Voriconazole Canon (Tablets) Instructions for Use

Marketing Authorization Holder

Canonpharma Production, CJS (Russia)

ATC Code

J02AC03 (Voriconazole)

Active Substance

Voriconazole (Rec.INN registered by WHO)

Dosage Forms

	Voriconazole Canon	Film-coated tablets 50 mg: 2, 7, 10, 14, 28, 30, 50, 56 or 100 pcs.
		Film-coated tablets 200 mg: 2, 7, 10, 14, 28, 30, 50, 56 or 100 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex; the cross-section is almost white.

Excipients: pregelatinized corn starch 81 mg, croscarmellose sodium 18 mg, mannitol 83 mg, magnesium stearate 3 mg, microcrystalline cellulose 65 mg.

Film coating composition Opadry II white 13 mg, including: polyvinyl alcohol 6.097 mg, macrogol 3.068 mg, talc 2.262 mg, titanium dioxide 1.573 mg.

2 pcs. – blister packs (aluminum/PVC) (1) – cardboard packs.
7 pcs. – blister packs (aluminum/PVC) (1) – cardboard packs.
7 pcs. – blister packs (aluminum/PVC) (2) – cardboard packs.
7 pcs. – blister packs (aluminum/PVC) (4) – cardboard packs.
7 pcs. – blister packs (aluminum/PVC) (8) – cardboard packs.
10 pcs. – blister packs (aluminum/PVC) (1) – cardboard packs.
10 pcs. – blister packs (aluminum/PVC) (3) – cardboard packs.
10 pcs. – blister packs (aluminum/PVC) (5) – cardboard packs.
10 pcs. – blister packs (aluminum/PVC) (10) – cardboard packs.
14 pcs. – blister packs (aluminum/PVC) (1) – cardboard packs.
14 pcs. – blister packs (aluminum/PVC) (2) – cardboard packs.
14 pcs. – blister packs (aluminum/PVC) (4) – cardboard packs.
15 pcs. – blister packs (aluminum/PVC) (2) – cardboard packs.

Film-coated tablets white or almost white, round, biconvex; the cross-section is almost white.

Excipients: pregelatinized corn starch 30 mg, croscarmellose sodium 5.5 mg, mannitol 30 mg, magnesium stearate 1 mg, microcrystalline cellulose 23.5 mg.

Film coating composition Opadry II white 4 mg, including: polyvinyl alcohol 1.876 mg, macrogol 0.944 mg, talc 0.696 mg, titanium dioxide 0.484 mg.

2 pcs. – blister packs (aluminum/PVC) (1) – cardboard packs.
7 pcs. – blister packs (aluminum/PVC) (1) – cardboard packs.
7 pcs. – blister packs (aluminum/PVC) (2) – cardboard packs.
7 pcs. – blister packs (aluminum/PVC) (4) – cardboard packs.
7 pcs. – blister packs (aluminum/PVC) (8) – cardboard packs.
10 pcs. – blister packs (aluminum/PVC) (1) – cardboard packs.
10 pcs. – blister packs (aluminum/PVC) (3) – cardboard packs.
10 pcs. – blister packs (aluminum/PVC) (5) – cardboard packs.
10 pcs. – blister packs (aluminum/PVC) (10) – cardboard packs.
20 pcs. – blister packs (aluminum/PVC) (5) – cardboard packs.
28 pcs. – blister packs (aluminum/PVC) (1) – cardboard packs.
28 pcs. – blister packs (aluminum/PVC) (2) – cardboard packs.
30 pcs. – blister packs (aluminum/PVC) (1) – cardboard packs.

Clinical-Pharmacological Group

Antifungal drug

Pharmacotherapeutic Group

Antifungal agent

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 P450, a key step in ergosterol biosynthesis.

