Vfend

voriconazole

Dosage Form: tablets, oral suspension, injection
FULL PRESCRIBING INFORMATION

Indications and Usage for Vfend

Vfend is indicated for use in patients 12 years of age and older in the treatment of the following fungal infections:

Invasive Aspergillosis

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), and Clinical Pharmacology (12.4)].

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), and Clinical Pharmacology (12.4)]

Esophageal Candidiasis

[see Clinical Studies (14.3), and Clinical Pharmacology (12.4)]

Serious Fungal Infections Caused by Scedosporium apiospermum (Asexual Form of Pseudallescheria boydii) and Fusarium spp. Including Fusarium solani, in Patients Intolerant of, or Refractory to, Other Therapy

[see Clinical Studies (14.4), and Clinical Pharmacology (12.4)]

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.

Vfend Dosage and Administration

Instructions for Use in All Patients

Vfend Tablets or Oral Suspension should be taken at least one hour before or after a meal.

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 2 hours.

Do not administer as an IV bolus injection.

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 Vfend therapy [see Warnings and Precautions (5.8)].

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.

Recommended Dosing 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 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 IV; a 300 mg oral dose achieves an exposure similar to 4 mg/kg IV. Switching between the intravenous and oral formulations is appropriate because of the high bioavailability of the oral formulation in adults [see Clinical Pharmacology (12)].

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

Infection	Loading dose	Maintenance Dose*,†
	IV	IV	Oral‡
* Increase dose when Vfend is co-administered with phenytoin or efavirenz (7); Decrease dose in patients with hepatic impairment (2.7) † In healthy volunteer studies, the 200 mg oral q12h dose provided an exposure (AUCτ) similar to a 3 mg/kg IV q12h dose; the 300 mg oral q12h dose provided an exposure (AUCτ) similar to a 4 mg/kg IV q12h dose [see Clinical Pharmacology (12)]. ‡ Adult patients who weigh less than 40 kg should receive half of the oral maintenance dose. § In a clinical study of invasive aspergillosis, the median duration of IV Vfend therapy was 10 days (range 2–90 days). The median duration of oral Vfend therapy was 76 days (range 2–232 days) [see Clinical Studies (14.1)]. ¶ In clinical trials, patients with candidemia received 3 mg/kg IV q12h as primary therapy, while patients with other deep tissue Candida infections received 4 mg/kg q12h as salvage therapy. Appropriate dose should be based on the severity and nature of the infection. # Not evaluated in patients with esophageal candidiasis.
Invasive Aspergillosis§	6 mg/kg q12h for the first 24 hours	4 mg/kg q12h	200 mg q12h
Candidemia in nonneutropenic patients and other deep tissue Candida infections	6 mg/kg q12h for the first 24 hours	3–4 mg/kg q12h¶	200 mg q12h
Esophageal Candidiasis	#	#	200 mg q12h
Scedosporiosis and Fusariosis	6 mg/kg q12h for the first 24 hours	4 mg/kg q12h	200 mg q12h

Dosage Adjustment

If patient response is inadequate, the oral maintenance dose may be increased from 200 mg every 12 hours (similar to 3 mg/kg IV q12h) to 300 mg every 12 hours (similar to 4 mg/kg IV q12h). 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 IV q12h, reduce the intravenous maintenance dose to 3 mg/kg q12h.

The maintenance dose of voriconazole should be increased when co-administered with phenytoin or efavirenz [see Drug Interactions (7)].

The maintenance dose of voriconazole should be reduced in patients with mild to moderate hepatic impairment, Child-Pugh Class A and B [see Dosage and Administration (2.7)]. 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.

Intravenous Administration

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 1–2 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 2).


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 1–2 hours at a maximum rate of 3 mg/kg per hour.

