VFEND (VORICONAZOLE) injection, powder, lyophilized, for solution
Roerig

Roerig
Pfizer Inc
Pharmacia & Upjohn Company LLC
Pfizer Ireland Pharmaceuticals
Upjohn Manufacturing Ireland Unlimited Company
VFEND
VORICONAZOLE
VORICONAZOLE
VORICONAZOLE
BETADEX SULFOBUTYL ETHER SODIUM

Warnings and Precautions, Photosensitivity (5.6)

10/2022

1 INDICATIONS AND USAGE

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)
  • Candidemia in non-neutropenics and other deep tissue Candida infections (1.2)
  • Esophageal candidiasis (1.3)
  • Serious fungal infections caused by Scedosporium apiospermum and Fusarium species including Fusarium solani, in patients intolerant of, or refractory to, other therapy (1.4)

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)].

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)].

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) in adults and pediatric patients 2 years of age and older [see Clinical Studies (14.3, 14.5) and Microbiology (12.4)].

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)].

1.5 Usage

Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.

2 DOSAGE AND ADMINISTRATION

  • Dosage in Adults (2.3)

Infection

Loading dose

Maintenance Dose

Intravenous infusion

Intravenous infusion

Oral

Invasive Aspergillosis

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

4 mg/kg every 12 hours

200 mg every 12 hours

Candidemia in nonneutropenics and other deep tissue Candida infections

3–4 mg/kg every 12 hours

200 mg every 12 hours

Scedosporiosis and Fusariosis

4 mg/kg every 12 hours

200 mg every 12 hours

Esophageal Candidiasis

Not Evaluated

Not Evaluated

200 mg 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)
  • o Renal Impairment: Avoid intravenous administration in adult patients with moderate to severe renal impairment (creatinine clearance <50 mL/min) (2.6)
  • Dosage in Pediatric Patients 2 years of age and older (2.4)
  • 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

Intravenous infusion

Oral

Invasive Aspergillosis

9 mg/kg every12 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)

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)

  • 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)
  • oDosage adjustment of VFEND in pediatric patients with renal or hepatic impairment has not been established (2.5, 2.6)
  • See full prescribing information for instructions on reconstitution of VFEND lyophilized powder for intravenous use and important administration instructions (2.1, 2.6, 2.7)

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.

2.2 Use of VFEND I.V. with Other Parenteral Drug Products

Blood products and concentrated electrolytes

VFEND I.V. must not be infused concomitantly with any blood product or short-term infusion of concentrated electrolytes, even if the two infusions are running in separate intravenous lines (or cannulas). Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of and during VFEND therapy [see Warnings and Precautions (5.10)].

Intravenous solutions containing (non-concentrated) electrolytes

VFEND I.V. can be infused at the same time as other intravenous solutions containing (non-concentrated) electrolytes, but must be infused through a separate line.

Total parenteral nutrition (TPN)

VFEND I.V. can be infused at the same time as total parenteral nutrition, but must be infused in a separate line. If infused through a multiple-lumen catheter, TPN needs to be administered using a different port from the one used for VFEND I.V.

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 (AUCτ) similar to a 3 mg/kg intravenous infusion every 12 hours dose; the 300 mg oral every 12 hours dose provided an exposure (AUCτ) similar to a 4 mg/kg intravenous infusion every 12 hours dose (12).

Intravenous infusion

Intravenous infusion

Oral Adult patients who weigh less than 40 kg should receive half of the oral maintenance dose.

 

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

 

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

 

Esophageal Candidiasis

Not EvaluatedNot evaluated in patients with EC.

Not Evaluated

200 mg 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

Method for Adjusting the Dosing Regimen in Adults

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

If 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)].

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

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.

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)

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.

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)

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 steps or 50 mg steps to a maximum of 350 mg every 12 hours. If patients are unable to tolerate the initial intravenous maintenance dose, reduce the dose by 1 mg/kg steps. If patients are unable to tolerate the oral maintenance dose, reduce the dose by 1 mg/kg or 50 mg 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)].

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)].

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)].

2.8 Preparation and Intravenous Administration of VFEND for Injection

Reconstitution

The powder is reconstituted with 19 mL of Water For Injection to obtain an extractable volume of 20 mL of clear concentrate containing 10 mg/mL of voriconazole. It is recommended that a standard 20 mL (non-automated) syringe be used to ensure that the exact amount (19.0 mL) of Water for Injection is dispensed. Discard the vial if a vacuum does not pull the diluent into the vial. Shake the vial until all the powder is dissolved.

Dilution

VFEND must be infused over 1 to 3 hours, at a concentration of 5 mg/mL or less. Therefore, the required volume of the 10 mg/mL VFEND concentrate should be further diluted as follows (appropriate diluents listed below):

  • 1.Calculate the volume of 10 mg/mL VFEND concentrate required based on the patient's weight (see Table 3).
  • 2.In order to allow the required volume of VFEND concentrate to be added, withdraw and discard at least an equal volume of diluent from the infusion bag or bottle to be used. The volume of diluent remaining in the bag or bottle should be such that when the 10 mg/mL VFEND concentrate is added, the final concentration is not less than 0.5 mg/mL nor greater than 5 mg/mL.
  • 3.Using a suitable size syringe and aseptic technique, withdraw the required volume of VFEND concentrate from the appropriate number of vials and add to the infusion bag or bottle. Discard Partially Used Vials.

The final VFEND solution must be infused over 1 to 3 hours at a maximum rate of 3 mg/kg per hour.

