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mechanism of action is Cytochrome P450 3A4 Inhibitors [MoA], Cytochrome P450 2C19 Inhibitors [MoA] or Cytochrome P450 2C9 Inhibitors [MoA]

Vfend

(Voriconazole)

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Vfend Prescribing Information

If the patient's response is inadequate, the oral maintenance dose for VFEND tablets or oral suspension may be increased from 200 mg (or 5 mL) every 12 hours to 300 mg (or 7.5 mL) every 12 hours.

For adult patients weighing less than 40 kg, the oral maintenance dose for VFEND tablets or oral suspension may be increased from 100 mg (or 2.5 mL) every 12 hours to 150 mg (or 3.75 mL) every 12 hours.

If the patient is unable to tolerate 300 mg (or 7.5 mL) orally every 12 hours, reduce the oral maintenance dose of VFEND tablets or oral suspension by 50 mg (or 1.25 mL) steps to a minimum of 200 mg (or 5 mL) every 12 hours for adult patients weighing more than 40 kg or to 100 mg (or 2.5 mL) every 12 hours for adult patients weighing less than 40 kg.

If the patient is unable to tolerate 4 mg/kg intravenously every 12 hours, reduce the intravenous maintenance dose to 3 mg/kg every 12 hours.

2.4 Recommended Dosing Regimen in Pediatric Patients

The recommended dosing regimen for pediatric patients 2 to less than 12 years of age and 12 to 14 years of age with body weight less than 50 kg is shown in Table 2. For pediatric patients 12 to 14 years of age with a body weight greater than or equal to 50 kg and those 15 years of age and above regardless of body weight, administer the adult dosing regimen of VFEND

[see Dosage and Administration (2.3)]

Dosage and Administration (

2.3 Recommended Dosing Regimen in Adults

Invasive aspergillosis and serious fungal infections due to

Fusarium

spp. and

Scedosporium apiospermum

See Table 1. Therapy must be initiated with the specified loading dose regimen of intravenous VFEND on Day 1 followed by the recommended maintenance dose (RMD) regimen. Intravenous treatment should be continued for at least 7 days. Once the patient has clinically improved and can tolerate medication given by mouth, the oral tablet form or oral suspension form of VFEND may be utilized. The recommended oral maintenance dose of 200 mg achieves a voriconazole exposure similar to 3 mg/kg intravenously; a 300 mg oral dose achieves an exposure similar to 4 mg/kg intravenously

[see Clinical Pharmacology (12.3)]

Candidemia in non-neutropenic patients and other deep tissue

Candida

infections

See Table 1. Patients should be treated for at least 14 days following resolution of symptoms or following last positive culture, whichever is longer.

Esophageal Candidiasis

See Table 1. Patients should be treated for a minimum of 14 days and for at least 7 days following resolution of symptoms.

Table 1: Recommended Dosing Regimen (Adults)
Infection	Loading Dose	Maintenance Dose Increase dose when VFEND is co-administered with phenytoin or efavirenz (7); Decrease dose in patients with hepatic impairment (2.5) ^, In healthy volunteer studies, the 200 mg oral every 12 hours dose provided an exposure (AUC_τ) similar to a 3 mg/kg intravenous infusion every 12 hours dose; the 300 mg oral every 12 hours dose provided an exposure (AUC_τ) similar to a 4 mg/kg intravenous infusion every 12 hours dose (12).
	Intravenous infusion	Intravenous infusion	Oral tablets Adult patients who weigh less than 40 kg should receive half of the oral maintenance dose.	Oral suspension
Invasive Aspergillosis In a clinical study of IA, the median duration of intravenous VFEND therapy was 10 days (range 2 to 85 days). The median duration of oral VFEND therapy was 76 days (range 2 to 232 days) (14.1 ) .	6 mg/kg every 12 hours for the first 24 hours	4 mg/kg every 12 hours	200 mg every 12 hours	5 mL every 12 hours
Candidemia in nonneutropenic patients and other deep tissue Candida infections	6 mg/kg every 12 hours for the first 24 hours	3–4 mg/kg every 12 hoursIn clinical trials, patients with candidemia received 3 mg/kg intravenous infusion every 12 hours as primary therapy, while patients with other deep tissue Candida infections received 4 mg/kg every 12 hours as salvage therapy. Appropriate dose should be based on the severity and nature of the infection.	200 mg every 12 hours	5 mL every 12 hours
Esophageal Candidiasis	Not EvaluatedNot evaluated in patients with EC.	Not Evaluated	200 mg every 12 hours	5 mL every 12 hours
Scedosporiosis and Fusariosis	6 mg/kg every 12 hours for the first 24 hours	4 mg/kg every 12 hours	200 mg every 12 hours	5 mL every 12 hours

Method for Adjusting the Dosing Regimen in Adults

Table 2: Recommended Dosing Regimen for Pediatric Patients 2 to less than 12 years of age and 12 to 14 years of age with body weight less than 50 kgBased on a population pharmacokinetic analysis in 112 immunocompromised pediatric patients aged 2 to less than 12 years of age and 26 immunocompromised pediatric patients aged 12 to less than 17 years of age.
	Loading Dose	Maintenance Dose
	Intravenous infusion	Intravenous infusion	Oral tablets	Oral suspension
Invasive Aspergillosis In the Phase 3 clinical trials, patients with IA received intravenous (IV) treatment for at least 6 weeks and up to a maximum of 12 weeks. Patients received IV treatment for at least the first 7 days of therapy and then could be switched to oral VFEND therapy.
Candidemia in nonneutropenics and other deep tissue Candida infections Study treatment for primary or salvage invasive candidiasis and candidemia (ICC) or EC consisted of intravenous VFEND, with an option to switch to oral therapy after at least 5 days of IV therapy, based on subjects meeting switch criteria. For subjects with primary or salvage ICC, VFEND was administered for at least 14 days after the last positive culture. A maximum of 42 days of treatment was permitted. Patients with primary or salvage EC were treated for at least 7 days after the resolution of clinical signs and symptoms. A maximum of 42 days of treatment was permitted.	9 mg/kg every 12 hours for the first 24 hours	8 mg/kg every 12 hours after the first 24 hours	9 mg/kg every 12 hours (maximum dose of 350 mg every 12 hours)	0.225 mL/kg every 12 hours [maximum dose of 8.75 mL (350 mg) every 12 hours]
Scedosporiosis and Fusariosis
Esophageal Candidiasis	Not Evaluated	4 mg/kg every 12 hours	9 mg/kg every 12 hours (maximum dose of 350 mg every 12 hours)	0.225 mL/kg every 12 hours [maximum dose of 8.75 mL (350 mg) every 12 hours]

Initiate therapy with an intravenous infusion regimen. Consider an oral regimen only after there is a significant clinical improvement. Note that an 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose.

Oral bioavailability may be limited in pediatric patients 2 to 12 years with malabsorption and very low body weight for age. In that case, intravenous VFEND administration is recommended.

Method for Adjusting the Dosing Regimen in Pediatric Patients

Pediatric Patients 2 to less than 12 years of age and 12 to 14 years of age with body weight less than 50 kg

If patient response is inadequate and the patient is able to tolerate the initial intravenous maintenance dose, the maintenance dose may be increased by 1 mg/kg steps. If patient response is inadequate and the patient is able to tolerate the oral maintenance dose, the dose may be increased by 1 mg/kg (0.025 mL/kg) steps or 50 mg (1.25 mL) steps to a maximum of 350 mg (8.75 mL) every 12 hours. If patients are unable to tolerate the initial intravenous maintenance dose, reduce the dose by 1 mg/kg (0.025 mL/kg) steps. If patients are unable to tolerate the oral maintenance dose, reduce the dose by 1 mg/kg or 50 mg (1.25 mL) steps.

Pediatric patients 12 to 14 years of age weighing greater than or equal to 50 kg and 15 years of age and older regardless of body weight:

Use the optimal method for titrating dosage recommended for adults

[see Dosage and Administration (2.3)]

)

8/2024

Contraindications (

4 CONTRAINDICATIONS

•VFEND is contraindicated in patients with known hypersensitivity to voriconazole or its excipients. There is no information regarding cross-sensitivity between VFEND (voriconazole) and other azole antifungal agents. Caution should be used when prescribing VFEND to patients with hypersensitivity to other azoles.
•Coadministration of pimozide, quinidine or ivabradine with VFEND is contraindicated because increased plasma concentrations of these drugs can lead to QT prolongation and rare occurrences of
torsade de pointes [see Drug Interactions (7)]
.
•Coadministration of VFEND with sirolimus is contraindicated because VFEND significantly increases sirolimus concentrations
[see Drug Interactions (7)and Clinical Pharmacology (12.3)]
.
•Coadministration of VFEND with rifampin, carbamazepine, long-acting barbiturates or St. John's Wort is contraindicated because these drugs are likely to decrease plasma voriconazole concentrations significantly
[see Drug Interactions (7)and Clinical Pharmacology (12.3)]
.
•Coadministration of standard doses of voriconazole with efavirenz doses of 400 mg every 24 hours or higher is contraindicated, because efavirenz significantly decreases plasma voriconazole concentrations in healthy subjects at these doses. Voriconazole also significantly increases efavirenz plasma concentrations
[see Drug Interactions (7)and Clinical Pharmacology (12.3)]
.
•Coadministration of VFEND with high-dose ritonavir (400 mg every 12 hours) is contraindicated because ritonavir (400 mg every 12 hours) significantly decreases plasma voriconazole concentrations. Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
[see Drug Interactions (7)and Clinical Pharmacology (12.3)]
.
•Coadministration of VFEND with rifabutin is contraindicated since VFEND significantly increases rifabutin plasma concentrations and rifabutin also significantly decreases voriconazole plasma concentrations
[see Drug Interactions (7)and Clinical Pharmacology (12.3)]
.
•Coadministration of VFEND with ergot alkaloids (ergotamine and dihydroergotamine) is contraindicated because VFEND may increase the plasma concentration of ergot alkaloids, which may lead to ergotism
[see Drug Interactions (7)]
.
•Coadministration of VFEND with naloxegol is contraindicated because VFEND may increase plasma concentrations of naloxegol which may precipitate opioid withdrawal symptoms
[see Drug Interactions (7)]
.
•Coadministration of VFEND with tolvaptan is contraindicated because VFEND may increase tolvaptan plasma concentrations and increase risk of adverse reactions
[see Drug Interactions (7)]
.
•Coadministration of VFEND with venetoclax at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome
[see Drug Interactions (7)]
.
•Coadministration of VFEND with lurasidone is contraindicated since it may result in significant increases in lurasidone exposure and the potential for serious adverse reactions
[see Drug Interactions (7)].
•
Coadministration of VFEND with finerenone is contraindicated since it may result in significant increases in finerenone exposure and the potential for serious adverse reactions
[see Drug Interactions (7)].

•Hypersensitivity to voriconazole or its excipients
•Coadministration with pimozide, quinidine, sirolimus or ivabradine due to risk of serious adverse reactions
•Coadministration with rifampin, carbamazepine, long-acting barbiturates, efavirenz, ritonavir, rifabutin, ergot alkaloids or St. John's Wort due to risk of loss of efficacy
•Coadministration with naloxegol, tolvaptan, lurasidone or finerenone due to risk of adverse reactions
•Coadministration of VFEND with venetoclax at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to increased risk of adverse reactions

)

3/2025

VFEND is an azole antifungal indicated for the treatment of adults and pediatric patients 2 years of age and older with:

•Invasive aspergillosis (
1.1 Invasive Aspergillosis
VFEND is indicated in adults and pediatric patients (2 years of age and older) for the treatment of invasive aspergillosis (IA). In clinical trials, the majority of isolates recovered were
Aspergillus fumigatus
. There was a small number of cases of culture-proven disease due to species of
Aspergillus
other than
A. fumigatus [see Clinical Studies (14.1, 14.5)and Microbiology (12.4)]
.
)
•Candidemia in non-neutropenics and other deep tissue
Candida
infections (
1.2 Candidemia in Non-neutropenic Patients and Other Deep Tissue
Candida
Infections
VFEND is indicated in adults and pediatric patients (2 years of age and older) for the treatment of candidemia in non-neutropenic patients and the following
Candida
infections: disseminated infections in skin and infections in abdomen, kidney, bladder wall, and wounds
[see Clinical Studies (14.2, 14.5)and Microbiology (12.4)].
)
•Esophageal candidiasis (
1.3 Esophageal Candidiasis
VFEND is indicated in adults and pediatric patients (2 years of age and older) for the treatment of esophageal candidiasis (EC)
[see Clinical Studies (14.3, 14.5)and Microbiology (12.4)].
)
•Serious fungal infections caused by
Scedosporium apiospermum
and
Fusarium
species including
Fusarium solani
, in patients intolerant of, or refractory to, other therapy (
1.4 Scedosporiosis and Fusariosis
VFEND is indicated for the treatment of serious fungal infections caused by
Scedosporium apiospermum
(asexual form of
Pseudallescheria boydii
) and
Fusarium spp.
including
Fusarium solani
, in adults and pediatric patients (2 years of age and older) intolerant of, or refractory to, other therapy
[see Clinical Studies (14.4)and Microbiology (12.4)].
)

•

Dosage in Adults (

2.3 Recommended Dosing Regimen in Adults

Invasive aspergillosis and serious fungal infections due to

Fusarium

spp. and

Scedosporium apiospermum

[see Clinical Pharmacology (12.3)]

Candidemia in non-neutropenic patients and other deep tissue

Candida

infections

See Table 1. Patients should be treated for at least 14 days following resolution of symptoms or following last positive culture, whichever is longer.

Esophageal Candidiasis

See Table 1. Patients should be treated for a minimum of 14 days and for at least 7 days following resolution of symptoms.

Table 1: Recommended Dosing Regimen (Adults)
Infection	Loading Dose	Maintenance Dose Increase dose when VFEND is co-administered with phenytoin or efavirenz (7); Decrease dose in patients with hepatic impairment (2.5) ^, In healthy volunteer studies, the 200 mg oral every 12 hours dose provided an exposure (AUC_τ) similar to a 3 mg/kg intravenous infusion every 12 hours dose; the 300 mg oral every 12 hours dose provided an exposure (AUC_τ) similar to a 4 mg/kg intravenous infusion every 12 hours dose (12).
	Intravenous infusion	Intravenous infusion	Oral tablets Adult patients who weigh less than 40 kg should receive half of the oral maintenance dose.	Oral suspension
Invasive Aspergillosis In a clinical study of IA, the median duration of intravenous VFEND therapy was 10 days (range 2 to 85 days). The median duration of oral VFEND therapy was 76 days (range 2 to 232 days) (14.1 ) .	6 mg/kg every 12 hours for the first 24 hours	4 mg/kg every 12 hours	200 mg every 12 hours	5 mL every 12 hours
Candidemia in nonneutropenic patients and other deep tissue Candida infections	6 mg/kg every 12 hours for the first 24 hours	3–4 mg/kg every 12 hoursIn clinical trials, patients with candidemia received 3 mg/kg intravenous infusion every 12 hours as primary therapy, while patients with other deep tissue Candida infections received 4 mg/kg every 12 hours as salvage therapy. Appropriate dose should be based on the severity and nature of the infection.	200 mg every 12 hours	5 mL every 12 hours
Esophageal Candidiasis	Not EvaluatedNot evaluated in patients with EC.	Not Evaluated	200 mg every 12 hours	5 mL every 12 hours
Scedosporiosis and Fusariosis	6 mg/kg every 12 hours for the first 24 hours	4 mg/kg every 12 hours	200 mg every 12 hours	5 mL every 12 hours

Method for Adjusting the Dosing Regimen in Adults

•
If the patient's response is inadequate, the oral maintenance dose for VFEND tablets or oral suspension may be increased from 200 mg (or 5 mL) every 12 hours to 300 mg (or 7.5 mL) every 12 hours.
•
For adult patients weighing less than 40 kg, the oral maintenance dose for VFEND tablets or oral suspension may be increased from 100 mg (or 2.5 mL) every 12 hours to 150 mg (or 3.75 mL) every 12 hours.
•
If the patient is unable to tolerate 300 mg (or 7.5 mL) orally every 12 hours, reduce the oral maintenance dose of VFEND tablets or oral suspension by 50 mg (or 1.25 mL) steps to a minimum of 200 mg (or 5 mL) every 12 hours for adult patients weighing more than 40 kg or to 100 mg (or 2.5 mL) every 12 hours for adult patients weighing less than 40 kg.
•
If the patient is unable to tolerate 4 mg/kg intravenously every 12 hours, reduce the intravenous maintenance dose to 3 mg/kg every 12 hours.

