Voriconazole

Class: Azoles
VA Class: AM700
Chemical Name: (αR,βS) - α - (2,4, - difluorophenyl) - 5 - fluoro - β - methyl - α - (1H - 1,2,4 - triazol - 1 - yl - methyl) - 4 - pyrimidineethanol
Molecular Formula: C₁₆H₁₄F₃N₅O
CAS Number: 137234-62-9
Brands: Vfend

Introduction

Antifungal; azole (triazole); synthetic derivative of fluconazole.^{1 2 3 4 5 6 7}

Uses for Voriconazole

Aspergillosis

Treatment of invasive aspergillosis.¹ A drug of choice.^{423 436 440 441}

Has been effective for primary and salvage therapy of invasive aspergillosis, including treatment of invasive aspergillosis in patients intolerant of, or whose disease was refractory to, other antifungals.¹

IDSA considers voriconazole the drug of choice for primary treatment of invasive aspergillosis in most patients and amphotericin B the preferred alternative.⁴²³ For salvage therapy in patients refractory to or intolerant of primary antifungal therapy, IDSA recommends amphotericin B, caspofungin, micafungin, posaconazole, or itraconazole.⁴²³ For empiric or preemptive therapy of presumed aspergillosis, IDSA recommends amphotericin B, caspofungin, itraconazole, or voriconazole.⁴²³

For treatment of invasive aspergillosis in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend voriconazole as the drug of choice;⁴⁴⁰ IV amphotericin B, IV caspofungin, and oral posaconazole are recommended as alternatives.⁴⁴⁰ Voriconazole also is considered the drug of choice for treatment of invasive aspergillosis in HIV-infected children†;⁴⁴¹ IV amphotericin B and IV caspofungin are alternatives.⁴⁴¹

Candidemia and Disseminated Candida Infections

Treatment of candidemia in nonneutropenic patients.¹ Has been effective in Candida albicans, C. tropicalis, C. parapsilosis, C. glabrata, or C. krusei infections.¹

Treatment of disseminated Candida infections involving the skin, abdomen, kidney, bladder wall, or wounds.¹

For the treatment of candidemia in nonneutropenic patients or for empiric treatment of suspected invasive candidiasis in such patients, IDSA recommends fluconazole or an IV echinocandin (caspofungin, micafungin, anidulafungin) for initial therapy;⁴²⁵ IV amphotericin B or voriconazole are the preferred alternatives.⁴²⁵ These experts state that voriconazole offers little advantage over fluconazole and generally has been reserved for step-down oral therapy for treatment of C. krusei candidiasis or for treatment of fluconazole-resistant, voriconazole-susceptible C. glabrata infections.⁴²⁵ Although an echinocandin is preferred for initial treatment of C. glabrata infections, if the patient initially received fluconazole or voriconazole, continuation of the azole antifungal until treatment completion is reasonable if the patient is clinically improved and follow-up cultures are negative.⁴²⁵

For the treatment of candidemia in neutropenic† patients, IDSA recommends an IV echinocandin (caspofungin, micafungin, anidulafungin) or IV amphotericin B for initial therapy;⁴²⁵ fluconazole is the preferred alternative in those who are less critically ill or have not recently received an azole;⁴²⁵ voriconazole can be used as an alternative when broader antifungal coverage is required.⁴²⁵ An echinocandin, amphotericin B, or voriconazole is recommended for C. krusei infections.⁴²⁵ An echinocandin is preferred for C. glabrata infections;⁴²⁵ fluconazole or amphotericin B is preferred for C. parapsilosis infections;⁴²⁵ an echinocandin, amphotericin B, or voriconazole is recommended for C. krusei infections.⁴²⁵ Although an echinocandin is preferred for initial treatment of C. glabrata infections, if the patient initially received fluconazole or voriconazole, continuation of the azole antifungal until treatment completion is reasonable if the patient is clinically improved and follow-up culture results are negative.⁴²⁵ For initial empiric treatment of suspected invasive candidiasis in neutropenic† patients, amphotericin B, caspofungin, or IV voriconazole is recommended;⁴²⁵ alternatives are fluconazole or itraconazole.⁴²⁵