Table 3: Required Volumes of 10 mg/mL VFEND Concentrate

Body Weight
(kg)

Volume of VFEND Concentrate (10 mg/mL) required for:

3 mg/kg dose
(number of vials)

4 mg/kg dose
(number of vials)

6 mg/kg dose
(number of vials)

8 mg/kg dose
(number of vials)

9 mg/kg dose
(number of vials)

10

-

4 mL (1)

-

8 mL (1)

9 mL (1)

15

-

6 mL (1)

-

12 mL (1)

13.5 mL (1)

20

-

8 mL (1)

-

16 mL (1)

18 mL (1)

25

-

10 mL (1)

-

20 mL (1)

22.5 mL (2)

30

9 mL (1)

12 mL (1)

18 mL (1)

24 mL (2)

27 mL (2)

35

10.5 mL (1)

14 mL (1)

21 mL (2)

28 mL (2)

31.5 mL (2)

40

12 mL (1)

16 mL (1)

24 mL (2)

32 mL (2)

36 mL (2)

45

13.5 mL (1)

18 mL (1)

27 mL (2)

36 mL (2)

40.5 mL (3)

50

15 mL (1)

20 mL (1)

30 mL (2)

40 mL (2)

45 mL (3)

55

16.5 mL (1)

22 mL (2)

33 mL (2)

44 mL (3)

49.5 mL (3)

60

18 mL (1)

24 mL (2)

36 mL (2)

48 mL (3)

54 mL (3)

65

19.5 mL (1)

26 mL (2)

39 mL (2)

52 mL (3)

58.5 mL (3)

70

21 mL (2)

28 mL (2)

42 mL (3)

-

-

75

22.5 mL (2)

30 mL (2)

45 mL (3)

-

-

80

24 mL (2)

32 mL (2)

48 mL (3)

-

-

85

25.5 mL (2)

34 mL (2)

51 mL (3)

-

-

90

27 mL (2)

36 mL (2)

54 mL (3)

-

-

95

28.5 mL (2)

38 mL (2)

57 mL (3)

-

-

100

30 mL (2)

40 mL (2)

60 mL (3)

-

-

VFEND I.V. for Injection is a single-dose unpreserved sterile lyophile. Therefore, from a microbiological point of view, once reconstituted, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2°C to 8°C (36°F to 46°F). This medicinal product is for single use only and any unused solution should be discarded. Only clear solutions without particles should be used.

The reconstituted solution can be diluted with:

0.9% Sodium Chloride USP

Lactated Ringers USP

5% Dextrose and Lactated Ringers USP

5% Dextrose and 0.45% Sodium Chloride USP

5% Dextrose USP

5% Dextrose and 20 mEq Potassium Chloride USP

0.45% Sodium Chloride USP

5% Dextrose and 0.9% Sodium Chloride USP

The compatibility of VFEND I.V. with diluents other than those described above is unknown (see Incompatibilities below).

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Incompatibilities

VFEND I.V. must not be diluted with 4.2% Sodium Bicarbonate Infusion. The mildly alkaline nature of this diluent caused slight degradation of VFEND after 24 hours storage at room temperature. Although refrigerated storage is recommended following reconstitution, use of this diluent is not recommended as a precautionary measure. Compatibility with other concentrations is unknown.

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 (3)

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).

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, and 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)].
  • Hypersensitivity to voriconazole or its excipients (4)
  • Coadministration with pimozide, quinidine, sirolimus or ivabradine due to risk of serious adverse reactions (4, 7)
  • Coadministration with rifampin, carbamazepine, long-acting barbiturates, efavirenz, ritonavir, rifabutin, ergot alkaloids, and St. John's Wort due to risk of loss of efficacy (4, 7)
  • Coadministration with naloxegol, tolvaptan, and lurasidone due to risk of adverse reactions (4, 7)
  • 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 (4, 7)

5 WARNINGS AND PRECAUTIONS

  • Hepatic Toxicity: Serious hepatic reactions reported. Evaluate liver function tests at start of and during VFEND therapy (5.1)
  • Arrhythmias and QT Prolongation: Correct potassium, magnesium, and calcium prior to use; caution patients with proarrhythmic conditions (5.2)
  • Infusion Related Reactions (including anaphylaxis): Stop the infusion (5.3)
  • Visual Disturbances (including optic neuritis and papilledema): Monitor visual function if treatment continues beyond 28 days (5.4)
  • Severe Cutaneous Adverse Reactions: Discontinue for exfoliative cutaneous reactions (5.5)
  • Photosensitivity: Avoid sunlight due to risk of photosensitivity (5.6)
  • Adrenal Dysfunction: Carefully monitor patients receiving VFEND and corticosteroids (via all routes of administration) for adrenal dysfunction both during and after VFEND treatment. Instruct patients to seek immediate medical care if they develop signs and symptoms of Cushing's syndrome or adrenal insufficiency (5.8)
  • Embryo-Fetal Toxicity: Voriconazole can cause fetal harm when administered to a pregnant woman. Inform pregnant patients of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during treatment with VFEND (5.9, 8.1, 8.3)
  • Skeletal Adverse Reactions: Fluorosis and periostitis with long-term voriconazole therapy. Discontinue if these adverse reactions occur (5.12)
  • Clinically Significant Drug Interactions: Review patient's concomitant medications (5.13, 7)

5.1 Hepatic Toxicity

In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with VFEND (including clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities). Instances of hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly hematological malignancy). Hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. Liver dysfunction has usually been reversible on discontinuation of therapy [see Adverse Reactions (6.1)].

A higher frequency of liver enzyme elevations was observed in the pediatric population [see Adverse Reactions (6.1)]. Hepatic function should be monitored in both adult and pediatric patients.

Measure serum transaminase levels and bilirubin at the initiation of VFEND therapy and monitor at least weekly for the first month of treatment. Monitoring frequency can be reduced to monthly during continued use if no clinically significant changes are noted. If liver function tests become markedly elevated compared to baseline, VFEND should be discontinued unless the medical judgment of the benefit/risk of the treatment for the patient justifies continued use [see Dosage and Administration (2.5), and Adverse Reactions (6.1)].

5.2 Arrhythmias and QT Prolongation

Some azoles, including VFEND, have been associated with prolongation of the QT interval on the electrocardiogram. During clinical development and postmarketing surveillance, there have been rare cases of arrhythmias, (including ventricular arrhythmias such as torsade de pointes), cardiac arrests and sudden deaths in patients taking voriconazole. These cases usually involved seriously ill patients with multiple confounding risk factors, such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant medications that may have been contributory.

VFEND should be administered with caution to patients with potentially proarrhythmic conditions, such as:

Rigorous attempts to correct potassium, magnesium and calcium should be made before starting and during voriconazole therapy [see Clinical Pharmacology (12.3)].

5.3 Infusion Related Reactions

During infusion of the intravenous formulation of VFEND in healthy subjects, anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus and rash, have occurred uncommonly. Symptoms appeared immediately upon initiating the infusion. Consideration should be given to stopping the infusion should these reactions occur.

