Voriconazole Sandoz lyophilizate solution concentrate for infusion 200mg, 1pc

Composition

>of 1 fl. contains: Active ingredients:  Voriconazole* – 200 mgsupport substances: betadex (betacyclodextrin) in the form of sodium sulfobutylate – 3200 mg*.

* taking into account the estimated excess of 5.65% to compensate for the unrecoverable volume to guarantee the claimed amount of voriconazole (211.3 mg) and betadex sodium sulfobutylate (3380.8 mg).

Pharmacological action

Pharmaco-therapeutic group: Antifungal agent

Pharmacological action

An antifungal agent derived from triazole. The mechanism of action is associated with the 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 against Candida spp. (including Candida krusei strains resistant to fluconazole and resistant strains of Candida glabrata and Candida albicans) and has a fungicidal effect against all the studied strains of Aspergillus spp. as well as pathogenic fungi, which has become relevant in recent years, including Scedosporium or Fusarium, which to a limited extent, sensitive to antifungal drugs.

The clinical efficacy of voriconazole has been demonstrated in infections caused by Aspergillus spp. (including Aspergillus flavus, Aspergillus fumigatus, Aspergillus terreus, Aspergillus niger, Aspergillus nidulans), Candida spp. (including strains of Candida albicans, Candida dubliniensis, Candida glabrata, Candida inconspicua, Candida krusei, Candida parapsilosis, Candida tropicalis and Candida guillermondii), Scedosporium spp. (including Scedosporium apiospermum /Pseudoallescheria boydii/, Scedosporium prolifecans) and Fusarium spp.

Other fungal infections in which a partial or complete antifungal effect was observed included isolated cases of infections caused by Alternaria spp., Blastomyces dermatitidis, Blastoschizomyces capitatus, Cladosporium spp., Coccidoides immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum, Exophiala spinifera, Fonsecaea pedrosoi, Madurella mycetomatis, Paecilomyces lilacinus, Penicillium spp. (including Penicillium marneffei), Philaphora richardsiae, Scopulariopsis brevicaulis and Trychosporon spp. (including Trychosporon beigelii).

In vitro activity of voriconazole was demonstrated against clinical strains of Acremonium spp., Alternaria spp., Bipolaris spp., Cladophialophora spp., and 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.

Indications

• Invasive aspergillosis;
• severe invasive Candida infections (including Candida krusei);
• candidiasis of the esophagus;
• serious fungal infections caused by Scedosporium spp. and Fusarium spp. ;
• serious fungal infections in case of intolerance or refractoriness to other drugs;
• prevention of breakthrough fungal infections in patients with fever of high-risk groups (recipients of allogenic bone marrow, patients with relapse of leukemia).

Use during pregnancy and lactation

Adequate and strictly controlled studies on the safety of voriconazole use during pregnancy have not been conducted. In experimental studies on animals, it was found that voriconazole in high doses has a toxic effect on reproductive function. The possible risk to humans is not known.

The elimination of voriconazole in breast milk has not been studied.

Voriconazole should not be used during pregnancy and lactation, unless the expected benefit to the mother exceeds the potential risk to the fetus or infant.

During treatment, women of reproductive age should use reliable methods of contraception.

Contraindications

Concomitant use of CYP3A4 substrates-terfenadine, astemizole, cisapride, pimozide and quinidine; concomitant use of sirolimus; concomitant 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 as a whole:  very often-fever, peripheral edema; often-chills, asthenia, chest pain, reactions and inflammation at the injection site, flu-like syndrome.

From the cardiovascular system:  often-decreased blood pressure, thrombophlebitis, phlebitis; rarely-atrial arrhythmias, bradycardia, tachycardia, ventricular arrhythmias; very rarely-supraventricular tachycardia, complete AV block, bundle branch block, nodal arrhythmias, ventricular tachycardia (including ventricular flutter), prolongation of the QT interval, ventricular fibrillation.

From the digestive system:  very often – nausea, vomiting, diarrhea, abdominal pain; often – increased activity of ALT, AST, ALP, LDH, GGT and bilirubin levels in blood plasma, jaundice, cheilitis, cholestasis; rarely – cholecystitis, cholelithiasis, constipation, duodenitis, dyspepsia, liver enlargement, gingivitis, glossitis, hepatitis, liver failure, pancreatitis, tongue edema, peritonitis; very rarely – pseudomembranous colitis, hepatic coma. In patients with serious underlying diseases (malignant hematological diseases), cases of severe hepatotoxicity (cases of jaundice, hepatitis, hepatocellular insufficiency leading to death) were rarely observed during the use of voriconazole.

From the endocrine system:  rarely-insufficiency of the adrenal cortex; very rarely-hyperthyroidism, hypothyroidism.

