Voriconazole

Dosage Forms & Strengths

oral suspension

• 200mg/5mL

injection, powder for reconstitution

• 200mg

tablets

• 50mg
• 200mg

Invasive Aspergillosis

In clinical trials, the majority of isolates recovered were Aspergillus fumigatus

6 mg/kg IV q12hr for first 24 hours, then 4 mg/kg IV q12hr or 200 mg PO q12hr  

Median duration of treatment: IV 10 days (range 2-90 days); PO 76 days (range 2-232 days)

Candidemia

Indicated for candidemia in non-neutropenic patients with other deep tissue Candida infections (eg, Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, Candida tropicalis)

6 mg/kg IV q12hr for first 24 hours, then 3- 4 mg/kg IV q12hr or 200 mg PO q12hr 

Esophageal Candidiasis

Candida albicans, Candida glabrata, Candida krusei

200 mg PO q12hr

Serious Fungal Infections

Caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii) and Fusarium spp. including Fusarium solani, in patients intolerant of or refractory to other therapy

6 mg/kg IV q12hr for first 24 hours, then 4 mg/kg IV q12hr or 200 mg PO q12hr 

Dosage Modification

Adults weighing <40 mg: Decrease PO maintenance dose by 50%

Renal impairment (CrCl <50 mL/min): Use oral form only for maintenance; avoid IV administration because of accumulation of IV vehicle (SBECD)

Hepatic impairment

• Mild-moderate (Child-Pugh A or B): Administer standard loading dose, but decrease maintenance dose by 50%
• Severe (Child-Pugh C): No data available
• Hepatitis B or C: No data available

Inadequate response

• Increase PO maintenance dose from 200 mg q12hr to 300 mg q12hr
• <40 kg: Increase PO maintenance dose from 100 mg q12hr to 150 mg q12hr

Administration

Infuse IV over 1-2 hr, not to exceed 3 mg/kg/hr

Take oral form 1 hr before or after meal

Dosage Forms & Strengths

oral suspension

• 200mg/5mL

injection, powder for reconstitution

• 200mg

tablets

• 50mg
• 200mg

Invasive Aspergillosis

In clinical trials, the majority of isolates recovered were Aspergillus fumigatus

<12 years: Safety and efficacy not established

≥12 years: 6 mg/kg IV q12hr for first 24 hours, then 4 mg/kg IV q12hr or 200 mg PO q12hr

Median duration of treatment: IV 10 days (range 2-90 days); PO 76 days (range 2-232 days)

Candidemia

Indicated for candidemia in non-neutropenic patients with other deep tissue Candida infections (eg, Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, Candida tropicalis)

<12 years: Safety and efficacy not established

≥12 years: 6 mg/kg IV q12hr for first 24 hours, then 3- 4 mg/kg IV q12hr or 200 mg PO q12hr

Esophageal Candidiasis

Candida albicans, Candida glabrata, Candida krusei

<12 years: Safety and efficacy not established

≥12 years: 200 mg PO q12hr

Serious Fungal Infections

Caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii) and Fusarium spp. including Fusarium solani, in patients intolerant of or refractory to other therapy

<12 years: Safety and efficacy not established

≥12 years: 6 mg/kg IV q12hr for first 24 hours, then 4 mg/kg IV q12hr or 200 mg PO q12hr

Susceptible Fungal Infections (Off-label, Aged 2-12 yr)

9 mg/kg/dose IV/PO q12hr; not to exceed 350 mg/dose

Voriconazole may cause changes in vision including blurred vision and sensitivity to light. Wear sunglasses during the day to protect your eyes from bright light. Be careful if you drive or do anything that requires you to have clear vision.

Avoid exposure to sunlight or tanning beds. Voriconazole can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Voriconazole may cause serious side effects including:

• liver problems. Symptoms of liver problems may include:
  • itchy skin
  • yellowing of your eyes
  • feeling very tired
  • flu-like symptoms
  • nausea or vomiting
• vision changes. Symptoms of vision changes may include:
  • blurred vision
  • changes in the way you see colors
  • sensitivity to light (photophobia)
• serious heart problems. Voriconazole may cause changes in your heart rate or rhythm, including your heart stopping (cardiac arrest).
• allergic reactions. Symptoms of an allergic reaction may include:
  • fever
  • sweating
  • feels like your heart is beating fast (tachycardia)
  • chest tightness
  • trouble breathing
  • feel faint
  • nausea
  • itching
  • skin rash
• kidney problems. Voriconazole may cause new or worse problems with kidney function, including kidney failure. Your healthcare provider should check your kidney function while you are taking voriconazole. Your healthcare provider will decide if you can keep taking voriconazole.
• serious skin reactions. Symptoms of serious skin reactions may include:
  • rash or hives
  • mouth sores
  • blistering or peeling of your skin
  • trouble swallowing or breathing

Call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the symptoms listed above.

The most common side effects of voriconazole include:

• vision changes
• rash
• vomiting
• nausea
• headache
• fast heart beat (tachycardia)
• hallucinations (seeing or hearing things that are not there)
• abnormal liver function tests

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of voriconazole. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

• Store voriconazole tablets and liquid at room temperature, 59° to 86° F (15° to 30°C). Do not refrigerate or freeze.
• Voriconazole suspension should be thrown away (discarded) after 14 days.
• Keep voriconazole tablets and oral suspension in a tightly closed container.
• Safely throw away medicine that is out of date or no longer needed.
• Keep voriconazole, as well as all other medicines, out of the reach of children.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Call your doctor for instructions if you miss a dose of injectable voriconazole.

Usual Adult Dose for Aspergillosis -- Invasive:

Loading Dose: 6 mg/kg IV every 12 hours for 2 doses

Maintenance Dose:
IV:
Invasive aspergillosis and serious fungal infections due to Fusarium species and Scedosporium apiospermum: 4 mg/kg IV every 12 hours

Comments:
-Therapy should start with the IV loading dose on Day 1 followed by the maintenance dose.
-IV therapy should continue for at least 7 days.
-Once the patient has clinically improved and can tolerate oral medication, oral voriconazole may be used.

Candidemia in nonneutropenic patients and other deep tissue Candida infections: 3 to 4 mg/kg IV every 12 hours

Comments:
-In clinical trials, candidemia was treated using 3 mg/kg IV every 12 hours as primary therapy, while other deep tissue Candida infections were treated using 4 mg/kg IV every 12 hours as salvage therapy; appropriate dose should be based on the nature and severity of the infection.

Oral:
Less than 40 kg: 100 mg orally every 12 hours
40 kg or more: 200 mg orally every 12 hours

Duration of Therapy:
-Invasive aspergillosis: In a clinical trial, the median duration of IV therapy was 10 days (range 2 to 85 days) and of oral therapy was 76 days (range 2 to 232 days).
-Infectious Diseases Society of America (IDSA) guidelines for invasive aspergillosis: At least 6 to 12 weeks; in immunosuppressed patients, throughout immunosuppression and until lesions resolve
-Candidemia in nonneutropenic patients and other deep tissue Candida infections: At least 14 days after symptoms resolve or after last positive culture, whichever is longer

Uses: Invasive aspergillosis; candidemia in nonneutropenic patients; disseminated Candida infections in skin; Candida infections in abdomen, kidney, bladder wall, wounds; serious fungal infections due to Fusarium species and S apiospermum in patients intolerant of (or refractory to) other therapy

IDSA guidelines for empirical and preemptive therapy:
-IV: 6 mg/kg IV every 12 hours for 2 doses, then 3 mg/kg IV every 12 hours
-Oral: 200 mg orally every 12 hours

Usual Adult Dose for Candidemia:

Loading Dose: 6 mg/kg IV every 12 hours for 2 doses

Maintenance Dose:
IV:
Invasive aspergillosis and serious fungal infections due to Fusarium species and Scedosporium apiospermum: 4 mg/kg IV every 12 hours

Comments:
-Therapy should start with the IV loading dose on Day 1 followed by the maintenance dose.
-IV therapy should continue for at least 7 days.
-Once the patient has clinically improved and can tolerate oral medication, oral voriconazole may be used.