5.4 Visual Disturbances

The effect of VFEND on visual function is not known if treatment continues beyond 28 days. There have been postmarketing reports of prolonged visual adverse reactions, including optic neuritis and papilledema. If treatment continues beyond 28 days, visual function including visual acuity, visual field, and color perception should be monitored [see Adverse Reactions (6.2)].

5.5 Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with VFEND. If a patient develops a severe cutaneous adverse reaction, VFEND should be discontinued [see Adverse Reactions (6.1, 6.2)].

5.6 Photosensitivity

VFEND has been associated with photosensitivity skin reaction. Patients, including pediatric patients, should avoid exposure to direct sunlight during VFEND treatment and should use measures such as protective clothing and sunscreen with high sun protection factor (SPF). If phototoxic reactions occur, the patient should be referred to a dermatologist and VFEND discontinuation should be considered. If VFEND is continued despite the occurrence of phototoxicity-related lesions, dermatologic evaluation should be performed on a systematic and regular basis to allow early detection and management of premalignant lesions. Squamous cell carcinoma of the skin (including cutaneous SCC in situ, or Bowen’s disease) and melanoma have been reported during long-term VFEND therapy in patients with photosensitivity skin reactions. If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, VFEND should be discontinued. In addition, VFEND has been associated with photosensitivity related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus, as well as increased risk of skin toxicity with concomitant use of methotrexate, a drug associated with ultraviolet (UV) reactivation. There is the potential for this risk to be observed with other drugs associated with UV reactivation. Patients should avoid strong, direct sunlight during VFEND therapy.

The frequency of phototoxicity reactions is higher in the pediatric population. Because squamous cell carcinoma has been reported in patients who experience photosensitivity reactions, stringent measures for photoprotection are warranted in children. In children experiencing photoaging injuries such as lentigines or ephelides, sun avoidance and dermatologic follow-up are recommended even after treatment discontinuation.

5.7 Renal Toxicity

Acute renal failure has been observed in patients undergoing treatment with VFEND. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and may have concurrent conditions that may result in decreased renal function.

Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation of serum creatinine [see Clinical Pharmacology (12.3) and Dosage and Administration (2.6)].

5.8 Adrenal Dysfunction

Reversible cases of azole-induced adrenal insufficiency have been reported in patients receiving azoles, including VFEND. Adrenal insufficiency has been reported in patients receiving azoles with or without concomitant corticosteroids. In patients receiving azoles without corticosteroids adrenal insufficiency is related to direct inhibition of steroidogenesis by azoles. In patients taking corticosteroids, voriconazole associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression [see Drug Interactions (7) and Clinical Pharmacology (12.3)]. Cushing's syndrome with and without subsequent adrenal insufficiency has also been reported in patients receiving VFEND concomitantly with corticosteroids.

Patients receiving VFEND and corticosteroids (via all routes of administration) should be carefully monitored for adrenal dysfunction both during and after VFEND treatment. Patients should be instructed to seek immediate medical care if they develop signs and symptoms of Cushing's syndrome or adrenal insufficiency.

5.9 Embryo-Fetal Toxicity

Voriconazole can cause fetal harm when administered to a pregnant woman.

In animals, voriconazole administration was associated with fetal malformations, embryotoxicity, increased gestational length, dystocia and embryomortality [see Use in Specific Populations (8.1)].

If VFEND is used during pregnancy, or if the patient becomes pregnant while taking VFEND, inform the patient of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during treatment with VFEND [see Use in Specific Populations (8.3)].

5.10 Laboratory Tests

Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of and during VFEND therapy.

Patient management should include laboratory evaluation of renal (particularly serum creatinine) and hepatic function (particularly liver function tests and bilirubin).

5.11 Pancreatitis

Pancreatitis has been observed in patients undergoing treatment with VFEND [see Adverse Reactions (6.1, 6.2)] Patients with risk factors for acute pancreatitis (e.g., recent chemotherapy, hematopoietic stem cell transplantation [HSCT]) should be monitored for the development of pancreatitis during VFEND treatment.

5.12 Skeletal Adverse Reactions

Fluorosis and periostitis have been reported during long-term VFEND therapy. If a patient develops skeletal pain and radiologic findings compatible with fluorosis or periostitis, VFEND should be discontinued [see Adverse Reactions (6.2)].

5.13 Clinically Significant Drug Interactions

See Table 10 for a listing of drugs that may significantly alter voriconazole concentrations. Also, see Table 11 for a listing of drugs that may interact with voriconazole resulting in altered pharmacokinetics or pharmacodynamics of the other drug [see Contraindications (4) and Drug Interactions (7)].

6 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling:

Hepatic Toxicity [see Warnings and Precautions (5.1)]

Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2)]

Infusion Related Reactions [see Warnings and Precautions (5.3)]

Visual Disturbances [see Warnings and Precautions (5.4)]

Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5)]

Photosensitivity [see Warnings and Precautions (5.6)]

Renal Toxicity [see Warnings and Precautions (5.7)]

  • Adult Patients: The most common adverse reactions (incidence ≥2%) were visual disturbances, fever, nausea, rash, vomiting, chills, headache, liver function test abnormal, tachycardia, hallucinations (6)
  • Pediatric Patients: The most common adverse reactions (incidence ≥5%) were visual disturbances, pyrexia, vomiting, epistaxis, nausea, rash, abdominal pain, diarrhea, hypertension, hypokalemia, cough, headache, thrombocytopenia, ALT abnormal, hypotension, peripheral edema, hyperglycemia, tachycardia, dyspnea, hypocalcemia, hypophosphatemia, LFT abnormal, mucosal inflammation, photophobia, abdominal distention, constipation, dizziness, hallucinations, hemoptysis, hypoalbuminemia, hypomagnesemia, renal impairment, upper respiratory tract infection (6)

To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials Experience in Adults

Overview

The most frequently reported adverse reactions (see Table 4) in the adult therapeutic trials were visual disturbances (18.7%), fever (5.7%), nausea (5.4%), rash (5.3%), vomiting (4.4%), chills (3.7%), headache (3.0%), liver function test increased (2.7%), tachycardia (2.4%), hallucinations (2.4%). The adverse reactions which most often led to discontinuation of voriconazole therapy were elevated liver function tests, rash, and visual disturbances [see Warning and Precautions (5.1, 5.4) and Adverse Reactions (6.1)].