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

From the hematopoietic system:  often-thrombocytopenia, anemia (including macrocytic, microcytic, normocytic, megaloblastic, aplastic), leukopenia, pancytopenia; rarely-lymphadenopathy, agranulocytosis, eosinophilia, disseminated intravascular coagulation syndrome, suppression of bone marrow hematopoiesis; very rarely-lymphangitis.

From the side of metabolism:  often-hypokalemia, hypoglycemia; rarely-hypocholesterolemia.

Musculoskeletal disorders:  often-back pain; rarely-arthritis.

From the central nervous system and peripheral nervous system:  very often-headache; often-dizziness, hallucinations, confusion, depression, anxiety, tremor, agitation, paresthesia; rarely-ataxia, cerebral edema, intracranial hypertension, hypesthesia, nystagmus, dizziness, fainting; very rarely – Guillain-Barre syndrome, oculomotor crisis, extrapyramidal syndrome.

Respiratory system disorders:  often – respiratory distress syndrome, pulmonary edema, sinusitis.

Dermatological reactions:  very often-rash; often-pruritus, maculopapular rash, photosensitization, alopecia, exfoliative dermatitis, facial edema, purpura; rarely-psoriasis; very rarely-discoid lupus erythematosus.

From the side of the senses:  often-visual disturbances (including impaired / enhanced visual perception, fog in front of the eyes, color perception changes, photophobia); rarely – blepharitis, optic neuritis, optic nipple edema, scleritis, taste perception disorders, diplopia; very rarely – retinal hemorrhage, corneal opacity, optic atrophy.

From the urinary system:  often-increased serum creatinine, acute renal failure, hematuria; rarely-increased residual urea nitrogen, albuminuria, nephritis; very rarely-necrosis of the renal tubules.

Interaction

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

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

When administered concomitantly with voriconazole, ritonavir (a CYP isoenzyme inducer, inhibitor, and CYP3A4 substrate) at a dose of 400 mg every 12 hours reduced _thesteady-state cmax and oral AUC of voriconazole by an average of 66% and 82%, respectively. The effect of lower doses of ritonavir on voriconazole concentrations is not yet known. Repeated oral use of voriconazole was found to have no significant effect on _thesteady-state cmax 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 combined with powerful inducers of CYP isoenzymes carbamazepine or long-acting barbiturates (phenobarbital), a significant decrease in the_cmax of voriconazole in plasma is possible, although their interaction has not been studied. This combination is contraindicated.

When combined with cimetidine (a non-specific inhibitor of CYP isoenzymes) at a dose of 400 mg 2 times/day, the_cmax and AUC of voriconazole increase by 18% and 23%, respectively (no dose adjustment of voriconazole is required).

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

Concomitant use of voriconazole with terfenadine, astemizole, cisapride, pimozide and quinidine may significantly increase their plasma concentrations, which may lead to prolongation of the QT interval and, in rare cases, to the development of ventricular fibrillation/flutter (the combination is contraindicated).

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

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

When used together in patients who have undergone kidney transplantation and are in a stable condition, voriconazole increases the_cmax and AUC of cyclosporine by at least 13% and 70%, respectively, which is accompanied by an increased risk of developing nephrotoxic reactions. When using voriconazole in patients receiving cyclosporine, it is recommended to reduce the dose of cyclosporine by 2 times and monitor its plasma levels. After discontinuation of voriconazole, it is necessary to monitor cyclosporine levels and, if necessary, increase its dose.

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

Concomitant use of voriconazole (300 mg twice daily) and 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.

Voriconazole, when co-administered, may cause an increase in plasma concentrations of phenprocumone, acenocoumarol (substrates of CYP2C9, CYP3A4) and prothrombin time. When using voriconazole in patients receiving coumarin preparations, it is necessary to monitor the prothrombin time at short intervals and adjust the dose of anticoagulants accordingly.

When used together, voriconazole can cause an increase in the concentration of sulfonylurea derivatives (CYP2C9 substrates) – tolbutamide, glipizide and glibenclamide in plasma and cause hypoglycemia. When they are used simultaneously, it is necessary to carefully monitor blood glucose levels.

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

In vitro, voriconazole inhibits the metabolism of midazolam (a CYP3A4 substrate). When used together, it is possible to increase the plasma concentration of benzodiazepines metabolized by CYP3A4 (midazolam, triazolam, alprazolam) and develop a prolonged sedative effect. With the simultaneous use of these drugs, it is recommended to discuss the feasibility of adjusting the dose of benzodiazepine.

When used together, voriconazole may increase the content of periwinkle alkaloids (CYP3A4 substrates) – vincristine, vinblastine in plasma and lead to the development of neurotoxic reactions. It is recommended to discuss the feasibility of adjusting the dose of periwinkle alkaloids.