Oropharyngeal Candidiasis

Treatment of oropharyngeal candidiasis† refractory to other antifungals.⁴²⁵

IDSA recommends topical treatment with clotrimazole lozenges or nystatin oral suspension for mild oropharyngeal candidiasis;⁴²⁵ oral fluconazole is recommended for moderate to severe disease.⁴²⁵ For refractory oropharyngeal candidiasis, including fluconazole-refractory infections, itraconazole oral solution, oral posaconazole, or oral voriconazole is recommended.⁴²⁵ An IV echinocandin (caspofungin, micafungin, anidulafungin) or IV amphotericin B also are recommended as alternatives for refractory infections.⁴²⁵

For the treatment of oropharyngeal candidiasis in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend oral fluconazole as the preferred drug of choice for initial episodes;⁴⁴⁰ other drugs of choice are clotrimazole lozenges or nystatin oral suspension.⁴⁴⁰ Alternatives for initial episodes are itraconazole oral solution or oral posaconazole.⁴⁴⁰ For fluconazole-refractory infections in HIV-infected adults or adolescents, itraconazole oral solution or oral posaconazole is preferred;⁴⁴⁰ alternatives include IV amphotericin B, an IV echinocandin (caspofungin, micafungin, anidulafungin), or oral or IV voriconazole.⁴⁴⁰

Although routine long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent relapse or recurrence is not usually recommended in patients adequately treated for oropharyngeal candidiasis, patients with frequent or severe recurrences (including HIV-infected adults, adolescents, and children) may benefit from secondary prophylaxis with oral fluconazole or itraconazole oral solution; however, the potential for azole resistance should be considered.^{425 440 441} Patients with fluconazole-refractory oropharyngeal candidiasis who responded to treatment with an echinocandin should receive voriconazole or posaconazole for secondary prophylaxis until antiretroviral therapy produces immune reconstitution.⁴⁴⁰

Esophageal Candidiasis

Treatment of esophageal candidiasis.^{1 12 425 436} Has been effective in immunocompromised patients with esophageal candidiasis caused by C. albicans, C. glabrata, or C. krusei.^{1 12}

Esophageal candidiasis requires treatment with a systemic antifungal (not a topical antifungal).^{425 440}

IDSA recommends oral fluconazole as the preferred drug of choice for the treatment of esophageal candidiasis;⁴²⁵ if oral therapy is not tolerated, IV fluconazole, IV amphotericin B, or an IV echinocandin (caspofungin, micafungin, anidulafungin) is recommended.⁴²⁵ For fluconazole-refractory infections, preferred alternatives are itraconazole oral solution, oral posaconazole, or oral or IV voriconazole;⁴²⁵ other alternatives are an IV echinocandin or IV amphotericin B.⁴²⁵

For the treatment of esophageal candidiasis in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend oral or IV fluconazole as the preferred drug of choice and itraconazole oral solution as a preferred alternative.⁴⁴⁰ Other alternatives include an IV echinocandin (caspofungin, micafungin, anidulafungin), oral or IV voriconazole, oral posaconazole, or IV amphotericin B.⁴⁴⁰ For refractory esophageal candidiasis in HIV-infected adults or adolescents, including fluconazole-refractory infections, itraconazole oral solution or oral posaconazole is preferred;⁴⁴⁰ alternatives including IV amphotericin B, an IV echinocandin (caspofungin, micafungin, anidulafungin), or oral or IV voriconazole.⁴⁴⁰

Although routine long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent relapse or recurrence is not usually recommended in patients adequately treated for esophageal candidiasis, patients with frequent or severe recurrences (including HIV-infected adults, adolescents, and children) may benefit from secondary prophylaxis with oral fluconazole or oral posaconazole; however, the potential for azole resistance should be considered.^{425 440 441} Patients with fluconazole-refractory esophageal candidiasis who responded to treatment with an echinocandin should receive voriconazole or posaconazole for secondary prophylaxis until antiretroviral therapy produces immune reconstitution.⁴⁴⁰

Fusarium and Scedosporium Infections

Treatment of serious Fusarium (including F. solani) or Scedosporium apiospermum (asexual form of Pseudallescheria boydii) infections in patients intolerant of, or whose disease is refractory to, other antifungals.¹

For treatment of fusariosis, select antifungal based on in vitro susceptibility testing.⁵⁷ IV amphotericin B may be preferred for infections caused by F. solani or F. verticillioides;⁵⁷ either voriconazole or amphotericin B are recommended for other Fusarium.⁵⁷

For treatment of scedosporiosis, some clinicians consider voriconazole the drug of choice and posaconazole the preferred alternative.⁴³⁶

Empiric Therapy in Febrile Neutropenic Patients

Has been used for empiric therapy of presumed fungal infections in febrile neutropenic patients†.^{5 436}

Voriconazole Dosage and Administration

Administration

Administer orally or by slow IV infusion.¹

IV route used for initial treatment of systemic fungal infections; oral route may replace IV when clinically indicated.¹

Correct electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypocalcemia) prior to initiation of voriconazole.¹ (See IV Infusion under Dosage and Administration and see Cardiovascular Effects under Cautions.)

