Biflurin (Tablets, Lyophilisate) Instructions for Use

ATC Code

J02AC03 (Voriconazole)

Active Substance

Voriconazole (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antifungal drug

Pharmacotherapeutic Group

Systemic antifungal agents; triazole and tetrazole derivatives

Pharmacological Action

Antifungal agent, a triazole derivative. 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, is active against Candida spp. (including fluconazole-resistant strains of Candida krusei, and resistant strains of Candida glabrata and Candida albicans) and has a fungicidal effect against all studied strains of Aspergillus spp., as well as pathogenic fungi that have become relevant recently, including Scedosporium or Fusarium, which have limited sensitivity to antifungal agents.

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 proliferans) and Fusarium spp.

Other fungal infections in which partial or complete antifungal effect was observed 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 Penicillium marneffei), Phialophora richardsiae, Scopulariopsis brevicaulis and Trichosporon spp. (including Trichosporon beigelii).

In vitro activity of voriconazole against clinical strains of Acremonium spp., Alternaria spp., Bipolaris spp., Cladophialophora spp., Histoplasma capsulatum has been demonstrated. Growth of most strains was suppressed at voriconazole concentrations from 0.05 to 2 µg/ml.

In vitro activity of voriconazole against Curvularia spp. and Sporothrix spp. has been identified, but its clinical significance is unknown.

Pharmacokinetics

The pharmacokinetic parameters of voriconazole are characterized by significant interindividual variability.

The pharmacokinetics of voriconazole is nonlinear due to saturation of its metabolism. A dose increase leads to a disproportionate (more pronounced) increase in AUC. Increasing the dose from 200 mg twice daily to 300 mg twice daily leads to an average 2.5-fold increase in AUC. With intravenous administration or oral loading doses, plasma concentrations approach steady-state within the first 24 hours. With twice-daily administration at average (non-loading) doses, accumulation of the active substance occurs, and C_ss is achieved in most cases by day 6.

Voriconazole is rapidly and almost completely absorbed after oral administration; C_max in plasma is reached 1-2 hours after administration. The bioavailability of oral voriconazole is 96%; with repeated administration with high-fat food, C_max and AUC decrease by 34% and 24%, respectively. The absorption of voriconazole does not depend on gastric juice pH.

The calculated V_d of voriconazole at steady state is 4.6 L/kg, indicating active distribution of voriconazole into tissues. Plasma protein binding is 58%.

Voriconazole penetrates the blood-brain barrier and is detected in the cerebrospinal fluid.

In vitro studies have established that Voriconazole is metabolized with the participation of hepatic isoenzymes CYP2C19, CYP2C9, CYP3A4, with CYP2C19 playing an important role in the metabolism of voriconazole. This enzyme exhibits pronounced genetic polymorphism, which is why reduced metabolism of voriconazole is possible in 15-20% of patients of Asian origin and in 3-5% of Caucasians and blacks. Studies in Caucasians and Japanese have shown that in patients with poor metabolism, the AUC of voriconazole is on average 4 times higher than in homozygous patients with extensive metabolism. In heterozygous patients with extensive metabolism, the AUC of voriconazole is on average 2 times higher than in homozygous patients.

The main metabolite of voriconazole is N-oxide (72% among radiolabeled metabolites circulating in plasma). This metabolite has minimal antifungal activity.

Less than 2% is excreted unchanged in the urine.

After repeated oral or intravenous administration, approximately 83% and 80% of the (radiolabeled) dose, respectively, is detected in the urine. The majority (>94%) of the total dose is excreted within the first 96 hours after oral and intravenous administration.

The T_1/2 of voriconazole in the terminal phase is dose-dependent and is approximately 6 hours when the drug is taken orally at a dose of 200 mg. Due to the nonlinear pharmacokinetics, the T_1/2 value does not allow prediction of the accumulation or elimination of voriconazole.