Candidemia in nonneutropenic patients and other deep tissue Candida infections: 3 to 4 mg/kg IV every 12 hours

Comments:
-In clinical trials, candidemia was treated using 3 mg/kg IV every 12 hours as primary therapy, while other deep tissue Candida infections were treated using 4 mg/kg IV every 12 hours as salvage therapy; appropriate dose should be based on the nature and severity of the infection.

Oral:
Less than 40 kg: 100 mg orally every 12 hours
40 kg or more: 200 mg orally every 12 hours

Duration of Therapy:
-Invasive aspergillosis: In a clinical trial, the median duration of IV therapy was 10 days (range 2 to 85 days) and of oral therapy was 76 days (range 2 to 232 days).
-Infectious Diseases Society of America (IDSA) guidelines for invasive aspergillosis: At least 6 to 12 weeks; in immunosuppressed patients, throughout immunosuppression and until lesions resolve
-Candidemia in nonneutropenic patients and other deep tissue Candida infections: At least 14 days after symptoms resolve or after last positive culture, whichever is longer

Uses: Invasive aspergillosis; candidemia in nonneutropenic patients; disseminated Candida infections in skin; Candida infections in abdomen, kidney, bladder wall, wounds; serious fungal infections due to Fusarium species and S apiospermum in patients intolerant of (or refractory to) other therapy

IDSA guidelines for empirical and preemptive therapy:
-IV: 6 mg/kg IV every 12 hours for 2 doses, then 3 mg/kg IV every 12 hours
-Oral: 200 mg orally every 12 hours

Usual Adult Dose for Fungal Pneumonia:

Loading Dose: 6 mg/kg IV every 12 hours for 2 doses

Maintenance Dose:
IV:
Invasive aspergillosis and serious fungal infections due to Fusarium species and Scedosporium apiospermum: 4 mg/kg IV every 12 hours

Comments:
-Therapy should start with the IV loading dose on Day 1 followed by the maintenance dose.
-IV therapy should continue for at least 7 days.
-Once the patient has clinically improved and can tolerate oral medication, oral voriconazole may be used.

Candidemia in nonneutropenic patients and other deep tissue Candida infections: 3 to 4 mg/kg IV every 12 hours

Comments:
-In clinical trials, candidemia was treated using 3 mg/kg IV every 12 hours as primary therapy, while other deep tissue Candida infections were treated using 4 mg/kg IV every 12 hours as salvage therapy; appropriate dose should be based on the nature and severity of the infection.

Oral:
Less than 40 kg: 100 mg orally every 12 hours
40 kg or more: 200 mg orally every 12 hours

Duration of Therapy:
-Invasive aspergillosis: In a clinical trial, the median duration of IV therapy was 10 days (range 2 to 85 days) and of oral therapy was 76 days (range 2 to 232 days).
-Infectious Diseases Society of America (IDSA) guidelines for invasive aspergillosis: At least 6 to 12 weeks; in immunosuppressed patients, throughout immunosuppression and until lesions resolve
-Candidemia in nonneutropenic patients and other deep tissue Candida infections: At least 14 days after symptoms resolve or after last positive culture, whichever is longer

Uses: Invasive aspergillosis; candidemia in nonneutropenic patients; disseminated Candida infections in skin; Candida infections in abdomen, kidney, bladder wall, wounds; serious fungal infections due to Fusarium species and S apiospermum in patients intolerant of (or refractory to) other therapy

IDSA guidelines for empirical and preemptive therapy:
-IV: 6 mg/kg IV every 12 hours for 2 doses, then 3 mg/kg IV every 12 hours
-Oral: 200 mg orally every 12 hours

Usual Adult Dose for Pseudoallescheriosis:

Loading Dose: 6 mg/kg IV every 12 hours for 2 doses

Maintenance Dose:
IV:
Invasive aspergillosis and serious fungal infections due to Fusarium species and Scedosporium apiospermum: 4 mg/kg IV every 12 hours

Comments:
-Therapy should start with the IV loading dose on Day 1 followed by the maintenance dose.
-IV therapy should continue for at least 7 days.
-Once the patient has clinically improved and can tolerate oral medication, oral voriconazole may be used.

Candidemia in nonneutropenic patients and other deep tissue Candida infections: 3 to 4 mg/kg IV every 12 hours

Comments:
-In clinical trials, candidemia was treated using 3 mg/kg IV every 12 hours as primary therapy, while other deep tissue Candida infections were treated using 4 mg/kg IV every 12 hours as salvage therapy; appropriate dose should be based on the nature and severity of the infection.

Oral:
Less than 40 kg: 100 mg orally every 12 hours
40 kg or more: 200 mg orally every 12 hours

Duration of Therapy:
-Invasive aspergillosis: In a clinical trial, the median duration of IV therapy was 10 days (range 2 to 85 days) and of oral therapy was 76 days (range 2 to 232 days).
-Infectious Diseases Society of America (IDSA) guidelines for invasive aspergillosis: At least 6 to 12 weeks; in immunosuppressed patients, throughout immunosuppression and until lesions resolve
-Candidemia in nonneutropenic patients and other deep tissue Candida infections: At least 14 days after symptoms resolve or after last positive culture, whichever is longer

Uses: Invasive aspergillosis; candidemia in nonneutropenic patients; disseminated Candida infections in skin; Candida infections in abdomen, kidney, bladder wall, wounds; serious fungal infections due to Fusarium species and S apiospermum in patients intolerant of (or refractory to) other therapy

IDSA guidelines for empirical and preemptive therapy:
-IV: 6 mg/kg IV every 12 hours for 2 doses, then 3 mg/kg IV every 12 hours
-Oral: 200 mg orally every 12 hours

Usual Adult Dose for Systemic Fungal Infection:

Loading Dose: 6 mg/kg IV every 12 hours for 2 doses

Maintenance Dose:
IV:
Invasive aspergillosis and serious fungal infections due to Fusarium species and Scedosporium apiospermum: 4 mg/kg IV every 12 hours

Comments:
-Therapy should start with the IV loading dose on Day 1 followed by the maintenance dose.
-IV therapy should continue for at least 7 days.
-Once the patient has clinically improved and can tolerate oral medication, oral voriconazole may be used.

Candidemia in nonneutropenic patients and other deep tissue Candida infections: 3 to 4 mg/kg IV every 12 hours

Comments:
-In clinical trials, candidemia was treated using 3 mg/kg IV every 12 hours as primary therapy, while other deep tissue Candida infections were treated using 4 mg/kg IV every 12 hours as salvage therapy; appropriate dose should be based on the nature and severity of the infection.

Oral:
Less than 40 kg: 100 mg orally every 12 hours
40 kg or more: 200 mg orally every 12 hours

Duration of Therapy:
-Invasive aspergillosis: In a clinical trial, the median duration of IV therapy was 10 days (range 2 to 85 days) and of oral therapy was 76 days (range 2 to 232 days).
-Infectious Diseases Society of America (IDSA) guidelines for invasive aspergillosis: At least 6 to 12 weeks; in immunosuppressed patients, throughout immunosuppression and until lesions resolve
-Candidemia in nonneutropenic patients and other deep tissue Candida infections: At least 14 days after symptoms resolve or after last positive culture, whichever is longer

Uses: Invasive aspergillosis; candidemia in nonneutropenic patients; disseminated Candida infections in skin; Candida infections in abdomen, kidney, bladder wall, wounds; serious fungal infections due to Fusarium species and S apiospermum in patients intolerant of (or refractory to) other therapy

IDSA guidelines for empirical and preemptive therapy:
-IV: 6 mg/kg IV every 12 hours for 2 doses, then 3 mg/kg IV every 12 hours
-Oral: 200 mg orally every 12 hours

Usual Adult Dose for Cutaneous Fungal Infection:

Loading Dose: 6 mg/kg IV every 12 hours for 2 doses

Maintenance Dose:
IV:
Invasive aspergillosis and serious fungal infections due to Fusarium species and Scedosporium apiospermum: 4 mg/kg IV every 12 hours

Comments:
-Therapy should start with the IV loading dose on Day 1 followed by the maintenance dose.
-IV therapy should continue for at least 7 days.
-Once the patient has clinically improved and can tolerate oral medication, oral voriconazole may be used.

