in the retina. Changes in ERG did not increase with continued treatment for 29 days and completely disappeared after discontinuation of voriconazole. The effect of longer voriconazole therapy (more than 29 days) on visual function is not known.

Skin reactions

Skin reactions occur in 19% of patients taking voriconazole. In most cases, the rash is mild or moderate. In rare cases, severe skin reactions develop during treatment with voriconazole, including Stevens-Johnson syndrome (infrequently), toxic epidermal necrolysis (rarely), and erythema multiforme (rarely).

If a rash appears, the patient should be carefully monitored, and if skin changes progress, it is advisable to cancel voriconazole. Patients receiving long-term voriconazole therapy may develop photosensitive skin reactions.

Liver function indicators

The overall rate of clinically significant increase in transaminase activity in patients receiving voriconazole is 13.4%. Hepatic impairment may be associated with higher plasma concentrations and / or doses of the drug. In most cases, deviations in liver function indicators disappear with continued treatment (without changing the dose or after its correction) or its termination.

When using voriconazole, cases of severe hepatotoxicity are rarely observed in patients with serious underlying diseases. These cases may include cases of jaundice, hepatitis, and hepatic cell failure leading to death.

Infusion-related reactions

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

Interaction

Effect of other drugs on the pharmacokinetics of voriconazole

Voriconazole is metabolized by the cytochrome P450 isoenzymes CYP2C19, CYP2C9, and CYP3A4. Inhibitors or inducers of these isoenzymes can cause, respectively, an increase or decrease in plasma concentrations of voriconazole. Plasma voriconazole levels are significantly reduced when used concomitantly with the following medications::Rifampicin (CYP450 inducer): Rifampicin (600 mg once daily) reduces the Cmax (maximum plasma concentration) and AUCt of voriconazole by 93% and 96%, respectively.

Concomitant use of voriconazole and rifampicin is contraindicated (see section Contraindications).

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

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

Given the small pharmacokinetic interaction or the absence of a significant interaction, dose adjustment of the following drugs is not required:Cimetidine (a non-specific inhibitor of CYP450, and also increases the pH of gastric juice): Cimetidine (400 mg twice daily) causes an increase in the Cmax and AUCX of voriconazole by 18% and 23%, respectively. Dose adjustment of voriconazole is not recommended. Ranitidine (increases the pH of gastric juice): Ranitidine (150 mg twice daily) has no significant effect on the Cmax and AUCt of voriconazole.

Macrolide antibiotics: Erythromycin (a CYP3A4 inhibitor; 1 g twice daily) and azithromycin (500 mg once daily) do not significantly affect the Cmax and AUCt of voriconazole.

Effect of voriconazole on other drugs

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

Concomitant use of voriconazole with the following medications is contraindicated:Terfenadine, astemizole, cisapride, pimozide and quinidine (CYP3A4 substrates): Although interaction with these drugs has not been studied, however, concomitant use of voriconazole with terfenadine, astemizole, cisapride, pimozide or quinidine is contraindicated, since an increase in their plasma concentrations can lead to prolongation of the QT interval and, in rare cases, to the development of ventricular fibrillation/flutter.

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

Ergot alkaloids (CYP3A4 substrates): Although interactions with these drugs have not been studied, 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. In this regard, when they are used simultaneously, constant monitoring and/or dose adjustment is necessary.

Cyclosporine (CYP3A4 substrate): In stable kidney transplant patients, voriconazole increases the Cmax and AUCt of cyclosporine by at least 13% and 70%, respectively. When prescribing voriconazole to patients receiving cyclosporine, it is recommended to reduce the dose of cyclosporine by half and monitor its plasma levels. An increase in the concentration of cyclosporine is accompanied by nephrotoxicity. After discontinuation of voriconazole, it is necessary to monitor cyclosporine levels and, if necessary, increase its dose.