The data described in Table 4 reflect exposure to voriconazole in 1655 patients in nine therapeutic studies. This represents a heterogeneous population, including immunocompromised patients, e.g., patients with hematological malignancy or HIV and non-neutropenic patients. This subgroup does not include healthy subjects and patients treated in the compassionate use and non-therapeutic studies. This patient population was 62% male, had a mean age of 46 years (range 11–90, including 51 patients aged 12–18 years), and was 78% White and 10% Black. Five hundred sixty one patients had a duration of voriconazole therapy of greater than 12 weeks, with 136 patients receiving voriconazole for over six months. Table 4 includes all adverse reactions which were reported at an incidence of ≥2% during voriconazole therapy in the all therapeutic studies population, studies 307/602 and 608 combined, or study 305, as well as events of concern which occurred at an incidence of <2%.

In study 307/602, 381 patients (196 on voriconazole, 185 on amphotericin B) were treated to compare voriconazole to amphotericin B followed by other licensed antifungal therapy (OLAT) in the primary treatment of patients with acute IA. The rate of discontinuation from voriconazole study medication due to adverse reactions was 21.4% (42/196 patients). In study 608, 403 patients with candidemia were treated to compare voriconazole (272 patients) to the regimen of amphotericin B followed by fluconazole (131 patients). The rate of discontinuation from voriconazole study medication due to adverse reactions was 19.5% out of 272 patients. Study 305 evaluated the effects of oral voriconazole (200 patients) and oral fluconazole (191 patients) in the treatment of EC. The rate of discontinuation from voriconazole study medication in Study 305 due to adverse reactions was 7% (14/200 patients). Laboratory test abnormalities for these studies are discussed under Clinical Laboratory Values below.

Table 4: Adverse Reactions Rate ≥ 2% on Voriconazole or Adverse Reactions of Concern in Therapeutic Studies Population, Studies 307/602–608 Combined, or Study 305. Possibly Related to Therapy or Causality UnknownStudy 307/602: IA; Study 608: candidemia; Study 305: EC

Therapeutic Studies Studies 303, 304, 305, 307, 309, 602, 603, 604, 608

Studies 307/602 and 608
(IV/ oral therapy)

Study 305
(oral therapy)

Voriconazole
N=1655

Voriconazole
N=468

Ampho B Amphotericin B followed by other licensed antifungal therapy
N=185

Ampho B→ Fluconazole
N=131

Voriconazole
N=200

Fluconazole
N=191

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

 

Special Senses See Warnings and Precautions (5.4)

Abnormal vision

310 (18.7)

63 (13.5)

1 (0.5)

0

31 (15.5)

8 (4.2)

Photophobia

37 (2.2)

8 (1.7)

0

0

5 (2.5)

2 (1.0)

Chromatopsia

20 (1.2)

2 (0.4)

0

0

2 (1.0)

0

 

Body as a Whole

Fever

94 (5.7)

8 (1.7)

25 (13.5)

5 (3.8)

0

0

Chills

61 (3.7)

1 (0.2)

36 (19.5)

8 (6.1)

1 (0.5)

0

Headache

49 (3.0)

9 (1.9)

8 (4.3)

1 (0.8)

0

1 (0.5)

 

Cardiovascular System

Tachycardia

39 (2.4)

6 (1.3)

5 (2.7)

0

0

0

 

Digestive System

Nausea

89 (5.4)

18 (3.8)

29 (15.7)

2 (1.5)

2 (1.0)

3 (1.6)

Vomiting

72 (4.4)

15 (3.2)

18 (9.7)

1 (0.8)

2 (1.0)

1 (0.5)

Liver function tests abnormal

45 (2.7)

15 (3.2)

4 (2.2)

1 (0.8)

6 (3.0)

2 (1.0)

Cholestatic jaundice

17 (1.0)

8 (1.7)

0

1 (0.8)

3 (1.5)

0

 

Metabolic and Nutritional Systems

Alkaline phosphatase increased

59 (3.6)

19 (4.1)

4 (2.2)

3 (2.3)

10 (5.0)

3 (1.6)

Hepatic enzymes increased

30 (1.8)

11 (2.4)

5 (2.7)

1 (0.8)

3 (1.5)

0

SGOT increased

31 (1.9)

9 (1.9)

0

1 (0.8)

8 (4.0)

2 (1.0)

SGPT increased

29 (1.8)

9 (1.9)

1 (0.5)

2 (1.5)

6 (3.0)

2 (1.0)

Hypokalemia

26 (1.6)

3 (0.6)

36 (19.5)

16 (12.2)

0

0

Bilirubinemia

15 (0.9)

5 (1.1)

3 (1.6)

2 (1.5)

1 (0.5)

0

Creatinine increased

4 (0.2)

0

59 (31.9)

10 (7.6)

1 (0.5)

0

 

Nervous System

Hallucinations

39 (2.4)

13 (2.8)

1 (0.5)

0

0

0

 

Skin and Appendages

Rash

88 (5.3)

20 (4.3)

7 (3.8)

1 (0.8)

3 (1.5)

1 (0.5)

 

Urogenital

Kidney function abnormal

10 (0.6)

6 (1.3)

40 (21.6)

9 (6.9)

1 (0.5)

1 (0.5)

Acute kidney failure

7 (0.4)

2 (0.4)

11 (5.9)

7 (5.3)

0

0

Visual Disturbances

VFEND treatment-related visual disturbances are common. In therapeutic trials, approximately 21% of patients experienced abnormal vision, color vision change and/or photophobia. Visual disturbances may be associated with higher plasma concentrations and/or doses.

The mechanism of action of the visual disturbance is unknown, although the site of action is most likely to be within the retina. In a study in healthy subjects investigating the effect of 28-day treatment with voriconazole on retinal function, VFEND caused a decrease in the electroretinogram (ERG) waveform amplitude, a decrease in the visual field, and an alteration in color perception. The ERG measures electrical currents in the retina. These effects were noted early in administration of VFEND and continued through the course of study drug treatment. Fourteen days after the end of dosing, ERG, visual fields and color perception returned to normal [see Warnings and Precautions (5.4)].

