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Voriconazole

Voriconazole is a synthetic triazole antifungal antibiotic.

Uses

Aspergillosis

Voriconazole is used for the treatment of invasive aspergillosis.

Efficacy has been demonstrated in clinical studies in patients for primary therapy of invasive aspergillosis, for primary and salvage therapy of invasive aspergillosis, and for treatment of invasive aspergillosis in patients whose disease was refractory to, or who were intolerant of, other antifungal therapy. Aspergillus fumigatus was the most frequent isolate in patients with aspergillosis participating in clinical trials with the drug.

Efficacy of voriconazole as primary or salvage therapy for invasive aspergillosis was evaluated in an open-label, noncomparative study in 116 patients 18-79 years of age with definite or probable invasive aspergillosis.

A complete or partial response was achieved in 48% of patients in this study, with lower response rates observed in patients with definite disease (38%) than in those with probable disease (58%). In a randomized, nonblinded study of voriconazole as primary therapy for invasive aspergillosis, 277 patients 12-79 years of age with definite or probable invasive aspergillosis received either voriconazole (6 mg/kg IV twice daily for 2 doses and then 4 mg/kg IV twice daily for at least 7 days, at which time therapy could be switched to voriconazole 200 mg orally twice daily) or amphotericin B (1-1.5 mg/kg IV once daily) for up to 12 weeks.

Voriconazole

At the end of the study, a complete or partial response was achieved in 53% of patients randomized to receive voriconazole compared with 32% of those randomized to receive amphotericin B; the survival rate at the end of the study was 71 or 58% in patients randomized to receive voriconazole or amphotericin B, respectively. Pooled analysis of data from this study and an additional study demonstrated response rates of 44 or 40% in patients with invasive infections caused by A. fumigatus or other Aspergillus species, respectively, whose disease was refractory to, or who were intolerant of, other antifungal therapy.

Other Fungal Infections

Voriconazole also is used in the treatment of serious fungal infections caused by Scedosporium apiospermum and Fusarium spp., including F. solani, in patients who are intolerant of, or whose disease is refractory to, other therapy.

Empiric Therapy in Febrile Neutropenic Patients

Voriconazole also has been used for empiric therapy of presumed fungal infections in febrile neutropenic patients. Efficacy of voriconazole for empiric therapy in febrile neutropenic patients has been evaluated in an open-label, randomized, multicenter study in patients 12-82 years of age who were neutropenic following chemotherapy or stem cell transplantation. In this study, patients received voriconazole or amphotericin B liposomal for up to 3 days following neutrophil recovery, or for a maximum of 12 weeks.

A response (based on a composite assessment including no breakthrough infections within 7 days of the completion of therapy, survival for 7 days following completion of therapy, discontinuance of the drug because of toxicity or lack of efficacy prior to recovery from neutropenia, resolution of fever during neutropenia, and complete or partial response in patients with baseline fungal infections by the completion of therapy) was obtained in 26 or 31% of patients receiving voriconazole or amphotericin B liposomal, respectively. The composite results failed to meet protocol-defined statistical criteria for concluding that voriconazole was not inferior to amphotericin B liposomal.

Exploratory analyses of the individual elements of the composite measure suggested that breakthrough infections occurred in a smaller proportion of patients receiving voriconazole (1.9%) compared with amphotericin B liposomal (5%); exploratory analyses of the other individual elements of the composite measure failed to identify other substantial differences between the 2 regimens.

Dosage and Administration

Reconstitution and Administration

Voriconazole is administered orally or by IV infusion. Voriconazole for IV infusion is administered at a maximum rate of 3 mg/kg per hour over 1-2 hours.

The drug should not be administered by rapid IV infusion. Commercially available voriconazole powder for injection should be stored at 15-30°C. The contents of a single-use vial labeled as containing 200 mg of voriconazole should be reconstituted with exactly 19 mL of sterile water for injection to prepare a solution containing 10 mg/mL of the drug. The vial should be shaken until all the powder is dissolved.

The manufacturer recommends that reconstituted voriconazole solutions be used immediately following reconstitution since they contain no preservative; if not used immediately, reconstituted solutions should be stored for no longer than 24 hours at 2-8°C.

Reconstituted solutions of the drug must be further diluted in a compatible IV infusion solution prior to administration. The reconstituted voriconazole solution is prepared for infusion by calculating the volume of reconstituted solution required to administer the appropriate weight-based dose and then withdrawing and discarding a volume of diluent from the final infusion container that equals or exceeds that volume.

The volume of diluent remaining in the container should be such that a final concentration of at least 0.5 mg/mL but not greater than 5 mg/mL will be achieved following addition of the reconstituted solution. The appropriate dose should then be withdrawn from the required number of vials and added to the infusion container.

Voriconazole

Any unused portion of reconstituted solution should be discarded. Voriconazole solutions should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. IV solutions of voriconazole should not be admixed or administered through the same catheter as other drugs. Orally administered voriconazole should be given at least 1 hour before or 1 hour after meals.

General Dosage

The recommended initial adult IV dosage of voriconazole in patients with invasive aspergillosis or infections caused by Scedosporium apiospermum or Fusarium spp. is 6 mg/kg by IV infusion every 12 hours for 2 doses, followed by a maintenance dosage of 4 mg/kg by IV infusion every 12 hours until the patient can be switched to oral therapy. If this dosage cannot be tolerated, the IV maintenance dosage can be decreased to 3 mg/kg every 12 hours.

The usual adult oral dosage of voriconazole is 200 mg every 12 hours in patients weighing 40 kg or more or 100 mg every 12 hours in those weighing less than 40 kg; if the therapeutic response is not adequate, the dosage may be increased to 300 mg every 12 hours in patients weighing 40 kg or more or 150 mg every 12 hours in patients weighing less than 40 kg. If this dosage cannot be tolerated, the dosage may be decreased by increments of 50 mg to a minimum of 200 mg every 12 hours in patients weighing 40 kg or more or 100 mg every 12 hours in patients weighing less than 40 kg.