Oral Administration

Administer orally at least 1 hour before or 1 hour after a meal.¹

Prior to withdrawal of each dose, shake reconstituted oral suspension for approximately 10 seconds.¹ Administer using the oral dispenser supplied by the manufacturer.¹

If a dose is missed, take the missed dose as soon as possible; however, if it has been >6 hours since the missed dose, take the next scheduled dose at the appropriate time.¹ Do not take a double dose.¹

Reconstitution

Reconstitute powder for oral suspension by adding 46 mL of water to the bottle containing 45 g to provide a suspension containing 40 mg/mL.¹ Shake closed bottle vigorously for about 1 minute.¹

Do not mix oral suspension with other drugs or additional flavoring agents; do not dilute reconstituted suspension further with water or other vehicles.¹

IV Infusion

Do not administer voriconazole IV solutions concomitantly with short-term infusions of concentrated electrolytes, even if the 2 infusions are running in separate IV lines or cannulas.¹ Voriconazole IV solutions may be administered at the same time as other IV solutions containing nonconcentrated electrolytes; however, the drug must be infused through a separate line.¹

Do not administer voriconazole IV solutions concomitantly with any blood product, even if the 2 infusions are running in separate IV lines or cannulas.¹

Voriconazole IV solutions may be administered at the same time as total parenteral nutrition (TPN); however, the drug must be infused through a separate line.¹ If infused through a multiple-lumen catheter, TPN must be administered using a different port from the one used for voriconazole.¹

Reconstitution and Dilution

Reconstitute single-use 200-mg vial with exactly 19 mL of sterile water for injection to provide a solution containing 10 mg/mL.¹ The vial should be shaken until all powder is dissolved.¹

Reconstituted solution must be further diluted in a compatible IV infusion solution prior to administration.¹

Calculate the volume of reconstituted solution required to administer the appropriate weight-based dose; withdraw and discard a volume of diluent from the final infusion container that equals or exceeds that volume.¹ Withdraw appropriate dose from the required number of vials and add to the infusion container.¹ Final concentration should be ≥0.5 mg/mL but ≤5 mg/mL.¹ Discard any unused portion of reconstituted solution.¹

Rate of Administration

Administer by IV infusion over 1–2 hours at a maximum rate of 3 mg/kg per hour.¹ Do not administer by rapid IV infusion.¹

Dosage

Pediatric Patients

Treatment of Aspergillosis

Oral

Children 2 through 11 years of age†: 200 mg twice daily (without loading dose) has been recommended.⁴³⁶

Children ≥12 years of age weighing <40 kg: Loading dose of 200 mg every 12 hours for 2 doses, then maintenance dosage of 100 mg every 12 hours has been recommended; if response is inadequate, may be increased to 150 mg every 12 hours.⁶⁰

Children ≥12 years of age weighing ≥40 kg: Loading dose of 400 mg every 12 hours for 2 doses, then maintenance dosage of 200 mg every 12 hours has been recommended; if response is inadequate, may be increased to 300 mg every 12 hours.⁶⁰

Duration of treatment is based on severity of underlying disease, recovery from immunosuppression, and response to the drug.¹ IDSA recommends treatment of invasive pulmonary aspergillosis be continued for at least 6–12 weeks and continued throughout the period of immunosuppression.⁴²³

HIV-infected children†: 8 mg/kg (maximum 400 mg) twice daily on day 1, followed by maintenance dosage of 7 mg/kg (maximum 200 mg) twice daily has been recommended.⁴⁴¹ Continue treatment for ≥12 weeks; individualize treatment duration according to clinical response.⁴⁴¹

IV

Children 2 through 11 years of age†: 7 mg/kg twice daily (without loading dose) has been recommended.⁴³⁶

Children ≥12 years of age: Loading dose regimen of 6 mg/kg every 12 hours for 2 doses, followed by IV maintenance regimen of 4 mg/kg every 12 hours has been recommended.⁶⁰ Decrease IV maintenance dosage to 3 mg/kg every 12 hours if higher dosage not tolerated.⁶⁰