Table 2: Required Volumes of 10 mg/mL Vfend Concentrate

	Volume of Vfend Concentrate (10 mg/mL) required for:
Body Weight (kg)	3 mg/kg dose (number of vials)	4 mg/kg dose (number of vials)	6 mg/kg dose (number of vials)
30	9.0 mL (1)	12 mL (1)	18 mL (1)
35	10.5 mL (1)	14 mL (1)	21 mL (2)
40	12.0 mL (1)	16 mL (1)	24 mL (2)
45	13.5 mL (1)	18 mL (1)	27 mL (2)
50	15.0 mL (1)	20 mL (1)	30 mL (2)
55	16.5 mL (1)	22 mL (2)	33 mL (2)
60	18.0 mL (1)	24 mL (2)	36 mL (2)
65	19.5 mL (1)	26 mL (2)	39 mL (2)
70	21.0 mL (2)	28 mL (2)	42 mL (3)
75	22.5 mL (2)	30 mL (2)	45 mL (3)
80	24.0 mL (2)	32 mL (2)	48 mL (3)
85	25.5 mL (2)	34 mL (2)	51 mL (3)
90	27.0 mL (2)	36 mL (2)	54 mL (3)
95	28.5 mL (2)	38 mL (2)	57 mL (3)
100	30.0 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° to 8°C (36° 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:

9 mg/mL (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.

Oral Suspension

Reconstitution

Tap the bottle to release the powder. Add 46 mL of water to the bottle. Shake the closed bottle vigorously for about 1 minute. Remove child-resistant cap and push bottle adaptor into the neck of the bottle. Replace the cap. Write the date of expiration of the reconstituted suspension on the bottle label (the shelf-life of the reconstituted suspension is 14 days at controlled room temperature 15–30°C [59–86°F]).

Instructions for use

Shake the closed bottle of reconstituted suspension for approximately 10 seconds before each use. The reconstituted oral suspension should only be administered using the oral dispenser supplied with each pack.

Incompatibilities

Vfend for Oral Suspension and the 40 mg/mL reconstituted oral suspension should not be mixed with any other medication or additional flavoring agent. It is not intended that the suspension be further diluted with water or other vehicles.

Use in Patients With Hepatic Impairment

In the clinical program, patients were included who had baseline liver function tests (ALT, AST) up to 5 times the upper limit of normal. No dose adjustment is necessary in patients with this degree of abnormal liver function, but continued monitoring of liver function tests for further elevations is recommended [see Warnings and Precautions (5.9)].

It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) [see Clinical Pharmacology (12.3)].

Vfend has not been studied in 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 clinical signs of liver damage, such as jaundice, and should only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with hepatic insufficiency must be carefully monitored for drug toxicity.

Use in Patients With Renal Impairment

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), 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 voriconazole. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral voriconazole therapy [see Warnings and Precautions (5.10)].

Voriconazole is hemodialyzed 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.

Dosage Forms and Strengths

Powder for Solution for Injection

Vfend I.V. for Injection is supplied in a single use vial as a sterile lyophilized powder equivalent to 200 mg Vfend and 3200 mg sulfobutyl ether beta-cyclodextrin sodium (SBECD).

Tablets

Vfend 50 mg tablets; white, film-coated, round, debossed with "Pfizer" on one side and "VOR50" on the reverse.

Vfend 200 mg tablets; white, film-coated, capsule shaped, debossed with "Pfizer" on one side and "VOR200" on the reverse.

Powder for Oral Suspension

Vfend for Oral Suspension is supplied in 100 mL high density polyethylene (HDPE) bottles. Each bottle contains 45 g of powder for oral suspension. Following reconstitution, the volume of the suspension is 75 mL, providing a usable volume of 70 mL (40 mg voriconazole/mL). A 5 mL oral dispenser and a press-in bottle adaptor are also provided.

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 terfenadine, astemizole, cisapride, pimozide or quinidine 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), and Clinical Pharmacology (12.3)].


• 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 and long-acting barbiturates is contraindicated because these drugs are likely to decrease plasma voriconazole concentrations significantly [see Drug Interactions (7), and Clinical Pharmacology (12.3)].


• Coadministration of Vfend with high-dose ritonavir (400 mg q12h) is contraindicated because ritonavir (400 mg q12h) significantly decreases plasma voriconazole concentrations. Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) 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), Clinical Pharmacology (12.3)].


• Coadministration of Vfend with St. John's Wort is contraindicated because this herbal supplement may decrease voriconazole plasma concentration [see Drug Interactions (7), and Clinical Pharmacology (12.3)].

Warnings and Precautions

Drug Interactions

See Table 7 for a listing of drugs that may significantly alter voriconazole concentrations. Also, see Table 8 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)].

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 Warnings and Precautions (5.9), and Adverse Reactions (6.3)].