Pharmacokinetics in special clinical cases

With repeated oral administration, C_max and AUC in healthy young women were 83% and 113% higher, respectively, than in healthy young men (18-45 years). There are no significant differences in C_max and AUC between healthy elderly men and healthy elderly women (≥ 65 years).

With repeated oral administration of voriconazole, C_max and AUC in healthy elderly men (≥ 65 years) were 61% and 86% higher, respectively, than in healthy young men (18-45 years).

Mean C_ss in plasma in children receiving Voriconazole 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 mean concentration was 1186 ng/ml in children and 1155 ng/ml in adults. Therefore, the recommended maintenance dose for children aged 2 to 12 years is 4 mg/kg every 12 hours.

After a single oral dose of 200 mg of voriconazole in patients with normal renal function and patients with mild (CrCl 41-60 ml/min) to severe (CrCl less than 20 ml/min) renal impairment, the pharmacokinetics of voriconazole does not significantly depend on the degree of impairment. Plasma protein binding is similar in patients with varying degrees of renal failure.

After a single oral dose of 200 mg, the AUC of voriconazole in patients with mild or moderate severity of liver cirrhosis (Child-Pugh classes 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 administration, the AUC of voriconazole was comparable in patients with moderate liver cirrhosis (Child-Pugh class B) receiving a maintenance dose of 100 mg twice daily and in patients with normal liver function receiving Voriconazole at a dose of 200 mg twice daily.

Indications

Invasive aspergillosis; severe invasive forms of candidal infections (including Candida krusei); esophageal candidiasis; severe fungal infections caused by Scedosporium spp. and Fusarium spp.; severe fungal infections with intolerance or refractoriness to other drugs; prevention of breakthrough fungal infections in high-risk febrile patients (recipients of allogeneic bone marrow transplantation, patients with relapsed leukemia).

ICD codes

Dosage Regimen

Administer orally or as an intravenous infusion. Individualize the dose based on indication, patient age, and body weight.

For adults, use a loading dose on the first day: 6 mg/kg IV every 12 hours, or 400 mg orally every 12 hours for patients ≥40 kg. For patients <40 kg, use 200 mg orally every 12 hours.

Switch to a maintenance dose after the first 24 hours: 4 mg/kg IV every 12 hours, or 200 mg orally every 12 hours for patients ≥40 kg. For patients <40 kg, use 100 mg orally every 12 hours.

For pediatric patients (2 to <12 years), use a loading dose of 9 mg/kg IV every 12 hours on the first day, then a maintenance dose of 8 mg/kg IV every 12 hours. For oral therapy, use 9 mg/kg (maximum 350 mg) every 12 hours on day one, then 8 mg/kg (maximum 350 mg) every 12 hours.

Increase the maintenance dose to 5 mg/kg IV every 12 hours or 300 mg orally every 12 hours (for ≥40 kg) if response is inadequate. Do not use 300 mg oral dose for patients <40 kg.

For esophageal candidiasis, use 200 mg orally every 12 hours. Continue for a minimum of 14 days and for at least 7 days after symptoms resolve.

In patients with moderate hepatic cirrhosis (Child-Pugh Class B), reduce the maintenance dose by half after the standard loading dose. Avoid use in patients with severe hepatic impairment (Child-Pugh Class C) unless the benefit justifies the risk.

Monitor renal function in all patients. In patients with moderate to severe renal impairment (CrCl <50 mL/min), use the oral formulation due to accumulation of the intravenous vehicle. Avoid IV administration unless the benefit outweighs the risk.

In patients who are poor metabolizers via CYP2C19, consider dose reduction. Regularly monitor for adverse events and therapeutic drug levels if available.

Take oral doses at least one hour before or one hour after a meal.

Adverse Reactions

General disorders very common – fever, peripheral edema; common – chills, asthenia, chest pain, injection site reactions and inflammation, flu-like syndrome.

Cardiovascular system common – decreased blood pressure, thrombophlebitis, phlebitis; rare – atrial arrhythmias, bradycardia, tachycardia, ventricular arrhythmias; very rare – supraventricular tachycardia, complete AV block, bundle branch block, nodal arrhythmias, ventricular tachycardia (including ventricular flutter), QT interval prolongation, ventricular fibrillation.