In vitro, Voriconazole has a broad spectrum of antifungal activity: it is active against Candida spp. (including strains of C. krusei, C. glabrata and C. albicans), 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. prolificans and Fusarium spp. Other fungal infections for which Voriconazole has been used 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 activity of voriconazole has been demonstrated against clinical strains of Acremonium spp., Alternaria spp., Bipolaris spp., Cladophialophora spp., Histoplasma capsulatum. In vitro activity of voriconazole has also been identified 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 nonlinear due to saturation of its metabolism. A disproportionate increase in the area under the concentration-time curve (AUC_t) is observed with increasing dose. Increasing the oral dose from 200 mg twice daily to 300 mg twice daily results in an average 2.5-fold increase in AUC_t. When oral loading doses of voriconazole are administered, its plasma concentrations approach steady-state within the first 24 hours. When the drug is prescribed twice daily at average doses, voriconazole accumulates, and steady-state concentrations are reached by the sixth day in most patients.

Absorption and distribution Voriconazole is rapidly and almost completely absorbed after oral administration; C_max is reached 1-2 hours after administration. The bioavailability of voriconazole when taken orally is 96%. With repeated administration of voriconazole with fatty foods, C_max and AUC_t 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. Plasma protein binding is 58%. Voriconazole penetrates the blood-brain barrier and is detected in the cerebrospinal fluid.

Metabolism Voriconazole is metabolized by the action of isoenzymes CYP2C19, CYP2C9, CYP3A4. The isoenzyme CYP2C19, which exhibits pronounced genetic polymorphism, plays an important role in the metabolism of voriconazole, which is why reduced metabolism of voriconazole is possible in 15-20% of individuals of Asian origin and in 3-5% of individuals of Caucasian and Negroid race. It has been established that in patients with reduced metabolism, the AUC_t of voriconazole is on average 4 times higher than in homozygous patients with high metabolism. In heterozygous patients with high metabolism, the AUC_t 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 plasma. This metabolite has minimal antifungal activity and does not contribute to the effect of voriconazole.

Excretion Voriconazole is excreted as metabolites; less than 2% of the administered dose of voriconazole is excreted unchanged by the kidneys. After repeated oral administration, approximately 83% of the voriconazole dose is detected in the urine. The majority (> 94%) of the total dose is excreted within the first 96 hours after oral administration. The T_1/2 of voriconazole is dose-dependent and is approximately 6 hours when the drug is taken orally at a dose of 200 mg. Due to the nonlinearity of pharmacokinetics, the T_1/2 value does not allow prediction of the accumulation or elimination of voriconazole.

Pharmacokinetics in special patient groups

Gender with repeated oral administration of the drug, C_max and AUC_t in healthy young women were 83% and 113% higher, respectively, than in healthy young men. There are no significant differences in C_max and AUC_t between 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 for dose adjustment based on gender. Plasma concentrations are similar in men and women.

Age with repeated oral administration of voriconazole, C_max and AUC_t in healthy elderly men (≥ 65 years) were 61% and 86% higher, respectively, than in healthy young men (18-45 years). There are no significant differences in C_max and AUC_t between 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 voriconazole concentrations in children comparable to those with the oral maintenance dose of voriconazole for adults of 200 mg twice daily, children require the same oral dose of voriconazole (200 mg twice daily, regardless of body weight). A loading dose is not required, nor is dose adjustment of voriconazole based on 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 malabsorption and sufficiently low body weight at this age.

Renal impairment after a single oral dose of 200 mg of voriconazole to patients with normal renal function and patients with renal impairment from mild (creatinine clearance (CrCl) 41-60 ml/min) to severe (CrCl < 20 ml/min), the pharmacokinetics of voriconazole do not significantly depend on the degree of renal impairment. The binding of voriconazole to plasma proteins is approximately the same in patients with varying degrees of renal failure.

Hepatic impairment after a single oral dose of 200 mg, the AUC_t of voriconazole in patients with mild or moderate 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 of the drug, the AUC_t of voriconazole is comparable in patients with moderate liver cirrhosis (Child-Pugh class B) receiving the drug at 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. There is no information on the pharmacokinetics of voriconazole in patients with severe liver cirrhosis (Child-Pugh class C).

Indications

• Invasive aspergillosis;
• Severe invasive forms of 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 resistance to other drugs;
• Prevention of breakthrough fungal infections in patients with reduced immune system function, fever and neutropenia at high risk (recipients of allogeneic bone marrow, patients with relapsed leukemia).