)

Infection	Loading Dose	Maintenance Dose
	Intravenous infusion	Intravenous infusion	Oral tablets	Oral suspension
Invasive Aspergillosis	6 mg/kg every 12 hours for the first 24 hours	4 mg/kg every 12 hours	200 mg every 12 hours	5 mL every 12 hours
Candidemia in nonneutropenics and other deep tissue Candida infections		3-4 mg/kg every 12 hours	200 mg every 12 hours	5 mL every 12 hours
Scedosporiosis and Fusariosis		4 mg/kg every 12 hours	200 mg every 12 hours	5 mL every 12 hours
Esophageal Candidiasis	Not Evaluated	Not Evaluated	200 mg every 12 hours	5 mL every 12 hours

oAdult patients weighing less than 40 kg: oral maintenance dose 100 mg or 150 mg every 12 hours
o
Hepatic Impairment
: Use half the maintenance dose in adult patients with mild to moderate hepatic impairment (Child-Pugh Class A and B) (
2.5 Dosage Modifications in Patients With Hepatic Impairment
Adults
The maintenance dose of VFEND should be reduced in adult patients with mild to moderate hepatic impairment, Child-Pugh Class A and B. There are no PK data to allow for dosage adjustment recommendations in patients with severe hepatic impairment (Child-Pugh Class C).
Duration of therapy should be based on the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response.
Adult patients with baseline liver function tests (ALT, AST) of up to 5 times the upper limit of normal (ULN) were included in the clinical program. Dose adjustments are not necessary for adult patients with this degree of abnormal liver function, but continued monitoring of liver function tests for further elevations is recommended
[see Warnings and Precautions (5.1)]
.
It is recommended that the recommended VFEND loading dose regimens be used, but that the maintenance dose be halved in adult patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B)
[see Clinical Pharmacology (12.3)]
.
VFEND has not been studied in adult patients with severe hepatic cirrhosis (Child-Pugh Class C) or in patients with chronic hepatitis B or chronic hepatitis C disease. VFEND has been associated with elevations in liver function tests and with clinical signs of liver damage, such as jaundice. VFEND should only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with hepatic impairment must be carefully monitored for drug toxicity.
Pediatric Patients
Dosage adjustment of VFEND in pediatric patients with hepatic impairment has not been established
[see Use in Specific Populations (8.4)]
.
)
o
Renal Impairment
: Avoid intravenous administration in adult patients with moderate to severe renal impairment (creatinine clearance <50 mL/min) (
2.6 Dosage Modifications in Patients With Renal Impairment
Adult Patients
The pharmacokinetics of orally administered VFEND are not significantly affected by renal impairment. Therefore, no adjustment is necessary for
oral
dosing in patients with mild to severe renal impairment
[see Clinical Pharmacology (12.3)]
.
In patients with moderate or severe renal impairment (creatinine clearance <50 mL/min) who are receiving an intravenous infusion of VFEND, accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous VFEND. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral VFEND therapy
[see Warnings and Precautions (5.7)]
.
Voriconazole and the intravenous vehicle, SBECD, are dialyzable. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment
[see Clinical Pharmacology (12.3)]
.
Pediatric Patients
Dosage adjustment of VFEND in pediatric patients with renal impairment has not been established
[see Use in Specific Populations (8.4)]
.
)

•

Dosage in Pediatric Patients 2 years of age and older (

2.4 Recommended Dosing Regimen in Pediatric Patients

[see Dosage and Administration (2.3)]

Table 2: Recommended Dosing Regimen for Pediatric Patients 2 to less than 12 years of age and 12 to 14 years of age with body weight less than 50 kgBased on a population pharmacokinetic analysis in 112 immunocompromised pediatric patients aged 2 to less than 12 years of age and 26 immunocompromised pediatric patients aged 12 to less than 17 years of age.
	Loading Dose	Maintenance Dose
	Intravenous infusion	Intravenous infusion	Oral tablets	Oral suspension
Invasive Aspergillosis In the Phase 3 clinical trials, patients with IA received intravenous (IV) treatment for at least 6 weeks and up to a maximum of 12 weeks. Patients received IV treatment for at least the first 7 days of therapy and then could be switched to oral VFEND therapy.
Candidemia in nonneutropenics and other deep tissue Candida infections Study treatment for primary or salvage invasive candidiasis and candidemia (ICC) or EC consisted of intravenous VFEND, with an option to switch to oral therapy after at least 5 days of IV therapy, based on subjects meeting switch criteria. For subjects with primary or salvage ICC, VFEND was administered for at least 14 days after the last positive culture. A maximum of 42 days of treatment was permitted. Patients with primary or salvage EC were treated for at least 7 days after the resolution of clinical signs and symptoms. A maximum of 42 days of treatment was permitted.	9 mg/kg every 12 hours for the first 24 hours	8 mg/kg every 12 hours after the first 24 hours	9 mg/kg every 12 hours (maximum dose of 350 mg every 12 hours)	0.225 mL/kg every 12 hours [maximum dose of 8.75 mL (350 mg) every 12 hours]
Scedosporiosis and Fusariosis
Esophageal Candidiasis	Not Evaluated	4 mg/kg every 12 hours	9 mg/kg every 12 hours (maximum dose of 350 mg every 12 hours)	0.225 mL/kg every 12 hours [maximum dose of 8.75 mL (350 mg) every 12 hours]

Oral bioavailability may be limited in pediatric patients 2 to 12 years with malabsorption and very low body weight for age. In that case, intravenous VFEND administration is recommended.

Method for Adjusting the Dosing Regimen in Pediatric Patients

Pediatric Patients 2 to less than 12 years of age and 12 to 14 years of age with body weight less than 50 kg

Pediatric patients 12 to 14 years of age weighing greater than or equal to 50 kg and 15 years of age and older regardless of body weight:

Use the optimal method for titrating dosage recommended for adults

[see Dosage and Administration (2.3)]

)

oFor pediatric patients 2 to less than 12 years of age and 12 to 14 years of age weighing less than 50 kg see Table below.

Infection

Loading Dose

Maintenance Dose

Intravenous infusion

Oral

tablets

Oral

suspension

Invasive Aspergillosis

9 mg/kg every 12 hours for the first 24 hours

8 mg/kg every 12 hours after the first 24 hours

9 mg/kg every 12 hours

(maximum dose of 350 mg every 12 hours)

0.225 mL/kg every 12 hours

[maximum dose of 8.75 mL (350 mg) every 12 hours]

Candidemia in nonneutropenics and other deep tissue

Candida

infections

Scedosporiosis and Fusariosis

Esophageal Candidiasis

Not Evaluated

4 mg/kg every 12 hours

9 mg/kg every 12 hours

(maximum dose of 350 mg every 12 hours)

0.225 mL/kg every 12 hours

[maximum dose of 8.75 mL (350 mg) every 12 hours]

oFor pediatric patients aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight use adult dosage (

2.4 Recommended Dosing Regimen in Pediatric Patients

[see Dosage and Administration (2.3)]

Table 2: Recommended Dosing Regimen for Pediatric Patients 2 to less than 12 years of age and 12 to 14 years of age with body weight less than 50 kgBased on a population pharmacokinetic analysis in 112 immunocompromised pediatric patients aged 2 to less than 12 years of age and 26 immunocompromised pediatric patients aged 12 to less than 17 years of age.
	Loading Dose	Maintenance Dose
	Intravenous infusion	Intravenous infusion	Oral tablets	Oral suspension
Invasive Aspergillosis In the Phase 3 clinical trials, patients with IA received intravenous (IV) treatment for at least 6 weeks and up to a maximum of 12 weeks. Patients received IV treatment for at least the first 7 days of therapy and then could be switched to oral VFEND therapy.
Candidemia in nonneutropenics and other deep tissue Candida infections Study treatment for primary or salvage invasive candidiasis and candidemia (ICC) or EC consisted of intravenous VFEND, with an option to switch to oral therapy after at least 5 days of IV therapy, based on subjects meeting switch criteria. For subjects with primary or salvage ICC, VFEND was administered for at least 14 days after the last positive culture. A maximum of 42 days of treatment was permitted. Patients with primary or salvage EC were treated for at least 7 days after the resolution of clinical signs and symptoms. A maximum of 42 days of treatment was permitted.	9 mg/kg every 12 hours for the first 24 hours	8 mg/kg every 12 hours after the first 24 hours	9 mg/kg every 12 hours (maximum dose of 350 mg every 12 hours)	0.225 mL/kg every 12 hours [maximum dose of 8.75 mL (350 mg) every 12 hours]
Scedosporiosis and Fusariosis
Esophageal Candidiasis	Not Evaluated	4 mg/kg every 12 hours	9 mg/kg every 12 hours (maximum dose of 350 mg every 12 hours)	0.225 mL/kg every 12 hours [maximum dose of 8.75 mL (350 mg) every 12 hours]

Oral bioavailability may be limited in pediatric patients 2 to 12 years with malabsorption and very low body weight for age. In that case, intravenous VFEND administration is recommended.

Method for Adjusting the Dosing Regimen in Pediatric Patients

Pediatric Patients 2 to less than 12 years of age and 12 to 14 years of age with body weight less than 50 kg

Pediatric patients 12 to 14 years of age weighing greater than or equal to 50 kg and 15 years of age and older regardless of body weight:

Use the optimal method for titrating dosage recommended for adults

[see Dosage and Administration (2.3)]

)

oDosage adjustment of VFEND in pediatric patients with renal or hepatic impairment has not been established (
2.5 Dosage Modifications in Patients With Hepatic Impairment
Adults
The maintenance dose of VFEND should be reduced in adult patients with mild to moderate hepatic impairment, Child-Pugh Class A and B. There are no PK data to allow for dosage adjustment recommendations in patients with severe hepatic impairment (Child-Pugh Class C).
Duration of therapy should be based on the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response.
Adult patients with baseline liver function tests (ALT, AST) of up to 5 times the upper limit of normal (ULN) were included in the clinical program. Dose adjustments are not necessary for adult patients with this degree of abnormal liver function, but continued monitoring of liver function tests for further elevations is recommended
[see Warnings and Precautions (5.1)]
.
It is recommended that the recommended VFEND loading dose regimens be used, but that the maintenance dose be halved in adult patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B)
[see Clinical Pharmacology (12.3)]
.
VFEND has not been studied in adult patients with severe hepatic cirrhosis (Child-Pugh Class C) or in patients with chronic hepatitis B or chronic hepatitis C disease. VFEND has been associated with elevations in liver function tests and with clinical signs of liver damage, such as jaundice. VFEND should only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with hepatic impairment must be carefully monitored for drug toxicity.
Pediatric Patients
Dosage adjustment of VFEND in pediatric patients with hepatic impairment has not been established
[see Use in Specific Populations (8.4)]
.
,
2.6 Dosage Modifications in Patients With Renal Impairment
Adult Patients
The pharmacokinetics of orally administered VFEND are not significantly affected by renal impairment. Therefore, no adjustment is necessary for
oral
dosing in patients with mild to severe renal impairment
[see Clinical Pharmacology (12.3)]
.
In patients with moderate or severe renal impairment (creatinine clearance <50 mL/min) who are receiving an intravenous infusion of VFEND, accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous VFEND. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral VFEND therapy
[see Warnings and Precautions (5.7)]
.
Voriconazole and the intravenous vehicle, SBECD, are dialyzable. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment
[see Clinical Pharmacology (12.3)]
.
Pediatric Patients
Dosage adjustment of VFEND in pediatric patients with renal impairment has not been established
[see Use in Specific Populations (8.4)]
.
)
•See full prescribing information for instructions on reconstitution of VFEND lyophilized powder for intravenous use and important administration instructions (
2.1 Important Administration Instructions for Use in All Patients
VFEND I.V. for Injection requires reconstitution to 10 mg/mL and subsequent dilution to 5 mg/mL or less prior to administration as an infusion, at a maximum rate of 3 mg/kg per hour over 1 to 3 hours.
Administer diluted VFEND I.V. by intravenous infusion over 1 to 3 hours only. Do not administer as an IV bolus injection.
,
2.6 Dosage Modifications in Patients With Renal Impairment
Adult Patients
The pharmacokinetics of orally administered VFEND are not significantly affected by renal impairment. Therefore, no adjustment is necessary for
oral
dosing in patients with mild to severe renal impairment
[see Clinical Pharmacology (12.3)]
.
In patients with moderate or severe renal impairment (creatinine clearance <50 mL/min) who are receiving an intravenous infusion of VFEND, accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous VFEND. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral VFEND therapy
[see Warnings and Precautions (5.7)]
.
Voriconazole and the intravenous vehicle, SBECD, are dialyzable. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment
[see Clinical Pharmacology (12.3)]
.
Pediatric Patients
Dosage adjustment of VFEND in pediatric patients with renal impairment has not been established
[see Use in Specific Populations (8.4)]
.
,
2.7 Dosage Adjustment When Co-Administered With Phenytoin or Efavirenz
The maintenance dose of voriconazole should be increased when co-administered with phenytoin or efavirenz. Use the optimal method for titrating dosage
[see Drug Interactions (7)and Dosage and Administration (2.3)]
.
)

•
For Injection
: Lyophilized powder containing 200 mg of voriconazole and 3,200 mg of sulfobutyl ether beta-cyclodextrin sodium (SBECD); after reconstitution 10 mg/mL of voriconazole and 160 mg/mL of SBECD (
3 DOSAGE FORMS AND STRENGTHS
•
For Injection
: Lyophilized powder containing 200 mg of voriconazole and 3,200 mg of sulfobutyl ether beta-cyclodextrin sodium (SBECD); after reconstitution 10 mg/mL of voriconazole and 160 mg/mL of SBECD
Powder for Solution for Injection
VFEND I.V. for Injection is supplied in a single-dose vial as a sterile lyophilized powder equivalent to 200 mg voriconazole and 3,200 mg sulfobutyl ether beta-cyclodextrin sodium (SBECD).
)

•
Pediatrics
: Safety and effectiveness in patients younger than 2 years has not been established (
8.4 Pediatric Use
The safety and effectiveness of VFEND have been established in pediatric patients 2 years of age and older based on evidence from adequate and well-controlled studies in adult and pediatric patients and additional pediatric pharmacokinetic and safety data.
A total of 105 pediatric patients aged 2 to less than 12 [N=26] and aged 12 to less than 18 [N=79] from two, non-comparative Phase 3 pediatric studies and eight adult therapeutic trials provided safety information for VFEND use in the pediatric population
[see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)]
.
Safety and effectiveness in pediatric patients below the age of 2 years has not been established. Therefore, VFEND is not recommended for pediatric patients less than 2 years of age.
A higher frequency of liver enzyme elevations was observed in the pediatric patients
[see Dosage and Administration (2.5), Warnings and Precautions (5.1), and Adverse Reactions (6.1)]
.
The frequency of phototoxicity reactions is higher in the pediatric population. Squamous cell carcinoma has been reported in patients who experience photosensitivity reactions. Stringent measures for photoprotection are warranted. Sun avoidance and dermatologic follow-up are recommended in pediatric patients experiencing photoaging injuries, such as lentigines or ephelides, even after treatment discontinuation
[see Warnings and Precautions (5.6)].
VFEND has not been studied in pediatric patients with hepatic or renal impairment
[see Dosage and Administration (2.5, 2.6)]
. Hepatic function and serum creatinine levels should be closely monitored in pediatric patients
[see Dosage and Administration (2.6)and Warnings and Precautions (5.1, 5.10)]
.
)

•VFEND is contraindicated in patients with known hypersensitivity to voriconazole or its excipients. There is no information regarding cross-sensitivity between VFEND (voriconazole) and other azole antifungal agents. Caution should be used when prescribing VFEND to patients with hypersensitivity to other azoles.

•Coadministration of pimozide, quinidine or ivabradine with VFEND is contraindicated because increased plasma concentrations of these drugs can lead to QT prolongation and rare occurrences of

torsade de pointes [see

7 DRUG INTERACTIONS

Voriconazole is metabolized by cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Therefore, inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively. Voriconazole is a strong inhibitor of CYP3A4, and also inhibits CYP2C19 and CYP2C9. Therefore, voriconazole may increase the plasma concentrations of substances metabolized by these CYP450 isoenzymes.

Tables 10 and 11 provide the clinically significant interactions between voriconazole and other medical products.

Table 10: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_maxand AUC_τafter 200 mg every 12 hours)	Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg every 12 hours voriconazole to healthy subjectsand Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg every 24 hours)Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (300 mg every 24 hours) (CYP450 Induction)	Slight Decrease in AUC _τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours.
High-dose Ritonavir (400 mg every 12 hours) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg every 12 hours) (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (e.g., phenobarbital, mephobarbital) (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hours or from 200 mg to 400 mg orally every 12 hours (100 mg to 200 mg orally every 12 hours in patients weighing less than 40 kg).
Letermovir (CYP2C9/2C19 Induction)	Reduced	If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole.
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse reactions and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse reactions and toxicity related to voriconazole is started within 24 hours after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole
	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

Table 11: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_maxand AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg every 24 hours)Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (300 mg every 24 hours) (CYP3A4 Inhibition)	Slight Increase in AUC_τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours
High-dose Ritonavir (400 mg every 12 hours) (CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_maxor AUC_τ	Contraindicated because of significant reduction of voriconazole C_maxand AUC_τ
Low-dose Ritonavir (100 mg every 12 hours)	Slight Decrease in Ritonavir C_maxand AUC_τ	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided (due to the reduction in voriconazole C_maxand AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Pimozide, Quinidine, Ivabradine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated
Naloxegol (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Contraindicated
Tolvaptan (CYP3A4 Inhibition)	Although Not Studied Clinically, Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Tolvaptan	Contraindicated
Lurasidone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Lurasidone	Contraindicated
Finerenone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Finerenone	Contraindicated
Venetoclax (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Venetoclax Plasma Exposure Likely to be Significantly Increased	Coadministration of voriconazole is contraindicated at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering VFEND with venetoclax. Refer to the venetoclax prescribing information for dosing instructions.
Lemborexant (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of VFEND with lemborexant.
Glasdegib (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Consider alternative therapies. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions including QTc interval prolongation.
Tyrosine kinase inhibitors (including but not limited to axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of VFEND. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor is recommended. Refer to the prescribing information for the relevant product.
Cyclosporine (CYP3A4 Inhibition)	AUC_τSignificantly Increased; No Significant Effect on C_max	When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg every 24 hours)(CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse reactions and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary .
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting were observed when coadministered with VFEND. Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse reactions may be necessary.
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Increased visual effects (heterophoria and miosis) of oxycodone were observed when coadministered with VFEND. Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary.
NSAIDsNon-Steroidal Anti-Inflammatory Drugincluding. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse reactions and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed.
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse reactions related to oral contraceptives is recommended during coadministration.
Prednisolone and other corticosteroids (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of VFEND on Prednisolone Exposure	No dosage adjustment for prednisolone when coadministered with VFEND [see Clinical Pharmacology (12.3)].
	Not Studied In Vitro or In Vivo for Other Corticosteroids, but Drug Exposure Likely to be Increased	Monitor for potential adrenal dysfunction when VFEND is administered with other corticosteroids [see Warnings and Precautions (5.8)].
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	If patients receiving coumarin preparations are treated simultaneously with voriconazole, the prothrombin time or other suitable anticoagulation tests should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly.
Other Oral Coumarin Anticoagulants (CYP2C9/3A4 Inhibition)	Not Studied In Vivo or In Vitro for other Oral Coumarin Anticoagulants, but Drug Plasma Exposure Likely to be Increased
Ivacaftor (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Dose reduction of ivacaftor is recommended. Refer to the prescribing information for ivacaftor
Eszopiclone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Sedative Effect of Eszopiclone	Dose reduction of eszopiclone is recommended. Refer to the prescribing information for eszopiclone.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with VFEND
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to NNRTI
Tretinoin (CYP3A4 Inhibition)	Although Not Studied, Voriconazole may Increase Tretinoin Concentrations and Increase the Risk of Adverse Reactions	Frequent monitoring for signs and symptoms of pseudotumor cerebri or hypercalcemia.
Midazolam (CYP3A4 Inhibition)	Significantly Increased	Increased plasma exposures may increase the risk of adverse reactions and toxicities related to benzodiazepines. Refer to drug-specific labeling for details.
Other benzodiazepines including triazolam and alprazolam (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse reactions and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Reserve azole antifungals, including voriconazole, for patients receiving a vinca alkaloid who have no alternative antifungal treatment options.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

•CYP3A4, CYP2C9, and CYP2C19 inhibitors and inducers: Adjust VFEND dosage and monitor for adverse reactions or lack of efficacy
•VFEND may increase the concentrations and activity of drugs that are CYP3A4, CYP2C9 and CYP2C19 substrates. Reduce dosage of these other drugs and monitor for adverse reactions
•Phenytoin or Efavirenz: With coadministration, increase maintenance oral and intravenous dosage of VFEND

]

•Coadministration of VFEND with sirolimus is contraindicated because VFEND significantly increases sirolimus concentrations

[see

7 DRUG INTERACTIONS

Tables 10 and 11 provide the clinically significant interactions between voriconazole and other medical products.

