FDA Label for Voriconazole

1 Indications And Usage

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

1.1 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)].

1.2 Candidemia

[see Clinical Studies (14.2) and Clinical Pharmacology (12.4)]

1.3 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 (14.3) 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.

2.1 Instructions For Use In All Patients

Voriconazole 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.

Administer diluted Voriconazole for injection by intravenous administration over 1-2 hours. Do not administer as an intravenous bolus injection.

2.2 Use Of Voriconazole For Injection With Other Parenteral Drug Products

Blood products and concentrated electrolytes

Voriconazole for injection 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 Voriconazole for injection therapy [see Warnings and Precautions (5.7)].

Intravenous solutions containing (non-concentrated) electrolytes

Voriconazole for injection 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)

Voriconazole for injection 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 Voriconazole for injection.

2.3 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 Voriconazole for injection 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 voriconazole 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. 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.

2.4 Dosage Adjustment

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

The maintenance dose of voriconazole should be increased when co-administered with phenytoin [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 (2.6)]. 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.

2.5 Preparation And 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.

Voriconazole for injection is an unpreserved sterile lyophile in a single dose vial. 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).

Dilution

Voriconazole for injection 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 Voriconazole for injection concentrate should be further diluted as follows (appropriate diluents listed below):

• Calculate the volume of 10 mg/mL Voriconazole for injection concentrate required based on the patient's weight (see Table 2).
• In order to allow the required volume of Voriconazole for injection 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 Voriconazole for injection concentrate is added, the final concentration is not less than 0.5 mg/mL nor greater than 5 mg/mL.
• Using a suitable size syringe and aseptic technique, withdraw the required volume of Voriconazole for injection concentrate from the appropriate number of vials and add to the infusion bag or bottle. Discard Unused Portion.

The final Voriconazole for injection solution must be infused over 1-2 hours at a maximum rate of 3 mg/kg per hour. Infusion should commence immediately after dilution of the concentrate.

Table 2: Required Volumes of 10 mg/mL Voriconazole for injection Concentrate

Body Weight (kg)	Volume of Voriconazole for injection 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)
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)

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 Voriconazole for injection with diluents other than those described above is unknown.

Incompatibilities

Voriconazole for injection must not be diluted with 4.2% Sodium Bicarbonate Infusion. The mildly alkaline nature of this diluent caused slight degradation of voriconazole 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.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Only clear solutions without particles should be used.

Once the reconstituted product is further diluted for infusion, it should be used immediately.  This medicinal product is for single use only and any unused solution should be discarded.  

2.6 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 (5.8)].

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)].

Voriconazole 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. Voriconazole 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 impairment must be carefully monitored for drug toxicity.

2.7 Use In Patients With Renal Impairment

In patients with moderate to severe renal impariment (creatinine clearance <50 mL/min), accumulation of the intravenous vehicle of Voriconazole for injection, hydroxypropyl ß-cyclodextrin (HPβCD), occurs.  There is insufficient information to recommend dosage adjustments to Voriconazole for injection in patients with renal impairment. Therefore, an alternate antifungal therapy should be considered in patients with renal impairment [see Warnings and Precautions (5.9)]. In patients on hemodialysis, a 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment  [see Clinical Pharmacology (12.3)].

3 Dosage Forms And Strengths

Powder for Solution for Injection

Voriconazole for injection is supplied in a single dose vial as a sterile lyophilized white to off white cake or powder equivalent to 200 mg voriconazole and 3200 mg hydroxypropyl ß-cyclodextrin (HPβCD).

4 Contraindications

• Voriconazole for injection is contraindicated in patients with known hypersensitivity to voriconazole or its excipients. There is no information regarding cross-sensitivity between voriconazole  and other azole antifungal agents. Caution should be used when prescribing voriconazole to patients with hypersensitivity to other azoles.
• Coadministration of terfenadine, astemizole, cisapride, pimozide or quinidine with Voriconazole for injection 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 Voriconazole for injection with sirolimus is contraindicated because voriconazole significantly increases sirolimus concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
• Coadministration of Voriconazole for injection 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 standard doses of voriconazole with efavirenz doses of 400 mg every 24h 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 Voriconazole for injection with high-dose ritonavir (400 mg every 12h) is contraindicated because ritonavir (400 mg every 12h) significantly decreases plasma voriconazole concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
• Coadministration of Voriconazole for injection with rifabutin is contraindicated since voriconazole significantly increases rifabutin plasma concentrations and rifabutin also significantly decreases voriconazole plasma concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
• Coadministration of Voriconazole for injection with ergot alkaloids (ergotamine and dihydroergotamine) is contraindicated because voriconazole may increase the plasma concentration of ergot alkaloids, which may lead to ergotism [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
• Coadministration of Voriconazole for injection 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)].