Candidemia in nonneutropenic patients and other deep tissue Candida infections: 3 to 4 mg/kg IV every 12 hours

Comments:
-In clinical trials, candidemia was treated using 3 mg/kg IV every 12 hours as primary therapy, while other deep tissue Candida infections were treated using 4 mg/kg IV every 12 hours as salvage therapy; appropriate dose should be based on the nature and severity of the infection.

Oral:
Less than 40 kg: 100 mg orally every 12 hours
40 kg or more: 200 mg orally every 12 hours

Duration of Therapy:
-Invasive aspergillosis: In a clinical trial, the median duration of IV therapy was 10 days (range 2 to 85 days) and of oral therapy was 76 days (range 2 to 232 days).
-Infectious Diseases Society of America (IDSA) guidelines for invasive aspergillosis: At least 6 to 12 weeks; in immunosuppressed patients, throughout immunosuppression and until lesions resolve
-Candidemia in nonneutropenic patients and other deep tissue Candida infections: At least 14 days after symptoms resolve or after last positive culture, whichever is longer

Uses: Invasive aspergillosis; candidemia in nonneutropenic patients; disseminated Candida infections in skin; Candida infections in abdomen, kidney, bladder wall, wounds; serious fungal infections due to Fusarium species and S apiospermum in patients intolerant of (or refractory to) other therapy

IDSA guidelines for empirical and preemptive therapy:
-IV: 6 mg/kg IV every 12 hours for 2 doses, then 3 mg/kg IV every 12 hours
-Oral: 200 mg orally every 12 hours

Usual Adult Dose for Fungal Infection -- Disseminated:

Loading Dose: 6 mg/kg IV every 12 hours for 2 doses

Maintenance Dose:
IV:
Invasive aspergillosis and serious fungal infections due to Fusarium species and Scedosporium apiospermum: 4 mg/kg IV every 12 hours

Comments:
-Therapy should start with the IV loading dose on Day 1 followed by the maintenance dose.
-IV therapy should continue for at least 7 days.
-Once the patient has clinically improved and can tolerate oral medication, oral voriconazole may be used.

Candidemia in nonneutropenic patients and other deep tissue Candida infections: 3 to 4 mg/kg IV every 12 hours

Comments:
-In clinical trials, candidemia was treated using 3 mg/kg IV every 12 hours as primary therapy, while other deep tissue Candida infections were treated using 4 mg/kg IV every 12 hours as salvage therapy; appropriate dose should be based on the nature and severity of the infection.

Oral:
Less than 40 kg: 100 mg orally every 12 hours
40 kg or more: 200 mg orally every 12 hours

Duration of Therapy:
-Invasive aspergillosis: In a clinical trial, the median duration of IV therapy was 10 days (range 2 to 85 days) and of oral therapy was 76 days (range 2 to 232 days).
-Infectious Diseases Society of America (IDSA) guidelines for invasive aspergillosis: At least 6 to 12 weeks; in immunosuppressed patients, throughout immunosuppression and until lesions resolve
-Candidemia in nonneutropenic patients and other deep tissue Candida infections: At least 14 days after symptoms resolve or after last positive culture, whichever is longer

Uses: Invasive aspergillosis; candidemia in nonneutropenic patients; disseminated Candida infections in skin; Candida infections in abdomen, kidney, bladder wall, wounds; serious fungal infections due to Fusarium species and S apiospermum in patients intolerant of (or refractory to) other therapy

IDSA guidelines for empirical and preemptive therapy:
-IV: 6 mg/kg IV every 12 hours for 2 doses, then 3 mg/kg IV every 12 hours
-Oral: 200 mg orally every 12 hours

Usual Adult Dose for Fungal Meningitis:

Loading Dose: 6 mg/kg IV every 12 hours for 2 doses

Maintenance Dose:
IV:
Invasive aspergillosis and serious fungal infections due to Fusarium species and Scedosporium apiospermum: 4 mg/kg IV every 12 hours

Comments:
-Therapy should start with the IV loading dose on Day 1 followed by the maintenance dose.
-IV therapy should continue for at least 7 days.
-Once the patient has clinically improved and can tolerate oral medication, oral voriconazole may be used.

Candidemia in nonneutropenic patients and other deep tissue Candida infections: 3 to 4 mg/kg IV every 12 hours

Comments:
-In clinical trials, candidemia was treated using 3 mg/kg IV every 12 hours as primary therapy, while other deep tissue Candida infections were treated using 4 mg/kg IV every 12 hours as salvage therapy; appropriate dose should be based on the nature and severity of the infection.

Oral:
Less than 40 kg: 100 mg orally every 12 hours
40 kg or more: 200 mg orally every 12 hours

Duration of Therapy:
-Invasive aspergillosis: In a clinical trial, the median duration of IV therapy was 10 days (range 2 to 85 days) and of oral therapy was 76 days (range 2 to 232 days).
-Infectious Diseases Society of America (IDSA) guidelines for invasive aspergillosis: At least 6 to 12 weeks; in immunosuppressed patients, throughout immunosuppression and until lesions resolve
-Candidemia in nonneutropenic patients and other deep tissue Candida infections: At least 14 days after symptoms resolve or after last positive culture, whichever is longer

Uses: Invasive aspergillosis; candidemia in nonneutropenic patients; disseminated Candida infections in skin; Candida infections in abdomen, kidney, bladder wall, wounds; serious fungal infections due to Fusarium species and S apiospermum in patients intolerant of (or refractory to) other therapy

IDSA guidelines for empirical and preemptive therapy:
-IV: 6 mg/kg IV every 12 hours for 2 doses, then 3 mg/kg IV every 12 hours
-Oral: 200 mg orally every 12 hours

Usual Adult Dose for Fusariosis:

Loading Dose: 6 mg/kg IV every 12 hours for 2 doses

Maintenance Dose:
IV:
Invasive aspergillosis and serious fungal infections due to Fusarium species and Scedosporium apiospermum: 4 mg/kg IV every 12 hours

Comments:
-Therapy should start with the IV loading dose on Day 1 followed by the maintenance dose.
-IV therapy should continue for at least 7 days.
-Once the patient has clinically improved and can tolerate oral medication, oral voriconazole may be used.

Candidemia in nonneutropenic patients and other deep tissue Candida infections: 3 to 4 mg/kg IV every 12 hours

Comments:
-In clinical trials, candidemia was treated using 3 mg/kg IV every 12 hours as primary therapy, while other deep tissue Candida infections were treated using 4 mg/kg IV every 12 hours as salvage therapy; appropriate dose should be based on the nature and severity of the infection.

Oral:
Less than 40 kg: 100 mg orally every 12 hours
40 kg or more: 200 mg orally every 12 hours

Duration of Therapy:
-Invasive aspergillosis: In a clinical trial, the median duration of IV therapy was 10 days (range 2 to 85 days) and of oral therapy was 76 days (range 2 to 232 days).
-Infectious Diseases Society of America (IDSA) guidelines for invasive aspergillosis: At least 6 to 12 weeks; in immunosuppressed patients, throughout immunosuppression and until lesions resolve
-Candidemia in nonneutropenic patients and other deep tissue Candida infections: At least 14 days after symptoms resolve or after last positive culture, whichever is longer

Uses: Invasive aspergillosis; candidemia in nonneutropenic patients; disseminated Candida infections in skin; Candida infections in abdomen, kidney, bladder wall, wounds; serious fungal infections due to Fusarium species and S apiospermum in patients intolerant of (or refractory to) other therapy

IDSA guidelines for empirical and preemptive therapy:
-IV: 6 mg/kg IV every 12 hours for 2 doses, then 3 mg/kg IV every 12 hours
-Oral: 200 mg orally every 12 hours

Usual Adult Dose for Esophageal Candidiasis:

Less than 40 kg: 100 mg orally every 12 hours
40 kg or more: 200 mg orally every 12 hours

Duration of therapy: At least 14 days and at least 7 days after symptoms resolve

Usual Adult Dose for Blastomycosis:

IDSA guidelines for CNS disease: 200 to 400 mg orally twice a day
Duration of therapy: At least 12 months and until CSF abnormalities resolve

Comments:
-An oral azole is recommended for step-down therapy after an initial regimen of liposomal amphotericin B.
-Not approved by US FDA.

Case report (n=1)
Cerebral blastomycosis: 200 mg orally twice a day

Comments:
-Dose was increased to 300 mg orally twice a day after 4 weeks in an attempt to achieve a higher CNS level.
-Therapy continued for 12 months.