Dermatological Reactions

Dermatological reactions were common in patients treated with VFEND. The mechanism underlying these dermatologic adverse reactions remains unknown.

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported during treatment with VFEND. Erythema multiforme has also been reported during treatment with VFEND [see Warnings and Precautions (5.5) and Adverse Reactions (6.2)].

VFEND has also been associated with additional photosensitivity related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus [see Warnings and Precautions (5.6) and Adverse Reactions (6.2) ].

Less Common Adverse Reactions

The following adverse reactions occurred in <2% of all voriconazole-treated patients in all therapeutic studies (N=1655). This listing includes events where a causal relationship to voriconazole cannot be ruled out or those which may help the physician in managing the risks to the patients. The list does not include events included in Table 4 above and does not include every event reported in the voriconazole clinical program.

Body as a Whole: abdominal pain, abdomen enlarged, allergic reaction, anaphylactoid reaction [see Warnings and Precautions (5.3)], ascites, asthenia, back pain, chest pain, cellulitis, edema, face edema, flank pain, flu syndrome, graft versus host reaction, granuloma, infection, bacterial infection, fungal infection, injection site pain, injection site infection/inflammation, mucous membrane disorder, multi-organ failure, pain, pelvic pain, peritonitis, sepsis, substernal chest pain.

Cardiovascular: atrial arrhythmia, atrial fibrillation, AV block complete, bigeminy, bradycardia, bundle branch block, cardiomegaly, cardiomyopathy, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident, congestive heart failure, deep thrombophlebitis, endocarditis, extrasystoles, heart arrest, hypertension, hypotension, myocardial infarction, nodal arrhythmia, palpitation, phlebitis, postural hypotension, pulmonary embolus, QT interval prolonged, supraventricular extrasystoles, supraventricular tachycardia, syncope, thrombophlebitis, vasodilatation, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia (including torsade de pointes) [see Warnings and Precautions (5.2)].

Digestive: anorexia, cheilitis, cholecystitis, cholelithiasis, constipation, diarrhea, duodenal ulcer perforation, duodenitis, dyspepsia, dysphagia, dry mouth, esophageal ulcer, esophagitis, flatulence, gastroenteritis, gastrointestinal hemorrhage, GGT/LDH elevated, gingivitis, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hepatic coma, hepatic failure, hepatitis, intestinal perforation, intestinal ulcer, jaundice, enlarged liver, melena, mouth ulceration, pancreatitis, parotid gland enlargement, periodontitis, proctitis, pseudomembranous colitis, rectal disorder, rectal hemorrhage, stomach ulcer, stomatitis, tongue edema.

Endocrine: adrenal cortex insufficiency, diabetes insipidus, hyperthyroidism, hypothyroidism.

Hemic and Lymphatic: agranulocytosis, anemia (macrocytic, megaloblastic, microcytic, normocytic), aplastic anemia, hemolytic anemia, bleeding time increased, cyanosis, DIC, ecchymosis, eosinophilia, hypervolemia, leukopenia, lymphadenopathy, lymphangitis, marrow depression, pancytopenia, petechia, purpura, enlarged spleen, thrombocytopenia, thrombotic thrombocytopenic purpura.

Metabolic and Nutritional: albuminuria, BUN increased, creatine phosphokinase increased, edema, glucose tolerance decreased, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperuricemia, hypocalcemia, hypoglycemia, hypomagnesemia, hyponatremia, hypophosphatemia, peripheral edema, uremia.

Musculoskeletal: arthralgia, arthritis, bone necrosis, bone pain, leg cramps, myalgia, myasthenia, myopathy, osteomalacia, osteoporosis.

Nervous System: abnormal dreams, acute brain syndrome, agitation, akathisia, amnesia, anxiety, ataxia, brain edema, coma, confusion, convulsion, delirium, dementia, depersonalization, depression, diplopia, dizziness, encephalitis, encephalopathy, euphoria, Extrapyramidal Syndrome, grand mal convulsion, Guillain-Barré syndrome, hypertonia, hypesthesia, insomnia, intracranial hypertension, libido decreased, neuralgia, neuropathy, nystagmus, oculogyric crisis, paresthesia, psychosis, somnolence, suicidal ideation, tremor, vertigo.

Respiratory System: cough increased, dyspnea, epistaxis, hemoptysis, hypoxia, lung edema, pharyngitis, pleural effusion, pneumonia, respiratory disorder, respiratory distress syndrome, respiratory tract infection, rhinitis, sinusitis, voice alteration.

Skin and Appendages: alopecia, angioedema, contact dermatitis, discoid lupus erythematosis, eczema, erythema multiforme, exfoliative dermatitis, fixed drug eruption, furunculosis, herpes simplex, maculopapular rash, melanoma, melanosis, photosensitivity skin reaction, pruritus, pseudoporphyria, psoriasis, skin discoloration, skin disorder, skin dry, Stevens-Johnson syndrome, squamous cell carcinoma (including cutaneous SCC in situ, or Bowen’s disease), sweating, toxic epidermal necrolysis, urticaria.

Special Senses: abnormality of accommodation, blepharitis, color blindness, conjunctivitis, corneal opacity, deafness, ear pain, eye pain, eye hemorrhage, dry eyes, hypoacusis, keratitis, keratoconjunctivitis, mydriasis, night blindness, optic atrophy, optic neuritis, otitis externa, papilledema, retinal hemorrhage, retinitis, scleritis, taste loss, taste perversion, tinnitus, uveitis, visual field defect.

Urogenital: anuria, blighted ovum, creatinine clearance decreased, dysmenorrhea, dysuria, epididymitis, glycosuria, hemorrhagic cystitis, hematuria, hydronephrosis, impotence, kidney pain, kidney tubular necrosis, metrorrhagia, nephritis, nephrosis, oliguria, scrotal edema, urinary incontinence, urinary retention, urinary tract infection, uterine hemorrhage, vaginal hemorrhage.