Digestive system very common – nausea, vomiting, diarrhea, abdominal pain; common – increased activity of ALT, AST, ALP, LDH, GGT and plasma bilirubin level, jaundice, cheilitis, cholestasis; rare – cholecystitis, cholelithiasis, constipation, duodenitis, dyspepsia, hepatomegaly, gingivitis, glossitis, hepatitis, hepatic failure, pancreatitis, tongue edema, peritonitis; very rare – pseudomembranous colitis, hepatic coma. In patients with serious underlying diseases (malignant hematological diseases) during voriconazole use, rare cases of severe hepatotoxicity (cases of jaundice, hepatitis, hepatocellular failure leading to death) have been noted.

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

Allergic reactions rare – toxic epidermal necrolysis, Stevens-Johnson syndrome, urticaria; very rare – angioedema, erythema multiforme. Anaphylactoid reactions have been described with intravenous infusion, including flushing, fever, sweating, tachycardia, chest tightness, dyspnea, fainting, itching, rash.

Hematopoietic system common – thrombocytopenia, anemia (including macrocytic, microcytic, normocytic, megaloblastic, aplastic), leukopenia, pancytopenia; rare – lymphadenopathy, agranulocytosis, eosinophilia, disseminated intravascular coagulation syndrome, bone marrow depression; very rare – lymphangitis.

Metabolism common – hypokalemia, hypoglycemia; rare – hypocholesterolemia.

Musculoskeletal system common – back pain; rare – arthritis.

Central and peripheral nervous system very common – headache; common – dizziness, hallucinations, confusion, depression, anxiety, tremor, agitation, paresthesia; rare – ataxia, cerebral edema, intracranial hypertension, hypoesthesia, nystagmus, vertigo, syncope; very rare – Guillain-Barré syndrome, oculogyric crisis, extrapyramidal syndrome.

Respiratory system common – respiratory distress syndrome, pulmonary edema, sinusitis.

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

Special senses common – visual disturbances (including impaired/enhanced visual perception, blurred vision, altered color perception, photophobia); rare – blepharitis, optic neuritis, papilledema, scleritis, taste perversion, diplopia; very rare – retinal hemorrhage, corneal opacity, optic atrophy.

Urinary system common – increased serum creatinine level, acute renal failure, hematuria; rare – increased blood urea nitrogen, albuminuria, nephritis; very rare – renal tubular necrosis.

Contraindications

Concomitant use of drugs that are substrates of CYP3A4 – 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.

Use in Pregnancy and Lactation

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

Excretion of voriconazole in breast milk has not been studied.

Voriconazole should not be used during pregnancy and lactation, except in cases where the expected benefit to the mother outweighs the potential risk to the fetus or breastfed infant.

Women of reproductive age should use reliable methods of contraception during treatment.

Use in Hepatic Impairment

Use with caution in patients with severe hepatic insufficiency. Liver function should be monitored regularly during treatment (if clinical signs of liver disease appear, the advisability of discontinuing therapy should be discussed).

Use in Renal Impairment

Use with caution in patients with severe renal impairment (with parenteral administration). Renal function (including serum creatinine level) should be monitored regularly during treatment.

Pediatric Use

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

Special Precautions

Use with caution in patients with severe hepatic insufficiency, with severe renal impairment (with parenteral administration), as well as with hypersensitivity to other azole derivative drugs.

Correction of electrolyte disturbances (hypokalemia, hypomagnesemia and hypocalcemia) is required before starting treatment.

Samples for culture and other laboratory tests (serological, histopathological) for the isolation and identification of pathogens should be taken before starting treatment. Therapy can be started before receiving the results of laboratory tests and then adjusted if necessary.

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

Liver function (if clinical signs of liver disease appear, the advisability of discontinuing therapy should be discussed) and renal function (including serum creatinine level) should be monitored regularly during treatment.