Usual Pediatric Dose for Aspergillosis -- Invasive:

2 to 11 years:
American Academy of Pediatrics recommendations: 9 mg/kg IV or orally every 12 hours
Maximum dose: 350 mg/dose

IDSA guidelines for invasive aspergillosis: 5 to 7 mg/kg IV every 12 hours

12 years or older:
Loading Dose: 6 mg/kg IV every 12 hours for 2 doses

Maintenance Dose:
IV:
Invasive aspergillosis and serious fungal infections due to Fusarium species and S apiospermum: 4 mg/kg IV every 12 hours

Comments:
-Therapy should start with the IV loading dose on Day 1 followed by the maintenance dose.
-IV therapy should continue for at least 7 days.
-Once the patient has clinically improved and can tolerate oral medication, oral voriconazole may be used.

Candidemia in nonneutropenic patients and other deep tissue Candida infections: 3 to 4 mg/kg IV every 12 hours

Comments:
-In clinical trials, candidemia was treated using 3 mg/kg IV every 12 hours as primary therapy, while other deep tissue Candida infections were treated using 4 mg/kg IV every 12 hours as salvage therapy; appropriate dose should be based on the nature and severity of the infection.

Oral:
Less than 40 kg: 100 mg orally every 12 hours
40 kg or more: 200 mg orally every 12 hours

Duration of Therapy:
-Invasive aspergillosis: In a clinical trial, the median duration of IV therapy was 10 days (range 2 to 85 days) and of oral therapy was 76 days (range 2 to 232 days).
-IDSA guidelines for invasive aspergillosis: At least 6 to 12 weeks; in immunosuppressed patients, throughout immunosuppression and until lesions resolve
-Candidemia in nonneutropenic patients and other deep tissue Candida infections: At least 14 days after symptoms resolve or after last positive culture, whichever is longer

Uses: Invasive aspergillosis; candidemia in nonneutropenic patients; disseminated Candida infections in skin; Candida infections in abdomen, kidney, bladder wall, wounds; serious fungal infections due to Fusarium species and S apiospermum in patients intolerant of (or refractory to) other therapy

Usual Pediatric Dose for Candidemia:

2 to 11 years:
American Academy of Pediatrics recommendations: 9 mg/kg IV or orally every 12 hours
Maximum dose: 350 mg/dose

IDSA guidelines for invasive aspergillosis: 5 to 7 mg/kg IV every 12 hours

12 years or older:
Loading Dose: 6 mg/kg IV every 12 hours for 2 doses

Maintenance Dose:
IV:
Invasive aspergillosis and serious fungal infections due to Fusarium species and S apiospermum: 4 mg/kg IV every 12 hours

Comments:
-Therapy should start with the IV loading dose on Day 1 followed by the maintenance dose.
-IV therapy should continue for at least 7 days.
-Once the patient has clinically improved and can tolerate oral medication, oral voriconazole may be used.

Candidemia in nonneutropenic patients and other deep tissue Candida infections: 3 to 4 mg/kg IV every 12 hours

Comments:
-In clinical trials, candidemia was treated using 3 mg/kg IV every 12 hours as primary therapy, while other deep tissue Candida infections were treated using 4 mg/kg IV every 12 hours as salvage therapy; appropriate dose should be based on the nature and severity of the infection.

Oral:
Less than 40 kg: 100 mg orally every 12 hours
40 kg or more: 200 mg orally every 12 hours

Duration of Therapy:
-Invasive aspergillosis: In a clinical trial, the median duration of IV therapy was 10 days (range 2 to 85 days) and of oral therapy was 76 days (range 2 to 232 days).
-IDSA guidelines for invasive aspergillosis: At least 6 to 12 weeks; in immunosuppressed patients, throughout immunosuppression and until lesions resolve
-Candidemia in nonneutropenic patients and other deep tissue Candida infections: At least 14 days after symptoms resolve or after last positive culture, whichever is longer

Uses: Invasive aspergillosis; candidemia in nonneutropenic patients; disseminated Candida infections in skin; Candida infections in abdomen, kidney, bladder wall, wounds; serious fungal infections due to Fusarium species and S apiospermum in patients intolerant of (or refractory to) other therapy

Usual Pediatric Dose for Fungal Pneumonia:

2 to 11 years:
American Academy of Pediatrics recommendations: 9 mg/kg IV or orally every 12 hours
Maximum dose: 350 mg/dose

IDSA guidelines for invasive aspergillosis: 5 to 7 mg/kg IV every 12 hours

12 years or older:
Loading Dose: 6 mg/kg IV every 12 hours for 2 doses

Maintenance Dose:
IV:
Invasive aspergillosis and serious fungal infections due to Fusarium species and S apiospermum: 4 mg/kg IV every 12 hours

Comments:
-Therapy should start with the IV loading dose on Day 1 followed by the maintenance dose.
-IV therapy should continue for at least 7 days.
-Once the patient has clinically improved and can tolerate oral medication, oral voriconazole may be used.

Candidemia in nonneutropenic patients and other deep tissue Candida infections: 3 to 4 mg/kg IV every 12 hours

Comments:
-In clinical trials, candidemia was treated using 3 mg/kg IV every 12 hours as primary therapy, while other deep tissue Candida infections were treated using 4 mg/kg IV every 12 hours as salvage therapy; appropriate dose should be based on the nature and severity of the infection.

Oral:
Less than 40 kg: 100 mg orally every 12 hours
40 kg or more: 200 mg orally every 12 hours

Duration of Therapy:
-Invasive aspergillosis: In a clinical trial, the median duration of IV therapy was 10 days (range 2 to 85 days) and of oral therapy was 76 days (range 2 to 232 days).
-IDSA guidelines for invasive aspergillosis: At least 6 to 12 weeks; in immunosuppressed patients, throughout immunosuppression and until lesions resolve
-Candidemia in nonneutropenic patients and other deep tissue Candida infections: At least 14 days after symptoms resolve or after last positive culture, whichever is longer

Uses: Invasive aspergillosis; candidemia in nonneutropenic patients; disseminated Candida infections in skin; Candida infections in abdomen, kidney, bladder wall, wounds; serious fungal infections due to Fusarium species and S apiospermum in patients intolerant of (or refractory to) other therapy

Usual Pediatric Dose for Pseudoallescheriosis:

2 to 11 years:
American Academy of Pediatrics recommendations: 9 mg/kg IV or orally every 12 hours
Maximum dose: 350 mg/dose

IDSA guidelines for invasive aspergillosis: 5 to 7 mg/kg IV every 12 hours

12 years or older:
Loading Dose: 6 mg/kg IV every 12 hours for 2 doses

Maintenance Dose:
IV:
Invasive aspergillosis and serious fungal infections due to Fusarium species and S apiospermum: 4 mg/kg IV every 12 hours

Comments:
-Therapy should start with the IV loading dose on Day 1 followed by the maintenance dose.
-IV therapy should continue for at least 7 days.
-Once the patient has clinically improved and can tolerate oral medication, oral voriconazole may be used.

Candidemia in nonneutropenic patients and other deep tissue Candida infections: 3 to 4 mg/kg IV every 12 hours

Comments:
-In clinical trials, candidemia was treated using 3 mg/kg IV every 12 hours as primary therapy, while other deep tissue Candida infections were treated using 4 mg/kg IV every 12 hours as salvage therapy; appropriate dose should be based on the nature and severity of the infection.