Tacrolimus (CYP3A4 substrate): Voriconazole increases the Cmax and AUCt (area under the concentration-time to last quantitative measurement curve) 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 tacrolimus levels are associated with nephrotoxicity. After discontinuation of voriconazole, it is necessary to monitor the concentration of tacrolimus and, if necessary, increase its dose.

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

Other oral anticoagulants, e. g. phenprocumone, acenocoumarol (substrates of CYP2C9, CYP3A4): Voriconazole may cause an increase in plasma coumarin concentrations and prothrombin time. If patients receiving coumarin preparations are prescribed voriconazole, it is necessary to monitor the prothrombin time at short intervals and adjust the dose of anticoagulants accordingly.

Sulfonylurea derivatives (CYP2C9 substrates): Voriconazole may increase plasma concentrations of sulfonylurea derivatives (e. g. tolbutamide, glipizide, and glibenclamide) and cause hypoglycemia. When they are used simultaneously, it is necessary to carefully monitor blood glucose levels.

Statins (CYP3A4 substrates): in vitro, voriconazole inhibits lovastatin metabolism (in human liver microsomes). In this regard, voriconazole may cause an increase in plasma concentrations of statins metabolized by CYP3A4. When they are used concomitantly, it is recommended to evaluate the feasibility of adjusting the statin dose. Elevated statin levels have sometimes been associated with 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 can cause an increase in plasma levels of benzodiazepines that are metabolized by CYP3A4 (midazolam, triazolam, alprazolam), and the development of a prolonged sedative effect. With the simultaneous use of these drugs, it is recommended to discuss the feasibility of adjusting the dose of benzodiazepine.

Periwinkle alkaloids (CYP3A4 substrates): Voriconazole can increase the content of periwinkle alkaloids in plasma (for example, vincristine and vinblastine) and cause neurotoxicity.

It is recommended to discuss the feasibility of adjusting the dose of vinca alkaloids.

When voriconazole is co-administered with the following drugs, no significant pharmacokinetic interaction was detected, so no dose adjustment is required:

Prednisone (CYP3A4 substrate): Voriconazole increases the Cmax and AUCt of prednisone (60 mg once) by 11% and 34%, respectively. No dose adjustment is recommended.

Digoxin (P-glycoprotein-mediated transport): Voriconazole does not significantly affect the Cmax and AUCt of digoxin (0.25 mg once daily).

Mycophenolic acid (UDP-glucuronyltransferase substrate): Voriconazole does not affect the Cmax and AUCt of mycophenolic acid (1 g once).

Phenytoin (CYP2C9 substrate and potent CYP450 inducer) : Concomitant use of voriconazole and phenytoin should be avoided unless the expected benefit outweighs the possible risk.

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

Rifabutin (CYP450 inducer): Rifabutin (300 mg once daily) reduces the Cmax and AUCt of voriconazole (200 mg twice daily) by 69% and 78%, respectively. With simultaneous use of rifabutin, the Cmax and AUCt of voriconazole at a dose of 350 mg 2 times a day are 96% and 68% of the indicators when using voriconazole separately at a dose of 200 mg 2 times a day. When using voriconazole at a dose of 400 mg twice a day, Cmax and AUCt, respectively, are 104% and 87% higher than when using voriconazole at a dose of 200 mg twice a day. Voriconazole 400 mg twice daily increases the Cmax and AUCt of rifabutin by 195% and 331%, respectively.

If the expected benefit of treatment outweighs the risk, rifabutin may 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 weighing less than 40 kg) (see section Dosage and use). With simultaneous treatment with rifabutin and voriconazole, it is recommended to regularly conduct a detailed blood test and monitor the undesirable effects of rifabutin (for example, uveitis).

Omeprazole (inhibitor of CYP2C19; substrate of CYP2C19 and CYP3A4): Omeprazole (40 mg once daily) increases the Cmax and AUCt of voriconazole by 15% and 41%, respectively. Dose adjustment of voriconazole is not recommended.