Clinical Laboratory Values in Adults

The overall incidence of transaminase increases >3× upper limit of normal (not necessarily comprising an adverse reaction) was 17.7% (268/1514) in adult subjects treated with VFEND for therapeutic use in pooled clinical trials. Increased incidence of liver function test abnormalities may be associated with higher plasma concentrations and/or doses. The majority of abnormal liver function tests either resolved during treatment without dose adjustment or resolved following dose adjustment, including discontinuation of therapy.

VFEND has been infrequently associated with cases of serious hepatic toxicity including cases of jaundice and rare cases of hepatitis and hepatic failure leading to death. Most of these patients had other serious underlying conditions.

Liver function tests should be evaluated at the start of and during the course of VFEND therapy. Patients who develop abnormal liver function tests during VFEND therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of VFEND must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to VFEND [see Warnings and Precautions (5.1)].

Acute renal failure has been observed in severely ill patients undergoing treatment with VFEND. Patients being treated with VFEND are likely to be treated concomitantly with nephrotoxic medications and may have concurrent conditions that can result in decreased renal function. It is recommended that patients are monitored for the development of abnormal renal function. This should include laboratory evaluation of serum creatinine.

Tables 5 to 7 show the number of patients with hypokalemia and clinically significant changes in renal and liver function tests in three randomized, comparative multicenter studies. In study 305, patients with EC were randomized to either oral VFEND or oral fluconazole. In study 307/602, patients with definite or probable IA were randomized to either VFEND or amphotericin B therapy. In study 608, patients with candidemia were randomized to either VFEND or the regimen of amphotericin B followed by fluconazole.

Table 5: Protocol 305 – Patients with Esophageal Candidiasis Clinically Significant Laboratory Test Abnormalities
n = number of patients with a clinically significant abnormality while on study therapy
N = total number of patients with at least one observation of the given lab test while on study therapy
AST = Aspartate aminotransferase; ALT= alanine aminotransferase
ULN = upper limit of normal

Criteria Without regard to baseline value

Voriconazole

Fluconazole

n/N (%)

n /N (%)

 

T. Bilirubin

>1.5× ULN

8/185 (4.3)

7/186 (3.8)

AST

>3.0× ULN

38/187 (20.3)

15/186 (8.1)

ALT

>3.0× ULN

20/187 (10.7)

12/186 (6.5)

Alkaline Phosphatase

>3.0× ULN

19/187 (10.2)

14/186 (7.5)

Table 6: Protocol 307/602 – Primary Treatment of Invasive Aspergillosis Clinically Significant Laboratory Test Abnormalities
n = number of patients with a clinically significant abnormality while on study therapy
N = total number of patients with at least one observation of the given lab test while on study therapy
AST = Aspartate aminotransferase; ALT= alanine aminotransferase
ULN = upper limit of normal
LLN = lower limit of normal

Criteria Without regard to baseline value

Voriconazole

Amphotericin B Amphotericin B followed by other licensed antifungal therapy

n/N (%)

n/N (%)

 

T. Bilirubin

>1.5× ULN

35/180 (19.4)

46/173 (26.6)

AST

>3.0× ULN

21/180 (11.7)

18/174 (10.3)

ALT

>3.0× ULN

34/180 (18.9)

40/173 (23.1)

Alkaline Phosphatase

>3.0× ULN

29/181 (16.0)

38/173 (22.0)

Creatinine

>1.3× ULN

39/182 (21.4)

102/177 (57.6)

Potassium

<0.9× LLN

30/181 (16.6)

70/178 (39.3)

Table 7: Protocol 608 – Treatment of Candidemia Clinically Significant Laboratory Test Abnormalities
n = number of patients with a clinically significant abnormality while on study therapy
N = total number of patients with at least one observation of the given lab test while on study therapy
AST = Aspartate aminotransferase; ALT= alanine aminotransferase
ULN = upper limit of normal
LLN = lower limit of normal

Criteria Without regard to baseline value

Voriconazole

Amphotericin B followed by Fluconazole

n/N (%)

n/N (%)

 

T. Bilirubin

>1.5× ULN

50/261 (19.2)

31/115 (27.0)

AST

>3.0× ULN

40/261 (15.3)

16/116 (13.8)

ALT

>3.0× ULN

22/261 (8.4)

15/116 (12.9)

Alkaline Phosphatase

>3.0× ULN

59/261 (22.6)

26/115 (22.6)

Creatinine

>1.3× ULN

39/260 (15.0)

32/118 (27.1)

Potassium

<0.9× LLN

43/258 (16.7)

35/118 (29.7)

Clinical Trials Experience in Pediatric Patients

The safety of VFEND was investigated in 105 pediatric patients aged 2 to less than 18 years, including 52 pediatric patients less than 18 years of age who were enrolled in the adult therapeutic studies.

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation

In clinical studies, serious adverse reactions occurred in 46% (48/105) of VFEND treated pediatric patients. Treatment discontinuations due to adverse reactions occurred in 12 /105 (11%) of all patients. Hepatic adverse reactions (i.e. ALT increased; liver function test abnormal; jaundice) 6% (6/105) accounted for the majority of VFEND treatment discontinuations.

Most Common Adverse Reactions

The most common adverse reactions occurring in ≥5% of pediatric patients receiving VFEND in the pooled pediatric clinical trials are displayed by body system, in Table 8.

Table 8: Adverse Reactions Occurring in ≥5% of Pediatric Patients Receiving VFEND in the Pooled Pediatric Clinical Trials
Abbreviations: ALT = alanine aminotransferase; LFT = liver function test

Body System

Adverse Reaction

Pooled Pediatric Data Reflects all adverse reactions and not treatment-related only.
N=105
n (%)

Blood and Lymphatic Systems Disorders

Thrombocytopenia

10 (10)

Cardiac Disorders

Tachycardia

7 (7)

Eye Disorders

Visual DisturbancesPooled reports include such terms as: amaurosis (partial or total blindness without visible change in the eye); asthenopia (eye strain); chromatopsia (abnormally colored vision); color blindness; diplopia; photopsia; retinal disorder; vision blurred, visual acuity decreased, visual brightness; visual impairment. Several patients had more than one visual disturbance.

27 (26)

Photophobia

6 (6)

Gastrointestinal Disorders

Vomiting

21 (20)

Nausea

14 (13)

Abdominal painPooled reports include such terms as: abdominal pain and abdominal pain, upper.