Table 10: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_maxand AUC_τafter 200 mg every 12 hours)	Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg every 12 hours voriconazole to healthy subjectsand Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg every 24 hours)Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (300 mg every 24 hours) (CYP450 Induction)	Slight Decrease in AUC _τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours.
High-dose Ritonavir (400 mg every 12 hours) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg every 12 hours) (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (e.g., phenobarbital, mephobarbital) (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hours or from 200 mg to 400 mg orally every 12 hours (100 mg to 200 mg orally every 12 hours in patients weighing less than 40 kg).
Letermovir (CYP2C9/2C19 Induction)	Reduced	If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole.
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse reactions and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse reactions and toxicity related to voriconazole is started within 24 hours after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole
	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

Table 11: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_maxand AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg every 24 hours)Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (300 mg every 24 hours) (CYP3A4 Inhibition)	Slight Increase in AUC_τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours
High-dose Ritonavir (400 mg every 12 hours) (CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_maxor AUC_τ	Contraindicated because of significant reduction of voriconazole C_maxand AUC_τ
Low-dose Ritonavir (100 mg every 12 hours)	Slight Decrease in Ritonavir C_maxand AUC_τ	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided (due to the reduction in voriconazole C_maxand AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Pimozide, Quinidine, Ivabradine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated
Naloxegol (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Contraindicated
Tolvaptan (CYP3A4 Inhibition)	Although Not Studied Clinically, Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Tolvaptan	Contraindicated
Lurasidone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Lurasidone	Contraindicated
Finerenone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Finerenone	Contraindicated
Venetoclax (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Venetoclax Plasma Exposure Likely to be Significantly Increased	Coadministration of voriconazole is contraindicated at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering VFEND with venetoclax. Refer to the venetoclax prescribing information for dosing instructions.
Lemborexant (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of VFEND with lemborexant.
Glasdegib (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Consider alternative therapies. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions including QTc interval prolongation.
Tyrosine kinase inhibitors (including but not limited to axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of VFEND. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor is recommended. Refer to the prescribing information for the relevant product.
Cyclosporine (CYP3A4 Inhibition)	AUC_τSignificantly Increased; No Significant Effect on C_max	When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg every 24 hours)(CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse reactions and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary .
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting were observed when coadministered with VFEND. Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse reactions may be necessary.
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Increased visual effects (heterophoria and miosis) of oxycodone were observed when coadministered with VFEND. Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary.
NSAIDsNon-Steroidal Anti-Inflammatory Drugincluding. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse reactions and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed.
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse reactions related to oral contraceptives is recommended during coadministration.
Prednisolone and other corticosteroids (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of VFEND on Prednisolone Exposure	No dosage adjustment for prednisolone when coadministered with VFEND [see Clinical Pharmacology (12.3)].
	Not Studied In Vitro or In Vivo for Other Corticosteroids, but Drug Exposure Likely to be Increased	Monitor for potential adrenal dysfunction when VFEND is administered with other corticosteroids [see Warnings and Precautions (5.8)].
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	If patients receiving coumarin preparations are treated simultaneously with voriconazole, the prothrombin time or other suitable anticoagulation tests should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly.
Other Oral Coumarin Anticoagulants (CYP2C9/3A4 Inhibition)	Not Studied In Vivo or In Vitro for other Oral Coumarin Anticoagulants, but Drug Plasma Exposure Likely to be Increased
Ivacaftor (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Dose reduction of ivacaftor is recommended. Refer to the prescribing information for ivacaftor
Eszopiclone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Sedative Effect of Eszopiclone	Dose reduction of eszopiclone is recommended. Refer to the prescribing information for eszopiclone.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with VFEND
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to NNRTI
Tretinoin (CYP3A4 Inhibition)	Although Not Studied, Voriconazole may Increase Tretinoin Concentrations and Increase the Risk of Adverse Reactions	Frequent monitoring for signs and symptoms of pseudotumor cerebri or hypercalcemia.
Midazolam (CYP3A4 Inhibition)	Significantly Increased	Increased plasma exposures may increase the risk of adverse reactions and toxicities related to benzodiazepines. Refer to drug-specific labeling for details.
Other benzodiazepines including triazolam and alprazolam (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse reactions and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Reserve azole antifungals, including voriconazole, for patients receiving a vinca alkaloid who have no alternative antifungal treatment options.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

•CYP3A4, CYP2C9, and CYP2C19 inhibitors and inducers: Adjust VFEND dosage and monitor for adverse reactions or lack of efficacy
•VFEND may increase the concentrations and activity of drugs that are CYP3A4, CYP2C9 and CYP2C19 substrates. Reduce dosage of these other drugs and monitor for adverse reactions
•Phenytoin or Efavirenz: With coadministration, increase maintenance oral and intravenous dosage of VFEND

and

12.3 Pharmacokinetics

The pharmacokinetics of voriconazole have been characterized in healthy subjects, special populations and patients.

The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. The interindividual variability of voriconazole pharmacokinetics is high. Greater than proportional increase in exposure is observed with increasing dose. It is estimated that, on average, increasing the oral dose from 200 mg every 12 hours to 300 mg every 12 hours leads to an approximately 2.5-fold increase in exposure (AUC_τ); similarly, increasing the intravenous dose from 3 mg/kg every 12 hours to 4 mg/kg every 12 hours produces an approximately 2.5-fold increase in exposure (Table 12).

Table 12: Geometric Mean (%CV) Plasma Voriconazole Pharmacokinetic Parameters in Adults Receiving Different Dosing Regimens
Note: Parameters were estimated based on non-compartmental analysis from 5 pharmacokinetic studies. AUC₁₂= area under the curve over 12 hour dosing interval, C_max= maximum plasma concentration, C_min= minimum plasma concentration. CV = coefficient of variation
	6 mg/kg IV (loading dose)	3 mg/kg IV every 12 hours	4 mg/kg IV every 12 hours	400 mg Oral (loading dose)	200 mg Oral every 12 hours	300 mg Oral every 12 hours
N	35	23	40	17	48	16
AUC₁₂(µg∙h/mL)	13.9 (32)	13.7 (53)	33.9 (54)	9.31 (38)	12.4 (78)	34.0 (53)
C_max(µg/mL)	3.13 (20)	3.03 (25)	4.77 (36)	2.30 (19)	2.31 (48)	4.74 (35)
C_min(µg/mL)	--	0.46 (97)	1.73 (74)	--	0.46 (120)	1.63 (79)

When the recommended intravenous loading dose regimen is administered to healthy subjects, plasma concentrations close to steady state are achieved within the first 24 hours of dosing (e.g., 6 mg/kg IV every 12 hours on day 1 followed by 3 mg/kg IV every 12 hours). Without the loading dose, accumulation occurs during twice daily multiple dosing with steady state plasma voriconazole concentrations being achieved by day 6 in the majority of subjects.

Absorption

The pharmacokinetic properties of voriconazole are similar following administration by the intravenous and oral routes. Based on a population pharmacokinetic analysis of pooled data in healthy subjects (N=207), the oral bioavailability of voriconazole is estimated to be 96% (CV 13%).

Maximum plasma concentrations (C_max) are achieved 1–2 hours after dosing. When multiple doses of voriconazole are administered with high-fat meals, the mean C_maxand AUC_τare reduced by 34% and 24%, respectively when administered as a tablet and by 58% and 37% respectively when administered as the oral suspension

[see Dosage and Administration (2)]

In healthy subjects, the absorption of voriconazole is not affected by coadministration of oral ranitidine, cimetidine, or omeprazole, drugs that are known to increase gastric pH.

Distribution

The volume of distribution at steady state for voriconazole is estimated to be 4.6 L/kg, suggesting extensive distribution into tissues. Plasma protein binding is estimated to be 58% and was shown to be independent of plasma concentrations achieved following single and multiple oral doses of 200 mg or 300 mg (approximate range: 0.9–15 µg/mL). Varying degrees of hepatic and renal impairment do not affect the protein binding of voriconazole.

Elimination

Metabolism

In vitro

studies showed that voriconazole is metabolized by the human hepatic cytochrome P450 enzymes, CYP2C19, CYP2C9 and CYP3A4

[see Drug Interactions (7)]

In vivo

studies indicated that CYP2C19 is significantly involved in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism

[see Clinical Pharmacology (12.5)]

The major metabolite of voriconazole is the N-oxide, which accounts for 72% of the circulating radiolabelled metabolites in plasma. Since this metabolite has minimal antifungal activity, it does not contribute to the overall efficacy of voriconazole.

Excretion

Voriconazole is eliminated via hepatic metabolism with less than 2% of the dose excreted unchanged in the urine. After administration of a single radiolabelled dose of either oral or IV voriconazole, preceded by multiple oral or IV dosing, approximately 80% to 83% of the radioactivity is recovered in the urine. The majority (>94%) of the total radioactivity is excreted in the first 96 hours after both oral and intravenous dosing.

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

Specific Populations

Male and Female Patients

In a multiple oral dose study, the mean C_maxand AUC_τfor healthy young females were 83% and 113% higher, respectively, than in healthy young males (18–45 years), after tablet dosing. In the same study, no significant differences in the mean C_maxand AUC_τwere observed between healthy elderly males and healthy elderly females (>65 years). In a similar study, after dosing with the oral suspension, the mean AUC for healthy young females was 45% higher than in healthy young males whereas the mean C_maxwas comparable between genders. The steady state trough voriconazole concentrations (C_min) seen in females were 100% and 91% higher than in males receiving the tablet and the oral suspension, respectively.

In the clinical program, no dosage adjustment was made on the basis of gender. The safety profile and plasma concentrations observed in male and female subjects were similar. Therefore, no dosage adjustment based on gender is necessary.

Geriatric Patients

In an oral multiple dose study the mean C_maxand AUC_τin healthy elderly males (≥65 years) were 61% and 86% higher, respectively, than in young males (18–45 years). No significant differences in the mean C_maxand AUC_τwere observed between healthy elderly females (≥65 years) and healthy young females (18–45 years).

In the clinical program, no dosage adjustment was made on the basis of age. An analysis of pharmacokinetic data obtained from 552 patients from 10 voriconazole clinical trials showed that the median voriconazole plasma concentrations in the elderly patients (>65 years) were approximately 80% to 90% higher than those in the younger patients (≤65 years) after either IV or oral administration. However, the safety profile of voriconazole in young and elderly subjects was similar and, therefore, no dosage adjustment is necessary for the elderly

[see Use in Special Populations (8.5)]

Pediatric Patients

The recommended doses in pediatric patients were based on a population pharmacokinetic analysis of data obtained from 112 immunocompromised pediatric patients aged 2 to less than 12 years and 26 immunocompromised pediatric patients aged 12 to less than 17 years.

A comparison of the pediatric and adult population pharmacokinetic data indicated that the predicted total exposure (AUC₁₂) in pediatric patients aged 2 to less than 12 years following administration of a 9 mg/kg intravenous loading dose was comparable to that in adults following a 6 mg/kg intravenous loading dose. The predicted total exposures in pediatric patients aged 2 to less than 12 years following intravenous maintenance doses of 4 and 8 mg/kg twice daily were comparable to those in adults following 3 and 4 mg/kg IV twice daily, respectively.

The predicted total exposure in pediatric patients aged 2 to less than 12 years following an oral maintenance dose of 9 mg/kg (maximum of 350 mg) twice daily was comparable to that in adults following 200 mg oral twice daily. An 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose in pediatric patients aged 2 to less than 12 years.

Voriconazole exposures in the majority of pediatric patients aged 12 to less than 17 years were comparable to those in adults receiving the same dosing regimens. However, lower voriconazole exposure was observed in some pediatric patients aged 12 to less than 17 years with low body weight compared to adults

[see Dosage and Administration (2.4)]

Limited voriconazole trough plasma samples were collected in pediatric patients aged 2 to less than 18 years with IA or invasive candidiasis including candidemia, and EC in two prospective, open-label, non-comparative, multicenter clinical studies. In eleven pediatric patients aged 2 to less than 12 years and aged 12 to 14 years, with body weight less than 50 kg, who received 9 mg/kg intravenously every 12 hours as a loading dose on the first day of treatment, followed by 8 mg/kg every 12 hours as an intravenous maintenance dose, or 9 mg/kg every 12 hours as an oral maintenance dose, the mean trough concentration of voriconazole was 3.6 mcg/mL (range 0.3 to 10.7 mcg/mL). In four pediatric patients aged 2 to less than 12 years and aged 12 to 14 years, with body weight less than 50 kg, who received 4 mg/kg intravenously every 12 hours, the mean trough concentration of voriconazole was 0.9 mcg/mL (range 0.3 to 1.6 mcg/mL)

[see Clinical Studies (14.5)]

Patients with Hepatic Impairment

After a single oral dose (200 mg) of voriconazole in 8 patients with mild (Child-Pugh Class A) and 4 patients with moderate (Child-Pugh Class B) hepatic impairment, the mean systemic exposure (AUC) was 3.2-fold higher than in age and weight matched controls with normal hepatic function. There was no difference in mean peak plasma concentrations (C_max) between the groups. When only the patients with mild (Child-Pugh Class A) hepatic impairment were compared to controls, there was still a 2.3-fold increase in the mean AUC in the group with hepatic impairment compared to controls.

In an oral multiple dose study, AUC_τwas similar in 6 subjects with moderate hepatic impairment (Child-Pugh Class B) given a lower maintenance dose of 100 mg twice daily compared to 6 subjects with normal hepatic function given the standard 200 mg twice daily maintenance dose. The mean peak plasma concentrations (C_max) were 20% lower in the hepatically impaired group. No pharmacokinetic data are available for patients with severe hepatic cirrhosis (Child-Pugh Class C)

[see Dosage and Administration (2.5)]

Patients with Renal Impairment

In a single oral dose (200 mg) study in 24 subjects with normal renal function and mild to severe renal impairment, systemic exposure (AUC) and peak plasma concentration (C_max) of voriconazole were not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment.

In a multiple dose study of IV voriconazole (6 mg/kg IV loading dose × 2, then 3 mg/kg IV × 5.5 days) in 7 patients with moderate renal dysfunction (creatinine clearance 30–50 mL/min), the systemic exposure (AUC) and peak plasma concentrations (C_max) were not significantly different from those in 6 subjects with normal renal function.

However, in patients with moderate renal dysfunction (creatinine clearance 30–50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. The mean systemic exposure (AUC) and peak plasma concentrations (C_max) of SBECD were increased 4-fold and almost 50%, respectively, in the moderately impaired group compared to the normal control group.

A pharmacokinetic study in subjects with renal failure undergoing hemodialysis showed that voriconazole is dialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment

[see Dosage and Administration (2.6)]

Patients at Risk of Aspergillosis

The observed voriconazole pharmacokinetics in patients at risk of aspergillosis (mainly patients with malignant neoplasms of lymphatic or hematopoietic tissue) were similar to healthy subjects.

Drug Interaction Studies

Effects of Other Drugs on Voriconazole

Voriconazole is metabolized by the human hepatic cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. Results of

in vitro

metabolism studies indicate that the affinity of voriconazole is highest for CYP2C19, followed by CYP2C9, and is appreciably lower for CYP3A4. Inhibitors or inducers of these three enzymes may increase or decrease voriconazole systemic exposure (plasma concentrations), respectively.

The systemic exposure to voriconazole is significantly reduced by the concomitant administration of the following agents and their use is contraindicated:

Rifampin

(potent CYP450 inducer)

–Rifampin (600 mg once daily) decreased the steady state C_maxand AUC_τof voriconazole (200 mg every 12 hours × 7 days) by an average of 93% and 96%, respectively, in healthy subjects. Doubling the dose of voriconazole to 400 mg every 12 hours does not restore adequate exposure to voriconazole during coadministration with rifampin

[see Contraindications (4)]

Ritonavir

(potent CYP450 inducer; CYP3A4 inhibitor and substrate)

–The effect of the coadministration of voriconazole and ritonavir (400 mg and 100 mg) was investigated in two separate studies. High-dose ritonavir (400 mg every 12 hours for 9 days) decreased the steady state C_maxand AUC_τof oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) by an average of 66% and 82%, respectively, in healthy subjects. Low-dose ritonavir (100 mg every 12 hours for 9 days) decreased the steady state C_maxand AUC_τof oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) by an average of 24% and 39%, respectively

in healthy subjects. Although repeat oral administration of voriconazole did not have a significant effect on steady state C_maxand AUC_τof high-dose ritonavir in healthy subjects, steady state C_maxand AUC_τof low-dose ritonavir decreased slightly by 24% and 14% respectively, when administered concomitantly with oral voriconazole in healthy subjects

[see Contraindications (4)]

St. John's Wort

(CYP450 inducer; P-gp inducer)

–In an independent published study in healthy volunteers who were given multiple oral doses of St. John's Wort (300 mg LI 160 extract three times daily for 15 days) followed by a single 400 mg oral dose of voriconazole, a 59% decrease in mean voriconazole AUC_0–∞was observed. In contrast, coadministration of single oral doses of St. John's Wort and voriconazole had no appreciable effect on voriconazole AUC_0–∞. Long-term use of St. John's Wort could lead to reduced voriconazole exposure

[see Contraindications (4)]

Significant drug interactions that may require voriconazole dosage adjustment, or frequent monitoring of voriconazole-related adverse reactions/toxicity:

Fluconazole

(CYP2C9, CYP2C19 and CYP3A4 inhibitor):

Concurrent administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) to 6 healthy male subjects resulted in an increase in C_maxand AUC_τof voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. In a follow-on clinical study involving 8 healthy male subjects, reduced dosing and/or frequency of voriconazole and fluconazole did not eliminate or diminish this effect

[see Drug Interactions (7)]

Letermovir

(CYP2C9/2C19 inducer)

–Coadministration of oral letermovir with oral voriconazole decreased the steady state C_maxand AUC_0–12of voriconazole by an average of 39% and 44%, respectively

[see Drug Interactions (7)]

Minor or no significant pharmacokinetic interactions that do not require dosage adjustment:

Cimetidine

(non-specific CYP450 inhibitor and increases gastric pH)

–Cimetidine (400 mg every 12 hours × 8 days) increased voriconazole steady state C_maxand AUC_τby an average of 18% (90% CI: 6%, 32%) and 23% (90% CI: 13%, 33%), respectively, following oral doses of 200 mg every 12 hours × 7 days to healthy subjects.