ICD codes

Dosage Regimen

Orally, 1 hour before meals or 1 hour after meals.

Adults and children from 12 years of age administration of Voriconazole Canon should be started with the recommended loading dose to achieve plasma concentrations close to steady-state on the first day.

Dose adjustment if the treatment response is insufficient, the maintenance dose of Voriconazole Canon can be increased to 300 mg every 12 hours. In patients weighing less than 40 kg, the dose can be increased to 150 mg every 12 hours.

If the patient does not tolerate the drug at a high dose (300 mg every 12 hours), then the maintenance dose is gradually reduced to 200 mg by 50 mg every 12 hours (for patients weighing less than 40 kg – to 100 mg every 12 hours).

Phenytoin can be used concomitantly with Voriconazole Canon if the maintenance dose of the latter is increased from 200 mg to 400 mg every 12 hours (from 100 mg to 200 mg every 12 hours in patients weighing less than 40 kg).

When voriconazole and efavirenz (at a dose of 300 mg once daily) are used concomitantly, the maintenance dose of Voriconazole Canon should be increased to 400 mg every 12 hours.

Renal impairment No dose adjustment of voriconazole is required in patients with mild to severe renal impairment.

Hepatic impairment in case of acute liver injury manifested by increased ALT, AST activity, dose adjustment is not required, but continued monitoring of liver function parameters is recommended. Patients with mild or moderate hepatic impairment (Child-Pugh classes A and B) should be prescribed the standard loading dose of Voriconazole Canon, and the maintenance dose should be reduced by half. Voriconazole Canon should be prescribed to patients with severe hepatic impairment only in cases where the expected benefit outweighs the possible risk, and under constant monitoring to detect signs of drug toxicity.

Elderly patients no dose adjustment is required in the elderly.

Children The drug in tablet form is prescribed to children only if the child can swallow tablets.

Recommended dose for children from 3 to 12 years If the child can swallow tablets, the dose is rounded to the nearest mg/kg dose that is a multiple of 50 mg and administered as whole tablets. Dosage regimen of voriconazole in children (aged 3 to 12 years) and adolescents aged 12 to 14 years and weighing less than 50 kg

The pharmacokinetics and tolerability of higher doses of voriconazole in children have not been studied.

Recommendations for the use of voriconazole in children are based on studies of its use in the form of a powder for oral suspension. The bioequivalence of voriconazole in the form of a powder for oral suspension and tablets when used in children has not been studied. Given that children have delayed gastrointestinal transit, it is likely that the absorption of voriconazole when taken orally will be different from that in adults. The use of voriconazole in children aged 3 to 12 years with hepatic or renal impairment has not been studied.

Dose adjustment In case of inadequate clinical response of the patient, the dose may be increased in increments of 1 mg/kg (or 50 mg if the initial maximum dose of 350 mg was used).

Adverse Reactions

WHO classification of frequency of side effects

Very common — ≥ 1/10

Common — from ≥1/100 to < 1/10

Uncommon — from ≥1/1000 to <1/100

Rare — from ≥ 1/10000 to <1/1000

Very rare — < 1/10000, including isolated reports.

Laboratory parameters common — impaired liver function (including increased activity of AST, ALT, alkaline phosphatase, GGT, LDH, bilirubin concentration), increased plasma creatinine concentration; uncommon — QT interval prolongation, increased blood urea nitrogen, hypercholesterolemia.

Cardiovascular system very common — peripheral edema; common — decreased blood pressure, thrombophlebitis, phlebitis; uncommon — ventricular fibrillation, ventricular arrhythmia, syncope, atrial arrhythmia, supraventricular arrhythmia, supraventricular tachycardia, bradycardia, tachycardia; rare — ventricular tachycardia (including ventricular flutter), torsades de pointes, complete atrioventricular block, bundle branch block, nodal arrhythmias, lymphangitis.

Hematopoietic and lymphatic system common — pancytopenia, bone marrow suppression, thrombocytopenia, leukopenia, purpura, anemia (including macrocytic, microcytic, normocytic, megaloblastic, aplastic); uncommon — disseminated intravascular coagulation syndrome, lymphadenopathy, agranulocytosis, eosinophilia.