Voriconazole increases the_cmax and AUC of prednisone (a CYP3A4 substrate) administered at a single dose of 60 mg by 11% and 34%, respectively. No dose adjustment is recommended.

When used concomitantly with voriconazole, efavirenz (a CYP3A4 substrate, according to a number of studies, depending on the dose – an inhibitor or inducer of CYP3A4), used at a dose of 400 mg 1 time/day at steady state, reduces the_cmax and AUC of voriconazole by an average of 61% and 77%, respectively. Voriconazole at steady state (400 mg orally every 12 hours on the first day, then 200 mg orally every 12 hours for 8 days) increases the steady_{-state cmax} and AUC of efavirenz by an average of 38% and 44%, respectively (this combination is contraindicated).

In a joint application phenytoin (CYP2 substrate 9 and a powerful inducer of cytochrome P450 isoenzymes), used at a dose of 300 mg 1 time/day, reduces C_max and AUC of voriconazole by 49% and 69%, respectively; and voriconazole (400 mg 2 times/day) increases C_max and AUC of phenytoin by 67% and 81%, respectively (if necessary, the joint use should be carefully evaluated the ratio of the expected benefits and potential risks of combination therapy, and carefully monitor the levels of phenytoin in plasma).

Co-use of rifabutin (a cytochrome P450 inducer) administered at a dose of 300 mg 1 time/day reduces the_cmax and AUC of voriconazole (200 mg 1 time/day) by 69% and 78%, respectively. When combined with rifabutin, the_cmax and AUC of voriconazole (350 mg 2 times/day) is 96% and 68%, respectively, of the values for monotherapy with voriconazole (200 mg 2 times/day). When using voriconazole at a dose of 400 mg 2 times / day With_max and AUC, respectively,104% and 87% higher than with monotherapy with voriconazole at a dose of 200 mg 2 times/day. Voriconazole 400 mg twice daily increases the_cmax and AUC of rifabutin by 195% and 331%, respectively. With simultaneous treatment with rifabutin and voriconazole, it is recommended to regularly conduct a detailed analysis of the peripheral blood picture and monitor the undesirable effects of rifabutin (for example, uveitis).

When used together, the dose of 40 mg 1 time/day omeprazole (CYP2C19 inhibitor; CYP2C19 and a substrate of CYP3A4) increases C_max and AUC of voriconazole by 15% and 41%, respectively, and voriconazole increases C_max and AUC of omeprazole 116% and 280%, respectively (and therefore the dose adjustment of voriconazole is not required, and the dose of omeprazole to be reduced by 2 times). The possibility of drug interaction of voriconazole with other H+-K+-ATPASE inhibitors, which are substrates of CYP2C19, should be considered.

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

How to take, course of use and dosage

Apply orally or parenterally as an infusion.

The dose is set individually, depending on the indications, the patient’s age and body weight, and the treatment regimen.

Special instructions

Use with caution in patients with severe hepatic insufficiency, with severe renal insufficiency (with parenteral use), as well as with hypersensitivity to other drugs-azole derivatives.

Before starting treatment, correction of electrolyte disturbances (hypokalemia, hypomagnesemia, and hypocalcemia) is required.

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

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

During treatment, liver function should be regularly monitored (if clinical signs of liver disease appear, the feasibility of discontinuing therapy should be discussed), kidney function (including serum creatinine).

If dermatological reactions progress, the drug should be discontinued.

During treatment, patients receiving voriconazole should avoid exposure to the sun and UV radiation.

When voriconazole is co-administered in patients receiving cyclosporine and tacrolimus, the dose of the latter should be adjusted and their plasma concentrations monitored. After discontinuation of voriconazole, the plasma concentrations of cyclosporine and tacrolimus should be evaluated and, if necessary, their dose should be increased.

If the combined use of voriconazole and phenytoin is necessary, the intended benefit and potential risk of combination therapy should be carefully evaluated and the level of phenytoin should be constantly monitored.

If the combined use of voriconazole and rifabutin is necessary, the intended benefit and potential risk of combination therapy should be carefully evaluated and carried out under the control of the peripheral blood picture, as well as other possible undesirable effects of rifabutin.

The safety and efficacy of voriconazole in children under 2 years of age have not been established.

Influence on the ability to drive vehicles and mechanisms

Since voriconazole can cause transient visual disturbances, including blurred vision, impaired/enhanced visual perception, and/or photophobia, patients should not engage in potentially dangerous activities such as driving a car or using complex equipment when these reactions occur. When using voriconazole, patients should not drive a car in the dark.

Active ingredient

Voriconazole

Conditions of release from pharmacies

By prescription

Dosage form

infusion solution