Monitoring of hepatic function: 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 (5.9), Dosage and Administration (2.4, 2.7), and Adverse Reactions (6.3)].

Visual Disturbances

The effect of Vfend on visual function is not known if treatment continues beyond 28 days. There have been post-marketing reports of prolonged visual adverse events, 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)].

Pregnancy Category D

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

In animals, voriconazole administration was associated with teratogenicity, embryotoxicity, increased gestational length, dystocia and embryomortality. Please refer to section 8.1 (Use in Pregnancy) for additional details.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to the fetus.

Galactose Intolerance

Vfend tablets contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Arrhythmias and QT Prolongation

Some azoles, including voriconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During clinical development and post-marketing 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.

Voriconazole should be administered with caution to patients with these potentially proarrhythmic conditions.

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

Infusion Related Reactions

During infusion of the intravenous formulation of voriconazole 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.

Laboratory Tests

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

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

Patients With Hepatic Impairment

It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) receiving Vfend [see Clinical Pharmacology (12.3), and Dosage and Administration (2.7)].

Vfend has not been studied in patients with severe cirrhosis (Child-Pugh Class C). Vfend has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice, and should only be used in patients with severe hepatic insufficiency if the benefit outweighs the potential risk. Patients with hepatic insufficiency must be carefully monitored for drug toxicity.

Patients With Renal Impairment

In patients with moderate to severe renal dysfunction (creatinine clearance <50 mL/min), 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 voriconazole. Serum creatinine levels should be closely monitored in these patients, and if increases occur, consideration should be given to changing to oral voriconazole therapy [see Clinical Pharmacology (12.3), and Dosage and Administration (2.8)].

Monitoring of Renal Function

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 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, particularly serum creatinine.

Monitoring of Pancreatic Function

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.

Dermatological Reactions

Serious exfoliative cutaneous reactions, such as Stevens-Johnson syndrome, have been reported during treatment with Vfend. If a patient develops an exfoliative cutaneous reaction, Vfend should be discontinued.

In addition Vfend has been associated with photosensitivity skin reaction. Patients should avoid intense or prolonged exposure to direct sunlight during Vfend treatment. In patients with photosensitivity skin reactions squamous cell carcinoma of the skin and melanoma have been reported during long-term therapy. If a patient develops a skin lesion consistent with squamous cell carcinoma or melanoma, Vfend should be discontinued.

Skeletal Adverse Events

Fluorosis and periostitis have been reported during long-term voriconazole therapy. If a patient develops skeletal pain and radiologic findings compatible with fluorosis or periostitis, voriconazole should be discontinued [see Adverse Reactions (6.4)].

Adverse Reactions

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.

Overview

The most frequently reported adverse events (all causalities) in the 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 treatment-related adverse events which most often led to discontinuation of voriconazole therapy were elevated liver function tests, rash, and visual disturbances [see Warning and Precautions (5.2, 5.3), and Adverse Reactions (6.2, 6.3)].

Clinical Trial Experience in Adults

The data described in Table 3 reflect exposure to voriconazole in 1655 patients in the 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 3 includes all adverse events 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 in the primary treatment of patients with acute invasive aspergillosis. The rate of discontinuation from voriconazole study medication due to adverse events 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 events 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 esophageal candidiasis. The rate of discontinuation from voriconazole study medication in Study 305 due to adverse events was 7% (14/200 patients). Laboratory test abnormalities for these studies are discussed under Clinical Laboratory Values below.

Table 3: Treatment Emergent Adverse Events Rate ≥ 2% on Voriconazole or Adverse Events of Concern in All Therapeutic Studies Population, Studies 307/602-608 Combined, or Study 305. Possibly Related to Therapy or Causality Unknown*

	All Therapeutic Studies	Studies 307/602 and 608 (IV/ oral therapy)			Study 305 (oral therapy)
	Voriconazole N=1655	Voriconazole N=468	Ampho B† N=185	Ampho B→ Fluconazole N=131	Voriconazole N=200	Fluconazole N=191
	N (%)	N (%)	N (%)	N (%)	N (%)	N (%)
* Study 307/602: invasive aspergillosis; Study 608: candidemia; Study 305: esophageal candidiasis † Amphotericin B followed by other licensed antifungal therapy ‡ See Warnings and Precautions (5.3)
Special Senses‡
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