Nervous system disorders very common — headache; common — dizziness, confusion, agitation, tremor, paresthesia; uncommon — cerebral edema, ataxia, diplopia, vertigo, hypesthesia; rare — convulsions, encephalopathy, Guillain-Barré syndrome, extrapyramidal disorders, somnolence during infusion, peripheral neuropathy.

Eye disorders very common — visual impairments (including impaired/enhanced visual perception, blurred vision, altered color perception, photophobia); uncommon — optic disc edema, scleritis, blepharitis, optic neuritis, nystagmus; rare — retinal hemorrhage, optic atrophy, corneal opacity, oculogyric crisis.

Ear and labyrinth disorders uncommon — hypoacusis, tinnitus.

Respiratory, thoracic and mediastinal disorders common — acute respiratory distress syndrome, pulmonary edema, dyspnea, chest pain.

Gastrointestinal disorders very common — nausea, vomiting, diarrhea, abdominal pain; uncommon — constipation, duodenitis, dyspepsia, gingivitis, glossitis, pancreatitis, tongue edema, peritonitis; rare — taste perversion.

Renal and urinary disorders common — acute renal failure, hematuria; uncommon — albuminuria, nephritis; rare — renal tubular necrosis.

Skin and subcutaneous tissue disorders very common — rash; common — facial edema, pruritus, maculopapular rash, macular rash, papular rash, photosensitivity, alopecia, exfoliative dermatitis, cheilitis, erythema; uncommon — Stevens-Johnson syndrome, angioedema, fixed drug eruption, eczema, psoriasis, urticaria; rare — discoid lupus erythematosus, erythema multiforme, toxic epidermal necrolysis, pseudoporphyria; frequency unknown — squamous cell carcinoma.

Musculoskeletal and connective tissue disorders: common — back pain; uncommon — arthritis; rare — hypertension; frequency unknown — periostitis.

Endocrine disorders: uncommon — adrenal cortex insufficiency; rare — hyperthyroidism, hypothyroidism.

Metabolism and nutrition disorders common — hypokalemia, hypoglycemia.

Infections and infestations common — gastroenteritis, influenza-like syndrome; rare — pseudomembranous colitis.

General disorders and administration site conditions very common — pyrexia; common — chills, asthenia.

Immune system disorders common — sinusitis; uncommon — allergic reactions, anaphylactoid reactions.

Hepatobiliary disorders common — jaundice, cholestatic jaundice; uncommon — cholecystitis, cholelithiasis, hepatomegaly, hepatitis, hepatic failure; rare — hepatic coma.

Psychiatric disorders common — hallucinations, depression, anxiety; rare — insomnia.

Use in children the undesirable effects of the drug in children are similar to those in adults.

Contraindications

• Hypersensitivity to voriconazole or any other component of the drug.
• Children under 3 years of age (for this dosage form).
• Concomitant use of Voriconazole Canon with terfenadine, astemizole, cisapride, pimozide, quinidine, sirolimus, rifampicin, carbamazepine, long-acting barbiturates (phenobarbital), ergot alkaloids (ergotamine, dihydroergotamine), efavirenz (400 mg and higher once daily), ritonavir (400 mg and higher, twice daily), rifabutin, as well as St. John’s wort is contraindicated (see section “Drug Interactions”).

With caution

Hypersensitivity to other azole derivatives. Severe hepatic impairment, severe renal impairment.

Voriconazole Canon should be used with caution in patients with proarrhythmic conditions: congenital or acquired QT interval prolongation, cardiomyopathy, especially with heart failure, sinus bradycardia, presence of symptomatic arrhythmia, concomitant use of drugs that cause QT interval prolongation. Electrolyte disturbances such as hypokalemia, hypomagnesemia, and hypocalcemia must be controlled and, if necessary, corrected before starting therapy with Voriconazole Canon or during therapy.

Use in Pregnancy and Lactation

There is insufficient information on the use of voriconazole in pregnant women. Studies in animals have shown that the drug has toxic effects on reproduction. The possible risk to humans is unknown.

Voriconazole should not be used in pregnant women except in cases where the expected benefit to the mother clearly outweighs the risk to the fetus.