Oral:
Less than 40 kg: 100 mg orally every 12 hours
40 kg or more: 200 mg orally every 12 hours

Duration of Therapy:
-Invasive aspergillosis: In a clinical trial, the median duration of IV therapy was 10 days (range 2 to 85 days) and of oral therapy was 76 days (range 2 to 232 days).
-IDSA guidelines for invasive aspergillosis: At least 6 to 12 weeks; in immunosuppressed patients, throughout immunosuppression and until lesions resolve
-Candidemia in nonneutropenic patients and other deep tissue Candida infections: At least 14 days after symptoms resolve or after last positive culture, whichever is longer

Uses: Invasive aspergillosis; candidemia in nonneutropenic patients; disseminated Candida infections in skin; Candida infections in abdomen, kidney, bladder wall, wounds; serious fungal infections due to Fusarium species and S apiospermum in patients intolerant of (or refractory to) other therapy

Usual Pediatric Dose for Systemic Fungal Infection:

2 to 11 years:
American Academy of Pediatrics recommendations: 9 mg/kg IV or orally every 12 hours
Maximum dose: 350 mg/dose

IDSA guidelines for invasive aspergillosis: 5 to 7 mg/kg IV every 12 hours

12 years or older:
Loading Dose: 6 mg/kg IV every 12 hours for 2 doses

Maintenance Dose:
IV:
Invasive aspergillosis and serious fungal infections due to Fusarium species and S apiospermum: 4 mg/kg IV every 12 hours

Comments:
-Therapy should start with the IV loading dose on Day 1 followed by the maintenance dose.
-IV therapy should continue for at least 7 days.
-Once the patient has clinically improved and can tolerate oral medication, oral voriconazole may be used.

Candidemia in nonneutropenic patients and other deep tissue Candida infections: 3 to 4 mg/kg IV every 12 hours

Comments:
-In clinical trials, candidemia was treated using 3 mg/kg IV every 12 hours as primary therapy, while other deep tissue Candida infections were treated using 4 mg/kg IV every 12 hours as salvage therapy; appropriate dose should be based on the nature and severity of the infection.

Oral:
Less than 40 kg: 100 mg orally every 12 hours
40 kg or more: 200 mg orally every 12 hours

Duration of Therapy:
-Invasive aspergillosis: In a clinical trial, the median duration of IV therapy was 10 days (range 2 to 85 days) and of oral therapy was 76 days (range 2 to 232 days).
-IDSA guidelines for invasive aspergillosis: At least 6 to 12 weeks; in immunosuppressed patients, throughout immunosuppression and until lesions resolve
-Candidemia in nonneutropenic patients and other deep tissue Candida infections: At least 14 days after symptoms resolve or after last positive culture, whichever is longer

Uses: Invasive aspergillosis; candidemia in nonneutropenic patients; disseminated Candida infections in skin; Candida infections in abdomen, kidney, bladder wall, wounds; serious fungal infections due to Fusarium species and S apiospermum in patients intolerant of (or refractory to) other therapy

Usual Pediatric Dose for Cutaneous Fungal Infection:

2 to 11 years:
American Academy of Pediatrics recommendations: 9 mg/kg IV or orally every 12 hours
Maximum dose: 350 mg/dose

IDSA guidelines for invasive aspergillosis: 5 to 7 mg/kg IV every 12 hours

12 years or older:
Loading Dose: 6 mg/kg IV every 12 hours for 2 doses

Maintenance Dose:
IV:
Invasive aspergillosis and serious fungal infections due to Fusarium species and S apiospermum: 4 mg/kg IV every 12 hours

Comments:
-Therapy should start with the IV loading dose on Day 1 followed by the maintenance dose.
-IV therapy should continue for at least 7 days.
-Once the patient has clinically improved and can tolerate oral medication, oral voriconazole may be used.

Candidemia in nonneutropenic patients and other deep tissue Candida infections: 3 to 4 mg/kg IV every 12 hours

Comments:
-In clinical trials, candidemia was treated using 3 mg/kg IV every 12 hours as primary therapy, while other deep tissue Candida infections were treated using 4 mg/kg IV every 12 hours as salvage therapy; appropriate dose should be based on the nature and severity of the infection.

Oral:
Less than 40 kg: 100 mg orally every 12 hours
40 kg or more: 200 mg orally every 12 hours

Duration of Therapy:
-Invasive aspergillosis: In a clinical trial, the median duration of IV therapy was 10 days (range 2 to 85 days) and of oral therapy was 76 days (range 2 to 232 days).
-IDSA guidelines for invasive aspergillosis: At least 6 to 12 weeks; in immunosuppressed patients, throughout immunosuppression and until lesions resolve
-Candidemia in nonneutropenic patients and other deep tissue Candida infections: At least 14 days after symptoms resolve or after last positive culture, whichever is longer

Uses: Invasive aspergillosis; candidemia in nonneutropenic patients; disseminated Candida infections in skin; Candida infections in abdomen, kidney, bladder wall, wounds; serious fungal infections due to Fusarium species and S apiospermum in patients intolerant of (or refractory to) other therapy

Usual Pediatric Dose for Fungal Infection -- Disseminated:

2 to 11 years:
American Academy of Pediatrics recommendations: 9 mg/kg IV or orally every 12 hours
Maximum dose: 350 mg/dose

IDSA guidelines for invasive aspergillosis: 5 to 7 mg/kg IV every 12 hours

12 years or older:
Loading Dose: 6 mg/kg IV every 12 hours for 2 doses

Maintenance Dose:
IV:
Invasive aspergillosis and serious fungal infections due to Fusarium species and S apiospermum: 4 mg/kg IV every 12 hours

Comments:
-Therapy should start with the IV loading dose on Day 1 followed by the maintenance dose.
-IV therapy should continue for at least 7 days.
-Once the patient has clinically improved and can tolerate oral medication, oral voriconazole may be used.

Candidemia in nonneutropenic patients and other deep tissue Candida infections: 3 to 4 mg/kg IV every 12 hours

Comments:
-In clinical trials, candidemia was treated using 3 mg/kg IV every 12 hours as primary therapy, while other deep tissue Candida infections were treated using 4 mg/kg IV every 12 hours as salvage therapy; appropriate dose should be based on the nature and severity of the infection.

Oral:
Less than 40 kg: 100 mg orally every 12 hours
40 kg or more: 200 mg orally every 12 hours

Duration of Therapy:
-Invasive aspergillosis: In a clinical trial, the median duration of IV therapy was 10 days (range 2 to 85 days) and of oral therapy was 76 days (range 2 to 232 days).
-IDSA guidelines for invasive aspergillosis: At least 6 to 12 weeks; in immunosuppressed patients, throughout immunosuppression and until lesions resolve
-Candidemia in nonneutropenic patients and other deep tissue Candida infections: At least 14 days after symptoms resolve or after last positive culture, whichever is longer

Uses: Invasive aspergillosis; candidemia in nonneutropenic patients; disseminated Candida infections in skin; Candida infections in abdomen, kidney, bladder wall, wounds; serious fungal infections due to Fusarium species and S apiospermum in patients intolerant of (or refractory to) other therapy

Usual Pediatric Dose for Fungal Meningitis:

2 to 11 years:
American Academy of Pediatrics recommendations: 9 mg/kg IV or orally every 12 hours
Maximum dose: 350 mg/dose

IDSA guidelines for invasive aspergillosis: 5 to 7 mg/kg IV every 12 hours

12 years or older:
Loading Dose: 6 mg/kg IV every 12 hours for 2 doses

Maintenance Dose:
IV:
Invasive aspergillosis and serious fungal infections due to Fusarium species and S apiospermum: 4 mg/kg IV every 12 hours

Comments:
-Therapy should start with the IV loading dose on Day 1 followed by the maintenance dose.
-IV therapy should continue for at least 7 days.
-Once the patient has clinically improved and can tolerate oral medication, oral voriconazole may be used.

Candidemia in nonneutropenic patients and other deep tissue Candida infections: 3 to 4 mg/kg IV every 12 hours

Comments:
-In clinical trials, candidemia was treated using 3 mg/kg IV every 12 hours as primary therapy, while other deep tissue Candida infections were treated using 4 mg/kg IV every 12 hours as salvage therapy; appropriate dose should be based on the nature and severity of the infection.