IDSA recommends that pediatric patients receive 5–7 mg/kg every 12 hours.⁴²³

Switch to oral maintenance when clinically indicated.⁹ Total duration of treatment is based on severity of underlying disease, recovery from immunosuppression, and response to the drug.¹

HIV-infected children†: Loading dose regimen of 6–8 mg/kg twice daily on day 1, followed by IV maintenance dosage of 7 mg/kg (maximum 200 mg) twice daily has been recommended.⁴⁴¹ Continue treatment for ≥12 weeks; individualize treatment duration according to clinical response.⁴⁴¹

HIV-infected adolescents: Loading dose regimen of 6 mg/kg twice daily on day 1, followed by IV maintenance dosage of 4 mg/kg twice daily.⁴⁴⁰ After clinical improvement, switch to an oral regimen of 200 mg twice daily.⁴⁴⁰ Optimal duration of therapy not established; continue antifungal therapy at least until CD4⁺ T-cell count increases to 200/mm³ as a result of potent antiretroviral therapy and there is evidence of clinical response.⁴⁴⁰

Candida Infections

Treatment of Candidemia and Disseminated Candida Infections

Oral

Children 2 through 11 years of age†: 200 mg twice daily (without loading dose) has been recommended.⁴³⁶

Children ≥12 years of age weighing <40 kg: Loading dose of 200 mg every 12 hours for 2 doses, then maintenance dosage of 100 mg every 12 hours has been recommended; if response is inadequate, may be increased to 150 mg every 12 hours.⁶⁰

Children ≥12 years of age weighing ≥40 kg: Loading dose of 400 mg every 12 hours for 2 doses, then maintenance dosage of 200 mg every 12 hours has been recommended; if response is inadequate, may be increased to 300 mg every 12 hours.⁶⁰

Manufacturer recommends that treatment be continued for at least 14 days after symptoms resolve or the last positive culture, whichever is longer.¹ IDSA and others recommend that antifungal treatment for candidemia (without persistent fungemia or metastatic complications) be continued for 14 days after first negative blood culture and resolutions of signs and symptoms of candidemia.^{425 436}

IV

Children 2 through 11 years of age†: 7 mg/kg twice daily (without loading dose) has been recommended.⁴³⁶

Children ≥12 years of age: Loading dose regimen of 6 mg/kg every 12 hours for 2 doses, followed by IV maintenance regimen of 4 mg/kg every 12 hours has been recommended⁶⁰ Decrease IV maintenance dosage to 3 mg/kg every 12 hours if higher dosage not tolerated.⁶⁰

Manufacturer recommends that treatment be continued for at least 14 days after symptoms resolve or the last positive culture, whichever is longer.¹ IDSA and others recommend that antifungal treatment for candidemia (without persistent fungemia or metastatic complications) be continued for 14 days after first negative blood culture and resolution of signs and symptoms of candidemia.^{425 436}

Treatment of Oropharyngeal Candidiasis†

Oral

Children 2 through 11 years of age†: 200 mg twice daily (without loading dose) has been recommended.⁴³⁶

HIV-infected adolescents: 200 mg twice daily.⁴⁴⁰

IDSA and others recommend a treatment duration of 7–14 days.^{425 440}

IV

Children 2 through 11 years of age†: 7 mg/kg twice daily (without loading dose) has been recommended.⁴³⁶

HIV-infected adolescents: 200 mg twice daily.⁴⁴⁰

IDSA and others recommend that a treatment duration of 7–14 days.^{425 440}

Treatment of Esophageal Candidiasis

Oral

Children 2 through 11 years of age†: 200 mg twice daily (without loading dose) has been recommended.⁴³⁶

Children ≥12 years of age weighing <40 kg: 100 mg every 12 hours has been recommended.⁶⁰

Children ≥12 years of age weighing ≥40 kg: 200 mg every 12 hours has been recommended.⁶⁰

HIV-infected adolescents: 200 mg twice daily.⁴⁴⁰

Manufacturer recommends that treatment be continued for at least 14 days and for at least 7 days after symptoms resolve.¹ IDSA and others recommend that a treatment duration of 14–21 days.^{425 436 440}

IV

Children 2 through 11 years of age†: 7 mg/kg twice daily (without loading dose) has been recommended.^{51 436}