Excretion of voriconazole in breast milk has not been studied. Breastfeeding should be discontinued during drug use. Women of reproductive age using Voriconazole Canon should use reliable methods of contraception.

Use in Hepatic Impairment

Use with caution in patients with severe hepatic impairment.

Use in Renal Impairment

Use with caution in patients with severe renal impairment.

Pediatric Use

The drug is contraindicated in children under 3 years of age (for this dosage form).

Geriatric Use

Dose adjustment in elderly patients is not required.

Special Precautions

Samples for laboratory tests for the isolation and identification of pathogens should be taken before starting treatment. Therapy can be started before the results of laboratory tests are obtained, but once available, treatment should be adjusted accordingly.

Cardiovascular adverse reactions. The use of voriconazole is associated with QT interval prolongation on the ECG, accompanied by rare cases of ventricular fibrillation/flutter in critically ill patients with multiple risk factors, such as cardiotoxic chemotherapy, cardiomyopathy, hypokalemia, and concomitant therapy, which could have contributed to the development of this complication.

Hepatotoxicity. Infrequent (0.1 – 1%) cases of serious liver reactions, including clinically apparent hepatitis, cholestasis, and hepatocellular failure, including fatal outcomes, have been observed during treatment with voriconazole. Liver adverse reactions are observed mainly in patients with hematological malignancies. In patients without any risk factors, transient liver reactions, including hepatitis and jaundice, have been observed. Liver function disorders are usually reversible and resolve after discontinuation of treatment. It is recommended to constantly monitor liver function during treatment with Voriconazole Canon. If clinical signs of liver dysfunction appear, the advisability of discontinuing treatment should be discussed (see section “Dosage and Administration”).

Visual impairments, such as blurred vision, optic neuritis, and optic disc edema, develop most often in critically ill patients and/or those receiving concomitant therapy that can cause similar adverse reactions. During treatment with voriconazole, approximately 21% of patients experience visual perception disturbances: blurred vision, altered color vision, or photophobia. Visual disturbances are transient and completely reversible; in most cases, they disappear spontaneously within 60 minutes. With repeated use of voriconazole, their severity decreases. Visual disturbances are usually mild, rarely require discontinuation of treatment, and do not lead to any long-term consequences.

Renal adverse reactions. Cases of acute renal failure have been observed in critically ill patients receiving Voriconazole, which was probably associated with therapy for the underlying or concomitant diseases, nephrotoxic drugs. Patients should be monitored for signs of renal impairment (see section “Dosage and Administration”).

Monitoring of pancreatic function. Adults and children with risk factors for acute pancreatitis should be examined to decide on voriconazole therapy.

Skin adverse reactions. If a patient develops exfoliative skin reactions, Voriconazole should be discontinued. Furthermore, long-term use of voriconazole is accompanied by photosensitivity skin reactions. During treatment, patients are advised to avoid intense or prolonged exposure to direct sunlight. If a patient develops skin lesions associated with squamous cell carcinoma of the skin or melanoma, discontinuation of voriconazole therapy should be considered.

Musculoskeletal adverse reactions. There are reports of cases of periostitis in transplant patients receiving long-term voriconazole therapy. Voriconazole therapy should be discontinued if a patient has bone pain and radiographic changes characteristic of periostitis are noted.

Effect on ability to drive and operate machinery

Voriconazole may cause transient and reversible visual disturbances, including blurred vision, impaired/enhanced visual perception and/or photophobia. In the presence of such symptoms, patients should avoid performing potentially hazardous activities, in particular, driving vehicles or using complex machinery requiring quick psychomotor reactions. When taking voriconazole, patients should not drive at night.

Overdose

In case of overdose, symptomatic and supportive therapy is indicated. There is no known antidote for voriconazole. In case of overdose, hemodialysis may aid in the removal of voriconazole from the body.

Drug Interactions

Effect of other drugs on the pharmacokinetics of voriconazole

Concomitant use of voriconazole is contraindicated with the following drugs

St. John’s wort has a short initial inhibitory effect on the metabolism of voriconazole, followed by its activation. Concomitant use of voriconazole and St. John’s wort is contraindicated (see section “Contraindications”).