Ranitidine

(increases gastric pH)

–Ranitidine (150 mg every 12 hours) had no significant effect on voriconazole C_maxand AUC_τfollowing oral doses of 200 mg every 12 hours × 7 days to healthy subjects.

Macrolide antibiotics

–Coadministration of

erythromycin

(CYP3A4 inhibitor; 1 gram every 12 hours for 7 days) or

azithromycin

(500 mg every 24 hours for 3 days) with voriconazole 200 mg every 12 hours for 14 days had no significant effect on voriconazole steady state C_maxand AUC_τin healthy subjects. The effects of voriconazole on the pharmacokinetics of either erythromycin or azithromycin are not known.

Effects of Voriconazole on Other Drugs

In vitro

studies with human hepatic microsomes show that voriconazole inhibits the metabolic activity of the cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. In these studies, the inhibition potency of voriconazole for CYP3A4 metabolic activity was significantly less than that of two other azoles, ketoconazole and itraconazole.

In vitro

studies also show that the major metabolite of voriconazole, voriconazole N-oxide, inhibits the metabolic activity of CYP2C9 and CYP3A4 to a greater extent than that of CYP2C19. Therefore, there is potential for voriconazole and its major metabolite to increase the systemic exposure (plasma concentrations) of other drugs metabolized by these CYP450 enzymes.

The systemic exposure of the following drug is significantly increased by coadministration of voriconazole and their use is contraindicated:

Sirolimus

(CYP3A4 substrate)

–Repeat dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) increased the C_maxand AUC of sirolimus (2 mg single dose) an average of 7-fold (90% CI: 5.7, 7.5) and 11-fold (90% CI: 9.9, 12.6), respectively, in healthy male subjects

[see Contraindications (4)]

Coadministration of voriconazole with the following agents results in increased exposure to these drugs. Therefore, careful monitoring and/or dosage adjustment of these drugs is needed:

Alfentanil

(CYP3A4 substrate)

–Coadministration of multiple doses of oral voriconazole (400 mg every 12 hours on day 1, 200 mg every 12 hours on day 2) with a single 20 mcg/kg intravenous dose of alfentanil with concomitant naloxone resulted in a 6-fold increase in mean alfentanil AUC_0–∞and a 4-fold prolongation of mean alfentanil elimination half-life, compared to when alfentanil was given alone

[see Drug Interactions (7)]

Fentanyl

(CYP3A4 substrate):

In an independent published study, concomitant use of voriconazole (400 mg every 12 hours on Day 1, then 200 mg every 12 hours on Day 2) with a single intravenous dose of fentanyl (5 µg/kg) resulted in an increase in the mean AUC_0–∞of fentanyl by 1.4-fold (range 0.81- to 2.04-fold)

[see Drug Interactions (7)]

Oxycodone

(CYP3A4 substrate):

In an independent published study, coadministration of multiple doses of oral voriconazole (400 mg every 12 hours, on Day 1 followed by five doses of 200 mg every 12 hours on Days 2 to 4) with a single 10 mg oral dose of oxycodone on Day 3 resulted in an increase in the mean C_maxand AUC_0–∞of oxycodone by 1.7-fold (range 1.4- to 2.2-fold) and 3.6-fold (range 2.7- to 5.6-fold), respectively. The mean elimination half-life of oxycodone was also increased by 2.0-fold (range 1.4- to 2.5-fold)

[see Drug Interactions (7)]

Cyclosporine

(CYP3A4 substrate)

–In stable renal transplant recipients receiving chronic cyclosporine therapy, concomitant administration of oral voriconazole (200 mg every 12 hours for 8 days) increased cyclosporine C_maxand AUC_τan average of 1.1 times (90% CI: 0.9, 1.41) and 1.7 times (90% CI: 1.5, 2.0), respectively, as compared to when cyclosporine was administered without voriconazole

[see Drug Interactions (7)]

Methadone

(CYP3A4, CYP2C19, CYP2C9 substrate)

–Repeat dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days) increased the C_maxand AUC_τof pharmacologically active Rmethadone by 31% (90% CI: 22%, 40%) and 47% (90% CI: 38%, 57%), respectively, in subjects receiving a methadone maintenance dose (30–100 mg every 24 hours). The C_maxand AUC of (S)-methadone increased by 65% (90% CI: 53%, 79%) and 103% (90% CI: 85%, 124%), respectively

[see Drug Interactions (7)]

Tacrolimus

(CYP3A4 substrate)

–Repeat oral dose administration of voriconazole (400 mg every 12 hours × 1 day, then 200 mg every 12 hours × 6 days) increased tacrolimus (0.1 mg/kg single dose) C_maxand AUC_τin healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively

[see Drug Interactions (7)]

Warfarin

(CYP2C9 substrate)

–Coadministration of voriconazole (300 mg every 12 hours × 12 days) with warfarin (30 mg single dose) significantly increased maximum prothrombin time by approximately 2 times that of placebo in healthy subjects

[see Drug Interactions (7)]

Non-Steroidal Anti-Inflammatory Drugs

(NSAIDs; CYP2C9 substrates):

In two independent published studies, single doses of ibuprofen (400 mg) and diclofenac (50 mg) were coadministered with the last dose of voriconazole (400 mg every 12 hours on Day 1, followed by 200 mg every 12 hours on Day 2). Voriconazole increased the mean C_maxand AUC of the pharmacologically active isomer, S (+)-ibuprofen by 20% and 100%, respectively. Voriconazole increased the mean C_maxand AUC of diclofenac by 114% and 78%, respectively

[see Drug Interactions (7)]

No significant pharmacokinetic interactions were observed when voriconazole was coadministered with the following agents. Therefore, no dosage adjustment for these agents is recommended:

Prednisolone

(CYP3A4 substrate)

–Voriconazole (200 mg every 12 hours × 30 days) increased C_maxand AUC of prednisolone (60 mg single dose) by an average of 11% and 34%, respectively, in healthy subjects

[see Warnings and Precautions (5.8)]

Digoxin

(P-glycoprotein mediated transport)

–Voriconazole (200 mg every 12 hours × 12 days) had no significant effect on steady state C_maxand AUC_τof digoxin (0.25 mg once daily for 10 days) in healthy subjects.

Mycophenolic acid

(UDP-glucuronyl transferase substrate)

–Voriconazole (200 mg every 12 hours × 5 days) had no significant effect on the C_maxand AUC_τof mycophenolic acid and its major metabolite, mycophenolic acid glucuronide after administration of a 1 gram single oral dose of mycophenolate mofetil.

Two-Way Interactions

Concomitant use of the following agents with voriconazole is contraindicated:

Rifabutin

(potent CYP450 inducer)

–Rifabutin (300 mg once daily) decreased the C_maxand AUC_τof voriconazole at 200 mg twice daily by an average of 67% (90% CI: 58%, 73%) and 79% (90% CI: 71%, 84%), respectively, in healthy subjects. During coadministration with rifabutin (300 mg once daily), the steady state C_maxand AUC_τof voriconazole following an increased dose of 400 mg twice daily were on average approximately 2 times higher, compared with voriconazole alone at 200 mg twice daily. Coadministration of voriconazole at 400 mg twice daily with rifabutin 300 mg twice daily increased the C_maxand AUC_τof rifabutin by an average of 3-times (90% CI: 2.2, 4.0) and 4 times (90% CI: 3.5, 5.4), respectively, compared to rifabutin given alone

[see Contraindications (4)]

Significant drug interactions that may require dosage adjustment, frequent monitoring of drug levels and/or frequent monitoring of drug-related adverse reactions/toxicity:

Efavirenz,

a non-nucleoside reverse transcriptase inhibitor (CYP450 inducer; CYP3A4 inhibitor and substrate)

–Standard doses of voriconazole and efavirenz (400 mg every 24 hours or higher) must not be coadministered

[see Drug Interactions (7)]

. Steady state efavirenz (400 mg PO every 24 hours) decreased the steady state C_maxand AUC_τof voriconazole (400 mg PO every 12 hours for 1 day, then 200 mg PO every 12 hours for 8 days) by an average of 61% and 77%, respectively, in healthy male subjects. Voriconazole at steady state (400 mg PO every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) increased the steady state C_maxand AUC_τof efavirenz (400 mg PO every 24 hours for 9 days) by an average of 38% and 44%, respectively, in healthy subjects.

The pharmacokinetics of adjusted doses of voriconazole and efavirenz were studied in healthy male subjects following administration of voriconazole (400 mg PO every 12 hours on Days 2 to 7) with efavirenz (300 mg PO every 24 hours on Days 1–7), relative to steady state administration of voriconazole (400 mg for 1 day, then 200 mg PO every 12 hours for 2 days) or efavirenz (600 mg every 24 hours for 9 days). Coadministration of voriconazole 400 mg every 12 hours with efavirenz 300 mg every 24 hours, decreased voriconazole AUC_τby 7% (90% CI: -23%, 13%) and increased C_maxby 23% (90% CI: -1%, 53%); efavirenz AUC_τwas increased by 17% (90% CI: 6%, 29%) and C_maxwas equivalent

[see Dosage and Administration (2.7), Contraindications (4), and Drug Interactions (7)]

Phenytoin

(CYP2C9 substrate and potent CYP450 inducer)

–Repeat dose administration of phenytoin (300 mg once daily) decreased the steady state C_maxand AUC_τof orally administered voriconazole (200 mg every 12 hours × 14 days) by an average of 50% and 70%, respectively, in healthy subjects. Administration of a higher voriconazole dose (400 mg every 12 hours × 7 days) with phenytoin (300 mg once daily) resulted in comparable steady state voriconazole C_maxand AUC_τestimates as compared to when voriconazole was given at 200 mg every 12 hours without phenytoin

[see Dosage and Administration (2.7)and Drug Interactions (7)]

Repeat dose administration of voriconazole (400 mg every 12 hours × 10 days) increased the steady state C_maxand AUC_τof phenytoin (300 mg once daily) by an average of 70% and 80%, respectively, in healthy subjects. The increase in phenytoin C_maxand AUC when coadministered with voriconazole may be expected to be as high as 2 times the C_maxand AUC estimates when phenytoin is given without voriconazole

[see Drug Interactions (7)]

Omeprazole

(CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate)

–Coadministration of omeprazole (40 mg once daily × 10 days) with oral voriconazole (400 mg every 12 hours × 1 day, then 200 mg every 12 hours × 9 days) increased the steady state C_maxand AUC_τof voriconazole by an average of 15% (90% CI: 5%, 25%) and 40% (90% CI: 29%, 55%), respectively, in healthy subjects. No dosage adjustment of voriconazole is recommended.

Coadministration of voriconazole (400 mg every 12 hours × 1 day, then 200 mg × 6 days) with omeprazole (40 mg once daily × 7 days) to healthy subjects significantly increased the steady state C_maxand AUC_τof omeprazole an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4), respectively, as compared to when omeprazole is given without voriconazole

[see Drug Interactions (7)]

Oral Contraceptives

(CYP3A4 substrate; CYP2C19 inhibitor)

–Coadministration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 3 days) and oral contraceptive (Ortho-Novum1/35^®consisting of 35 mcg ethinyl estradiol and 1 mg norethindrone, every 24 hours) to healthy female subjects at steady state increased the C_maxand AUC_τof ethinyl estradiol by an average of 36% (90% CI: 28%, 45%) and 61% (90% CI: 50%, 72%), respectively, and that of norethindrone by 15% (90% CI: 3%, 28%) and 53% (90% CI: 44%, 63%), respectively in healthy subjects. Voriconazole C_maxand AUC_τincreased by an average of 14% (90% CI: 3%, 27%) and 46% (90% CI: 32%, 61%), respectively

[see Drug Interactions (7)]

No significant pharmacokinetic interaction was seen and no dosage adjustment of these drugs is recommended:

Indinavir

(CYP3A4 inhibitor and substrate)

–Repeat dose administration of indinavir (800 mg TID for 10 days) had no significant effect on voriconazole C_maxand AUC following repeat dose administration (200 mg every 12 hours for 17 days) in healthy subjects.

Repeat dose administration of voriconazole (200 mg every 12 hours for 7 days) did not have a significant effect on steady state C_maxand AUC_τof indinavir following repeat dose administration (800 mg TID for 7 days) in healthy subjects.

]

•Coadministration of VFEND with rifampin, carbamazepine, long-acting barbiturates or St. John's Wort is contraindicated because these drugs are likely to decrease plasma voriconazole concentrations significantly

[see

7 DRUG INTERACTIONS

Tables 10 and 11 provide the clinically significant interactions between voriconazole and other medical products.

Table 10: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_maxand AUC_τafter 200 mg every 12 hours)	Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg every 12 hours voriconazole to healthy subjectsand Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg every 24 hours)Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (300 mg every 24 hours) (CYP450 Induction)	Slight Decrease in AUC _τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours.
High-dose Ritonavir (400 mg every 12 hours) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg every 12 hours) (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (e.g., phenobarbital, mephobarbital) (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hours or from 200 mg to 400 mg orally every 12 hours (100 mg to 200 mg orally every 12 hours in patients weighing less than 40 kg).
Letermovir (CYP2C9/2C19 Induction)	Reduced	If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole.
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse reactions and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse reactions and toxicity related to voriconazole is started within 24 hours after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole
	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

Table 11: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_maxand AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg every 24 hours)Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (300 mg every 24 hours) (CYP3A4 Inhibition)	Slight Increase in AUC_τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours
High-dose Ritonavir (400 mg every 12 hours) (CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_maxor AUC_τ	Contraindicated because of significant reduction of voriconazole C_maxand AUC_τ
Low-dose Ritonavir (100 mg every 12 hours)	Slight Decrease in Ritonavir C_maxand AUC_τ	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided (due to the reduction in voriconazole C_maxand AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Pimozide, Quinidine, Ivabradine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated
Naloxegol (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Contraindicated
Tolvaptan (CYP3A4 Inhibition)	Although Not Studied Clinically, Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Tolvaptan	Contraindicated
Lurasidone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Lurasidone	Contraindicated
Finerenone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Finerenone	Contraindicated
Venetoclax (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Venetoclax Plasma Exposure Likely to be Significantly Increased	Coadministration of voriconazole is contraindicated at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering VFEND with venetoclax. Refer to the venetoclax prescribing information for dosing instructions.
Lemborexant (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of VFEND with lemborexant.
Glasdegib (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Consider alternative therapies. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions including QTc interval prolongation.
Tyrosine kinase inhibitors (including but not limited to axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of VFEND. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor is recommended. Refer to the prescribing information for the relevant product.
Cyclosporine (CYP3A4 Inhibition)	AUC_τSignificantly Increased; No Significant Effect on C_max	When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg every 24 hours)(CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse reactions and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary .
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting were observed when coadministered with VFEND. Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse reactions may be necessary.
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Increased visual effects (heterophoria and miosis) of oxycodone were observed when coadministered with VFEND. Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary.
NSAIDsNon-Steroidal Anti-Inflammatory Drugincluding. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse reactions and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed.
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse reactions related to oral contraceptives is recommended during coadministration.
Prednisolone and other corticosteroids (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of VFEND on Prednisolone Exposure	No dosage adjustment for prednisolone when coadministered with VFEND [see Clinical Pharmacology (12.3)].
	Not Studied In Vitro or In Vivo for Other Corticosteroids, but Drug Exposure Likely to be Increased	Monitor for potential adrenal dysfunction when VFEND is administered with other corticosteroids [see Warnings and Precautions (5.8)].
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	If patients receiving coumarin preparations are treated simultaneously with voriconazole, the prothrombin time or other suitable anticoagulation tests should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly.
Other Oral Coumarin Anticoagulants (CYP2C9/3A4 Inhibition)	Not Studied In Vivo or In Vitro for other Oral Coumarin Anticoagulants, but Drug Plasma Exposure Likely to be Increased
Ivacaftor (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Dose reduction of ivacaftor is recommended. Refer to the prescribing information for ivacaftor
Eszopiclone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Sedative Effect of Eszopiclone	Dose reduction of eszopiclone is recommended. Refer to the prescribing information for eszopiclone.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with VFEND
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to NNRTI
Tretinoin (CYP3A4 Inhibition)	Although Not Studied, Voriconazole may Increase Tretinoin Concentrations and Increase the Risk of Adverse Reactions	Frequent monitoring for signs and symptoms of pseudotumor cerebri or hypercalcemia.
Midazolam (CYP3A4 Inhibition)	Significantly Increased	Increased plasma exposures may increase the risk of adverse reactions and toxicities related to benzodiazepines. Refer to drug-specific labeling for details.
Other benzodiazepines including triazolam and alprazolam (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse reactions and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Reserve azole antifungals, including voriconazole, for patients receiving a vinca alkaloid who have no alternative antifungal treatment options.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

•CYP3A4, CYP2C9, and CYP2C19 inhibitors and inducers: Adjust VFEND dosage and monitor for adverse reactions or lack of efficacy
•VFEND may increase the concentrations and activity of drugs that are CYP3A4, CYP2C9 and CYP2C19 substrates. Reduce dosage of these other drugs and monitor for adverse reactions
•Phenytoin or Efavirenz: With coadministration, increase maintenance oral and intravenous dosage of VFEND

and

12.3 Pharmacokinetics

The pharmacokinetics of voriconazole have been characterized in healthy subjects, special populations and patients.