HIV-infected adolescents: 200 mg twice daily.⁴⁴⁰

Manufacturer recommends that treatment be continued for at least 14 days and for at least 7 days after symptoms resolve.¹ IDSA and others recommend a treatment duration of 14–21 days.^{425 436 440}

Treatment of Fusarium and Scedosporium Infections

Oral

Children 2 through 11 years of age†: 200 mg twice daily (without loading dose) has been recommended.⁴³⁶

Children ≥12 years of age weighing <40 kg: Loading dose of 200 mg every 12 hours for 2 doses, then maintenance dosage of 100 mg every 12 hours has been recommended; if response is inadequate, may be increased to 150 mg every 12 hours.⁶⁰

Children ≥12 years of age weighing ≥40 kg: Loading dose of 400 mg every 12 hours for 2 doses, then maintenance dosage of 200 mg every 12 hours has been recommended; if response is inadequate, may be increased to 300 mg every 12 hours.⁶⁰

Duration of treatment is based on severity of underlying disease, recovery from immunosuppression, and response to the drug.¹

IV

Children 2 through 11 years of age†: 7 mg/kg twice daily (without loading dose) has been recommended.^{51 436}

Children ≥12 years of age: Loading dose regimen of 6 mg/kg every 12 hours for 2 doses, followed by IV maintenance regimen of 4 mg/kg every 12 hours has been recommended.⁶⁰ Decrease IV maintenance dosage to 3 mg/kg every 12 hours if higher dosage not tolerated.⁶⁰

Duration of treatment is based on severity of underlying disease, recovery from immunosuppression, and response to the drug.¹

Adults

Treatment of Aspergillosis

Oral

Adults weighing <40 kg: After initial IV regimen, maintenance dosage of 100 mg every 12 hours; if response is inadequate, increase to 150 mg every 12 hours.^{1 10} If not tolerated, decrease dosage by increments of 50 mg to a minimum of 100 mg every 12 hours.^{1 10}

Adults weighing ≥40 kg: After initial IV regimen, maintenance dosage of 200 mg every 12 hours; if response is inadequate, increase to 300 mg every 12 hours.^{1 10} If not tolerated, decrease dosage by increments of 50 mg to a minimum of 200 mg every 12 hours.^{1 10}

Duration of treatment is based on severity of underlying disease, recovery from immunosuppression, and response to the drug.¹ IDSA recommends treatment of invasive pulmonary aspergillosis be continued for at least 6–12 weeks and continued throughout the period of immunosuppression.⁴²³

IV

Loading dose regimen of 6 mg/kg every 12 hours for 2 doses, followed by IV maintenance regimen of 4 mg/kg every 12 hours.^{1 436} Decrease IV maintenance dosage to 3 mg/kg every 12 hours if higher dosage not tolerated.¹ Switch to oral maintenance when clinically indicated.^{1 436}

HIV-infected adults: Loading dose regimen of 6 mg/kg twice daily on day 1, followed by IV maintenance regimen of 4 mg/kg twice daily.⁴⁴⁰ After clinical improvement, switch to an oral regimen of 200 mg twice daily.⁴⁴⁰ Optimal duration of therapy not established; continue antifungal therapy at least until CD4⁺ T-cell count increases to 200/mm³ as a result of potent antiretroviral therapy and there is evidence of clinical response.⁴⁴⁰

Candida Infections

Treatment of Candidemia and Disseminated Infections

Oral

Adults weighing <40 kg: After initial IV regimen, maintenance dosage of 100 mg every 12 hours; if response is inadequate, increase to 150 mg every 12 hours.¹ If not tolerated, decrease dosage by increments of 50 mg to a minimum of 100 mg every 12 hours.¹

Adults weighing ≥40 kg: After initial IV regimen, maintenance dosage of 200 mg every 12 hours; if response is inadequate, increase to 300 mg every 12 hours.¹ If not tolerated, decrease dosage by increments of 50 mg to a minimum of 200 mg every 12 hours.¹

Manufacturer recommends that treatment be continued for at least 14 days after symptoms resolve or the last positive culture, whichever is longer.¹ IDSA and others recommend that antifungal treatment for candidemia (without persistent fungemia or metastatic complications) be continued for 14 days after first negative blood culture and resolution of signs and symptoms of candidemia.^{425 436}