The plasma concentration of voriconazole is significantly reduced when used concomitantly with the following drugs

Rifampicin (600 mg once daily) reduces the C_max and AUC_t of voriconazole by 93% and 96%, respectively. Concomitant use of voriconazole and rifampicin is contraindicated (see section “Contraindications”).

Ritonavir. Administration of ritonavir (400 mg every 12 h) reduced the C_max and AUC_t of orally administered voriconazole by an average of 66% and 82%, respectively.
Administration of ritonavir (100 mg every 12 h) reduced the C_max and AUC_t of orally administered voriconazole by an average of 24% and 39%, respectively. Repeated oral administration of voriconazole was found to have no significant effect on the steady-state C_max and AUC_t of ritonavir administered at a dose of 400 mg every 12 h. At the same time, a sustained decrease in C_max and AUC_t by 25% and 13%, respectively, was observed when ritonavir was administered at a dose of 100 mg every 12 h. Concomitant use of voriconazole and ritonavir (400 mg every 12 h) is contraindicated (see section “Contraindications”). Concomitant use of voriconazole and ritonavir at a dose of 100 mg every 12 h should be avoided.

It is highly probable that carbamazepine and long-acting barbiturates (phenobarbital) significantly reduce the plasma concentration of voriconazole. Concomitant use of voriconazole with carbamazepine and long-acting barbiturates is contraindicated (see section “Contraindications”).

Given the insignificant pharmacokinetic interaction, dose adjustment of the following drugs is not required

Cimetidine (400 mg twice daily) causes an increase in the C_max and AUC_t of voriconazole by 18% and 23%, respectively. Dose adjustment of voriconazole is not required.

Ranitidine (150 mg twice daily) does not have a significant effect on the C_max and AUC_t of voriconazole.

Erythromycin (1 g twice daily) and azithromycin (500 mg once daily) do not have a significant effect on the C_max and AUC_t of voriconazole. The effect of voriconazole on the metabolism of erythromycin or azithromycin is unknown. Dose adjustment is not required.

Effect of voriconazole on the pharmacokinetics of other drugs

Concomitant use of voriconazole with the following drugs is contraindicated

Terfenadine, astemizole, cisapride, pimozide and quinidine. Concomitant use of voriconazole with these drugs is contraindicated, as it may lead to an increase in their plasma concentration. This, in turn, can cause QT interval prolongation and, in rare cases, lead to the development of ventricular fibrillation/flutter (see section “Contraindications”).

Sirolimus. Voriconazole increases the C_max and AUC_t of sirolimus (2 mg single dose) by 556% and 1014%, respectively. Concomitant use of voriconazole and sirolimus is contraindicated (see section “Contraindications”).

It is highly probable that Voriconazole may cause an increase in the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) and the development of ergotism. Concomitant use of ergot alkaloids with voriconazole is contraindicated (see section “Contraindications”).

Interaction with voriconazole may lead to an increase in the plasma concentration of the following drugs

Cyclosporine. In stable kidney transplant patients, Voriconazole increases the C_max and AUC_t of cyclosporine by at least 13% and 70%, respectively. When voriconazole is prescribed to patients receiving cyclosporine, it is recommended to reduce the dose of cyclosporine by half and monitor its plasma concentration.

Tacrolimus. Voriconazole increases the C_max and AUC_t of tacrolimus (0.1 mg/kg single dose) by 117% and 221%, respectively. When voriconazole is prescribed to patients receiving tacrolimus, it is recommended to reduce the dose of the latter to one third and monitor its plasma concentration.

Methadone. Multiple oral administration of voriconazole increases the C_max and AUC_t of the pharmacologically active R-methadone by 31% and 47%, respectively, in patients receiving a maintenance dose of methadone (30 – 100 mg daily). An increase in methadone plasma concentration leads to the manifestation of toxic effects, including QT interval prolongation. With concomitant use of voriconazole and methadone, careful monitoring for adverse and toxic effects is necessary. If necessary, the dose of methadone may be reduced.

