Voriconazole Canon pills 200mg, 14pcs

Composition

Active ingredient:

voriconazole 200 mg;

Auxiliary substances:

pregelatinized corn starch 81 mg,

croscarmellose sodium 18 mg,

mannitol 83 mg,

magnesium stearate 3 mg,

microcrystalline cellulose 65 mg.

Composition of the film shell:

 opadray II white 13 mg, including: polyvinyl alcohol 6.097 mg, macrogol 3.068 mg, talc 2.262 mg, titanium dioxide 1.573 mg

Pharmacological action

Voriconazole is a broad-spectrum antifungal drug from the triazole group. The mechanism of action of voriconazole is associated with the inhibition of 14 alpha-sterol demethylation mediated by fungal cytochrome P 450, a key step in ergosterol biosynthesis.

In vitro voriconazole has a broad spectrum of antifungal action: active against Candida spp. (including C. krusei, C. glabrata and C. albicans strains), Aspergillus sp., Scedosporium spp., Fusarium spp. Clinical efficacy of voriconazole 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. glabrata, C. krusei, C. parapsilosis, C. tropicalis, as well as against a limited number of strains of C. dubliniensis, C. inconspicua, C. guillermondii, Scedosporium spp., including S. apiospermum, S. prolifecans and Fusarium spp. Other fungal infections in which voriconazole was used 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 P. marneffei, Philaphora richardsiae, Scopulariopsis brevicaulis and Trychosporon spp., including T. beigelii. Voriconazole was shown to be active in vitro against clinical strains of Acremonium spp., Alternaria spp., Bipolaris spp., Cladophialophora spp., and liistoplasma capsulatum. Voriconazole was also found to be active in vitro against Curvularia spp. and Sporothrix spp., but the clinical significance of this effect is unknown.

Pharmacokinetics

General characteristics: The pharmacokinetic parameters of voriconazole are characterized by significant interindividual variability. The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. When the dose is increased, there is a disproportionate increase in the area under the concentration-time curve (AUCt). 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. When voriconazole is administered orally in saturating doses, its plasma concentrations approach equilibrium within the first 24 hours. If the drug is prescribed 2 times a day in medium doses, then voriconazole accumulates, and equilibrium concentrations are reached by the sixth day in most patients.

Suction and distribution: voriconazole is rapidly and almost completely absorbed after oral use; Cmax is 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 average volume of distribution of voriconazole at steady state is 4.6 l / kg. Binding to plasma proteins is 58%. Voriconazole penetrates the blood-brain barrier and is detected in the cerebrospinal fluid.

Metabolism: voriconazole is metabolized by the isoenzymes CYP2C19, CYP2C9, and CYP3A4. An important role in the metabolism of voriconazole is played by the CYP2C19 isoenzyme, which exhibits a pronounced genetic polymorphism, and therefore, a reduced metabolism of voriconazole is possible in 15-20% of representatives of Asian origin and in 3-5%of representatives of the Caucasian and Black races. It was found that in patients with reduced metabolism, the AUC of voriconazole is on average 4 times higher than in homozygous patients with high metabolism. In heterozygous patients with high metabolism, the AUC 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 total amount of radiolabeled metabolites circulating in the blood plasma. This metabolite has minimal antifungal activity and does not contribute to the effect of voriconazole.

Deduction: voriconazole is excreted as metabolites; less than 2% of the administered dose of voriconazole is excreted unchanged by the kidneys. After repeated oral use, about 83% of the voriconazole dose is detected in the urine. Most (>94%) of the total dose is eliminated within the first 96 hours after oral use. T1 / 2 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 T1/2 value does not allow predicting the accumulation or elimination of voriconazole.

Pharmacokinetics of special patient groups

Paul: when repeated oral use of the drug, Cmax and AUCt in healthy young women were 83% and 113%, respectively, higher than in young healthy men. There were no significant differences in Cmax and AUCt in healthy elderly men and healthy elderly women (≥ 65 years). The steady-state plasma concentration of voriconazole in women was 100% higher than in men after taking the drug in tablet form. There is no need to adjust the dose depending on the gender. Plasma concentrations in men and women are similar.

Age: with repeated oral use of voriconazole, Cmax and AUCt in healthy elderly men (≥ 65 years) are 61% and 86% higher, respectively, 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). There is no need to adjust the dose of voriconazole depending on age.

Children: to achieve a voriconazole concentration in children comparable to that of the maintenance dose of voriconazole for oral use to adults of 200 mg 2 times a day, for children the same dose of voriconazole for oral use is required (200 mg 2 times a day, regardless of body weight). No saturating dose is required, as well as age-dependent dose adjustment of voriconazole for children within the age range from 2 to 12 years. However, the bioavailability of the drug when taken orally in children may be limited by malabsorption and a fairly low body weight at this age.

Impaired renal function: with a single oral dose of voriconazole 200 mg in patients with normal renal function and patients with impaired renal function from mild (creatinine clearance (creatinine clearance) 41-60 ml / min) to severe (creatinine clearance The binding of voriconazole to plasma proteins is approximately the same in patients with varying degrees of renal insufficiency.

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

Indications

invasive aspergillosis;

— severe invasive forms of candidiasis (including C. krusei);

— esophageal candidiasis;

— candidemia in patients without neutropenia;

— serious fungal infections caused by Scedosporium spp. and Fusarium spp;

— other severe invasive fungal infections in case of intolerance or refractoriness to other drugs;

— prevention of breakthrough fungal infections in patients with reduced function of the immune system, fever and neutropenia at high risk (recipients of allogenic bone marrow, patients with relapse of leukemia).

Contraindications

-hypersensitivity to voriconazole or any other component of the drug.

– children under 3 years of age (for this dosage form).

– simultaneous use of the drug Voriconazole Canon and terfenadine, astemizole, cisapride, pimozide, quinidine, sirolimus, rifampicin, carbamazepine, long-acting barbiturates (phenobarbital), ergot alkaloids (ergotamine, dihydroergotamine), efavirenz (400 mg and above 1 time a day), ritonavir (400 mg and above,2 times a day), rifabutin, and also St. John’s wort is contraindicated (see the section “Interaction with other drugs”).

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, hyposthesia, nystagmus, dizziness, fainting; very rarely-Guillenne-Barre syndrome, oculomotor crisis, extrapyramidal syndrome.

From the respiratory system: 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 sensory organs: 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 the steady-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 the steady-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). When co-administered, phenytoin (a CYP2C9 substrate and a potent inducer of cytochrome P450 isoenzymes), administered at a dose of 300 mg 1 time/day, reduces the Cmax and AUC of voriconazole by 49% and 69%, respectively; and voriconazole (400 mg 2 times/day) increases the Cmax and AUC of phenytoin by 67% and 81%, respectively (if necessary, co-use should carefully assess the ratio of the intended benefit and potential risk of combination therapy, as well as 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, Cmax and AUC are 104% and 87% higher, respectively, than when using voriconazole at a dose of 200 mg 2 times/day. Voriconazole 400 mg twice daily increases rifabutin Cmax and AUC 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 co-administered at a dose of 40 mg 1 time/day, omeprazole (an inhibitor of CYP2C19; a substrate of CYP2C19 and CYP3A4) increases the Cmax and AUC of voriconazole by 15% and 41%, respectively, and voriconazole increases the Cmax and AUC of omeprazole by 116% and 280%, respectively (therefore, no dose adjustment of voriconazole is required, and the dose of omeprazole should be reduced 2-fold). 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 motor vehicles and manage 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

Tablets

Purpose

Adult Doctor’s prescription