Table 12: Geometric Mean (%CV) Plasma Voriconazole Pharmacokinetic Parameters in Adults Receiving Different Dosing Regimens
Note: Parameters were estimated based on non-compartmental analysis from 5 pharmacokinetic studies. AUC₁₂= area under the curve over 12 hour dosing interval, C_max= maximum plasma concentration, C_min= minimum plasma concentration. CV = coefficient of variation
	6 mg/kg IV (loading dose)	3 mg/kg IV every 12 hours	4 mg/kg IV every 12 hours	400 mg Oral (loading dose)	200 mg Oral every 12 hours	300 mg Oral every 12 hours
N	35	23	40	17	48	16
AUC₁₂(µg∙h/mL)	13.9 (32)	13.7 (53)	33.9 (54)	9.31 (38)	12.4 (78)	34.0 (53)
C_max(µg/mL)	3.13 (20)	3.03 (25)	4.77 (36)	2.30 (19)	2.31 (48)	4.74 (35)
C_min(µg/mL)	--	0.46 (97)	1.73 (74)	--	0.46 (120)	1.63 (79)

Absorption

[see Dosage and Administration (2)]

In healthy subjects, the absorption of voriconazole is not affected by coadministration of oral ranitidine, cimetidine, or omeprazole, drugs that are known to increase gastric pH.

Distribution

Elimination

Metabolism

In vitro

studies showed that voriconazole is metabolized by the human hepatic cytochrome P450 enzymes, CYP2C19, CYP2C9 and CYP3A4

[see Drug Interactions (7)]

In vivo

studies indicated that CYP2C19 is significantly involved in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism

[see Clinical Pharmacology (12.5)]

Excretion

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

Specific Populations

Male and Female Patients

Geriatric Patients

[see Use in Special Populations (8.5)]

Pediatric Patients

[see Dosage and Administration (2.4)]

[see Clinical Studies (14.5)]

Patients with Hepatic Impairment

[see Dosage and Administration (2.5)]

Patients with Renal Impairment

[see Dosage and Administration (2.6)]

Patients at Risk of Aspergillosis

The observed voriconazole pharmacokinetics in patients at risk of aspergillosis (mainly patients with malignant neoplasms of lymphatic or hematopoietic tissue) were similar to healthy subjects.

Drug Interaction Studies

Effects of Other Drugs on Voriconazole

Voriconazole is metabolized by the human hepatic cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. Results of

in vitro

The systemic exposure to voriconazole is significantly reduced by the concomitant administration of the following agents and their use is contraindicated:

Rifampin

(potent CYP450 inducer)

[see Contraindications (4)]

Ritonavir

(potent CYP450 inducer; CYP3A4 inhibitor and substrate)

[see Contraindications (4)]

St. John's Wort

(CYP450 inducer; P-gp inducer)

[see Contraindications (4)]

Significant drug interactions that may require voriconazole dosage adjustment, or frequent monitoring of voriconazole-related adverse reactions/toxicity:

Fluconazole

(CYP2C9, CYP2C19 and CYP3A4 inhibitor):

[see Drug Interactions (7)]

Letermovir

(CYP2C9/2C19 inducer)

–Coadministration of oral letermovir with oral voriconazole decreased the steady state C_maxand AUC_0–12of voriconazole by an average of 39% and 44%, respectively

[see Drug Interactions (7)]

Minor or no significant pharmacokinetic interactions that do not require dosage adjustment:

Cimetidine

(non-specific CYP450 inhibitor and increases gastric pH)

Ranitidine

(increases gastric pH)

–Ranitidine (150 mg every 12 hours) had no significant effect on voriconazole C_maxand AUC_τfollowing oral doses of 200 mg every 12 hours × 7 days to healthy subjects.

Macrolide antibiotics

–Coadministration of

erythromycin

(CYP3A4 inhibitor; 1 gram every 12 hours for 7 days) or

azithromycin

Effects of Voriconazole on Other Drugs

In vitro

The systemic exposure of the following drug is significantly increased by coadministration of voriconazole and their use is contraindicated:

Sirolimus

(CYP3A4 substrate)

[see Contraindications (4)]

Coadministration of voriconazole with the following agents results in increased exposure to these drugs. Therefore, careful monitoring and/or dosage adjustment of these drugs is needed:

Alfentanil

(CYP3A4 substrate)

[see Drug Interactions (7)]

Fentanyl

(CYP3A4 substrate):

[see Drug Interactions (7)]

Oxycodone

(CYP3A4 substrate):

[see Drug Interactions (7)]

Cyclosporine

(CYP3A4 substrate)

[see Drug Interactions (7)]

Methadone

(CYP3A4, CYP2C19, CYP2C9 substrate)

[see Drug Interactions (7)]

Tacrolimus

(CYP3A4 substrate)

[see Drug Interactions (7)]

Warfarin

(CYP2C9 substrate)

[see Drug Interactions (7)]

Non-Steroidal Anti-Inflammatory Drugs

(NSAIDs; CYP2C9 substrates):

[see Drug Interactions (7)]

No significant pharmacokinetic interactions were observed when voriconazole was coadministered with the following agents. Therefore, no dosage adjustment for these agents is recommended:

Prednisolone

(CYP3A4 substrate)

–Voriconazole (200 mg every 12 hours × 30 days) increased C_maxand AUC of prednisolone (60 mg single dose) by an average of 11% and 34%, respectively, in healthy subjects

[see Warnings and Precautions (5.8)]

Digoxin

(P-glycoprotein mediated transport)

–Voriconazole (200 mg every 12 hours × 12 days) had no significant effect on steady state C_maxand AUC_τof digoxin (0.25 mg once daily for 10 days) in healthy subjects.

Mycophenolic acid

(UDP-glucuronyl transferase substrate)

Two-Way Interactions

Concomitant use of the following agents with voriconazole is contraindicated:

Rifabutin

(potent CYP450 inducer)

[see Contraindications (4)]

Significant drug interactions that may require dosage adjustment, frequent monitoring of drug levels and/or frequent monitoring of drug-related adverse reactions/toxicity:

Efavirenz,

a non-nucleoside reverse transcriptase inhibitor (CYP450 inducer; CYP3A4 inhibitor and substrate)

–Standard doses of voriconazole and efavirenz (400 mg every 24 hours or higher) must not be coadministered

[see Drug Interactions (7)]

[see Dosage and Administration (2.7), Contraindications (4), and Drug Interactions (7)]

Phenytoin

(CYP2C9 substrate and potent CYP450 inducer)

[see Dosage and Administration (2.7)and Drug Interactions (7)]

[see Drug Interactions (7)]

Omeprazole

(CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate)

[see Drug Interactions (7)]

Oral Contraceptives

(CYP3A4 substrate; CYP2C19 inhibitor)

[see Drug Interactions (7)]

No significant pharmacokinetic interaction was seen and no dosage adjustment of these drugs is recommended:

Indinavir

(CYP3A4 inhibitor and substrate)

]

•Coadministration of standard doses of voriconazole with efavirenz doses of 400 mg every 24 hours or higher is contraindicated, because efavirenz significantly decreases plasma voriconazole concentrations in healthy subjects at these doses. Voriconazole also significantly increases efavirenz plasma concentrations

[see

7 DRUG INTERACTIONS

Tables 10 and 11 provide the clinically significant interactions between voriconazole and other medical products.

Table 10: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_maxand AUC_τafter 200 mg every 12 hours)	Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg every 12 hours voriconazole to healthy subjectsand Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg every 24 hours)Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (300 mg every 24 hours) (CYP450 Induction)	Slight Decrease in AUC _τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours.
High-dose Ritonavir (400 mg every 12 hours) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg every 12 hours) (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (e.g., phenobarbital, mephobarbital) (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hours or from 200 mg to 400 mg orally every 12 hours (100 mg to 200 mg orally every 12 hours in patients weighing less than 40 kg).
Letermovir (CYP2C9/2C19 Induction)	Reduced	If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole.
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse reactions and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse reactions and toxicity related to voriconazole is started within 24 hours after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole
	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

Table 11: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_maxand AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg every 24 hours)Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (300 mg every 24 hours) (CYP3A4 Inhibition)	Slight Increase in AUC_τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours
High-dose Ritonavir (400 mg every 12 hours) (CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_maxor AUC_τ	Contraindicated because of significant reduction of voriconazole C_maxand AUC_τ
Low-dose Ritonavir (100 mg every 12 hours)	Slight Decrease in Ritonavir C_maxand AUC_τ	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided (due to the reduction in voriconazole C_maxand AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Pimozide, Quinidine, Ivabradine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated
Naloxegol (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Contraindicated
Tolvaptan (CYP3A4 Inhibition)	Although Not Studied Clinically, Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Tolvaptan	Contraindicated
Lurasidone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Lurasidone	Contraindicated
Finerenone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Finerenone	Contraindicated
Venetoclax (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Venetoclax Plasma Exposure Likely to be Significantly Increased	Coadministration of voriconazole is contraindicated at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering VFEND with venetoclax. Refer to the venetoclax prescribing information for dosing instructions.
Lemborexant (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of VFEND with lemborexant.
Glasdegib (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Consider alternative therapies. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions including QTc interval prolongation.
Tyrosine kinase inhibitors (including but not limited to axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of VFEND. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor is recommended. Refer to the prescribing information for the relevant product.
Cyclosporine (CYP3A4 Inhibition)	AUC_τSignificantly Increased; No Significant Effect on C_max	When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg every 24 hours)(CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse reactions and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary .
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting were observed when coadministered with VFEND. Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse reactions may be necessary.
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Increased visual effects (heterophoria and miosis) of oxycodone were observed when coadministered with VFEND. Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary.
NSAIDsNon-Steroidal Anti-Inflammatory Drugincluding. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse reactions and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed.
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse reactions related to oral contraceptives is recommended during coadministration.
Prednisolone and other corticosteroids (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of VFEND on Prednisolone Exposure	No dosage adjustment for prednisolone when coadministered with VFEND [see Clinical Pharmacology (12.3)].
	Not Studied In Vitro or In Vivo for Other Corticosteroids, but Drug Exposure Likely to be Increased	Monitor for potential adrenal dysfunction when VFEND is administered with other corticosteroids [see Warnings and Precautions (5.8)].
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	If patients receiving coumarin preparations are treated simultaneously with voriconazole, the prothrombin time or other suitable anticoagulation tests should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly.
Other Oral Coumarin Anticoagulants (CYP2C9/3A4 Inhibition)	Not Studied In Vivo or In Vitro for other Oral Coumarin Anticoagulants, but Drug Plasma Exposure Likely to be Increased
Ivacaftor (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Dose reduction of ivacaftor is recommended. Refer to the prescribing information for ivacaftor
Eszopiclone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Sedative Effect of Eszopiclone	Dose reduction of eszopiclone is recommended. Refer to the prescribing information for eszopiclone.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with VFEND
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to NNRTI
Tretinoin (CYP3A4 Inhibition)	Although Not Studied, Voriconazole may Increase Tretinoin Concentrations and Increase the Risk of Adverse Reactions	Frequent monitoring for signs and symptoms of pseudotumor cerebri or hypercalcemia.
Midazolam (CYP3A4 Inhibition)	Significantly Increased	Increased plasma exposures may increase the risk of adverse reactions and toxicities related to benzodiazepines. Refer to drug-specific labeling for details.
Other benzodiazepines including triazolam and alprazolam (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse reactions and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Reserve azole antifungals, including voriconazole, for patients receiving a vinca alkaloid who have no alternative antifungal treatment options.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

•CYP3A4, CYP2C9, and CYP2C19 inhibitors and inducers: Adjust VFEND dosage and monitor for adverse reactions or lack of efficacy
•VFEND may increase the concentrations and activity of drugs that are CYP3A4, CYP2C9 and CYP2C19 substrates. Reduce dosage of these other drugs and monitor for adverse reactions
•Phenytoin or Efavirenz: With coadministration, increase maintenance oral and intravenous dosage of VFEND

and

12.3 Pharmacokinetics

The pharmacokinetics of voriconazole have been characterized in healthy subjects, special populations and patients.

Table 12: Geometric Mean (%CV) Plasma Voriconazole Pharmacokinetic Parameters in Adults Receiving Different Dosing Regimens
Note: Parameters were estimated based on non-compartmental analysis from 5 pharmacokinetic studies. AUC₁₂= area under the curve over 12 hour dosing interval, C_max= maximum plasma concentration, C_min= minimum plasma concentration. CV = coefficient of variation
	6 mg/kg IV (loading dose)	3 mg/kg IV every 12 hours	4 mg/kg IV every 12 hours	400 mg Oral (loading dose)	200 mg Oral every 12 hours	300 mg Oral every 12 hours
N	35	23	40	17	48	16
AUC₁₂(µg∙h/mL)	13.9 (32)	13.7 (53)	33.9 (54)	9.31 (38)	12.4 (78)	34.0 (53)
C_max(µg/mL)	3.13 (20)	3.03 (25)	4.77 (36)	2.30 (19)	2.31 (48)	4.74 (35)
C_min(µg/mL)	--	0.46 (97)	1.73 (74)	--	0.46 (120)	1.63 (79)

Absorption

[see Dosage and Administration (2)]

In healthy subjects, the absorption of voriconazole is not affected by coadministration of oral ranitidine, cimetidine, or omeprazole, drugs that are known to increase gastric pH.

Distribution

Elimination

Metabolism

In vitro

studies showed that voriconazole is metabolized by the human hepatic cytochrome P450 enzymes, CYP2C19, CYP2C9 and CYP3A4

[see Drug Interactions (7)]

In vivo

studies indicated that CYP2C19 is significantly involved in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism

[see Clinical Pharmacology (12.5)]

Excretion

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

Specific Populations

Male and Female Patients

Geriatric Patients

[see Use in Special Populations (8.5)]

Pediatric Patients

[see Dosage and Administration (2.4)]

[see Clinical Studies (14.5)]

Patients with Hepatic Impairment

[see Dosage and Administration (2.5)]

Patients with Renal Impairment

[see Dosage and Administration (2.6)]

Patients at Risk of Aspergillosis

The observed voriconazole pharmacokinetics in patients at risk of aspergillosis (mainly patients with malignant neoplasms of lymphatic or hematopoietic tissue) were similar to healthy subjects.

Drug Interaction Studies

Effects of Other Drugs on Voriconazole

Voriconazole is metabolized by the human hepatic cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. Results of

in vitro

The systemic exposure to voriconazole is significantly reduced by the concomitant administration of the following agents and their use is contraindicated:

Rifampin

(potent CYP450 inducer)

[see Contraindications (4)]

Ritonavir

(potent CYP450 inducer; CYP3A4 inhibitor and substrate)

[see Contraindications (4)]

St. John's Wort

(CYP450 inducer; P-gp inducer)

[see Contraindications (4)]

Significant drug interactions that may require voriconazole dosage adjustment, or frequent monitoring of voriconazole-related adverse reactions/toxicity:

Fluconazole

(CYP2C9, CYP2C19 and CYP3A4 inhibitor):

[see Drug Interactions (7)]

Letermovir

(CYP2C9/2C19 inducer)

–Coadministration of oral letermovir with oral voriconazole decreased the steady state C_maxand AUC_0–12of voriconazole by an average of 39% and 44%, respectively

[see Drug Interactions (7)]

Minor or no significant pharmacokinetic interactions that do not require dosage adjustment:

Cimetidine

(non-specific CYP450 inhibitor and increases gastric pH)

Ranitidine

(increases gastric pH)

–Ranitidine (150 mg every 12 hours) had no significant effect on voriconazole C_maxand AUC_τfollowing oral doses of 200 mg every 12 hours × 7 days to healthy subjects.

Macrolide antibiotics

–Coadministration of

erythromycin

(CYP3A4 inhibitor; 1 gram every 12 hours for 7 days) or

azithromycin

Effects of Voriconazole on Other Drugs

In vitro

The systemic exposure of the following drug is significantly increased by coadministration of voriconazole and their use is contraindicated:

Sirolimus

(CYP3A4 substrate)

[see Contraindications (4)]

Coadministration of voriconazole with the following agents results in increased exposure to these drugs. Therefore, careful monitoring and/or dosage adjustment of these drugs is needed:

Alfentanil

(CYP3A4 substrate)

[see Drug Interactions (7)]

Fentanyl

(CYP3A4 substrate):

[see Drug Interactions (7)]

Oxycodone

(CYP3A4 substrate):

[see Drug Interactions (7)]

Cyclosporine

(CYP3A4 substrate)

[see Drug Interactions (7)]

Methadone

(CYP3A4, CYP2C19, CYP2C9 substrate)

[see Drug Interactions (7)]

Tacrolimus

(CYP3A4 substrate)

[see Drug Interactions (7)]

Warfarin

(CYP2C9 substrate)

[see Drug Interactions (7)]

Non-Steroidal Anti-Inflammatory Drugs

(NSAIDs; CYP2C9 substrates):

[see Drug Interactions (7)]

No significant pharmacokinetic interactions were observed when voriconazole was coadministered with the following agents. Therefore, no dosage adjustment for these agents is recommended:

Prednisolone

(CYP3A4 substrate)

–Voriconazole (200 mg every 12 hours × 30 days) increased C_maxand AUC of prednisolone (60 mg single dose) by an average of 11% and 34%, respectively, in healthy subjects

[see Warnings and Precautions (5.8)]

Digoxin

(P-glycoprotein mediated transport)

–Voriconazole (200 mg every 12 hours × 12 days) had no significant effect on steady state C_maxand AUC_τof digoxin (0.25 mg once daily for 10 days) in healthy subjects.