13 (12)

Diarrhea

12 (11)

Abdominal distention

5 (5)

Constipation

5 (5)

General Disorders and Administration Site Conditions

Pyrexia

25 (25)

Peripheral edema

9 (9)

Mucosal inflammation

6 (6)

Infections and Infestations

Upper respiratory tract infection

5 (5)

Investigations

ALT abnormalPooled reports include such terms as: ALT abnormal and ALT increased.

9 (9)

LFT abnormal

6 (6)

Metabolism and Nutrition Disorders

Hypokalemia

11 (11)

Hyperglycemia

7 (7)

Hypocalcemia

6 (6)

Hypophosphotemia

6 (6)

Hypoalbuminemia

5 (5)

Hypomagnesemia

5 (5)

Nervous System Disorders

Headache

10 (10)

Dizziness

5 (5)

Psychiatric Disorders

HallucinationsPooled reports include such terms as: hallucination; hallucination, auditory; hallucination, visual. Several patients had both visual and auditory hallucinations.

5 (5)

Renal and Urinary Disorders

Renal impairmentPooled reports include such terms as: renal failure and a single patient with renal impairment.

5 (5)

Respiratory Disorders

Epistaxis

17 (16)

Cough

10 (10)

Dyspnea

6 (6)

Hemoptysis

5 (5)

Skin and Subcutaneous Tissue Disorders

RashPooled reports include such terms as: rash; rash generalized; rash macular; rash maculopapular; rash pruritic.

14 (13)

Vascular Disorders

Hypertension

12 (11)

Hypotension

9 (9)

The following adverse reactions with incidence less than 5% were reported in 105 pediatric patients treated with VFEND:

Blood and Lymphatic System Disorders: anemia, leukopenia, pancytopenia

Cardiac Disorders: bradycardia, palpitations, supraventricular tachycardia

Eye Disorders: dry eye, keratitis

Ear and Labyrinth Disorders: tinnitus, vertigo

Gastrointestinal Disorders: abdominal tenderness, dyspepsia

General Disorders and Administration Site Conditions: asthenia, catheter site pain, chills, hypothermia, lethargy

Hepatobiliary Disorders: cholestasis, hyperbilirubinemia, jaundice

Immune System Disorders: hypersensitivity, urticaria

Infections and Infestations: conjunctivitis

Laboratory Investigations: AST increased, blood creatinine increased, gamma-glutamyl transferase increased

Metabolism and Nutrition Disorders: hypercalcemia, hypermagnesemia, hyperphosphatemia, hypoglycemia

Musculoskeletal and Connective Tissue Disorders: arthralgia, myalgia

Nervous System Disorders: ataxia, convulsion, dizziness, nystagmus, paresthesia, syncope

Psychiatric Disorders: affect lability, agitation, anxiety, depression, insomnia

Respiratory Disorders: bronchospasm, nasal congestion, respiratory failure, tachypnea

Skin and Subcutaneous Tissue Disorders: alopecia, dermatitis (allergic, contact, and exfoliative), pruritus

Vascular Disorders: flushing, phlebitis

Hepatic-Related Adverse Reactions in Pediatric Patients

The frequency of hepatic-related adverse reactions in pediatric patients exposed to VFEND in therapeutic studies was numerically higher than that of adults (28.6% compared to 24.1%, respectively). The higher frequency of hepatic adverse reactions in the pediatric population was mainly due to an increased frequency of liver enzyme elevations (21.9% in pediatric patients compared to 16.1% in adults), including transaminase elevations (ALT and AST combined) 7.6% in the pediatric patients compared to 5.1% in adults.

Clinical Laboratory Values in Pediatric Patients

The overall incidence of transaminase increases >3× upper limit of normal was 27.2% (28/103) in pediatric and 17.7% (268/1514) in adult patients treated with VFEND in pooled clinical trials. The majority of abnormal liver function tests either resolved on treatment with or without dose adjustment or after VFEND discontinuation.

A higher frequency of clinically significant liver laboratory abnormalities, irrespective of baseline laboratory values (>3× ULN ALT or AST), was consistently observed in the combined therapeutic pediatric population (15.5% AST and 22.5% ALT) when compared to adults (12.9% AST and 11.6% ALT). The incidence of bilirubin elevation was comparable between adult and pediatric patients. The incidence of hepatic abnormalities in pediatric patients is shown in Table 9.

Table 9: Incidence of Hepatic Abnormalities among Pediatric Subjects
n = number of patients with a clinically significant abnormality while on study therapy
N = total number of patients with at least one observation of the given lab test while on study therapy
AST = Aspartate aminotransferase; ALT = alanine aminotransferase
ULN = upper limit of normal

Criteria

n/N (%)

Total bilirubin

>1.5× ULN

19/102 (19)

AST

>3.0× ULN

16/103 (16)

ALT

>3.0× ULN

23/102 (23)

Alkaline Phosphatase

>3.0× ULN

8/97 (8)

6.2 Postmarketing Experience in Adult and Pediatric Patients

The following adverse reactions have been identified during post-approval use of VFEND. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Dermatological Reactions

Increased risk of skin toxicity with concomitant use of methotrexate, a drug associated with UV reactivation, was observed in postmarketing reports [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)].

Adults

Skeletal: fluorosis and periostitis have been reported during long-term voriconazole therapy [see Warnings and Precautions (5.12)].

Eye disorders: prolonged visual adverse reactions, including optic neuritis and papilledema [see Warnings and Precautions (5.4)].

Skin and Appendages: drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].

Endocrine disorders: adrenal insufficiency, Cushing's syndrome (when voriconazole has been used concomitantly with corticosteroids) [see Warnings and Precautions (5.8)].

Pediatric Patients

There have been postmarketing reports of pancreatitis in pediatric patients.

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
(Cmax and AUCτ after 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 subjects and 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
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)

No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir.
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
(Cmax and AUCτ)

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 AUCτ

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 Cmax or AUCτ

Contraindicated because of significant reduction of voriconazole Cmax and AUCτ.

Low-dose Ritonavir (100 mg every 12 hours)

Slight Decrease in Ritonavir Cmax and AUCτ

Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) 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

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.