Short-acting opioid analgesics. Continuous oral administration of voriconazole increases the AUC of a single dose of alfentanil by 6 times. With concomitant use of voriconazole and alfentanil or other short-acting opioid analgesics, its structural analogs (e.g., sufentanil), a dose reduction of the latter should be considered. Since the T_1/2 of alfentanil increases 4-fold when co-administered with voriconazole, careful monitoring of adverse reactions associated with the use of opioid analgesics is necessary, including more prolonged monitoring of respiratory function.

Fentanyl. Concomitant use of voriconazole and a single intravenous dose of fentanyl (5 mcg/kg) increases the AUC of fentanyl by an average of 1.4 times. If necessary, the dose of fentanyl should be reduced.

Oxycodone. Concomitant use of voriconazole and a single oral dose of oxycodone (10 mg) increases the C_max and AUC of oxycodone by 1.7 times and 3.6 times, respectively. The T_1/2 of oxycodone increases 2-fold. Careful monitoring for adverse reactions is necessary. A dose reduction of oxycodone may be required during combination therapy with voriconazole.

Warfarin. Concomitant use of voriconazole (300 mg twice daily) with warfarin (30 mg single dose) was accompanied by an increase in maximum prothrombin time by 93%. When warfarin and voriconazole are used concomitantly, it is recommended to monitor prothrombin time.

Other oral anticoagulants, e.g., phenprocoumon, acenocoumarol. Voriconazole may cause an increase in the plasma concentration of coumarin derivatives and prothrombin time. During concomitant use, prothrombin time should be monitored at short intervals and the doses of anticoagulants should be adjusted accordingly.

Sulfonylurea derivatives. Voriconazole may increase the plasma concentration of sulfonylurea derivatives (tolbutamide, glipizide, and glibenclamide) and cause hypoglycemia. With concomitant use of voriconazole with these drugs, blood glucose should be carefully monitored.

Statins. Voriconazole may cause an increase in the plasma concentrations of statins. During concomitant use, it is recommended to assess the advisability of adjusting the dose of statins. An increase in statin concentrations is sometimes accompanied by the development of rhabdomyolysis.

Benzodiazepines. Voriconazole may cause an increase in the plasma concentrations of benzodiazepines (midazolam, triazolam, alprazolam) and the development of a prolonged sedative effect. With concomitant use of voriconazole and benzodiazepines, it is recommended to assess the advisability of adjusting the dose of benzodiazepines.

Vinca alkaloids. Voriconazole may increase the plasma levels of vinca alkaloids (vincristine and vinblastine) and cause neurotoxicity. With concomitant use of voriconazole and vinca alkaloids, it is recommended to assess the advisability of adjusting the dose of vinca alkaloids.

NSAIDs. Voriconazole increases the C_max and AUC_t of ibuprofen (400 mg single dose) by 20% and 100%, respectively, and the C_max and AUC_t of diclofenac (50 mg single dose) by 114% and 78%, respectively. In case of concomitant use of voriconazole and NSAIDs, patients should be monitored for possible toxic effects and the dose of NSAIDs should be adjusted if necessary.

No significant pharmacokinetic interaction was found with concomitant use of voriconazole with the following drugs, so dose adjustment is not required.

Prednisolone. Voriconazole increases the C_max and AUC_t of prednisolone (60 mg single dose) by 11% and 34%, respectively. Dose adjustment is not required.

Digoxin. Voriconazole does not have a significant effect on the C_max and AUC_t of digoxin (0.25 mg once daily).

Mycophenolic acid. Voriconazole does not affect the C_max and AUC_t of mycophenolic acid (1 g single dose).

Bidirectional interaction.

Phenytoin. Concomitant use of voriconazole and phenytoin should be avoided, except in cases where the expected benefit outweighs the possible risk. Phenytoin (300 mg once daily) reduces the C_max and AUC_t of voriconazole by 49% and 69%, respectively. Voriconazole (400 mg once daily) increases the C_max and AUC_t of phenytoin (300 mg once daily) by 67% and 81%, respectively. With concomitant use of phenytoin and voriconazole, it is recommended to monitor the plasma concentration of phenytoin. Phenytoin can be used concomitantly with voriconazole if the maintenance dose of the latter is increased from 200 to 400 mg every 12 h orally (from 100 to 200 mg every 12 h orally).