Mycophenolic acid

(UDP-glucuronyl transferase substrate)

Two-Way Interactions

Concomitant use of the following agents with voriconazole is contraindicated:

Rifabutin

(potent CYP450 inducer)

[see Contraindications (4)]

Significant drug interactions that may require dosage adjustment, frequent monitoring of drug levels and/or frequent monitoring of drug-related adverse reactions/toxicity:

Efavirenz,

a non-nucleoside reverse transcriptase inhibitor (CYP450 inducer; CYP3A4 inhibitor and substrate)

–Standard doses of voriconazole and efavirenz (400 mg every 24 hours or higher) must not be coadministered

[see Drug Interactions (7)]

[see Dosage and Administration (2.7), Contraindications (4), and Drug Interactions (7)]

Phenytoin

(CYP2C9 substrate and potent CYP450 inducer)

[see Dosage and Administration (2.7)and Drug Interactions (7)]

[see Drug Interactions (7)]

Omeprazole

(CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate)

[see Drug Interactions (7)]

Oral Contraceptives

(CYP3A4 substrate; CYP2C19 inhibitor)

[see Drug Interactions (7)]

No significant pharmacokinetic interaction was seen and no dosage adjustment of these drugs is recommended:

Indinavir

(CYP3A4 inhibitor and substrate)

]

•Coadministration of VFEND with high-dose ritonavir (400 mg every 12 hours) is contraindicated because ritonavir (400 mg every 12 hours) significantly decreases plasma voriconazole concentrations. Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole

[see

7 DRUG INTERACTIONS

Tables 10 and 11 provide the clinically significant interactions between voriconazole and other medical products.

Table 10: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_maxand AUC_τafter 200 mg every 12 hours)	Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg every 12 hours voriconazole to healthy subjectsand Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg every 24 hours)Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (300 mg every 24 hours) (CYP450 Induction)	Slight Decrease in AUC _τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours.
High-dose Ritonavir (400 mg every 12 hours) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg every 12 hours) (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (e.g., phenobarbital, mephobarbital) (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hours or from 200 mg to 400 mg orally every 12 hours (100 mg to 200 mg orally every 12 hours in patients weighing less than 40 kg).
Letermovir (CYP2C9/2C19 Induction)	Reduced	If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole.
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse reactions and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse reactions and toxicity related to voriconazole is started within 24 hours after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole
	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

Table 11: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_maxand AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg every 24 hours)Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (300 mg every 24 hours) (CYP3A4 Inhibition)	Slight Increase in AUC_τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours
High-dose Ritonavir (400 mg every 12 hours) (CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_maxor AUC_τ	Contraindicated because of significant reduction of voriconazole C_maxand AUC_τ
Low-dose Ritonavir (100 mg every 12 hours)	Slight Decrease in Ritonavir C_maxand AUC_τ	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided (due to the reduction in voriconazole C_maxand AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Pimozide, Quinidine, Ivabradine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated
Naloxegol (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Contraindicated
Tolvaptan (CYP3A4 Inhibition)	Although Not Studied Clinically, Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Tolvaptan	Contraindicated
Lurasidone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Lurasidone	Contraindicated
Finerenone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Finerenone	Contraindicated
Venetoclax (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Venetoclax Plasma Exposure Likely to be Significantly Increased	Coadministration of voriconazole is contraindicated at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering VFEND with venetoclax. Refer to the venetoclax prescribing information for dosing instructions.
Lemborexant (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of VFEND with lemborexant.
Glasdegib (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Consider alternative therapies. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions including QTc interval prolongation.
Tyrosine kinase inhibitors (including but not limited to axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of VFEND. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor is recommended. Refer to the prescribing information for the relevant product.
Cyclosporine (CYP3A4 Inhibition)	AUC_τSignificantly Increased; No Significant Effect on C_max	When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg every 24 hours)(CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse reactions and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary .
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting were observed when coadministered with VFEND. Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse reactions may be necessary.
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Increased visual effects (heterophoria and miosis) of oxycodone were observed when coadministered with VFEND. Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary.
NSAIDsNon-Steroidal Anti-Inflammatory Drugincluding. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse reactions and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed.
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse reactions related to oral contraceptives is recommended during coadministration.
Prednisolone and other corticosteroids (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of VFEND on Prednisolone Exposure	No dosage adjustment for prednisolone when coadministered with VFEND [see Clinical Pharmacology (12.3)].
	Not Studied In Vitro or In Vivo for Other Corticosteroids, but Drug Exposure Likely to be Increased	Monitor for potential adrenal dysfunction when VFEND is administered with other corticosteroids [see Warnings and Precautions (5.8)].
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	If patients receiving coumarin preparations are treated simultaneously with voriconazole, the prothrombin time or other suitable anticoagulation tests should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly.
Other Oral Coumarin Anticoagulants (CYP2C9/3A4 Inhibition)	Not Studied In Vivo or In Vitro for other Oral Coumarin Anticoagulants, but Drug Plasma Exposure Likely to be Increased
Ivacaftor (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Dose reduction of ivacaftor is recommended. Refer to the prescribing information for ivacaftor
Eszopiclone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Sedative Effect of Eszopiclone	Dose reduction of eszopiclone is recommended. Refer to the prescribing information for eszopiclone.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with VFEND
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to NNRTI
Tretinoin (CYP3A4 Inhibition)	Although Not Studied, Voriconazole may Increase Tretinoin Concentrations and Increase the Risk of Adverse Reactions	Frequent monitoring for signs and symptoms of pseudotumor cerebri or hypercalcemia.
Midazolam (CYP3A4 Inhibition)	Significantly Increased	Increased plasma exposures may increase the risk of adverse reactions and toxicities related to benzodiazepines. Refer to drug-specific labeling for details.
Other benzodiazepines including triazolam and alprazolam (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse reactions and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Reserve azole antifungals, including voriconazole, for patients receiving a vinca alkaloid who have no alternative antifungal treatment options.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

•CYP3A4, CYP2C9, and CYP2C19 inhibitors and inducers: Adjust VFEND dosage and monitor for adverse reactions or lack of efficacy
•VFEND may increase the concentrations and activity of drugs that are CYP3A4, CYP2C9 and CYP2C19 substrates. Reduce dosage of these other drugs and monitor for adverse reactions
•Phenytoin or Efavirenz: With coadministration, increase maintenance oral and intravenous dosage of VFEND

and

12.3 Pharmacokinetics

The pharmacokinetics of voriconazole have been characterized in healthy subjects, special populations and patients.

Table 12: Geometric Mean (%CV) Plasma Voriconazole Pharmacokinetic Parameters in Adults Receiving Different Dosing Regimens
Note: Parameters were estimated based on non-compartmental analysis from 5 pharmacokinetic studies. AUC₁₂= area under the curve over 12 hour dosing interval, C_max= maximum plasma concentration, C_min= minimum plasma concentration. CV = coefficient of variation
	6 mg/kg IV (loading dose)	3 mg/kg IV every 12 hours	4 mg/kg IV every 12 hours	400 mg Oral (loading dose)	200 mg Oral every 12 hours	300 mg Oral every 12 hours
N	35	23	40	17	48	16
AUC₁₂(µg∙h/mL)	13.9 (32)	13.7 (53)	33.9 (54)	9.31 (38)	12.4 (78)	34.0 (53)
C_max(µg/mL)	3.13 (20)	3.03 (25)	4.77 (36)	2.30 (19)	2.31 (48)	4.74 (35)
C_min(µg/mL)	--	0.46 (97)	1.73 (74)	--	0.46 (120)	1.63 (79)

Absorption

[see Dosage and Administration (2)]

In healthy subjects, the absorption of voriconazole is not affected by coadministration of oral ranitidine, cimetidine, or omeprazole, drugs that are known to increase gastric pH.

Distribution

Elimination

Metabolism

In vitro

studies showed that voriconazole is metabolized by the human hepatic cytochrome P450 enzymes, CYP2C19, CYP2C9 and CYP3A4

[see Drug Interactions (7)]

In vivo

studies indicated that CYP2C19 is significantly involved in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism

[see Clinical Pharmacology (12.5)]

Excretion

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

Specific Populations

Male and Female Patients

Geriatric Patients

[see Use in Special Populations (8.5)]

Pediatric Patients

[see Dosage and Administration (2.4)]

[see Clinical Studies (14.5)]

Patients with Hepatic Impairment

[see Dosage and Administration (2.5)]

Patients with Renal Impairment

[see Dosage and Administration (2.6)]

Patients at Risk of Aspergillosis

The observed voriconazole pharmacokinetics in patients at risk of aspergillosis (mainly patients with malignant neoplasms of lymphatic or hematopoietic tissue) were similar to healthy subjects.

Drug Interaction Studies

Effects of Other Drugs on Voriconazole

Voriconazole is metabolized by the human hepatic cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. Results of

in vitro

The systemic exposure to voriconazole is significantly reduced by the concomitant administration of the following agents and their use is contraindicated:

Rifampin

(potent CYP450 inducer)

[see Contraindications (4)]

Ritonavir

(potent CYP450 inducer; CYP3A4 inhibitor and substrate)

[see Contraindications (4)]

St. John's Wort

(CYP450 inducer; P-gp inducer)

[see Contraindications (4)]

Significant drug interactions that may require voriconazole dosage adjustment, or frequent monitoring of voriconazole-related adverse reactions/toxicity:

Fluconazole

(CYP2C9, CYP2C19 and CYP3A4 inhibitor):

[see Drug Interactions (7)]

Letermovir

(CYP2C9/2C19 inducer)

–Coadministration of oral letermovir with oral voriconazole decreased the steady state C_maxand AUC_0–12of voriconazole by an average of 39% and 44%, respectively

[see Drug Interactions (7)]

Minor or no significant pharmacokinetic interactions that do not require dosage adjustment:

Cimetidine

(non-specific CYP450 inhibitor and increases gastric pH)

Ranitidine

(increases gastric pH)

–Ranitidine (150 mg every 12 hours) had no significant effect on voriconazole C_maxand AUC_τfollowing oral doses of 200 mg every 12 hours × 7 days to healthy subjects.

Macrolide antibiotics

–Coadministration of

erythromycin

(CYP3A4 inhibitor; 1 gram every 12 hours for 7 days) or

azithromycin

Effects of Voriconazole on Other Drugs

In vitro

The systemic exposure of the following drug is significantly increased by coadministration of voriconazole and their use is contraindicated:

Sirolimus

(CYP3A4 substrate)

[see Contraindications (4)]

Coadministration of voriconazole with the following agents results in increased exposure to these drugs. Therefore, careful monitoring and/or dosage adjustment of these drugs is needed:

Alfentanil

(CYP3A4 substrate)

[see Drug Interactions (7)]

Fentanyl

(CYP3A4 substrate):

[see Drug Interactions (7)]

Oxycodone

(CYP3A4 substrate):

[see Drug Interactions (7)]

Cyclosporine

(CYP3A4 substrate)

[see Drug Interactions (7)]

Methadone

(CYP3A4, CYP2C19, CYP2C9 substrate)

[see Drug Interactions (7)]

Tacrolimus

(CYP3A4 substrate)

[see Drug Interactions (7)]

Warfarin

(CYP2C9 substrate)

[see Drug Interactions (7)]

Non-Steroidal Anti-Inflammatory Drugs

(NSAIDs; CYP2C9 substrates):

[see Drug Interactions (7)]

No significant pharmacokinetic interactions were observed when voriconazole was coadministered with the following agents. Therefore, no dosage adjustment for these agents is recommended:

Prednisolone

(CYP3A4 substrate)

–Voriconazole (200 mg every 12 hours × 30 days) increased C_maxand AUC of prednisolone (60 mg single dose) by an average of 11% and 34%, respectively, in healthy subjects

[see Warnings and Precautions (5.8)]

Digoxin

(P-glycoprotein mediated transport)

–Voriconazole (200 mg every 12 hours × 12 days) had no significant effect on steady state C_maxand AUC_τof digoxin (0.25 mg once daily for 10 days) in healthy subjects.

Mycophenolic acid

(UDP-glucuronyl transferase substrate)

Two-Way Interactions

Concomitant use of the following agents with voriconazole is contraindicated:

Rifabutin

(potent CYP450 inducer)

[see Contraindications (4)]

Significant drug interactions that may require dosage adjustment, frequent monitoring of drug levels and/or frequent monitoring of drug-related adverse reactions/toxicity:

Efavirenz,

a non-nucleoside reverse transcriptase inhibitor (CYP450 inducer; CYP3A4 inhibitor and substrate)

–Standard doses of voriconazole and efavirenz (400 mg every 24 hours or higher) must not be coadministered

[see Drug Interactions (7)]

[see Dosage and Administration (2.7), Contraindications (4), and Drug Interactions (7)]

Phenytoin

(CYP2C9 substrate and potent CYP450 inducer)

[see Dosage and Administration (2.7)and Drug Interactions (7)]

[see Drug Interactions (7)]

Omeprazole

(CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate)

[see Drug Interactions (7)]

Oral Contraceptives

(CYP3A4 substrate; CYP2C19 inhibitor)

[see Drug Interactions (7)]

No significant pharmacokinetic interaction was seen and no dosage adjustment of these drugs is recommended:

Indinavir

(CYP3A4 inhibitor and substrate)

]

•Coadministration of VFEND with rifabutin is contraindicated since VFEND significantly increases rifabutin plasma concentrations and rifabutin also significantly decreases voriconazole plasma concentrations

[see

7 DRUG INTERACTIONS

Tables 10 and 11 provide the clinically significant interactions between voriconazole and other medical products.

Table 10: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_maxand AUC_τafter 200 mg every 12 hours)	Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg every 12 hours voriconazole to healthy subjectsand Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg every 24 hours)Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (300 mg every 24 hours) (CYP450 Induction)	Slight Decrease in AUC _τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours.
High-dose Ritonavir (400 mg every 12 hours) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg every 12 hours) (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (e.g., phenobarbital, mephobarbital) (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hours or from 200 mg to 400 mg orally every 12 hours (100 mg to 200 mg orally every 12 hours in patients weighing less than 40 kg).
Letermovir (CYP2C9/2C19 Induction)	Reduced	If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole.
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse reactions and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse reactions and toxicity related to voriconazole is started within 24 hours after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole
	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

Table 11: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_maxand AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg every 24 hours)Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (300 mg every 24 hours) (CYP3A4 Inhibition)	Slight Increase in AUC_τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours
High-dose Ritonavir (400 mg every 12 hours) (CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_maxor AUC_τ	Contraindicated because of significant reduction of voriconazole C_maxand AUC_τ
Low-dose Ritonavir (100 mg every 12 hours)	Slight Decrease in Ritonavir C_maxand AUC_τ	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided (due to the reduction in voriconazole C_maxand AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Pimozide, Quinidine, Ivabradine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated
Naloxegol (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Contraindicated
Tolvaptan (CYP3A4 Inhibition)	Although Not Studied Clinically, Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Tolvaptan	Contraindicated
Lurasidone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Lurasidone	Contraindicated
Finerenone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Finerenone	Contraindicated
Venetoclax (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Venetoclax Plasma Exposure Likely to be Significantly Increased	Coadministration of voriconazole is contraindicated at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering VFEND with venetoclax. Refer to the venetoclax prescribing information for dosing instructions.
Lemborexant (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of VFEND with lemborexant.
Glasdegib (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Consider alternative therapies. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions including QTc interval prolongation.
Tyrosine kinase inhibitors (including but not limited to axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of VFEND. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor is recommended. Refer to the prescribing information for the relevant product.
Cyclosporine (CYP3A4 Inhibition)	AUC_τSignificantly Increased; No Significant Effect on C_max	When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg every 24 hours)(CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse reactions and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary .
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting were observed when coadministered with VFEND. Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse reactions may be necessary.
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Increased visual effects (heterophoria and miosis) of oxycodone were observed when coadministered with VFEND. Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary.
NSAIDsNon-Steroidal Anti-Inflammatory Drugincluding. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse reactions and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed.
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse reactions related to oral contraceptives is recommended during coadministration.
Prednisolone and other corticosteroids (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of VFEND on Prednisolone Exposure	No dosage adjustment for prednisolone when coadministered with VFEND [see Clinical Pharmacology (12.3)].
	Not Studied In Vitro or In Vivo for Other Corticosteroids, but Drug Exposure Likely to be Increased	Monitor for potential adrenal dysfunction when VFEND is administered with other corticosteroids [see Warnings and Precautions (5.8)].
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	If patients receiving coumarin preparations are treated simultaneously with voriconazole, the prothrombin time or other suitable anticoagulation tests should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly.
Other Oral Coumarin Anticoagulants (CYP2C9/3A4 Inhibition)	Not Studied In Vivo or In Vitro for other Oral Coumarin Anticoagulants, but Drug Plasma Exposure Likely to be Increased
Ivacaftor (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Dose reduction of ivacaftor is recommended. Refer to the prescribing information for ivacaftor
Eszopiclone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Sedative Effect of Eszopiclone	Dose reduction of eszopiclone is recommended. Refer to the prescribing information for eszopiclone.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with VFEND
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to NNRTI
Tretinoin (CYP3A4 Inhibition)	Although Not Studied, Voriconazole may Increase Tretinoin Concentrations and Increase the Risk of Adverse Reactions	Frequent monitoring for signs and symptoms of pseudotumor cerebri or hypercalcemia.
Midazolam (CYP3A4 Inhibition)	Significantly Increased	Increased plasma exposures may increase the risk of adverse reactions and toxicities related to benzodiazepines. Refer to drug-specific labeling for details.
Other benzodiazepines including triazolam and alprazolam (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse reactions and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Reserve azole antifungals, including voriconazole, for patients receiving a vinca alkaloid who have no alternative antifungal treatment options.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

•CYP3A4, CYP2C9, and CYP2C19 inhibitors and inducers: Adjust VFEND dosage and monitor for adverse reactions or lack of efficacy
•VFEND may increase the concentrations and activity of drugs that are CYP3A4, CYP2C9 and CYP2C19 substrates. Reduce dosage of these other drugs and monitor for adverse reactions
•Phenytoin or Efavirenz: With coadministration, increase maintenance oral and intravenous dosage of VFEND

and

12.3 Pharmacokinetics

The pharmacokinetics of voriconazole have been characterized in healthy subjects, special populations and patients.