Oral:
Less than 40 kg: 100 mg orally every 12 hours
40 kg or more: 200 mg orally every 12 hours

Duration of Therapy:
-Invasive aspergillosis: In a clinical trial, the median duration of IV therapy was 10 days (range 2 to 85 days) and of oral therapy was 76 days (range 2 to 232 days).
-IDSA guidelines for invasive aspergillosis: At least 6 to 12 weeks; in immunosuppressed patients, throughout immunosuppression and until lesions resolve
-Candidemia in nonneutropenic patients and other deep tissue Candida infections: At least 14 days after symptoms resolve or after last positive culture, whichever is longer

Uses: Invasive aspergillosis; candidemia in nonneutropenic patients; disseminated Candida infections in skin; Candida infections in abdomen, kidney, bladder wall, wounds; serious fungal infections due to Fusarium species and S apiospermum in patients intolerant of (or refractory to) other therapy

Usual Pediatric Dose for Fusariosis:

2 to 11 years:
American Academy of Pediatrics recommendations: 9 mg/kg IV or orally every 12 hours
Maximum dose: 350 mg/dose

IDSA guidelines for invasive aspergillosis: 5 to 7 mg/kg IV every 12 hours

12 years or older:
Loading Dose: 6 mg/kg IV every 12 hours for 2 doses

Maintenance Dose:
IV:
Invasive aspergillosis and serious fungal infections due to Fusarium species and S apiospermum: 4 mg/kg IV every 12 hours

Comments:
-Therapy should start with the IV loading dose on Day 1 followed by the maintenance dose.
-IV therapy should continue for at least 7 days.
-Once the patient has clinically improved and can tolerate oral medication, oral voriconazole may be used.

Candidemia in nonneutropenic patients and other deep tissue Candida infections: 3 to 4 mg/kg IV every 12 hours

Comments:
-In clinical trials, candidemia was treated using 3 mg/kg IV every 12 hours as primary therapy, while other deep tissue Candida infections were treated using 4 mg/kg IV every 12 hours as salvage therapy; appropriate dose should be based on the nature and severity of the infection.

Oral:
Less than 40 kg: 100 mg orally every 12 hours
40 kg or more: 200 mg orally every 12 hours

Duration of Therapy:
-Invasive aspergillosis: In a clinical trial, the median duration of IV therapy was 10 days (range 2 to 85 days) and of oral therapy was 76 days (range 2 to 232 days).
-IDSA guidelines for invasive aspergillosis: At least 6 to 12 weeks; in immunosuppressed patients, throughout immunosuppression and until lesions resolve
-Candidemia in nonneutropenic patients and other deep tissue Candida infections: At least 14 days after symptoms resolve or after last positive culture, whichever is longer

Uses: Invasive aspergillosis; candidemia in nonneutropenic patients; disseminated Candida infections in skin; Candida infections in abdomen, kidney, bladder wall, wounds; serious fungal infections due to Fusarium species and S apiospermum in patients intolerant of (or refractory to) other therapy

Usual Pediatric Dose for Esophageal Candidiasis:

12 years or older:
Less than 40 kg: 100 mg orally every 12 hours
40 kg or more: 200 mg orally every 12 hours

Duration of therapy: At least 14 days and at least 7 days after symptoms resolve

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 HIV-infected adults and adolescents with invasive aspergillosis, CDC, NIH, and IDSA recommend voriconazole as the drug of choice;440 IV amphotericin B, IV echinocandins (caspofungin, micafungin, anidulafungin), and oral posaconazole are alternatives.440 Voriconazole also considered 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 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 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

Has been used prophylactically to reduce the incidence of candidiasis in patients at risk, including hematopoietic stem cell transplant recipients†.422 436

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 HIV-infected adults and adolescents with oropharyngeal candidiasis, CDC, NIH, and IDSA recommend oral fluconazole as drug of choice for treatment of initial episodes;440 if topical therapy used for treatment of mild to moderate episodes, drugs of choice are miconazole buccal tablets or clotrimazole lozenges.440 Alternatives for systemic treatment are itraconazole oral solution or oral posaconazole;440 alternative for topical treatment is nystatin oral suspension.440 For fluconazole-refractory oropharyngeal infections in HIV-infected adults and adolescents, oral posaconazole is preferred;440 itraconazole oral solution is an alternative.440

Although routine long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent relapse or recurrence 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 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 HIV-infected adults and adolescents with esophageal candidiasis, CDC, NIH, and IDSA recommend oral or IV fluconazole as drug of choice for treatment and itraconazole oral solution as the 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 and 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 long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent relapse or recurrence 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

Coccidioidomycosis

Has been used for treatment of coccidioidomycosis† caused by Coccidioides immitis or C. posadasii.426 440

Antifungal treatment may not be necessary for mild, uncomplicated coccidioidal pneumonia since such infections may resolve spontaneously;426 treatment recommended for patients with more severe or rapidly progressing infections, those with chronic pulmonary or disseminated infections, and immunocompromised or debilitated individuals (e.g., HIV-infected individuals, organ transplant recipients, those receiving immunosuppressive therapy, those with diabetes or cardiopulmonary disease).426 440

For HIV-infected adults and adolescents with clinically mild coccidioidomycosis (e.g., focal pneumonia), CDC, NIH, and IDSA recommend oral fluconazole or oral itraconazole for initial treatment;440 although data are limited, oral voriconazole or oral posaconazole are alternatives if there is no response to fluconazole or itraconazole.440

Long-term suppressive or maintenance therapy (secondary prophylaxis) with oral fluconazole or oral itraconazole recommended to prevent relapse or recurrence of coccidioidomycosis in HIV-infected individuals who have been adequately treated for the disease;440 voriconazole or posaconazole are alternatives if patient did not initially respond to fluconazole or itraconazole.440

Exserohilum Infections

Treatment of infections known or suspected to be caused by Exserohilum rostratum†.476 477 484 485 487 489 490 491 492

Exserohilum, a common mold found in soil and on plants (especially grasses),477 478 481 482 is rarely involved in human infections.478 480 481 482 487 E. rostratum has caused cutaneous and subcutaneous infections or keratitis, typically from skin or eye trauma;478 480 481 482 487 also has rarely caused more invasive or life-threatening infections (e.g., sinuses, heart, lungs, bones), usually in immunocompromised individuals.478 480 481 482 487 Exserohilum infections cannot be transmitted person-to-person.478

Although data limited and clinical relevance of in vitro testing remains uncertain,477 480 Exserohilum is inhibited in vitro by some triazole antifungals (e.g., voriconazole, itraconazole, posaconazole) and amphotericin B;477 480 481 482 489 echinocandins (e.g., caspofungin, micafungin) have variable in vitro activity480 481 482 and fluconazole has poor in vitro activity against the fungus.481

E. rostratum was the predominant pathogen in the 2012–2013 US outbreak of fungal meningitis and other fungal infections in patients who received contaminated preservative-free methylprednisolone acetate injections prepared by a compounding pharmacy (New England Compounding Center [NECC]).477 478 488 490 491

As of September 6, 2013, total of 750 cases of fungal infections (including 64 deaths) reported in 20 states and linked to 3 lots of contaminated methylprednisolone acetate injections.477 Majority of initial cases involved fungal meningitis (some with stroke);477 483 486 488 490 491 492 subsequent reports involved localized spinal or paraspinal infections (e.g., epidural abscess).477 483 486 491 More than 6 months after the outbreak, CDC continued to receive reports of patients presenting with localized spinal and paraspinal infections (e.g., epidural abscess, phlegmon, discitis, vertebral osteomyelitis, arachnoiditis, or other complications at or near the injection site).477 483 486 Localized infections have occurred in patients with or without a diagnosis of fungal meningitis.477 483

Consultation with an infectious disease expert recommended to assist with diagnosis, management, and follow-up, which may be complex and prolonged.484 485 Clinical consultant network for clinicians can be reached by calling CDC at 800-232-4636.484 485

Because of evidence of latent disease, CDC cautions clinicians to maintain high index of suspicion and remain vigilant for fungal infections in patients who received the contaminated products (especially in those who have mild or baseline symptoms) and to consider MRI evaluation for localized infections if clinically warranted.483 486

Consult most recent CDC treatment guidance documents () for the most current recommendations for selection of antifungal agents and appropriate dosages and duration of treatment for CNS and parameningeal infections and osteoarticular infections associated with the contaminated methylprednisolone acetate products.477 The following information was current when the voriconazole monograph was finalized for publication.477