5.1 Drug Interactions

See Table 6 for a listing of drugs that may significantly alter voriconazole concentrations. Also, see Table 7 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)].

5.2 Hepatic Toxicity

In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with voriconazole (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 (5.8) and Adverse Reactions (6.1)].

Measure serum transaminase levels and bilirubin at the initiation of Voriconazole for injection 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, Voriconazole for injection should be discontinued unless the medical judgment of the benefit-risk of the treatment for the patient justifies continued use [see Warnings and Precautions (5.8), Dosage and Administration (2.4, 2.6), and Adverse Reactions (6.1)].

5.3 Visual Disturbances

The effect of voriconazole 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 (6.1)].

5.4 Embryo-Fetal Toxicity

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 [see Use in Specific Populations (8.1)] for additional details.

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.

5.5 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 potentially proarrhythmic conditions, such as:

• Congenital or acquired QT-prolongation
• Cardiomyopathy, in particular when heart failure is present
• Sinus bradycardia
• Existing symptomatic arrhythmias
• Concomitant medicinal product that is known to prolong QT interval [see Contraindications (4), Drug Interactions (7), and Clinical Pharmacology (12.3)]

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

5.6 Infusion Related Reactions

During infusion of the intravenous formulation of voriconazole in healthy subjects, anaphylactic 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.

5.7 Monitoring: Laboratory Tests

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

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

5.8 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 Voriconazole for injection [see Clinical Pharmacology (12.3) and Dosage and Administration (2.6)].

Voriconazole has not been studied in patients with severe cirrhosis (Child-Pugh Class C). Voriconazole 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 impairment must be carefully monitored for drug toxicity.

5.9 Risk In Patients With Renal Impairment

Hydroxypropyl-β-cyclodextrin (HPβCD), the intravenous vehicle of Voriconazole for injection, is eliminated through glomerular filtration.  Therefore, in patients with moderate to severe renal impairment (creatinine clearance <50 mL/min), accumulation of HPβCD occurs.  Serum creatinine (S_cr) levels should be closely monitored in patients with renal impairment.  If increases in S_cr occur, consideration should be given to changing to alternate antifungal therapy with similar coverage, unless an assessment of the benefit/risk to the patient justifies the continued use of intravenous voriconazole [see Dosage and Administration (2.7) and Clinical Pharmacology (12.3)].

5.10 Monitoring Of Renal Function

Acute renal failure has been observed in patients undergoing treatment with voriconazole. 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.

5.11 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 Voriconazole for injection treatment. 

5.12 Dermatological Reactions

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

Voriconazole has been associated with photosensitivity skin reaction. Patients, including children, should avoid exposure to direct sunlight during Voriconazole for injection 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 Voriconazole for injection discontinuation should be considered. If Voriconazole for injection 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 and melanoma have been reported during long-term voriconazole therapy in patients with photosensitivity skin reactions. If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, Voriconazole for injection should be discontinued.

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.

5.13 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 (6.2)].

6 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.

6.1 Clinical Trials Experience

The most frequently reported adverse reactions (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 reactions 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), Clinical Trial Experience in Adult and Pediatric Patients, and Clinical Laboratory Values].

Clinical Trial Experience in Adult and Pediatric Patients

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, 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 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. Laboratory test abnormalities for these studies are discussed under Clinical Laboratory Values below.

Visual Disturbances

Voriconazole 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.

There have been post-marketing reports of prolonged visual adverse events, including optic neuritis and papilledema [see Warnings and Precautions (5.3)].

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, voriconazole 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. The effects were noted early in administration of voriconazole and continued through the course of study drug dosing. Fourteen days after end of dosing, ERG, visual fields and color perception returned to normal [see Warnings and Precautions (5.6)].