Table 12: Geometric Mean (%CV) Plasma Voriconazole Pharmacokinetic Parameters in Adults Receiving Different Dosing Regimens
Note: Parameters were estimated based on non-compartmental analysis from 5 pharmacokinetic studies. AUC₁₂= area under the curve over 12 hour dosing interval, C_max= maximum plasma concentration, C_min= minimum plasma concentration. CV = coefficient of variation
	6 mg/kg IV (loading dose)	3 mg/kg IV every 12 hours	4 mg/kg IV every 12 hours	400 mg Oral (loading dose)	200 mg Oral every 12 hours	300 mg Oral every 12 hours
N	35	23	40	17	48	16
AUC₁₂(µg∙h/mL)	13.9 (32)	13.7 (53)	33.9 (54)	9.31 (38)	12.4 (78)	34.0 (53)
C_max(µg/mL)	3.13 (20)	3.03 (25)	4.77 (36)	2.30 (19)	2.31 (48)	4.74 (35)
C_min(µg/mL)	--	0.46 (97)	1.73 (74)	--	0.46 (120)	1.63 (79)

Absorption

[see Dosage and Administration (2)]

In healthy subjects, the absorption of voriconazole is not affected by coadministration of oral ranitidine, cimetidine, or omeprazole, drugs that are known to increase gastric pH.

Distribution

Elimination

Metabolism

In vitro

studies showed that voriconazole is metabolized by the human hepatic cytochrome P450 enzymes, CYP2C19, CYP2C9 and CYP3A4

[see Drug Interactions (7)]

In vivo

studies indicated that CYP2C19 is significantly involved in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism

[see Clinical Pharmacology (12.5)]

Excretion

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

Specific Populations

Male and Female Patients

Geriatric Patients

[see Use in Special Populations (8.5)]

Pediatric Patients

[see Dosage and Administration (2.4)]

[see Clinical Studies (14.5)]

Patients with Hepatic Impairment

[see Dosage and Administration (2.5)]

Patients with Renal Impairment

[see Dosage and Administration (2.6)]

Patients at Risk of Aspergillosis

The observed voriconazole pharmacokinetics in patients at risk of aspergillosis (mainly patients with malignant neoplasms of lymphatic or hematopoietic tissue) were similar to healthy subjects.

Drug Interaction Studies

Effects of Other Drugs on Voriconazole

Voriconazole is metabolized by the human hepatic cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. Results of

in vitro

The systemic exposure to voriconazole is significantly reduced by the concomitant administration of the following agents and their use is contraindicated:

Rifampin

(potent CYP450 inducer)

[see Contraindications (4)]

Ritonavir

(potent CYP450 inducer; CYP3A4 inhibitor and substrate)

[see Contraindications (4)]

St. John's Wort

(CYP450 inducer; P-gp inducer)

[see Contraindications (4)]

Significant drug interactions that may require voriconazole dosage adjustment, or frequent monitoring of voriconazole-related adverse reactions/toxicity:

Fluconazole

(CYP2C9, CYP2C19 and CYP3A4 inhibitor):

[see Drug Interactions (7)]

Letermovir

(CYP2C9/2C19 inducer)

–Coadministration of oral letermovir with oral voriconazole decreased the steady state C_maxand AUC_0–12of voriconazole by an average of 39% and 44%, respectively

[see Drug Interactions (7)]

Minor or no significant pharmacokinetic interactions that do not require dosage adjustment:

Cimetidine

(non-specific CYP450 inhibitor and increases gastric pH)

Ranitidine

(increases gastric pH)

–Ranitidine (150 mg every 12 hours) had no significant effect on voriconazole C_maxand AUC_τfollowing oral doses of 200 mg every 12 hours × 7 days to healthy subjects.

Macrolide antibiotics

–Coadministration of

erythromycin

(CYP3A4 inhibitor; 1 gram every 12 hours for 7 days) or

azithromycin

Effects of Voriconazole on Other Drugs

In vitro

The systemic exposure of the following drug is significantly increased by coadministration of voriconazole and their use is contraindicated:

Sirolimus

(CYP3A4 substrate)

[see Contraindications (4)]

Coadministration of voriconazole with the following agents results in increased exposure to these drugs. Therefore, careful monitoring and/or dosage adjustment of these drugs is needed:

Alfentanil

(CYP3A4 substrate)

[see Drug Interactions (7)]

Fentanyl

(CYP3A4 substrate):

[see Drug Interactions (7)]

Oxycodone

(CYP3A4 substrate):

[see Drug Interactions (7)]

Cyclosporine

(CYP3A4 substrate)

[see Drug Interactions (7)]

Methadone

(CYP3A4, CYP2C19, CYP2C9 substrate)

[see Drug Interactions (7)]

Tacrolimus

(CYP3A4 substrate)

[see Drug Interactions (7)]

Warfarin

(CYP2C9 substrate)

[see Drug Interactions (7)]

Non-Steroidal Anti-Inflammatory Drugs

(NSAIDs; CYP2C9 substrates):

[see Drug Interactions (7)]

No significant pharmacokinetic interactions were observed when voriconazole was coadministered with the following agents. Therefore, no dosage adjustment for these agents is recommended:

Prednisolone

(CYP3A4 substrate)

–Voriconazole (200 mg every 12 hours × 30 days) increased C_maxand AUC of prednisolone (60 mg single dose) by an average of 11% and 34%, respectively, in healthy subjects

[see Warnings and Precautions (5.8)]

Digoxin

(P-glycoprotein mediated transport)

–Voriconazole (200 mg every 12 hours × 12 days) had no significant effect on steady state C_maxand AUC_τof digoxin (0.25 mg once daily for 10 days) in healthy subjects.

Mycophenolic acid

(UDP-glucuronyl transferase substrate)

Two-Way Interactions

Concomitant use of the following agents with voriconazole is contraindicated:

Rifabutin

(potent CYP450 inducer)

[see Contraindications (4)]

Significant drug interactions that may require dosage adjustment, frequent monitoring of drug levels and/or frequent monitoring of drug-related adverse reactions/toxicity:

Efavirenz,

a non-nucleoside reverse transcriptase inhibitor (CYP450 inducer; CYP3A4 inhibitor and substrate)

–Standard doses of voriconazole and efavirenz (400 mg every 24 hours or higher) must not be coadministered

[see Drug Interactions (7)]

[see Dosage and Administration (2.7), Contraindications (4), and Drug Interactions (7)]

Phenytoin

(CYP2C9 substrate and potent CYP450 inducer)

[see Dosage and Administration (2.7)and Drug Interactions (7)]

[see Drug Interactions (7)]

Omeprazole

(CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate)

[see Drug Interactions (7)]

Oral Contraceptives

(CYP3A4 substrate; CYP2C19 inhibitor)

[see Drug Interactions (7)]

No significant pharmacokinetic interaction was seen and no dosage adjustment of these drugs is recommended:

Indinavir

(CYP3A4 inhibitor and substrate)

]

•Coadministration of VFEND with ergot alkaloids (ergotamine and dihydroergotamine) is contraindicated because VFEND may increase the plasma concentration of ergot alkaloids, which may lead to ergotism

[see

7 DRUG INTERACTIONS

Tables 10 and 11 provide the clinically significant interactions between voriconazole and other medical products.

Table 10: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_maxand AUC_τafter 200 mg every 12 hours)	Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg every 12 hours voriconazole to healthy subjectsand Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg every 24 hours)Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (300 mg every 24 hours) (CYP450 Induction)	Slight Decrease in AUC _τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours.
High-dose Ritonavir (400 mg every 12 hours) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg every 12 hours) (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (e.g., phenobarbital, mephobarbital) (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hours or from 200 mg to 400 mg orally every 12 hours (100 mg to 200 mg orally every 12 hours in patients weighing less than 40 kg).
Letermovir (CYP2C9/2C19 Induction)	Reduced	If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole.
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse reactions and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse reactions and toxicity related to voriconazole is started within 24 hours after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole
	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

Table 11: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_maxand AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg every 24 hours)Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (300 mg every 24 hours) (CYP3A4 Inhibition)	Slight Increase in AUC_τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours
High-dose Ritonavir (400 mg every 12 hours) (CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_maxor AUC_τ	Contraindicated because of significant reduction of voriconazole C_maxand AUC_τ
Low-dose Ritonavir (100 mg every 12 hours)	Slight Decrease in Ritonavir C_maxand AUC_τ	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided (due to the reduction in voriconazole C_maxand AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Pimozide, Quinidine, Ivabradine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated
Naloxegol (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Contraindicated
Tolvaptan (CYP3A4 Inhibition)	Although Not Studied Clinically, Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Tolvaptan	Contraindicated
Lurasidone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Lurasidone	Contraindicated
Finerenone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Finerenone	Contraindicated
Venetoclax (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Venetoclax Plasma Exposure Likely to be Significantly Increased	Coadministration of voriconazole is contraindicated at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering VFEND with venetoclax. Refer to the venetoclax prescribing information for dosing instructions.
Lemborexant (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of VFEND with lemborexant.
Glasdegib (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Consider alternative therapies. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions including QTc interval prolongation.
Tyrosine kinase inhibitors (including but not limited to axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of VFEND. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor is recommended. Refer to the prescribing information for the relevant product.
Cyclosporine (CYP3A4 Inhibition)	AUC_τSignificantly Increased; No Significant Effect on C_max	When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg every 24 hours)(CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse reactions and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary .
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting were observed when coadministered with VFEND. Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse reactions may be necessary.
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Increased visual effects (heterophoria and miosis) of oxycodone were observed when coadministered with VFEND. Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary.
NSAIDsNon-Steroidal Anti-Inflammatory Drugincluding. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse reactions and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed.
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse reactions related to oral contraceptives is recommended during coadministration.
Prednisolone and other corticosteroids (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of VFEND on Prednisolone Exposure	No dosage adjustment for prednisolone when coadministered with VFEND [see Clinical Pharmacology (12.3)].
	Not Studied In Vitro or In Vivo for Other Corticosteroids, but Drug Exposure Likely to be Increased	Monitor for potential adrenal dysfunction when VFEND is administered with other corticosteroids [see Warnings and Precautions (5.8)].
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	If patients receiving coumarin preparations are treated simultaneously with voriconazole, the prothrombin time or other suitable anticoagulation tests should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly.
Other Oral Coumarin Anticoagulants (CYP2C9/3A4 Inhibition)	Not Studied In Vivo or In Vitro for other Oral Coumarin Anticoagulants, but Drug Plasma Exposure Likely to be Increased
Ivacaftor (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Dose reduction of ivacaftor is recommended. Refer to the prescribing information for ivacaftor
Eszopiclone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Sedative Effect of Eszopiclone	Dose reduction of eszopiclone is recommended. Refer to the prescribing information for eszopiclone.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with VFEND
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to NNRTI
Tretinoin (CYP3A4 Inhibition)	Although Not Studied, Voriconazole may Increase Tretinoin Concentrations and Increase the Risk of Adverse Reactions	Frequent monitoring for signs and symptoms of pseudotumor cerebri or hypercalcemia.
Midazolam (CYP3A4 Inhibition)	Significantly Increased	Increased plasma exposures may increase the risk of adverse reactions and toxicities related to benzodiazepines. Refer to drug-specific labeling for details.
Other benzodiazepines including triazolam and alprazolam (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse reactions and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Reserve azole antifungals, including voriconazole, for patients receiving a vinca alkaloid who have no alternative antifungal treatment options.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

•CYP3A4, CYP2C9, and CYP2C19 inhibitors and inducers: Adjust VFEND dosage and monitor for adverse reactions or lack of efficacy
•VFEND may increase the concentrations and activity of drugs that are CYP3A4, CYP2C9 and CYP2C19 substrates. Reduce dosage of these other drugs and monitor for adverse reactions
•Phenytoin or Efavirenz: With coadministration, increase maintenance oral and intravenous dosage of VFEND

]

•Coadministration of VFEND with naloxegol is contraindicated because VFEND may increase plasma concentrations of naloxegol which may precipitate opioid withdrawal symptoms

[see

7 DRUG INTERACTIONS

Tables 10 and 11 provide the clinically significant interactions between voriconazole and other medical products.

Table 10: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_maxand AUC_τafter 200 mg every 12 hours)	Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg every 12 hours voriconazole to healthy subjectsand Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg every 24 hours)Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (300 mg every 24 hours) (CYP450 Induction)	Slight Decrease in AUC _τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours.
High-dose Ritonavir (400 mg every 12 hours) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg every 12 hours) (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (e.g., phenobarbital, mephobarbital) (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hours or from 200 mg to 400 mg orally every 12 hours (100 mg to 200 mg orally every 12 hours in patients weighing less than 40 kg).
Letermovir (CYP2C9/2C19 Induction)	Reduced	If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole.
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse reactions and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse reactions and toxicity related to voriconazole is started within 24 hours after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole
	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

Table 11: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_maxand AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg every 24 hours)Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (300 mg every 24 hours) (CYP3A4 Inhibition)	Slight Increase in AUC_τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours
High-dose Ritonavir (400 mg every 12 hours) (CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_maxor AUC_τ	Contraindicated because of significant reduction of voriconazole C_maxand AUC_τ
Low-dose Ritonavir (100 mg every 12 hours)	Slight Decrease in Ritonavir C_maxand AUC_τ	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided (due to the reduction in voriconazole C_maxand AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Pimozide, Quinidine, Ivabradine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated
Naloxegol (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Contraindicated
Tolvaptan (CYP3A4 Inhibition)	Although Not Studied Clinically, Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Tolvaptan	Contraindicated
Lurasidone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Lurasidone	Contraindicated
Finerenone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Finerenone	Contraindicated
Venetoclax (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Venetoclax Plasma Exposure Likely to be Significantly Increased	Coadministration of voriconazole is contraindicated at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering VFEND with venetoclax. Refer to the venetoclax prescribing information for dosing instructions.
Lemborexant (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of VFEND with lemborexant.
Glasdegib (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Consider alternative therapies. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions including QTc interval prolongation.
Tyrosine kinase inhibitors (including but not limited to axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of VFEND. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor is recommended. Refer to the prescribing information for the relevant product.
Cyclosporine (CYP3A4 Inhibition)	AUC_τSignificantly Increased; No Significant Effect on C_max	When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg every 24 hours)(CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse reactions and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary .
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting were observed when coadministered with VFEND. Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse reactions may be necessary.
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Increased visual effects (heterophoria and miosis) of oxycodone were observed when coadministered with VFEND. Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary.
NSAIDsNon-Steroidal Anti-Inflammatory Drugincluding. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse reactions and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed.
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse reactions related to oral contraceptives is recommended during coadministration.
Prednisolone and other corticosteroids (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of VFEND on Prednisolone Exposure	No dosage adjustment for prednisolone when coadministered with VFEND [see Clinical Pharmacology (12.3)].
	Not Studied In Vitro or In Vivo for Other Corticosteroids, but Drug Exposure Likely to be Increased	Monitor for potential adrenal dysfunction when VFEND is administered with other corticosteroids [see Warnings and Precautions (5.8)].
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	If patients receiving coumarin preparations are treated simultaneously with voriconazole, the prothrombin time or other suitable anticoagulation tests should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly.
Other Oral Coumarin Anticoagulants (CYP2C9/3A4 Inhibition)	Not Studied In Vivo or In Vitro for other Oral Coumarin Anticoagulants, but Drug Plasma Exposure Likely to be Increased
Ivacaftor (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Dose reduction of ivacaftor is recommended. Refer to the prescribing information for ivacaftor
Eszopiclone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Sedative Effect of Eszopiclone	Dose reduction of eszopiclone is recommended. Refer to the prescribing information for eszopiclone.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with VFEND
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to NNRTI
Tretinoin (CYP3A4 Inhibition)	Although Not Studied, Voriconazole may Increase Tretinoin Concentrations and Increase the Risk of Adverse Reactions	Frequent monitoring for signs and symptoms of pseudotumor cerebri or hypercalcemia.
Midazolam (CYP3A4 Inhibition)	Significantly Increased	Increased plasma exposures may increase the risk of adverse reactions and toxicities related to benzodiazepines. Refer to drug-specific labeling for details.
Other benzodiazepines including triazolam and alprazolam (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse reactions and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Reserve azole antifungals, including voriconazole, for patients receiving a vinca alkaloid who have no alternative antifungal treatment options.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

•CYP3A4, CYP2C9, and CYP2C19 inhibitors and inducers: Adjust VFEND dosage and monitor for adverse reactions or lack of efficacy
•VFEND may increase the concentrations and activity of drugs that are CYP3A4, CYP2C9 and CYP2C19 substrates. Reduce dosage of these other drugs and monitor for adverse reactions
•Phenytoin or Efavirenz: With coadministration, increase maintenance oral and intravenous dosage of VFEND

]

•Coadministration of VFEND with tolvaptan is contraindicated because VFEND may increase tolvaptan plasma concentrations and increase risk of adverse reactions

[see

7 DRUG INTERACTIONS

Tables 10 and 11 provide the clinically significant interactions between voriconazole and other medical products.