Duration of therapy should be based on the severity of the patient’s underlying disease, recovery from immunosuppression, and response to the drug.

Special Populations

In patients with mild-to-moderate hepatic cirrhosis (Child-Pugh class A or B), usual IV or oral loading dosages of voriconazole should be used, but IV or oral maintenance dosages should be decreased by 50%. Voriconazole has not been studied in patients with severe hepatic cirrhosis (Child-Pugh class C) or in those with chronic hepatitis B or hepatitis C virus infection. In patients with moderate-to-severe renal impairment (creatinine clearance less than 50 mL/minute), IV voriconazole should be used only when clearly needed because of potential accumulation of the IV vehicle, sulfobutyl ether β-cyclodextrin sodium. No adjustment of oral voriconazole dosage is necessary in patients with renal impairment.

Cautions

Contraindications

Known hypersensitivity to voriconazole or any ingredient in the formulation. Concomitant therapy with terfenadine (no longer commercially available in the US), astemizole (no longer commercially available in the US), cisapride, pimozide, quinidine, sirolimus, rifampin, carbamazepine, long-acting barbiturates (e.g., phenobarbital, mephobarbital), rifabutin, or ergot alkaloids (e.g., ergotamine, dihydroergotamine).

Warnings/Precautions

Warnings Ocular Effects

Effect of voriconazole on visual function is unknown if duration of therapy exceeds 28 days. Monitor visual function (visual acuity, visual field, and color perception) if duration of therapy exceeds 28 days.

Hepatic Effects

Serious hepatic effects, including hepatitis, cholestasis, and fulminant hepatic failure, have been reported rarely in clinical trials.

Hepatic effects usually are reversible when voriconazole therapy is discontinued; however, fatalities have occurred. If abnormal liver function test results occur during voriconazole therapy, the patient should be monitored for the development of more severe hepatic injury.

Voriconazole therapy should be discontinued if signs and symptoms consistent with liver disease develop.

Galactose Intolerance

Patients with a history of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not be given voriconazole tablets, since lactose is used in the manufacture of the tablets.

Sensitivity Reactions

Anaphylactoid reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus, and rash, and occurring immediately upon initiation of the infusion have been reported rarely.

General Precautions

Laboratory Monitoring

Liver function tests should be performed prior to and during voriconazole therapy. Renal function (e.g., serum creatinine concentrations) should be monitored in patients receiving voriconazole.

Acute renal failure has occurred in severely ill patients receiving voriconazole; such patients are likely to have other factors (e.g., underlying conditions, concomitant drugs) predisposing to impaired renal function.

Dermatologic Effects

Serious cutaneous reactions (e.g., Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis) have occurred rarely in patients receiving voriconazole. If rash develops, consideration should be given to discontinuance of the drug.

Photosensitivity reactions have occurred infrequently in patients receiving voriconazole, particularly during long-term therapy. Avoidance of strong, direct sunlight during voriconazole therapy is recommended.

Specific Populations Pregnancy Category D.

Lactation It is not known whether voriconazole is distributed into milk. Caution should be exercised if voriconazole is used in nursing women.

Pediatric Use

Safety and efficacy not established in children younger than 12 years of age. However, a limited number of pediatric patients 9 months to 15 years of age whose disease was refractory to, or who were intolerant of, other antifungal therapy have received voriconazole IV (6 mg/kg every 12 hours for 2 doses, followed by 4 mg/kg every 12 hours) or orally (100 mg twice daily in patients weighing less than 40 kg or 200 mg twice daily in patients weighing 40 kg or more) in the treatment of aspergillosis, infections caused by Scedosporium spp., candidiasis, or other invasive fungal infections.

At the completion of therapy, 45% of pediatric patients receiving voriconazole had a complete or partial response. Adverse effects in children receiving voriconazole were similar to those reported in adults.

Based on a comparison of pharmacokinetic data from pediatric patients (2 years to less than 12 years of age) with data from adults, the manufacturer states that the predicted steady-state plasma voriconazole concentrations were similar in pediatric patients or adults (median concentration of 1.19 or 1.16 mcg/mL, respectively) at a maintenance IV dosage of 4 mg/kg every 12 hours in children or 3 mg/kg every 12 hours in adults.

Geriatric Use

Clinical experience with voriconazole in geriatric patients is limited. Plasma voriconazole concentrations are increased, but overall safety profile is similar to that in younger adults. Hepatic Impairment Patients with hepatic impairment should be monitored carefully for voriconazole toxicity. Voriconazole should be used in patients with severe hepatic impairment only when the benefits outweigh the risks. Renal Impairment Patients with moderate-to-severe renal impairment receiving IV voriconazole should be monitored carefully for increases in serum creatinine concentrations. If such increases occur, consideration should be given to switching the patient to oral voriconazole therapy.

Common Adverse Effects

Common adverse effects include visual disturbances (e.g., altered or enhanced visual perception, blurred vision, color vision change, photophobia), fever, rash, vomiting, nausea, diarrhea, headache, sepsis, peripheral edema, abdominal pain, and respiratory disorder. The most commonly reported adverse effects resulting in discontinuance of voriconazole therapy include elevated liver function test results, rash, and visual disturbances.

Preparations

Voriconazole Oral Tablets, film- 50 mg Vfend®, (with povidone) coated Pfizer 200 mg Vfend®, (with povidone) Pfizer Parenteral Injection, for IV 200 mg Vfend®, (with sulfobutyl ether infusion only b-cyclodextrin sodium 3.2 g) Pfizer

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