For treatment of CNS infections (including meningitis, stroke, and arachnoiditis) and/or parameningeal infections (epidural or paraspinal abscess, discitis or osteomyelitis, and sacroiliac infection) in adults who received contaminated methylprednisolone acetate injections, CDC recommends voriconazole.484 In most of these patients, use IV voriconazole initially; consider transitioning to oral voriconazole only after patient is clinically stable or improving and consider initial treatment with oral voriconazole only in those with mild disease who can be monitored closely.484 Strongly consider use of IV amphotericin B liposomal in addition to IV voriconazole in patients who present with severe disease and in those who do not improve or experience clinical deterioration or manifest new sites of disease activity while receiving voriconazole monotherapy.484 IV amphotericin B liposomal also is an alternative in patients unable to tolerate voriconazole.484 Although posaconazole or itraconazole has been used in some patients who could not tolerate voriconazole or amphotericin B, efficacy for treatment of these fungal infections not established; expert consultation advised when making decisions regarding alternative regimens.484

For treatment of osteoarticular infections (discitis, vertebral osteomyelitis, and epidural abscess or osteoarticular infections not involving the spine) in adults who received intra-articular injections of contaminated methylprednisolone acetate injections, CDC recommends voriconazole.485 Use IV voriconazole initially in those with more severe osteoarticular infections, clinical instability, discitis, vertebral osteomyelitis, or epidural abscess; consider transitioning to oral voriconazole only after patient is clinically stable or improving and consider initial treatment with oral voriconazole only in patients with mild osteoarticular infections not involving the spine who can be monitored closely.485 Consider use of a lipid formulation of IV amphotericin B in addition to IV voriconazole in patients with severe osteoarticular infection and/or clinical instability.485 A lipid formulation of IV amphotericin B, posaconazole, or itraconazole are alternatives in patients who cannot tolerate voriconazole; expert consultation advised when making decisions regarding alternative regimens.485

Adequate duration of antifungal treatment for these Exserohilum infections not known, but prolonged therapy (at least 3–6 months) required.484 485 (See Exserohilum Infections under Dosage and Administration.) Close follow-up monitoring after completion of treatment is essential in all patients to detect potential relapse.484 485

Consult CDC website at and FDA website at for most recent information.477 CDC website includes information regarding case definitions and diagnostic testing as well as management and treatment of these infections.477

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

Select most appropriate antifungal based on in vitro susceptibility testing.57 Amphotericin B may be preferred for infections caused by F. solani or F. verticillioides;57 either voriconazole or amphotericin B recommended for other Fusarium infections.57

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

Histoplasmosis

Has been used for treatment of histoplasmosis† caused by Histoplasma capsulatum.428 440

For HIV-infected adults and adolescents with less severe disseminated histoplasmosis, CDC, NIH, and IDSA recommend initial treatment with oral itraconazole;440 although clinical data are limited, voriconazole or posaconazole may be used as alternatives for treatment of less severe histoplasmosis† in those intolerant of itraconazole who are only moderately ill.440

Long-term suppressive or maintenance therapy (secondary prophylaxis) with itraconazole recommended to prevent recurrence or relapse in HIV-infected individuals who have been adequately treated for histoplasmosis.440 Role of voriconazole for secondary prophylaxis not evaluated to date.440

Penicilliosis

Has been used for treatment of penicilliosis† caused by Penicillium marneffei.440

For HIV-infected adults and adolescents with severe acute penicilliosis, CDC, NIH, and IDSA recommend treatment with IV amphotericin B liposomal initially followed by oral itraconazole.440 Voriconazole is an alternative, and may be used in those who do not respond to amphotericin B followed by itraconazole.440

For HIV-infected adults and adolescents with mild penicilliosis†, CDC, NIH, and IDSA recommend itraconazole as drug of choice for treatment and voriconazole as an alternative.440

Long-term suppressive or maintenance therapy (secondary prophylaxis) with itraconazole recommended to prevent recurrence or relapse in HIV-infected individuals who were treated for penicilliosis.440 An optimal voriconazole regimen for secondary prophylaxis of penicilliosis not identified to date.440

Empiric Therapy in Febrile Neutropenic Patients

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

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 (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 40 200 (See Specific Drugs under Interactions.)

Warnings/Precautions

Sensitivity 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

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

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, including 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

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

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 patients who have risk factors for acute pancreatitis (e.g., recent chemotherapy, hematopoietic stem cell transplantation [HSCT]) for the development of pancreatitis.1

Dermatologic Effects

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

Photosensitivity skin reactions reported.1 Avoid intense or prolonged exposure to direct sunlight during voriconazole therapy.1

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

Skeletal Effects

Fluorosis and periostitis reported during long-term therapy.1 If skeletal pain and radiologic findings compatible with fluorosis or periostitis occur, discontinue voriconazole.1

Specific Populations

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

Do not use during pregnancy except when benefits for the mother clearly outweigh potential risks for the fetus.1

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

Not known whether distributed into milk.1 Discontinue nursing or the drug.1

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 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

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

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

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

IV voriconazole should not be used in patients with Clcr <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, chills, headache, abnormalities in liver function test results, tachycardia, hallucinations.1

Absorption

Bioavailability

Oral bioavailability estimated to be 96%.1 34 35 Following oral administration, peak plasma concentrations achieved within 1–2 hours.1 24 34

In adults, the 200-mg tablet and 40-mg/mL oral suspension are bioequivalent when administered with a loading dose regimen (400 mg every 12 hours) followed by maintenance dosage (200 mg every 12 hours).1

Food

When multiple doses are administered with a high-fat meal, mean peak plasma concentrations and extent of absorption are reduced by 34 and 24%, respectively.1

Plasma Concentrations

Nonlinear pharmacokinetics because of saturation of its metabolism.1 24 34 423

When recommended IV or oral loading dose regimens are administered in adults, peak plasma concentrations close to steady state are achieved within the first 24 hours of dosing.1 34 Without the loading dose regimen, steady-state concentrations are achieved within 5–7 days in adults.34

Special Populations

Peak plasma concentrations and AUCs after oral or IV administration are higher in geriatric patients ≥65 years of age compared with younger adults.1

In a population pharmacokinetic analysis of voriconazole concentrations in children 2 to <12 years of age who received various dosage regimens, AUCs achieved with IV dosage of 7 mg/kg twice daily or oral dosage of 200 mg twice daily (oral suspension) were comparable to AUCs observed in adults receiving usual voriconazole dosages.58 Data from this study also indicated that loading doses do not appear to reduce the length of time required to reach steady-state in children 2 to <12 years of age and appear to offer little benefit in this age group.58 Based on a comparison of pharmacokinetic data from pediatric patients (2 to <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 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.1

Distribution

Extent

Probably extensively distributed into tissues.1

Not known whether distributed into milk.1

Plasma Protein Binding

Approximately 58%.1

Elimination

Metabolism

In vitro studies indicate voriconazole is metabolized by CYP2C9, 2C19, and 3A4.1 3 4 34 423 The major metabolite is the N-oxide, which has minimal antifungal activity.1

Elimination Route

After initial load dosage regimen, 80–83% of an oral or IV dose is eliminated in urine; <2% of a dose excreted unchanged in urine.1

Small amounts of voriconazole removed by hemodialysis.1

Half-life

As a result of non-linear pharmacokinetics, terminal half-life is dose dependent and therefore not useful in predicting accumulation or elimination of the drug.1

Special Populations

In patients with mild or moderate hepatic impairment (Child-Pugh class A or B), AUC is increased but peak plasma concentrations not affected.1 Pharmacokinetic data not available for patients with severe hepatic impairment (Child-Pugh class C).1

Peak plasma concentrations and AUC following oral or IV administration not substantially affected by renal impairment.1 However, in patients with moderate renal impairment (Clcr 30–50 mL/minute) receiving IV voriconazole, accumulation of the IV vehicle, sulfobutyl ether beta-cyclodextrin sodium (SBECD) can occur.1

There is some evidence that voriconazole systemic metabolism and first-pass metabolism are greater in children than in adults.58

It is very important that your doctor check the progress of you or your child at regular visits to make sure that voriconazole is working properly. Blood and urine tests will be needed to check for unwanted effects.

If your or your child's symptoms do not improve, or if they become worse, check with your doctor. You may need to take voriconazole for several months before your infection gets better.

Using voriconazole while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away.