IV

Loading dose regimen of 6 mg/kg every 12 hours for 2 doses, followed by IV maintenance regimen of 3–4 mg/kg every 12 hours.¹ Decrease IV maintenance dosage to 3 mg/kg every 12 hours if higher dosage not tolerated.¹

In clinical studies, patients with candidemia received 3 mg/kg every 12 hours and those with deep tissue infections received 4 mg/kg every 12 hours as salvage therapy.¹

Switch to oral maintenance when clinically indicated.¹

Manufacturer recommends that treatment be continued for at least 14 days after symptoms resolve or the last positive culture, whichever is longer.¹ IDSA and others recommend antifungal treatment for candidemia (without persistent fungemia or metastatic complications) be continued for 14 days after first negative blood culture and resolution of signs and symptoms of candidemia.^{425 436}

Treatment of Oropharyngeal Candidiasis†

Oral

200 mg twice daily.^{425 436}

HIV-infected adults: 200 mg twice daily.⁴⁴⁰

IDSA and others recommend that a treatment duration of 7–14 days.^{425 440}

IV

HIV-infected adults: 200 mg twice daily.⁴⁴⁰

IDSA and others recommend a treatment duration of 7–14 days.^{425 440}

Treatment of Esophageal Candidiasis

Oral

Adults weighing <40 kg: 100 mg every 12 hours.¹

Adults weighing ≥40 kg: 200 mg every 12 hours.¹

HIV-infected adults: 200 mg twice daily.⁴⁴⁰

Manufacturer recommends that treatment be continued for at least 14 days and for at least 7 days after symptoms resolve.¹ IDSA and others recommend a treatment duration of 14–21 days.^{425 436 440}

IV

HIV-infected adults: 200 mg twice daily.⁴⁴⁰

Manufacturer recommends that treatment be continued for at least 14 days and for at least 7 days after symptoms resolve.¹ IDSA and others recommend a treatment duration of 14–21 days.^{425 436 440}

Treatment of Fusarium and Scedosporium Infections

Oral

Adults weighing <40 kg: After initial IV regimen, maintenance dosage of 100 mg every 12 hours; if response is inadequate, increase to 150 mg every 12 hours.^{1 10} If not tolerated, decrease dosage by increments of 50 mg to a minimum of 100 mg every 12 hours.^{1 10}

Adults weighing ≥40 kg: After initial IV regimen, maintenance dosage of 200 mg every 12 hours; if response is inadequate, increase to 300 mg every 12 hours.^{1 10} If not tolerated, decrease dosage by increments of 50 mg to a minimum of 200 mg every 12 hours.^{1 10}

Duration of treatment is based on severity of underlying disease, recovery from immunosuppression, and response to the drug.¹

IV

Loading dose regimen of 6 mg/kg every 12 hours for 2 doses, followed by IV maintenance regimen of 4 mg/kg every 12 hours.¹ Decrease IV maintenance dosage to 3 mg/kg every 12 hours if higher dosage not tolerated.¹

Switch to oral maintenance when clinically indicated.¹

Duration of treatment is based on severity of underlying disease, recovery from immunosuppression, and response to the drug.¹

Special Populations

Hepatic Impairment

Mild to moderate hepatic cirrhosis (Child-Pugh class A or B): Use usual loading dose regimen, but decrease maintenance dosages by 50%.^{1 10}

Severe hepatic impairment: Use only if benefits outweigh risks.¹ Not studied in patients with severe cirrhosis (Child-Pugh class C) or chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.¹ (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage adjustment of oral voriconazole not needed.¹

Moderate to severe renal impairment (Cl_cr <50 mL/minute): Use IV voriconazole in only if possible benefits outweigh risks.¹ (See Renal Impairment under Cautions.) Monitor serum creatinine closely; if increases occur, consider switching to oral voriconazole.¹

Geriatric Patients

Dosage adjustments not necessary based on age.¹

Concomitant Therapy with Efavirenz or Phenytoin

If used with efavirenz or phenytoin, voriconazole dosage adjustment recommended.^{1 34 431 440} (See Specific Drugs under Interactions.)

Cautions for Voriconazole

Contraindications

• 
  

  Known hypersensitivity to voriconazole or any ingredient in the formulation.¹

  
  


• 
  

  Concomitant use with astemizole or terfenadine (drugs no longer commercially available in US), carbamazepine, cisapride (currently commercially available in the US only under a limited-access protocol), ergot alkaloids (e.g., ergotamine, dihydroergotamine), pimozide, quinidine, rifabutin, rifampin, sirolimus, St. John’s wort (Hypericum perforatum), or long-acting barbiturates (e.g., phenobarbital, mephobarbital).^{1 40 431} (See Specific Drugs under Interactions.)