Table 10: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_maxand AUC_τafter 200 mg every 12 hours)	Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg every 12 hours voriconazole to healthy subjectsand Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg every 24 hours)Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (300 mg every 24 hours) (CYP450 Induction)	Slight Decrease in AUC _τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours.
High-dose Ritonavir (400 mg every 12 hours) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg every 12 hours) (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (e.g., phenobarbital, mephobarbital) (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hours or from 200 mg to 400 mg orally every 12 hours (100 mg to 200 mg orally every 12 hours in patients weighing less than 40 kg).
Letermovir (CYP2C9/2C19 Induction)	Reduced	If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole.
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse reactions and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse reactions and toxicity related to voriconazole is started within 24 hours after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole
	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

Table 11: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_maxand AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg every 24 hours)Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (300 mg every 24 hours) (CYP3A4 Inhibition)	Slight Increase in AUC_τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours
High-dose Ritonavir (400 mg every 12 hours) (CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_maxor AUC_τ	Contraindicated because of significant reduction of voriconazole C_maxand AUC_τ
Low-dose Ritonavir (100 mg every 12 hours)	Slight Decrease in Ritonavir C_maxand AUC_τ	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided (due to the reduction in voriconazole C_maxand AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Pimozide, Quinidine, Ivabradine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated
Naloxegol (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Contraindicated
Tolvaptan (CYP3A4 Inhibition)	Although Not Studied Clinically, Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Tolvaptan	Contraindicated
Lurasidone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Lurasidone	Contraindicated
Finerenone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Finerenone	Contraindicated
Venetoclax (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Venetoclax Plasma Exposure Likely to be Significantly Increased	Coadministration of voriconazole is contraindicated at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering VFEND with venetoclax. Refer to the venetoclax prescribing information for dosing instructions.
Lemborexant (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of VFEND with lemborexant.
Glasdegib (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Consider alternative therapies. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions including QTc interval prolongation.
Tyrosine kinase inhibitors (including but not limited to axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of VFEND. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor is recommended. Refer to the prescribing information for the relevant product.
Cyclosporine (CYP3A4 Inhibition)	AUC_τSignificantly Increased; No Significant Effect on C_max	When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg every 24 hours)(CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse reactions and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary .
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting were observed when coadministered with VFEND. Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse reactions may be necessary.
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Increased visual effects (heterophoria and miosis) of oxycodone were observed when coadministered with VFEND. Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary.
NSAIDsNon-Steroidal Anti-Inflammatory Drugincluding. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse reactions and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed.
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse reactions related to oral contraceptives is recommended during coadministration.
Prednisolone and other corticosteroids (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of VFEND on Prednisolone Exposure	No dosage adjustment for prednisolone when coadministered with VFEND [see Clinical Pharmacology (12.3)].
	Not Studied In Vitro or In Vivo for Other Corticosteroids, but Drug Exposure Likely to be Increased	Monitor for potential adrenal dysfunction when VFEND is administered with other corticosteroids [see Warnings and Precautions (5.8)].
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	If patients receiving coumarin preparations are treated simultaneously with voriconazole, the prothrombin time or other suitable anticoagulation tests should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly.
Other Oral Coumarin Anticoagulants (CYP2C9/3A4 Inhibition)	Not Studied In Vivo or In Vitro for other Oral Coumarin Anticoagulants, but Drug Plasma Exposure Likely to be Increased
Ivacaftor (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Dose reduction of ivacaftor is recommended. Refer to the prescribing information for ivacaftor
Eszopiclone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Sedative Effect of Eszopiclone	Dose reduction of eszopiclone is recommended. Refer to the prescribing information for eszopiclone.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with VFEND
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to NNRTI
Tretinoin (CYP3A4 Inhibition)	Although Not Studied, Voriconazole may Increase Tretinoin Concentrations and Increase the Risk of Adverse Reactions	Frequent monitoring for signs and symptoms of pseudotumor cerebri or hypercalcemia.
Midazolam (CYP3A4 Inhibition)	Significantly Increased	Increased plasma exposures may increase the risk of adverse reactions and toxicities related to benzodiazepines. Refer to drug-specific labeling for details.
Other benzodiazepines including triazolam and alprazolam (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse reactions and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Reserve azole antifungals, including voriconazole, for patients receiving a vinca alkaloid who have no alternative antifungal treatment options.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

•CYP3A4, CYP2C9, and CYP2C19 inhibitors and inducers: Adjust VFEND dosage and monitor for adverse reactions or lack of efficacy
•VFEND may increase the concentrations and activity of drugs that are CYP3A4, CYP2C9 and CYP2C19 substrates. Reduce dosage of these other drugs and monitor for adverse reactions
•Phenytoin or Efavirenz: With coadministration, increase maintenance oral and intravenous dosage of VFEND

]

•Coadministration of VFEND with venetoclax at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome

[see

7 DRUG INTERACTIONS

Tables 10 and 11 provide the clinically significant interactions between voriconazole and other medical products.

Table 10: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_maxand AUC_τafter 200 mg every 12 hours)	Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg every 12 hours voriconazole to healthy subjectsand Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg every 24 hours)Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (300 mg every 24 hours) (CYP450 Induction)	Slight Decrease in AUC _τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours.
High-dose Ritonavir (400 mg every 12 hours) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg every 12 hours) (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (e.g., phenobarbital, mephobarbital) (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hours or from 200 mg to 400 mg orally every 12 hours (100 mg to 200 mg orally every 12 hours in patients weighing less than 40 kg).
Letermovir (CYP2C9/2C19 Induction)	Reduced	If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole.
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse reactions and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse reactions and toxicity related to voriconazole is started within 24 hours after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole
	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

Table 11: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_maxand AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg every 24 hours)Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (300 mg every 24 hours) (CYP3A4 Inhibition)	Slight Increase in AUC_τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours
High-dose Ritonavir (400 mg every 12 hours) (CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_maxor AUC_τ	Contraindicated because of significant reduction of voriconazole C_maxand AUC_τ
Low-dose Ritonavir (100 mg every 12 hours)	Slight Decrease in Ritonavir C_maxand AUC_τ	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided (due to the reduction in voriconazole C_maxand AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Pimozide, Quinidine, Ivabradine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated
Naloxegol (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Contraindicated
Tolvaptan (CYP3A4 Inhibition)	Although Not Studied Clinically, Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Tolvaptan	Contraindicated
Lurasidone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Lurasidone	Contraindicated
Finerenone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Finerenone	Contraindicated
Venetoclax (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Venetoclax Plasma Exposure Likely to be Significantly Increased	Coadministration of voriconazole is contraindicated at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering VFEND with venetoclax. Refer to the venetoclax prescribing information for dosing instructions.
Lemborexant (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of VFEND with lemborexant.
Glasdegib (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Consider alternative therapies. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions including QTc interval prolongation.
Tyrosine kinase inhibitors (including but not limited to axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of VFEND. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor is recommended. Refer to the prescribing information for the relevant product.
Cyclosporine (CYP3A4 Inhibition)	AUC_τSignificantly Increased; No Significant Effect on C_max	When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg every 24 hours)(CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse reactions and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary .
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting were observed when coadministered with VFEND. Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse reactions may be necessary.
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Increased visual effects (heterophoria and miosis) of oxycodone were observed when coadministered with VFEND. Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary.
NSAIDsNon-Steroidal Anti-Inflammatory Drugincluding. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse reactions and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed.
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse reactions related to oral contraceptives is recommended during coadministration.
Prednisolone and other corticosteroids (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of VFEND on Prednisolone Exposure	No dosage adjustment for prednisolone when coadministered with VFEND [see Clinical Pharmacology (12.3)].
	Not Studied In Vitro or In Vivo for Other Corticosteroids, but Drug Exposure Likely to be Increased	Monitor for potential adrenal dysfunction when VFEND is administered with other corticosteroids [see Warnings and Precautions (5.8)].
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	If patients receiving coumarin preparations are treated simultaneously with voriconazole, the prothrombin time or other suitable anticoagulation tests should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly.
Other Oral Coumarin Anticoagulants (CYP2C9/3A4 Inhibition)	Not Studied In Vivo or In Vitro for other Oral Coumarin Anticoagulants, but Drug Plasma Exposure Likely to be Increased
Ivacaftor (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Dose reduction of ivacaftor is recommended. Refer to the prescribing information for ivacaftor
Eszopiclone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Sedative Effect of Eszopiclone	Dose reduction of eszopiclone is recommended. Refer to the prescribing information for eszopiclone.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with VFEND
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to NNRTI
Tretinoin (CYP3A4 Inhibition)	Although Not Studied, Voriconazole may Increase Tretinoin Concentrations and Increase the Risk of Adverse Reactions	Frequent monitoring for signs and symptoms of pseudotumor cerebri or hypercalcemia.
Midazolam (CYP3A4 Inhibition)	Significantly Increased	Increased plasma exposures may increase the risk of adverse reactions and toxicities related to benzodiazepines. Refer to drug-specific labeling for details.
Other benzodiazepines including triazolam and alprazolam (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse reactions and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Reserve azole antifungals, including voriconazole, for patients receiving a vinca alkaloid who have no alternative antifungal treatment options.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

•CYP3A4, CYP2C9, and CYP2C19 inhibitors and inducers: Adjust VFEND dosage and monitor for adverse reactions or lack of efficacy
•VFEND may increase the concentrations and activity of drugs that are CYP3A4, CYP2C9 and CYP2C19 substrates. Reduce dosage of these other drugs and monitor for adverse reactions
•Phenytoin or Efavirenz: With coadministration, increase maintenance oral and intravenous dosage of VFEND

]

•Coadministration of VFEND with lurasidone is contraindicated since it may result in significant increases in lurasidone exposure and the potential for serious adverse reactions

[see

7 DRUG INTERACTIONS

Tables 10 and 11 provide the clinically significant interactions between voriconazole and other medical products.

Table 10: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_maxand AUC_τafter 200 mg every 12 hours)	Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg every 12 hours voriconazole to healthy subjectsand Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg every 24 hours)Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (300 mg every 24 hours) (CYP450 Induction)	Slight Decrease in AUC _τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours.
High-dose Ritonavir (400 mg every 12 hours) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg every 12 hours) (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (e.g., phenobarbital, mephobarbital) (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hours or from 200 mg to 400 mg orally every 12 hours (100 mg to 200 mg orally every 12 hours in patients weighing less than 40 kg).
Letermovir (CYP2C9/2C19 Induction)	Reduced	If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole.
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse reactions and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse reactions and toxicity related to voriconazole is started within 24 hours after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole
	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

Table 11: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_maxand AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg every 24 hours)Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (300 mg every 24 hours) (CYP3A4 Inhibition)	Slight Increase in AUC_τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours
High-dose Ritonavir (400 mg every 12 hours) (CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_maxor AUC_τ	Contraindicated because of significant reduction of voriconazole C_maxand AUC_τ
Low-dose Ritonavir (100 mg every 12 hours)	Slight Decrease in Ritonavir C_maxand AUC_τ	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided (due to the reduction in voriconazole C_maxand AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Pimozide, Quinidine, Ivabradine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated
Naloxegol (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Contraindicated
Tolvaptan (CYP3A4 Inhibition)	Although Not Studied Clinically, Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Tolvaptan	Contraindicated
Lurasidone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Lurasidone	Contraindicated
Finerenone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Finerenone	Contraindicated
Venetoclax (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Venetoclax Plasma Exposure Likely to be Significantly Increased	Coadministration of voriconazole is contraindicated at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering VFEND with venetoclax. Refer to the venetoclax prescribing information for dosing instructions.
Lemborexant (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of VFEND with lemborexant.
Glasdegib (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Consider alternative therapies. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions including QTc interval prolongation.
Tyrosine kinase inhibitors (including but not limited to axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of VFEND. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor is recommended. Refer to the prescribing information for the relevant product.
Cyclosporine (CYP3A4 Inhibition)	AUC_τSignificantly Increased; No Significant Effect on C_max	When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg every 24 hours)(CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse reactions and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary .
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting were observed when coadministered with VFEND. Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse reactions may be necessary.
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Increased visual effects (heterophoria and miosis) of oxycodone were observed when coadministered with VFEND. Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary.
NSAIDsNon-Steroidal Anti-Inflammatory Drugincluding. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse reactions and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed.
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse reactions related to oral contraceptives is recommended during coadministration.
Prednisolone and other corticosteroids (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of VFEND on Prednisolone Exposure	No dosage adjustment for prednisolone when coadministered with VFEND [see Clinical Pharmacology (12.3)].
	Not Studied In Vitro or In Vivo for Other Corticosteroids, but Drug Exposure Likely to be Increased	Monitor for potential adrenal dysfunction when VFEND is administered with other corticosteroids [see Warnings and Precautions (5.8)].
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	If patients receiving coumarin preparations are treated simultaneously with voriconazole, the prothrombin time or other suitable anticoagulation tests should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly.
Other Oral Coumarin Anticoagulants (CYP2C9/3A4 Inhibition)	Not Studied In Vivo or In Vitro for other Oral Coumarin Anticoagulants, but Drug Plasma Exposure Likely to be Increased
Ivacaftor (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Dose reduction of ivacaftor is recommended. Refer to the prescribing information for ivacaftor
Eszopiclone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Sedative Effect of Eszopiclone	Dose reduction of eszopiclone is recommended. Refer to the prescribing information for eszopiclone.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with VFEND
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to NNRTI
Tretinoin (CYP3A4 Inhibition)	Although Not Studied, Voriconazole may Increase Tretinoin Concentrations and Increase the Risk of Adverse Reactions	Frequent monitoring for signs and symptoms of pseudotumor cerebri or hypercalcemia.
Midazolam (CYP3A4 Inhibition)	Significantly Increased	Increased plasma exposures may increase the risk of adverse reactions and toxicities related to benzodiazepines. Refer to drug-specific labeling for details.
Other benzodiazepines including triazolam and alprazolam (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse reactions and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Reserve azole antifungals, including voriconazole, for patients receiving a vinca alkaloid who have no alternative antifungal treatment options.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

•CYP3A4, CYP2C9, and CYP2C19 inhibitors and inducers: Adjust VFEND dosage and monitor for adverse reactions or lack of efficacy
•VFEND may increase the concentrations and activity of drugs that are CYP3A4, CYP2C9 and CYP2C19 substrates. Reduce dosage of these other drugs and monitor for adverse reactions
•Phenytoin or Efavirenz: With coadministration, increase maintenance oral and intravenous dosage of VFEND

•

Coadministration of VFEND with finerenone is contraindicated since it may result in significant increases in finerenone exposure and the potential for serious adverse reactions

[see

7 DRUG INTERACTIONS

Tables 10 and 11 provide the clinically significant interactions between voriconazole and other medical products.

Table 10: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_maxand AUC_τafter 200 mg every 12 hours)	Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg every 12 hours voriconazole to healthy subjectsand Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg every 24 hours)Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (300 mg every 24 hours) (CYP450 Induction)	Slight Decrease in AUC _τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours.
High-dose Ritonavir (400 mg every 12 hours) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg every 12 hours) (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (e.g., phenobarbital, mephobarbital) (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hours or from 200 mg to 400 mg orally every 12 hours (100 mg to 200 mg orally every 12 hours in patients weighing less than 40 kg).
Letermovir (CYP2C9/2C19 Induction)	Reduced	If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole.
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse reactions and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse reactions and toxicity related to voriconazole is started within 24 hours after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole
	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

Table 11: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_maxand AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg every 24 hours)Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (300 mg every 24 hours) (CYP3A4 Inhibition)	Slight Increase in AUC_τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours
High-dose Ritonavir (400 mg every 12 hours) (CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_maxor AUC_τ	Contraindicated because of significant reduction of voriconazole C_maxand AUC_τ
Low-dose Ritonavir (100 mg every 12 hours)	Slight Decrease in Ritonavir C_maxand AUC_τ	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided (due to the reduction in voriconazole C_maxand AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Pimozide, Quinidine, Ivabradine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated
Naloxegol (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Contraindicated
Tolvaptan (CYP3A4 Inhibition)	Although Not Studied Clinically, Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Tolvaptan	Contraindicated
Lurasidone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Lurasidone	Contraindicated
Finerenone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Finerenone	Contraindicated
Venetoclax (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Venetoclax Plasma Exposure Likely to be Significantly Increased	Coadministration of voriconazole is contraindicated at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering VFEND with venetoclax. Refer to the venetoclax prescribing information for dosing instructions.
Lemborexant (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of VFEND with lemborexant.
Glasdegib (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Consider alternative therapies. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions including QTc interval prolongation.
Tyrosine kinase inhibitors (including but not limited to axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of VFEND. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor is recommended. Refer to the prescribing information for the relevant product.
Cyclosporine (CYP3A4 Inhibition)	AUC_τSignificantly Increased; No Significant Effect on C_max	When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg every 24 hours)(CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse reactions and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary .
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting were observed when coadministered with VFEND. Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse reactions may be necessary.
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Increased visual effects (heterophoria and miosis) of oxycodone were observed when coadministered with VFEND. Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary.
NSAIDsNon-Steroidal Anti-Inflammatory Drugincluding. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse reactions and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed.
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse reactions related to oral contraceptives is recommended during coadministration.
Prednisolone and other corticosteroids (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of VFEND on Prednisolone Exposure	No dosage adjustment for prednisolone when coadministered with VFEND [see Clinical Pharmacology (12.3)].
	Not Studied In Vitro or In Vivo for Other Corticosteroids, but Drug Exposure Likely to be Increased	Monitor for potential adrenal dysfunction when VFEND is administered with other corticosteroids [see Warnings and Precautions (5.8)].
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	If patients receiving coumarin preparations are treated simultaneously with voriconazole, the prothrombin time or other suitable anticoagulation tests should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly.
Other Oral Coumarin Anticoagulants (CYP2C9/3A4 Inhibition)	Not Studied In Vivo or In Vitro for other Oral Coumarin Anticoagulants, but Drug Plasma Exposure Likely to be Increased
Ivacaftor (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Dose reduction of ivacaftor is recommended. Refer to the prescribing information for ivacaftor
Eszopiclone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Sedative Effect of Eszopiclone	Dose reduction of eszopiclone is recommended. Refer to the prescribing information for eszopiclone.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with VFEND
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to NNRTI
Tretinoin (CYP3A4 Inhibition)	Although Not Studied, Voriconazole may Increase Tretinoin Concentrations and Increase the Risk of Adverse Reactions	Frequent monitoring for signs and symptoms of pseudotumor cerebri or hypercalcemia.
Midazolam (CYP3A4 Inhibition)	Significantly Increased	Increased plasma exposures may increase the risk of adverse reactions and toxicities related to benzodiazepines. Refer to drug-specific labeling for details.
Other benzodiazepines including triazolam and alprazolam (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse reactions and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Reserve azole antifungals, including voriconazole, for patients receiving a vinca alkaloid who have no alternative antifungal treatment options.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

•CYP3A4, CYP2C9, and CYP2C19 inhibitors and inducers: Adjust VFEND dosage and monitor for adverse reactions or lack of efficacy
•VFEND may increase the concentrations and activity of drugs that are CYP3A4, CYP2C9 and CYP2C19 substrates. Reduce dosage of these other drugs and monitor for adverse reactions
•Phenytoin or Efavirenz: With coadministration, increase maintenance oral and intravenous dosage of VFEND

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