Omeprazole (40 mg once daily) increases the C_max and AUC_t of voriconazole by 15% and 41%, respectively. No dose adjustment of voriconazole is recommended. Voriconazole increases the C_max and AUC_t of omeprazole by 116% and 280%, respectively. When voriconazole is co-administered to patients receiving omeprazole, it is recommended to reduce the dose of omeprazole by half. Voriconazole may also inhibit the metabolism of other proton pump inhibitors that are substrates of the CYP2C19 isoenzyme.

Oral contraceptives. Concomitant administration of voriconazole and an oral contraceptive (1 mg norethisterone and 0.035 mg ethinylestradiol once daily) resulted in an increase in the C_max and AUC_t of norethisterone by 15% and 53%, respectively, and of ethinylestradiol by 36% and 61%, respectively. The C_max and AUC_t of voriconazole increased by 14% and 46%, respectively. Since the ratio between norethisterone and ethinylestradiol remains approximately the same during the interaction with voriconazole, it can be assumed that their contraceptive activity is not altered. If voriconazole and oral contraceptives are used concomitantly, monitoring should be performed to detect possible adverse effects. Low-dose oral contraceptives have not been studied.

Indinavir (800 mg three times daily) does not significantly affect the C_max and AUC_t of voriconazole. Voriconazole does not significantly affect the C_min, C_max, and AUC_t of indinavir (800 mg three times daily).

Other HIV protease inhibitors. Voriconazole may inhibit the metabolism of HIV protease inhibitors: saquinavir, amprenavir, and nelfinavir. In turn, HIV protease inhibitors may suppress the metabolism of voriconazole. If voriconazole is co-administered with HIV protease inhibitors, patients should be monitored for possible toxic effects.

Efavirenz. At steady state, efavirenz (400 mg once daily) reduces the steady-state C_max and AUC_t of voriconazole by an average of 61% and 77%, respectively. Voriconazole at steady state increases the steady-state C_max and AUC_t of efavirenz by an average of 38% and 44%, respectively. Standard doses of voriconazole and efavirenz (400 mg once daily) are contraindicated. Concomitant use is possible if the maintenance dose of voriconazole is increased to 400 mg twice daily and the dose of efavirenz is reduced to 300 mg once daily. When voriconazole therapy is discontinued, the initial dose of efavirenz should be restored.

Other non-nucleoside reverse transcriptase inhibitors. Delavirdine may inhibit the metabolism of voriconazole. Nevirapine may induce the metabolism of voriconazole. Voriconazole may suppress 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.

Fluconazole (200 mg once daily). Concomitant oral administration of voriconazole and fluconazole results in an increase in the C_max and AUC_t of voriconazole by 57% and 79%, respectively. Changes in the C_max and AUC_t of fluconazole have not been established. An appropriate regimen for dose and/or frequency adjustment of voriconazole and fluconazole has not been established. If Voriconazole is administered after fluconazole, careful monitoring for adverse reactions associated with voriconazole is recommended.

Everolimus. The interaction has not been studied; however, concomitant use is not recommended, as voriconazole is expected to significantly increase plasma concentrations of everolimus. At present, there is insufficient information to recommend a dosage adjustment.

Concomitant use of voriconazole is contraindicated with the following drugs

Rifabutin (300 mg once daily) reduces the C_max and AUC_t of voriconazole (200 mg twice daily) by 69% and 78%, respectively. When co-administered with rifabutin, the C_max and AUC_t of voriconazole at a dose of 350 mg twice daily were 96% and 68% of the values with voriconazole alone at a dose of 200 mg twice daily. When voriconazole was administered at a dose of 400 mg twice daily, the C_max and AUC_t were 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_t of rifabutin by 195% and 331%, respectively. Concomitant use of voriconazole and rifabutin is contraindicated (see section “Contraindications”).

Storage Conditions

Store in a dry place, protected from light, at a temperature not exceeding 25°C (77°F).

Keep out of reach of children.

Shelf Life

The shelf life is 2 years.

Dispensing Status

The drug is dispensed by prescription.

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.