  
  


• 
  

  Concomitant use with full-dose ritonavir (≥400 mg twice daily) is contraindicated; avoid concomitant use with low-dose ritonavir (100 mg every 12 hours) unless benefits outweigh risks.^{1 40 431} (See Specific Drugs under Interactions.)

  
  

Warnings/Precautions

Warnings

Ocular Effects

Visual disturbances (e.g., abnormal vision, blurred vision, color vision change, photophobia) reported; may be related to high dosage and high plasma voriconazole concentrations.¹

Postmarketing reports of prolonged visual disturbances, inlcuding optic neuritis and papilledema.¹

Effect on visual function unknown if duration of therapy is >28 days.¹ Monitor visual function (visual acuity, visual field, and color perception) if duration is >28 days.¹

Hepatic Effects

Hepatitis, cholestasis, and fulminant hepatic failure reported rarely.¹ Hepatic effects (including hepatitis and jaundice) have occurred in patients with no identifiable risk factors.¹ Hepatic effects usually are reversible when voriconazole discontinued, but fatalities have occurred.¹

Perform liver function tests prior to and during voriconazole therapy.¹

If abnormal liver function tests occur during therapy, monitor for development of more severe hepatic injury using appropriate laboratory evaluations (particularly liver function tests and bilirubin).¹ Consider discontinuing voriconazole if clinical signs and symptoms consistent with liver disease develop that may be attributable to the drug.¹

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity demonstrated in animals.¹ (See Pregnancy under Cautions.)

Pregnancy should be avoided.¹ Women of childbearing potential should use effective contraception during voriconazole treatment.¹ (See Specific Drugs under Interactions.)

If used during pregnancy or if patient becomes pregnant while receiving voriconazole, advise patient of the potential hazard to the fetus.¹

Fructose or Galactose Intolerance

Voriconazole tablets contain lactose and should not be used in those with galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.¹

Voriconazole oral suspension contains sucrose and should not be used in those with fructose intolerance, sucrase-isomaltase deficiency, or glucose-galactose malabsorption.¹

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylactoid reactions (e.g., flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus, rash) reported rarely immediately after initiation of voriconazole IV infusion.¹ Consider stopping the infusion if these reactions occur.¹

Serious cutaneous reactions (e.g., Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis) and photosensitivity reactions reported rarely.¹ (See Dermatologic Effects under Cautions.)

Data regarding cross-sensitivity with other azole antifungals not available.¹ Use with caution in patients hypersensitive to other azoles.¹

General Precautions

Cardiovascular Effects

Prolonged QT interval reported with voriconazole and other azoles.¹ Arrhythmias (e.g., torsades de pointes), cardiac arrest, and sudden death reported rarely.¹

Most reported cases involved seriously ill patients with multiple confounding risk factors that may have contributed (e.g., history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia, concomitant drugs).¹

Use with caution in patients with potentially proarrhythmic conditions.¹

Rigorous attempts should be made to correct potassium, magnesium, and calcium before starting voriconazole.¹

Laboratory Monitoring

Evaluate liver function (e.g., liver function tests, bilirubin) prior to and during voriconazole therapy.¹

Evaluate serum electrolytes (i.e., potassium, magnesium, calcium) and correct any abnormalities prior to initiating therapy.¹

Monitor renal function (e.g., Serum creatinine) during voriconazole therapy.¹

Monitor adults and children with risk factors for acute pancreatitis (e.g., recent chemotherapy, hematopoietic stem cell transplantation [HSCT]) for the development of pancreatitis.¹

Dermatologic Effects

Serious cutaneous reactions (e.g., Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis) reported rarely.¹ If an exfoliative cutaneous reaction occurs, discontinue voriconazole.¹

Squamous cell carcinoma of the skin and melanoma have been reported during long-term voriconazole therapy in patients with photosensitivity reactions.¹

Avoid intense or prolonged exposure to direct sunlight during voriconazole therapy.¹

If skin lesion consistent with squamous cell carcinoma or melanoma develops, discontinue voriconazole.¹

Renal Effects

Acute renal failure reported in severely ill patients with other factors predisposing to impaired renal function (e.g., underlying conditions, concomitant nephrotoxic drugs).¹