Dermatological Reactions

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

Serious cutaneous reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme have been reported during treatment with voriconazole. If a patient develops an exfoliative cutaneous reaction, Voriconazole for injection should be discontinued.

In addition, voriconazole has been associated with photosensitivity skin reactions. Patients should avoid strong, direct sunlight during Voriconazole for injection therapy. 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, Voriconazole for injection should be discontinued [see Warnings and Precautions (5.12)].

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 3 above and does not include every event reported in the voriconazole clinical program.

Body as a Whole: abdominal pain, abdomen enlarged, allergic reaction, anaphylactic reaction [see Warnings and Precautions (5.5) ], 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 (5.5)].

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, 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

The overall incidence of clinically significant transaminase abnormalities in all therapeutic studies was 12.4% (206/1655) of patients treated with voriconazole. 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 following dose adjustment, including discontinuation of therapy.

Voriconazole 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 Voriconazole for injection therapy. Patients who develop abnormal liver function tests during Voriconazole for injection 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 Voriconazole for injection must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to Voriconazole for injection [see Warnings and Precautions (5.2)].

Acute renal failure has been observed in severely ill patients undergoing treatment with voriconazole. 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. It is recommended that patients are monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.

Tables 4 and 5 show the number of patients with hypokalemia and clinically significant changes in renal and liver function tests in two randomized, comparative multicenter studies. In study 307/602, patients with definite or probable invasive aspergillosis were randomized to either voriconazole or amphotericin B therapy. In study 608, patients with candidemia were randomized to either voriconazole or the regimen of amphotericin B followed by fluconazole.

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post approval use of voriconazole. 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.

Skeletal: fluorosis and periostitis have been reported during long-term voriconazole therapy [see Warnings and Precautions (5.13)].

7 Drug Interactions

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 Voriconazole for injection in pregnant women. In animal reproduction studies, oral voriconazole was teratogenic in rats and embryotoxic in rabbits. Cleft palates and hydronephrosis/hydroureter were observed in rat pups exposed to voriconazole during organogenesis at and above 10 mg/kg (0.3 times the recommended maintenance dose of 200 mg every 12 hours based on body surface area comparisons). In rabbits, embryomortality, reduced fetal weight and increased incidence of skeletal variations, cervical ribs and extrasternal ossification sites were observed in pups when pregnant rabbits were orally dosed at 100 mg/kg (6 times the RMD based on body surface area comparisons) during organogenesis. Rats exposed to voriconazole from implantation to weaning experienced increased gestational length and dystocia, which were associated with increased perinatal pup mortality at the 10 mg/kg dose. [see Data]. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to the fetus see Warnings and Precautions (5.4)].

The background risk of major birth defects and miscarriage for the indicated population 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 teratogenic with increased incidences in hydroureter and hydronephrosis at 10 mg/kg/day or greater, approximately 0.3 times the recommended human dose (RMD) based on mg/m², and cleft palate at 60 mg/kg, approximately 2 times the recommended human dose (RMD) based on mg/m². Reduced ossification of sacral and caudal vertebrae, skull, pubic, and hyoid bone, supernumerary ribs, anomalies of the sternbrae, and dilatation of the ureter/renal pelvis were also observed at doses of 10 mg/kg or greater. There was no evidence of maternal toxicity at any dose.

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

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

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 Voriconazole for injection and any potential adverse effects on the breastfed child from Voriconazole for injection 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 Voriconazole for injection. 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 events associated with oral contraceptives and voriconazole is recommended [see  Drug Interactions (7) and Clinical Pharmacology (12.3)].

8.4 Pediatric Use

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

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

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

There have been post-marketing reports of pancreatitis in pediatric patients.

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 (C_max) 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 intravenously 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 event 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, HPβCD, is hemodialyzed with clearance of 37.5±24 mL/min. In an overdose, hemodialysis may assist in the removal of voriconazole and HPβCD from the body.

11 Description

Voriconazole for injection, an azole antifungal is available as a lyophilized cake or powder for solution for intravenous infusion. The structural formula is:

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 or almost white powder.

Voriconazole for injection, is a white to off white lyophilized cake or powder containing nominally 200 mg voriconazole and 3200 mg hydroxypropyl ß-cyclodextrin (HPβCD) in a 30 mL Type I clear glass vial.

