Voriconazole Canon, 200 mg 14 pcs

Voriconazole is a broad-spectrum antifungal drug from the triazole group. The mechanism of action of voriconazole is associated with the inhibition of demethylation of alpha-sterol mediated by fungal cytochrome P450 – a key step in ergosterol biosynthesis.

In vitro voriconazole has a broad spectrum of antifungal action: it is active against Candida spp. (including C. krusei, C. glabrata and C. albicans strains), Aspergillus sp., Scedosporium spp. The 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, and 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 for which voriconazole was used included isolated 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. In vitro activity of voriconazole was demonstrated against clinical strains of Acremonium spp., Alternaria spp., Bipolaris spp., Cladophialophora spp. and Listoplasma capsulatum. In vitro activity of voriconazole against Curvularia spp. and Sporothrix spp. was also detected, but the clinical significance of this effect is unknown.

Pharmacokinetics

General characteristics:Voriconazole pharmacokinetic parameters are characterized by significant interindividual variability. The pharmacokinetics of voriconazole is nonlinear due to its metabolic saturation. A disproportionate increase in the area under the “concentration-time curve” (AUCt) is observed when the dose is increased. 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 AUСt. When administered orally, saturating doses of voriconazole, its plasma concentrations are close to equilibrium concentrations during the first 24 hours. If the drug is administered twice daily in medium doses, voriconazole is cumulated, and equilibrium concentrations are reached by the sixth day in most patients.

absorption and distribution:Voriconazole is rapidly and almost completely absorbed after oral administration; Cmaõ is reached 1-2 h after administration. Bioavailability of voriconazole when taken orally is 96%. When voriconazole is repeatedly taken with a fatty food, Cmaõ and AUСt are decreased by 34% and 24%, respectively. Absorption of voriconazole is independent of the pH of gastric juice. The average volume of distribution of voriconazole in equilibrium is 4.6 l/kg. Binding to plasma proteins is 58%. Voriconazole penetrates through the blood-brain barrier and is determined in the cerebrospinal fluid.

Metabolism: Voriconazole is metabolized by the isoenzymes CYP2C19, CYP2C9, CYP3A4. The CYP2C19 isoenzyme plays an important role in the metabolism of voriconazole, with a pronounced genetic polymorphism. In this regard, reduced voriconazole metabolism is possible in 15-20% of Asian people and 3-5% of Caucasian and Negroid people. It was found that voriconazole AUСt is on average 4 times higher in patients with decreased metabolism than in homozygous patients with high metabolism. Heterozygous patients with high metabolism have, on average, 2 times higher voriconazole AUCt than homozygous patients.

The main metabolite of voriconazole is N-oxide, which accounts for 72% of the total number of radioactively labeled metabolites circulating in plasma. This metabolite has minimal antifungal activity and does not contribute to the effect of voriconazole.

Elimation: voriconazole is excreted as metabolites; less than 2% of the administered dose of voriconazole is excreted unchanged by the kidneys. After repeated oral administration, about 83% of the voriconazole dose is detected in the urine. Most (> 94%) of the total dose is excreted within the first 96 h after oral administration. The T1/2 of voriconazole is dose-dependent and is approximately 6 h when administered orally at a dose of 200 mg. Because of nonlinearity of pharmacokinetics, the T1/2 value does not allow predicting cumulation or excretion of voriconazole.

Pharmacokinetics of special patient groups

Gender:When repeated oral administration of the drug, Cmaõ and AUCt were 83% and 113% higher, respectively, in healthy young women than in young healthy men. There were no significant differences in CmaX and AUCt in healthy elderly men and healthy elderly women (≥65 years). Equilibrium 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 according to sex. Plasma concentrations in men and women are similar.

Age:when repeated oral voriconazole administration, Cmax and AUCt in healthy older 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 AUСt in healthy older women (≥65 years) and healthy young women (18-45 years). There is no need to adjust the dose of voriconazole according to age.

Children:The same oral dose of voriconazole (200 mg 2 times daily, regardless of body weight) is required for children to achieve a concentration in children that is comparable to that of the maintenance dose of voriconazole for oral administration in adults 200 mg 2 times daily. No saturation dose is required, nor is the dose of voriconazole required to be adjusted according to age for children within the age range of 2 to 12 years. However, the bioavailability of the drug when taken orally in children may be limited by impaired absorption and fairly low body weight at this age.

Kidney function impairment:With a single oral dose of 200 mg of voriconazole in patients with normal renal function and in patients with renal impairment ranging from mild (creatinine clearance (CK) 41-60 ml/min) to severe (CK < 20 ml/min) the pharmacokinetics of voriconazole are not significantly affected by renal impairment. Binding of voriconazole to plasma proteins is approximately the same in patients with different degrees of renal impairment.