Specific Populations

Pregnancy

Category D.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

In animal studies, teratogenic effects (cleft palate, hydronephrosis/hydroureter) and embrytoxic effects reported.¹

Lactation

Not known whether distributed into milk.¹ Should not be used unless potential benefits clearly outweigh risks.¹

Pediatric Use

Safety and efficacy not established in children <12 years of age.¹

Has been recommended for treatment of fungal infections in children;^{51 423 436 441} dosage recommendations have been made for children 2 through 11 years of age†.⁴³⁶ (See Pediatric Patients under Dosage and Administration.) Some clinicians consider voriconazole the drug of choice for treatment of invasive aspergillosis in HIV-infected children†, but state that data are insufficient to recommend use of the drug for treatment of candidemia or esophageal candidiasis in these children.⁴⁴¹

Has been used in children 9 months to 15 years of age† in clinical studies.⁹

Adverse effects in pediatric patients similar to those reported in adults.⁹

Cases of pancreatitis in pediatric patients documented in postmarketing reports;¹ monitor for the development of pancreatitis in children with risk factors for acute pancreatitis (e.g., recent chemotherapy, HSCT).¹

Geriatric Use

Plasma voriconazole concentrations increased in geriatric patients, but overall safety profile is similar to that in younger adults.¹

Hepatic Impairment

Monitor carefully for adverse effects, including adverse hepatic effects.¹ (See Hepatic Effects under Cautions.)

Not evaluated in patients with severe hepatic cirrhosis (Child-Pugh class C) or with HBV or HCV infection.¹

Not recommended in patients with severe hepatic impairment unless potential benefits outweigh risks.¹

Renal Impairment

IV voriconazole contains sulfobutyl ether β-cyclodextrin sodium (SBECD) which may accumulate in patients with moderate-to-severe renal impairment (Cl_cr <50 mL/minute).¹

IV voriconazole should not be used in patients with Cl_cr <50 mL/minute, unless potential benefits outweigh risks.¹ If IV voriconazole is used in these patients, monitor serum creatinine concentrations closely; if increases occur, consider switching to oral voriconazole.¹

Common Adverse Effects

Visual disturbances (abnormal vision, blurred vision, color vision change, photophobia), GI effects (nausea, vomiting, diarrhea, abdominal pain), fever, rash, headache, sepsis, peripheral edema, respiratory disorder.¹

Interactions for Voriconazole

Metabolized by CYP2C9, 2C19, and 3A4.¹

Inhibits CYP2C9, 2C19, and 3A4; the major metabolite (voriconazole N-oxide) also inhibits these enzymes.¹ Voriconazole appears to be a less potent inhibitor of CYP3A4 than some other azoles (e.g., itraconazole, ketoconazole).¹

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Potential pharmacokinetic interactions with drugs that are inhibitors, inducers, or substrates of CYP2C9, 2C19, or 3A4 with possible alteration in metabolism of voriconazole and/or other drug.¹

Specific Drugs

Drug	Interaction	Comments
Alfentanil	Increased mean AUC and elimination half-life of alfentanil when administered with voriconazole and naloxone1 Increased incidence of delayed and persistent alfentanil-induced nausea and vomiting when administered with voriconazole1	If voriconazole used concomitantly with alfentanil or other opiate agonist metabolized by CYP3A4 (e.g., sufentanil), reduced dosage of the opiate agonist may be necessary1 34 Extended close monitoring for opiate-related adverse events (e.g., respiratory depression) may be necessary1 34
Anticoagulants, oral (warfarin)	Potentiates warfarin’s effect on PT1 16 34	Monitor PT or other appropriate tests closely if used with warfarin; reduce anticoagulant dosage if necessary1 16 34
Antidiabetic agents, sulfonylureas (glipizide, glyburide, tolbutamide)	Possible increased concentrations of glipizide, glyburide, tolbutamide and risk of hypoglycemia1	Monitor blood glucose and observe patient for signs and symptoms of hypoglycemia; adjust dosage of antidiabetic agent as necessary1
Antihistamines (astemizole, terfenadine)	Possible pharmacokinetic interaction and potential for serious or life-threatening reactions (e.g., cardiac arrhythmias) with astemizole or terfenadine (drugs no longer commercially available in the US)1	Concomitant use contraindicated1
Antimycobacterials, rifamycins (rifabutin, rifampin)	Rifabutin: Decreased voriconazole concentrations and AUC and increased