Voriconazole for injection is intended for administration by intravenous infusion. It is an  unpreserved product in a single dose vial. Vials containing 200 mg lyophilized voriconazole are intended for reconstitution with Water for Injection to produce a solution containing 10 mg/mL Voriconazole for injection and 160 mg/mL of hydroxypropyl ß-cyclodextrin (HPβCD). The resultant solution is further diluted prior to administration as an intravenous infusion [see Dosage and Administration (2)].

12.1 Mechanism Of Action

Voriconazole is an azole 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 intravenous dose from 3 mg/kg every 12h to 4 mg/kg every 12h produces an approximately 2.5-fold increase in exposure (Table 8).

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 intravenously every 12h on day 1 followed by 3 mg/kg intravenously every 12h). 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.

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 (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 intravenous voriconazole, preceded by multiple intravenous 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 intravenous dosing.

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

Specific Populations

Male and Female Patients

In a multiple oral dose study, the mean C_max and AUC_Τ 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 C_max and AUC_Τ 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 C_max was comparable between genders. The steady state trough voriconazole concentrations (C_min) seen in females were 100% and 91% higher than in males receiving the tablet and the oral suspension, respectively.

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

Geriatric Patients

In an oral multiple dose study the mean C_max and AUC_Τ 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 C_max and AUC_Τ 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 intravenous 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 Specific Populations (8.5)].

Pediatric Patients

Sparse plasma sampling for pharmacokinetics was conducted in the therapeutic studies in patients aged 12-18 years. In 11 adolescent patients who received a mean voriconazole maintenance dose of 4 mg/kg IV, the median of the calculated mean plasma concentrations was 1.60 µg/mL (inter-quartile range 0.28 to 2.73 µg/mL). In 17 adolescent patients for whom mean plasma concentrations were calculated following a mean oral maintenance dose of 200 mg every 12h, the median of the calculated mean plasma concentrations was 1.16 µg/mL (inter-quartile range 0.85 to 2.14 µg/mL).

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 insufficiency, the mean systemic exposure (AUC) was 3.2-fold higher than in age and weight matched controls with normal hepatic function. There was no difference in mean peak plasma concentrations (C_max) between the groups. When only the patients with mild (Child-Pugh Class A) hepatic insufficiency were compared to controls, there was still a 2.3-fold increase in the mean AUC in the group with hepatic insufficiency compared to controls.

In an oral multiple dose study, AUC_Τ 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 (C_max) were 20% lower in the hepatically impaired group.

No pharmacokinetic data are available for patients with severe hepatic cirrhosis (Child-Pugh Class C) [see Dosage and Administration (2.6)].

Patients with Renal Impairment

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

In patients with normal renal function, the pharmacokinetic profile of hydroxypropylbetacyclodextrin (HPβCD), an ingredient of Voriconazole for injection, has a short half-life of 1 to 2 hours, and demonstrates no accumulation following successive daily doses. In healthy subjects and in patients with mild to severe renal insufficiency, the majority (>85 %) of an 8 g dose of HPβCD is eliminated in the urine. In a study investigating  another antifungal drug, itraconazole, following a single intravenous 200 mg dose, clearance of hydroxypropyl-ß-cyclodextrin was reduced in subjects with renal impairment, resulting in higher exposure to hydroxypropyl-ß-cyclodextrin. In subjects with mild, moderate, and severe renal impairment, half-life values were increased over normal values by approximately two-, four-, and six-fold, respectively. In these patients, successive infusions may result in accumulation of HPβCD  until steady state is reached. HPβCD is removed by hemodialysis.

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

Patients at Risk of Asperillosis

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 Interactions 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 or is expected to be reduced by the concomitant administration of the following agents and their use is contraindicated:

Rifampin (potent CYP450 inducer) - Rifampin (600 mg once daily) decreased the steady state C_max and AUC_Τ of voriconazole (200 mg every 12h × 7 days) by an average of 93% and 96%, respectively, in healthy subjects. Doubling the dose of voriconazole to 400 mg every 12h does not restore adequate exposure to voriconazole during coadministration with rifampin. Coadministration of voriconazole and rifampin is contraindicated [see Contraindications (4) and Warnings and Precautions (5.1)].