You or your child should not use astemizole (Hismanal®), barbiturates (eg, phenobarbital, Luminal®), carbamazepine (Tegretol®), cisapride (Propulsid®), efavirenz (Sustiva®), ergot medicines (eg, dihydroergotamine, ergotamine, Cafergot®, Ergomar®, Wigraine®), pimozide (Orap®), quinidine (Quinaglute®), rifabutin (Mycobutin®), rifampin (Rifadin®, Rimactane®), ritonavir (Norvir®), sirolimus (Rapamune®), St. John's wort, or terfenadine (Seldane®). Using any of them together with voriconazole may increase the chance of unwanted effects.

voriconazole may cause vision problems. Avoid driving (especially at night), using machines, or doing anything else that could be dangerous if you cannot see well. Call your doctor if you or your child have any vision changes or if bright lights bother your eyes.

Check with your doctor right away if you or your child have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, unusual tiredness or weakness, or yellow eyes or skin. These could be symptoms of a serious liver problem.

Voriconazole tablets contain lactose (milk sugar) while the oral liquid contains sucrose (table sugar), which can make patients with conditions that makes it hard for them to digest sugars or dairy products worse. Talk to your doctor if you or your child have concerns about this.

Contact your doctor right away if you or your child have any changes to your heart rhythm. You might feel dizzy or faint, or you might have a fast, pounding, or uneven heartbeat. Make sure your doctor knows if you or anyone in your family has ever had a heart rhythm problem, such as QT prolongation.

Voriconazole may increase your or your child's risk of having kidney problems, including acute kidney failure. Check with your doctor right away if you have blood in the urine, decreased urine output, muscle twitching, nausea, rapid weight gain, seizures, decreased awareness or responsiveness, severe sleepiness, swelling of the face, ankles, or hands, or unusual tiredness or weakness.

Pancreatitis may occur while you or your child are using voriconazole. Check with your doctor right away if you or your child have sudden and severe stomach pain, chills, constipation, nausea, vomiting, fever, or lightheadedness.

voriconazole may make your or your child's skin more sensitive to sunlight. Use sunscreen when you are outdoors. Avoid sunlamps and tanning beds.

Serious skin reactions can occur during treatment with voriconazole. Check with your doctor right away if you or your child have blistering, peeling, or loosening of the skin, red skin lesions, severe acne or skin rash, sores or ulcers on the skin, or fever or chills while you are using voriconazole.

voriconazole may cause bone pain when used for a long period of time. Check with your doctor right away if you or your child have bone pain while using voriconazole.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Pregnancy

Risk Summary

Voriconazole can cause fetal harm when administered to a pregnant woman. There are no available data on the use of Voriconazole in pregnant women. In animal reproduction studies, oral Voriconazole was teratogenic in rats and embryotoxic in rabbits. Cleft palates and hydronephrosis/hydroureter were observed in rat pups exposed to Voriconazole during organogenesis at and above 10 mg/kg (0.3 times the recommended maintenance dose of 200 mg every 12 hours based on body surface area comparisons). In rabbits, embryomortality, reduced fetal weight and increased incidence of skeletal variations, cervical ribs and extrasternal ossification sites were observed in pups when pregnant rabbits were orally dosed at 100 mg/kg (6 times the RMD based on body surface area comparisons) during organogenesis. Rats exposed to Voriconazole from implantation to weaning experienced increased gestational length and dystocia, which were associated with increased perinatal pup mortality at the 10 mg/kg dose. [see Data]. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to the fetus [see Warnings and Precautions (5.4)].

The background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20% respectively.

Data

Animal Data

Voriconazole was administered orally to pregnant rats during organogenesis (gestation days 6 to 17) at 10, 30, and 60 mg/kg/day. Voriconazole was teratogenic with increased incidences in hydroureter and hydronephrosis at 10 mg/kg/day or greater, approximately 0.3 times the recommended human dose (RMD) based on mg/m2, and cleft palate at 60 mg/kg, approximately 2 times the recommended human dose (RMD) based on mg/m2. Reduced ossification of sacral and caudal vertebrae, skull, pubic, and hyoid bone, supernumerary ribs, anomalies of the sternbrae, and dilatation of the ureter/renal pelvis were also observed at doses of 10 mg/kg or greater. There was no evidence of maternal toxicity at any dose.

Voriconazole was administered orally to pregnant rabbits during the period of organogenesis (gestation days 7 to 19) at 10, 40, and 100 mg/kg/day. Voriconazole produced embryofetal toxicity (increased post-implantation loss, decreased fetal body weight) in association with maternal toxicity (decreased body weight gain and food consumption) at 100 mg/kg/day (6 times the RMD based on mg/m2). Fetal skeletal variations (increases in the incidence of cervical rib and extra sternebral ossification sites) were observed at 100 mg/kg/day.

In a peri- and postnatal toxicity study in rats, Voriconazole was administered orally to female rats from implantation through the end of lactation at 1, 3, and 10 mg/kg/day. Voriconazole prolonged the duration of gestation and labor and produced dystocia with related increases in maternal mortality and decreases in perinatal survival of F1 pups at 10 mg/kg/day, approximately 0.3 times the RMD.

Lactation

Risk Summary

No data are available regarding the presence of Voriconazole in human milk, the effects of Voriconazole on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Voriconazole and any potential adverse effects on the breastfed child from Voriconazole or from the underlying maternal condition.

Females and Males of Reproductive Potential

Contraception

Advise females of reproductive potential to use effective contraception during treatment with Voriconazole. The coadministration of Voriconazole with the oral contraceptive, Ortho-Novum®(35 mcg ethinyl estradiol and 1 mg norethindrone), results in an interaction between these two drugs, but is unlikely to reduce the contraceptive effect. Monitoring for adverse reactions associated with oral contraceptives and Voriconazole is recommended [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 12 years have not been established.

A total of 22 patients aged 12 to 18 years with invasive aspergillosis were included in the therapeutic studies. Twelve out of 22 (55%) patients had successful response after treatment with a maintenance dose of Voriconazole 4 mg/kg q12h.

Sparse plasma sampling for pharmacokinetics in adolescents was conducted in the therapeutic studies [see Clinical Pharmacology (12.3)]. A population pharmacokinetic analysis was conducted on pooled data from 35 immunocompromised pediatric patients aged 2 to <12 years old who were included in two pharmacokinetic studies of intravenous Voriconazole (single dose and multiple dose). Twenty-four of these patients received multiple intravenous maintenance doses of 3 mg/kg and 4 mg/kg. A comparison of the pediatric and adult population pharmacokinetic data revealed that the predicted average steady state plasma concentrations were similar at the maintenance dose of 4 mg/kg every 12 hours in children and 3 mg/kg every 12 hours in adults (medians of 1.19 mcg/mL and 1.16 mcg/mL in children and adults, respectively).

There have been postmarketing reports of pancreatitis in pediatric patients.

Geriatric Use

In multiple dose therapeutic trials of Voriconazole, 9.2% of patients were ≥ 65 years of age and 1.8% of patients were ≥ 75 years of age. In a study in healthy subjects, the systemic exposure (AUC) and peak plasma concentrations (Cmax) were increased in elderly males compared to young males. Pharmacokinetic data obtained from 552 patients from 10 Voriconazole therapeutic trials showed that Voriconazole plasma concentrations in the elderly patients were approximately 80% to 90% higher than those in younger patients after either IV or oral administration. However, the overall safety profile of the elderly patients was similar to that of the young so no dosage adjustment is recommended [see Clinical Pharmacology (12.3)].

• UK109496

Accumulation of the IV vehicle sulfobutyl ether beta-cyclodextrin sodium (SBECD) occurs in patients with renal impairment (CrCl <50 mL/minute).

Treatment of fungal infections: Treatment of invasive aspergillosis; treatment of esophageal candidiasis; treatment of candidemia (in non-neutropenic patients); treatment of disseminated Candida infections of the skin and abdomen, kidney, bladder wall, and wounds; treatment of serious fungal infections caused by Scedosporium apiospermum and Fusarium spp. (including Fusarium solani) in patients intolerant of, or refractory to, other therapy

Mild to moderate impairment (Child-Pugh class A or B): Following standard loading dose, reduce maintenance dosage by 50%

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). Should only be used if benefit outweighs risk; monitor closely for toxicity

Voriconazole can cause fetal harm when administered to a pregnant woman. Voriconazole was teratogenic and embryotoxic in animal studies, and lowered plasma estradiol in animal models. Women of childbearing potential should use effective contraception during treatment. Should be used in pregnant woman only if benefit to mother justifies potential risk to the fetus.