Lurasidone
(CYP3A4 Inhibition)

Not Studied In Vivo or In Vitro, but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Lurasidone

Contraindicated

Cyclosporine


(CYP3A4 Inhibition)

AUCτ Significantly Increased; No Significant Effect on Cmax

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 Drug including. 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
Not Studied In Vitro or In vivo for Other Corticosteroids, but Drug Exposure Likely to be Increased

No dosage adjustment for prednisolone when coadministered with VFEND [see Clinical Pharmacology (12.3)].
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
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism
(Increased Plasma Exposure)

No dosage adjustment for indinavir when coadministered with VFEND.
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 (4, 7)
  • 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 (4, 7)
  • Phenytoin or Efavirenz: With coadministration, increase maintenance oral and intravenous dosage of VFEND (2.3, 2.7, 7)

8 USE IN SPECIFIC POPULATIONS

  • Pediatrics: Safety and effectiveness in patients younger than 2 years has not been established (8.4)

8.1 Pregnancy

Risk Summary

Voriconazole can cause fetal harm when administered to a pregnant woman. There are no available data on the use of VFEND in pregnant women. In animal reproduction studies, oral voriconazole was associated with fetal malformations in rats and fetal toxicity in rabbits. Cleft palates and hydronephrosis/hydroureter were observed in rat pups exposed to voriconazole during organogenesis at and above 10 mg/kg (0.3 times the RMD of 200 mg every 12 hours based on body surface area comparisons). In rabbits, embryomortality, reduced fetal weight and increased incidence of skeletal variations, cervical ribs and extrasternal ossification sites were observed in pups when pregnant rabbits were orally dosed at 100 mg/kg (6 times the RMD based on body surface area comparisons) during organogenesis. Rats exposed to voriconazole from implantation to weaning experienced increased gestational length and dystocia, which were associated with increased perinatal pup mortality at the 10 mg/kg dose [see Data]. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to the fetus [see Warnings and Precautions (5.9)].

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

Data

Animal Data

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

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

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

8.2 Lactation

Risk Summary

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

8.3 Females and Males of Reproductive Potential

Contraception

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

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)].

8.5 Geriatric Use

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

10 OVERDOSAGE

In clinical trials, there were three cases of accidental overdose. All occurred in pediatric patients who received up to five times the recommended intravenous dose of voriconazole. A single adverse reaction of photophobia of 10 minutes duration was reported.

There is no known antidote to voriconazole.

Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. In an overdose, hemodialysis may assist in the removal of voriconazole and SBECD from the body.

11 DESCRIPTION

VFEND (voriconazole), an azole antifungal agent is available as a lyophilized powder for solution for intravenous infusion. The structural formula is:

Chemical Structure

Voriconazole is designated chemically as (2R,3S)-2-(2, 4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol with an empirical formula of C16H14F3N5O and a molecular weight of 349.3.

Voriconazole drug substance is a white to light-colored powder.

VFEND I.V. is a white lyophilized powder containing nominally 200 mg voriconazole and 3200 mg sulfobutyl ether beta-cyclodextrin sodium in a 30 mL Type I clear glass vial.

VFEND I.V. is intended for administration by intravenous infusion. It is a single-dose, unpreserved product. Vials containing 200 mg lyophilized voriconazole are intended for reconstitution with Water for Injection to produce a solution containing 10 mg/mL VFEND and 160 mg/mL of sulfobutyl ether beta-cyclodextrin sodium. The resultant solution is further diluted prior to administration as an intravenous infusion [see Dosage and Administration (2)].

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Voriconazole is an antifungal drug [see Microbiology (12.4)].

12.2 Pharmacodynamics

Exposure-Response Relationship For Efficacy and Safety

In 10 clinical trials (N=1121), the median values for the average and maximum voriconazole plasma concentrations in individual patients across these studies was 2.51 µg/mL (inter-quartile range 1.21 to 4.44 µg/mL) and 3.79 µg/mL (inter-quartile range 2.06 to 6.31 µg/mL), respectively. A pharmacokinetic-pharmacodynamic analysis of patient data from 6 of these 10 clinical trials (N=280) could not detect a positive association between mean, maximum or minimum plasma voriconazole concentration and efficacy. However, pharmacokinetic/pharmacodynamic analyses of the data from all 10 clinical trials identified positive associations between plasma voriconazole concentrations and rate of both liver function test abnormalities and visual disturbances [see Adverse Reactions (6)].

Cardiac Electrophysiology

A placebo-controlled, randomized, crossover study to evaluate the effect on the QT interval of healthy male and female subjects was conducted with three single oral doses of voriconazole and ketoconazole. Serial ECGs and plasma samples were obtained at specified intervals over a 24-hour post dose observation period. The placebo-adjusted mean maximum increases in QTc from baseline after 800, 1200, and 1600 mg of voriconazole and after ketoconazole 800 mg were all <10 msec. Females exhibited a greater increase in QTc than males, although all mean changes were <10 msec. Age was not found to affect the magnitude of increase in QTc. No subject in any group had an increase in QTc of ≥60 msec from baseline. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec. However, the QT effect of voriconazole combined with drugs known to prolong the QT interval is unknown [see Contraindications (4) and Drug Interactions (7)].

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 (AUCτ); 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, Cmax = maximum plasma concentration, Cmin = 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)

Cmax (μg/mL)

3.13 (20)

3.03 (25)

4.77 (36)

2.30 (19)

2.31 (48)

4.74 (35)

Cmin (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 (Cmax) are achieved 1–2 hours after dosing. When multiple doses of voriconazole are administered with high-fat meals, the mean Cmax and AUCτ are 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 Cmax and AUCτ for 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 Cmax and AUCτ were 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 Cmax was comparable between genders. The steady state trough voriconazole concentrations (Cmin) 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 Cmax and AUCτ in healthy elderly males (≥65 years) were 61% and 86% higher, respectively, than in young males (18–45 years). No significant differences in the mean Cmax and AUCτ were 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 (Cmax) 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, AUCτ was 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 (Cmax) 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 (Cmax) 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 (Cmax) 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 (Cmax) 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 Cmax and AUCτ of 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 Cmax and AUCτ of 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 Cmax and AUCτ of 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 Cmax and AUCτ of high-dose ritonavir in healthy subjects, steady state Cmax and AUCτ of 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