Hepatic dysfunction:After a single oral dose of 200 mg AUtvoriconazole in patients with mild to moderate cirrhosis (Child-Pugh grades 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. In repeated oral administration of this medicine AUСtvoriconazole was comparable in patients with medium degree of liver cirrhosis (class B according to Child-Pugh classification) who received this medicine in maintenance dose of 100 mg twice per day, and in patients with normal liver function who received voriconazole in dose 200 mg twice per day. There are no data about voriconazole pharmacokinetics in patients with severe cirrhosis of liver (class C according to Child-Pugh classification).

Indications

– invasive aspergillosis;

– severe invasive candidiasis (including C. krusei);

– esophageal candidiasis;

– candidemia in patients without neutropenia;

– severe fungal infections caused by Scedosporium spp. and Fusarium spp;

– other severe invasive fungal infections with intolerance or refractory to other medications;

– prevention of “breakthrough” fungal infections in patients with reduced immune system function, fever and neutropenia in the high-risk group (allogeneic bone marrow recipients, patients with relapsed leukemia).

Active ingredient

Composition

Active ingredient:

Voriconazole 200 mg;

Ancillary substances:

Pregelatinized corn starch 81 mg,

croscarmellose sodium 18 mg,

mannitol 83 mg,

magnesium stearate 3 mg,

microcrystalline cellulose 65 mg.

Composition of film coating:

Opadray II white 13 mg, including: polyvinyl alcohol 6.097 mg, macrogol 3.068 mg, talc 2.262 mg, titanium dioxide 1.573 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 patient’s age and body weight, and the treatment regimen.

Interaction

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

In concomitant use with rifampicin (inducer of CYP isoenzymes) at a dose of 600 mg/day Cmax and AUC of voriconazole are decreased by 93% and 96% respectively (combination is contraindicated).

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

Co-administration with cimetidine (nonspecific inhibitor of CYP isoenzymes) at a dose of 400 mg 2 times per day increases Cmax and AUC of voriconazole by 18% and 23% respectively (no dose adjustment of voriconazole is required).

Voriconazole inhibits the activity of CYP2C19, CYP2C9, CYP3A4, therefore it is possible to increase plasma concentrations of drugs, which 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 QT interval and in rare cases to the development of ventricular fibrillation/tripping (the combination is contraindicated).

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

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

When co-administered in patients with stable kidney transplantation, voriconazole increases Cmax and AUC of cyclosporine by at least 13% and 70%, respectively, which is accompanied by an increased risk of nephrotoxic reactions. When using voriconazole in patients receiving cyclosporine, it is recommended to reduce the dose of cyclosporine by half and monitor its plasma levels. After voriconazole withdrawal it is necessary to control cyclosporine levels and if necessary to increase its dose.

When used together voriconazole increases Cmax and AUC of tacrolimus (used in 0.1 mg/kg single dose) 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 voriconazole withdrawal it is necessary to control the concentration of tacrolimus and increase its dose if necessary.

Special Instructions

With caution use in patients with severe hepatic insufficiency, with severe renal failure (when parenteral administration), as well as with hypersensitivity to other drugs – azole derivatives.

Before starting treatment it is necessary to correct electrolyte disorders (hypokalemia, hypomagnesemia and hypocalcemia).

Sampling for cultural and other laboratory studies (serological, histopathological) in order to isolate and identify pathogens should be performed 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 using it the liver function should be monitored regularly (in case of clinical signs of liver disease the decision concerning discontinuation of therapy should be discussed), renal function (including creatinine level in serum).

In case of progressive dermatological reactions, the drug should be discontinued.

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

In concomitant use of voriconazole in patients receiving cyclosporine and tacrolimus the dose of the latter should be corrected and their plasma concentrations should be monitored. After voriconazole withdrawal the plasma concentrations of cyclosporine and tacrolimus should be evaluated and if necessary their doses should be increased.

If co-administration of voriconazole and phenytoin is necessary, the anticipated benefit and potential risk of combined therapy should be carefully evaluated and phenytoin levels should be monitored continuously.

If co-administration of voriconazole and rifabutin is required, 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

Because voriconazole may cause transient visual impairment, including blurred vision, impairment/enhancement of visual perception and/or photophobia, patients should not engage in potentially dangerous activities, such as driving a car or using complex machinery, if these reactions occur. During the use of voriconazole patients should not drive a car at night.

Contraindications

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

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

. – concomitant 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 or more once daily), ritonavir (400 mg or more, twice daily), rifabutin, and St. John’s wort is contraindicated (see “Interaction with other medicinal products” on page 75). section “Interaction with other medicinal products”).

Side effects

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: Frequent – 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; often – 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 disorders: 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. Anaphylactoid reactions including hot flushes, fever, sweating, tachycardia, tightness in the chest, shortness of breath, fainting, itching, rash have been described during IV infusion.

Hematopoietic system disorders: frequently – thrombocytopenia, anemia (including 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.

Respiratory system disorders: 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, edema of the optic nerve papilla, scleritis, disorders of taste perception, diplopia; very rarely – retinal hemorrhage, corneal clouding, optic atrophy.

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

Similarities