If dermatological reactions progress, the drug should be discontinued.

During treatment, patients receiving Voriconazole should avoid sun exposure and UV radiation.

With simultaneous use of voriconazole in patients receiving cyclosporine and tacrolimus, the dose of the latter should be adjusted and their plasma concentration monitored. After discontinuation of voriconazole, the plasma concentration of cyclosporine and tacrolimus should be assessed and their dose increased if necessary.

If concomitant use of voriconazole and phenytoin is necessary, the expected benefit and potential risk of combination therapy should be carefully assessed and phenytoin levels should be constantly monitored.

If concomitant use of voriconazole and rifabutin is necessary, the expected benefit and potential risk of combination therapy should be carefully assessed and it should be carried out under the control of peripheral blood picture, as well as other possible adverse effects of rifabutin.

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

Effect on ability to drive vehicles and operate machinery

Since Voriconazole can cause transient visual disturbances, including blurred vision, impaired/enhanced visual perception and/or photophobia, if such reactions occur, patients should not engage in potentially hazardous activities such as driving a car or operating complex machinery. While taking voriconazole, patients should not drive at night.

Drug Interactions

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

With simultaneous use with rifampicin (an inducer of CYP isoenzymes) at a dose of 600 mg/day, C_max and AUC of voriconazole decrease by 93% and 96%, respectively (combination is contraindicated).

With simultaneous use with voriconazole, ritonavir (an inducer of CYP isoenzymes, inhibitor and substrate of CYP3A4) at a dose of 400 mg every 12 hours reduced the steady-state C_max and AUC of orally administered voriconazole by an average of 66% and 82%, respectively. The effect of lower doses of ritonavir on voriconazole concentrations is not yet known. It has been established that repeated oral administration of voriconazole does not have a significant effect on the steady-state C_max and AUC of ritonavir, also taken repeatedly (simultaneous use of voriconazole and ritonavir at a dose of 400 mg every 12 hours is contraindicated).

When used concomitantly with potent inducers of CYP isoenzymes carbamazepine or long-acting barbiturates (phenobarbital), a significant decrease in the C_max of voriconazole in plasma is possible, although their interaction has not been studied. Such a combination is contraindicated.

When used concomitantly with cimetidine (a nonspecific inhibitor of CYP isoenzymes) at a dose of 400 mg twice daily, the C_max 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; therefore, it may increase plasma concentrations of drugs metabolized by these isoenzymes.

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

Concomitant use of Voriconazole increases the C_max and AUC of sirolimus (2 mg single dose) by 556% and 1014%, respectively (this combination is contraindicated).

Concomitant use of Voriconazole may increase plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) and lead to the development of ergotism (this combination is contraindicated).

In concomitant use in stable kidney transplant patients, Voriconazole increases the C_max and AUC of cyclosporine by at least 13% and 70%, respectively, which is associated with an increased risk of nephrotoxic reactions. When voriconazole is used in patients receiving cyclosporine, it is recommended to reduce the cyclosporine dose by half and monitor its plasma levels. After discontinuation of voriconazole, cyclosporine levels should be monitored and its dose increased if necessary.

Concomitant use of Voriconazole increases the C_max and AUC of tacrolimus (administered as a single 0.1 mg/kg dose) by 117% and 221%, respectively, which may be accompanied by nephrotoxic reactions. When voriconazole is used in patients receiving tacrolimus, it is recommended to reduce the tacrolimus dose to one-third and monitor its plasma levels. After discontinuation of voriconazole, the tacrolimus concentration should be monitored and its dose increased if necessary.

Concomitant administration of voriconazole (at a dose of 300 mg twice daily) and warfarin (30 mg once daily) resulted in an increase in maximum prothrombin time by up to 93%. When warfarin and voriconazole are co-administered, prothrombin time should be monitored.