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 12h for 9 days) decreased the steady state C_max and AUC_Τ of oral voriconazole (400 mg every 12h for 1 day, then 200 mg every 12h for 8 days) by an average of 66% and 82%, respectively, in healthy subjects. Low-dose ritonavir (100 mg every 12h for 9 days) decreased the steady state C_max and AUC_Τ of oral voriconazole (400 mg every 12h for 1 day, then 200 mg every 12h for 8 days) by an average of 24% and 39%, respectively, in healthy subjects. Although repeat oral administration of voriconazole did not have a significant effect on steady state C_max and AUC_Τ of high-dose ritonavir in healthy subjects, steady state C_max and AUC_Τ of low-dose ritonavir decreased slightly by 24% and 14% respectively, when administered concomitantly with oral voriconazole in healthy subjects. Coadministration of voriconazole and high-dose ritonavir (400 mg every 12h) is contraindicated. Coadministration of voriconazole and low-dose ritonavir (100 mg every 12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole [see Contraindications (4) and Warnings and Precautions (5.1)].

St. John's Wort (CYP450 inducer; P-gp inducer) - In an independent published study in healthy volunteers who were given multiple oral doses of St. John's Wort (300 mg LI 160 extract three times daily for 15 days) followed by a single 400 mg oral dose of voriconazole, a 59% decrease in mean voriconazole AUC_0-∞ was observed. In contrast, coadministration of single oral doses of St. John's Wort and voriconazole had no appreciable effect on voriconazole AUC_0-∞. Because long-term use of St. John's Wort could lead to reduced voriconazole exposure, concomitant use of voriconazole with St. John's Wort is contraindicated [see Contraindications (4)].

Carbamazepine and long-acting barbiturates (potent CYP450 inducers) - Although not studied in vitro or in vivo, carbamazepine and long-acting barbiturates (e.g., phenobarbital, mephobarbital) are likely to significantly decrease plasma voriconazole concentrations. Coadministration of voriconazole with carbamazepine or long-acting barbiturates is contraindicated [see Contraindications (4) and Warnings and Precautions (5.1)].

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

Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor): Concurrent administration of oral voriconazole (400 mg every 12h for 1 day, then 200 mg every 12h for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg every 24h for 4 days) to 6 healthy male subjects resulted in an increase in C_max and AUC_Τ of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. In a follow-on clinical study involving 8 healthy male subjects, reduced dosing and/or frequency of voriconazole and fluconazole did not eliminate or diminish this effect. Concomitant administration of voriconazole and fluconazole at any dose is not recommended. Close monitoring for adverse events related to voriconazole is recommended if voriconazole is used sequentially after fluconazole, especially within 24 hours of the last dose of fluconazole [see Warnings and Precautions (5.1)].

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

Cimetidine (non-specific CYP450 inhibitor and increases gastric pH) - Cimetidine (400 mg every 12h × 8 days) increased voriconazole steady state C_max and AUC_Τ by an average of 18% (90% CI: 6%, 32%) and 23% (90% CI: 13%, 33%), respectively, following oral doses of 200 mg every 12h × 7 days to healthy subjects.

Ranitidine (increases gastric pH) - Ranitidine (150 mg every 12h) had no significant effect on voriconazole C_max and AUC_Τ following oral doses of 200 mg every 12h × 7 days to healthy subjects.

Macrolide antibiotics - Coadministration of erythromycin (CYP3A4 inhibitor; 1g every 12h for 7 days) or azithromycin (500 mg every 24h for 3 days) with voriconazole 200 mg every 12h for 14 days had no significant effect on voriconazole steady state C_max and AUC_Τ in healthy subjects. The effects of voriconazole on the pharmacokinetics of either erythromycin or azithromycin are not known.

Effects of Voriconazole on Other Drugs

In vitro studies with human hepatic microsomes show that voriconazole inhibits the metabolic activity of the cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. In these studies, the inhibition potency of voriconazole for CYP3A4 metabolic activity was significantly less than that of two other azoles, ketoconazole and itraconazole. In vitro studies also show that the major metabolite of voriconazole, voriconazole N-oxide, inhibits the metabolic activity of CYP2C9 and CYP3A4 to a greater extent than that of CYP2C19. Therefore, there is potential for voriconazole and its major metabolite to increase the systemic exposure (plasma concentrations) of other drugs metabolized by these CYP450 enzymes.