Voriconazole increases the Cmax and AUCt of omeprazole by 116% and 280%, respectively. When prescribing voriconazole to patients receiving omeprazole, the dose of the latter is recommended to be halved.

Voriconazole may also inhibit the metabolism of other proton pump blockers that are substrates of CYP2C19. Indinavir (CYP3A4 inhibitor and substrate): Indinavir (800 mg three times daily) does not significantly affect the Cmax and AUCt of voriconazole.

Voriconazole does not significantly affect the Cmax, Cmin and AUCt of indinavir (800 mg 3 times a day).

Other HIV protease inhibitors (substrates and inhibitors of CYP3A4): In vitro studies suggest that voriconazole may 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 voriconazole metabolism. If voriconazole is co-administered with HIV protease inhibitors, patients should be monitored for possible toxic effects.

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

How to take it, course of use and dosage

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

Use in adults

Intravenous or oral use of voriconazole should begin with the recommended saturating dose to achieve a serum concentration close to equilibrium on the first day.

Given the high oral bioavailability (96%, see section Pharmacokinetics), if there are clinical indications, you can switch from intravenous to oral use of the drug. The table shows detailed information on the dosage of the drug:

 Intravenous intravenous patients with a body weight of 40 kg and more patients with a body weight of less than 40 kg Saturating dose-all indications (first 24 hours)6 mg / kg every 12 hours (during the first 24 hours)400 mg every 12 hours (during the first 24 hours) 200 mg every 12 hours (for the first 24 hours)Maintenance dose(after the first 24 hours)Prevention of recurrent infections 3 mg / kg every 12 hours 200 mg every 12 hours 100 mg every 12havigate invasive candida infections resistant to fluconazole/invasive aspergillosis/Scedosporium and Fusarium infections/Other serious mold infections 4 mg / kg every 12 hours 200 mg every 12 hours 100 mg every 12 hours Esophageal candidiasis caused by C. albicans in immunodeficient patients

No recommendations 200 mg every 12 hours 100 mg every 12 hours

Dose selection If treatment is not effective enough, the maintenance dose can be increased to 300 mg every 12 hours by mouth. In patients with a body weight of less than 40 kg, the dose can be increased to 150 mg every 12 hours by mouth. If the patient does not tolerate the drug in a high dose, then it is reduced in steps of 50 mg to 200 mg every 12 hours orally (or 100 mg every 12 hours in patients with a body weight of 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 a body weight of less than 40 kg). The duration of treatment depends on the clinical effect and the results of mycological analysis.

Use in the elderly

No dose adjustment is required in the elderly. Use in patients with impaired renal function Coated tablets:Impaired renal function does not affect the pharmacokinetics of voriconazole when taken orally. Therefore, no dose adjustment of voriconazole for oral use is required in patients with mild, moderate or severe renal impairment. Use in patients with impaired liver functionin case of acute liver damage, manifested by an increase in the activity of “hepatic” transaminases (AJIT, ACT), no dose adjustment is required. In such cases, it is recommended to continue monitoring liver function indicators in order to detect their further increase.

In patients with mild or moderate cirrhosis of the liver (Child-Pugh A and B), it is recommended to prescribe a standard shock dose of voriconazole, and reduce the maintenance dose by 2 times.

Patients with severe hepatic impairment should be prescribed voriconazole only in cases where the expected benefit outweighs the possible risk. In patients with severe hepatic impairment, treatment should be carried out under constant monitoring in order to detect signs of drug toxicity.

The safety and efficacy of voriconazole in children under 2 years of age have not been established, and therefore voriconazole is not recommended for use in children under 2 years of age.