Voriconazole, when used concomitantly, may increase the plasma concentrations of phenprocoumon and acenocoumarol (substrates of CYP2C9 and CYP3A4) and increase prothrombin time. When voriconazole is used in patients receiving coumarin drugs, prothrombin time should be monitored at short intervals and anticoagulant doses adjusted accordingly.

Concomitant use of Voriconazole may increase the plasma concentrations of sulfonylurea derivatives (CYP2C9 substrates) – tolbutamide, glipizide, and glibenclamide – and cause hypoglycemia. When used concomitantly, blood glucose levels should be carefully monitored.

In vitro, Voriconazole inhibits the metabolism of lovastatin (a CYP3A4 substrate). Concomitant use may increase plasma concentrations of statins metabolized by CYP3A4, which may increase the risk of rhabdomyolysis. When used concomitantly, the need for statin dose adjustment should be assessed.

In vitro, Voriconazole inhibits the metabolism of midazolam (a CYP3A4 substrate). Concomitant use may increase plasma concentrations of benzodiazepines metabolized by CYP3A4 (midazolam, triazolam, alprazolam) and lead to prolonged sedative effects. When these drugs are used concomitantly, the need for benzodiazepine dose adjustment should be discussed.

Concomitant use of Voriconazole may increase plasma concentrations of vinca alkaloids (CYP3A4 substrates) – vincristine and vinblastine – and lead to the development of neurotoxic reactions. The need for dose adjustment of vinca alkaloids should be discussed.

Voriconazole increases the C_max and AUC of prednisolone (a CYP3A4 substrate) administered as a single 60 mg dose by 11% and 34%, respectively. Dose adjustment is not recommended.

When used concomitantly with voriconazole, efavirenz (a CYP3A4 substrate, and according to several studies, depending on the dose, an inhibitor or inducer of CYP3A4), administered at a dose of 400 mg once daily at steady state, reduces the C_max 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 C_max and AUC of efavirenz by an average of 38% and 44%, respectively (this combination is contraindicated).

Concomitant use with phenytoin (a CYP2C9 substrate and a potent inducer of cytochrome P450 isoenzymes), administered at a dose of 300 mg once daily, reduces the C_max and AUC of voriconazole by 49% and 69%, respectively; and Voriconazole (400 mg twice daily) increases the C_max and AUC of phenytoin by 67% and 81%, respectively (if concomitant use is necessary, the benefit-risk ratio of the combined therapy should be carefully assessed, and phenytoin plasma levels should be closely monitored).

Concomitant use with rifabutin (an inducer of cytochrome P450), administered at a dose of 300 mg once daily, reduces the C_max and AUC of voriconazole (200 mg once daily) by 69% and 78%, respectively. When used concomitantly with rifabutin, the C_max and AUC of voriconazole (350 mg twice daily) are 96% and 68%, respectively, of those with voriconazole monotherapy (200 mg twice daily). When voriconazole is used at a dose of 400 mg twice daily, the C_max and AUC are 104% and 87% higher, respectively, than with voriconazole monotherapy at a dose of 200 mg twice daily. Voriconazole at a dose of 400 mg twice daily increases the C_max and AUC of rifabutin by 195% and 331%, respectively. During concomitant therapy with rifabutin and voriconazole, a complete blood count should be regularly performed and adverse effects of rifabutin (e.g., uveitis) should be monitored.

Concomitant use with omeprazole at a dose of 40 mg once daily (an inhibitor of CYP2C19; a substrate of CYP2C19 and CYP3A4) increases the C_max and AUC of voriconazole by 15% and 41%, respectively, and Voriconazole increases the C_max and AUC of omeprazole by 116% and 280%, respectively (therefore, no dose adjustment of voriconazole is required, but the omeprazole dose should be reduced by half). The possibility of drug interaction between voriconazole and other H⁺/K⁺ ATPase inhibitors that 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 potential toxic effects, as in vitro studies have shown that Voriconazole and HIV protease inhibitors (saquinavir, amprenavir, nelfinavir) may mutually inhibit each other’s metabolism.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.