The experience of using it in children is limited, which makes it difficult to choose the optimal dosage. However, in pharmacokinetic studies in children, voriconazole was used according to the following schemes. Children aged 2 to :

 Intravenous saturating dose (first 24 hours) 6 mg / kg every 12 hours (during the first 24 hours)6 mg / kg every 12 hours (during the first 24 hours)Maintenance dose (after the first 24 hours)4 mg / kg every 12 hours 4 mg / kg every 12 hours

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

Overdose

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

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

Special instructions

Sampling for culture and other laboratory tests (serology, histopathology) in order to isolate and identify pathogens should be carried out before starting treatment. Therapy can be initiated before receiving the results of culture and other laboratory tests, but if they are available, treatment should be adjusted accordingly. Clinical strains with reduced sensitivity to voriconazole were identified.

However, elevated minimum inhibitory concentrations (MPC) do not always predict clinical ineffectiveness; voriconazole has been shown 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 studies; the values of borderline concentrations of voriconazole that allow us to assess sensitivity to this drug have not been established. Hypersensitivity: Patients with hypersensitivity to other azoles should be prescribed voriconazole with caution

Adverse events from the cardiovascular system: 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 seriously ill patients with multiple risk factors, such as cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant therapy, which could contribute to the development of this complication). In patients with these potentially proarrhythmic conditions, voriconazole should be administered with caution (see section Dosage and use). Hepatotoxicity: When treated with voriconazole, there are infrequent (0.1-1%%) cases of serious liver reactions (including clinically manifested hepatitis, cholestasis and hepatic cell failure, including with a fatal outcome). Adverse events from the liver are mainly observed in patients with serious diseases (mainly malignant blood tumors). Patients without any risk factors have transient liver reactions, including hepatitis and jaundice. Liver function disorders are usually reversible and resolve after discontinuation of treatment.

Monitoring of liver function: During treatment with voriconazole, it is recommended to regularly monitor liver function, especially liver tests and bilirubin. If there are clinical signs of liver disease that may be associated with voriconazole, it is necessary to discuss the feasibility of discontinuing therapy. Adverse events from the kidneys: Severe patients receiving voriconazole have cases of acute renal failure.

Monitoring of renal function:Patients should be monitored for signs of impaired renal function. To do this, it is necessary to conduct laboratory tests, in particular to determine the serum creatinine level. Infusion reactions: When voriconazole is administered intravenously, infusion reactions are observed, mainly “flushes of blood to the face” and nausea. If these symptoms are severe, the advisability of discontinuing treatment should be discussed (see section Side effects). Skin reactions: In rare cases, patients treated with voriconazole develop exfoliative skin reactions, such as Stevens-Johnson syndrome. When a rash appears, patients should be monitored. With the progression of skin lesions, voriconazole should be discontinued. In addition, the use of voriconazole was accompanied by skin reactions of photosensitivity, especially during 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 potent CYP450 inducer): When phenytoin is co-administered with voriconazole, continuous monitoring of phenytoin levels is recommended. If possible, the concomitant use of voriconazole and phenytoin should be avoided unless the expected benefit outweighs the possible risk (see section Interactions with other drugs and other forms of interaction).

Rifabutin (CYP450 inducer): When rifabutin is co-administered with voriconazole, it is recommended to conduct a clinical blood test and monitor for undesirable effects of rifabutin (for example, uveitis). Concomitant use of voriconazole and rifabutin should be avoided unless the expected benefit outweighs the possible risk (see section Interactions with other drugs and other forms of interaction). Women of reproductive agewomen of reproductive age should always use effective methods of contraception during treatment.

Effects on the ability to drive and use Technicoloriconazole may cause transient and reversible visual disturbances, including blurred vision, impaired / enhanced visual perception, and / or photophobia. If these symptoms are present, patients should avoid performing potentially dangerous activities such as driving a car or using complex machinery. When taking voriconazole, patients should not drive at night.

Form of production

Coated tablets.

Storage conditions

At a temperature not exceeding 30 °C

Shelf life

3 years

Active ingredient

Voriconazole

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

Adult Doctor’s prescription