The systemic exposure of the following drugs is significantly increased or is expected to be significantly increased by coadministration of voriconazole and their use is contraindicated:

Sirolimus (CYP3A4 substrate) - Repeat dose administration of oral voriconazole (400 mg every 12h for 1 day, then 200 mg every 12h for 8 days) increased the C_max and AUC of sirolimus (2 mg single dose) an average of 7-fold (90% CI: 5.7, 7.5) and 11-fold (90% CI: 9.9, 12.6), respectively, in healthy male subjects. Coadministration of voriconazole and sirolimus is contraindicated [see Contraindications (4) and Warnings and Precautions (5.1)].

Terfenadine, astemizole, cisapride, pimozide and quinidine (CYP3A4 substrates) - Although not studied in vitro or in vivo, concomitant administration of voriconazole with terfenadine, astemizole, cisapride, pimozide or quinidine may result in inhibition of the metabolism of these drugs. Increased plasma concentrations of these drugs can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of voriconazole and terfenadine, astemizole, cisapride, pimozide and quinidine is contraindicated [see Contraindications (4) and Warnings and Precautions (5.1)].

Ergot alkaloids - Although not studied in vitro or in vivo, voriconazole may increase the plasma concentration of ergot alkaloids (ergotamine and dihydroergotamine) and lead to ergotism. Coadministration of voriconazole with ergot alkaloids is contraindicated [see Contraindications (4) and Warnings and Precautions (5.1)].

Everolimus (CYP3A4 substrate, P-gp substrate) - Although not studied in vitro or in vivo, voriconazole may increase plasma concentrations of everolimus, which could potentially lead to exacerbation of everolimus toxicity. Currently there are insufficient data to allow dosing recommendations in this situation. Therefore, co-administration of voriconazole with everolimus is not recommended [see Drug Interactions (7)].

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

Alfentanil (CYP3A4 substrate) - Coadministration of multiple doses of oral voriconazole (400 mg every 12h on day 1, 200 mg every 12h on day 2) with a single 20 mcg/kg intravenous dose of alfentanil with concomitant naloxone resulted in a 6-fold increase in mean alfentanil AUC_0-∞ and a 4-fold prolongation of mean alfentanil elimination half-life, compared to when alfentanil was given alone. An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting during co-administration of voriconazole and alfentanil was also observed. Reduction in the dose of alfentanil or other opiates that are also metabolized by CYP3A4 (e.g., sufentanil), and extended close monitoring of patients for respiratory and other opiate-associated adverse events, may be necessary when any of these opiates is coadministered with voriconazole [see Warnings and Precautions (5.1)].

Fentanyl (CYP3A4 substrate): In an independent published study, concomitant use of voriconazole (400 mg every 12h on Day 1, then 200 mg every 12h on Day 2) with a single intravenous dose of fentanyl (5 µg/kg) resulted in an increase in the mean AUC_0-∞ of fentanyl by 1.4-fold (range 0.81- to 2.04-fold). When voriconazole is co-administered with fentanyl intravenous, oral or transdermal dosage forms, extended and frequent monitoring of patients for respiratory depression and other fentanyl-associated adverse events is recommended, and fentanyl dosage should be reduced if warranted [see Warnings and Precautions (5.1)].

Oxycodone (CYP3A4 substrate): In an independent published study, coadministration of multiple doses of oral voriconazole (400 mg every 12h, on Day 1 followed by five doses of 200 mg every 12h on Days 2 to 4) with a single 10 mg oral dose of oxycodone on Day 3 resulted in an increase in the mean C_max and AUC_0-∞ of oxycodone by 1.7-fold (range 1.4- to 2.2-fold) and 3.6-fold (range 2.7- to 5.6-fold), respectively. The mean elimination half-life of oxycodone was also increased by 2.0-fold (range 1.4- to 2.5-fold). Voriconazole also increased the visual effects (heterophoria and miosis) of oxycodone. A reduction in oxycodone dosage may be needed during voriconazole treatment to avoid opioid related adverse effects. Extended and frequent monitoring for adverse effects associated with oxycodone and other long-acting opiates metabolized by CYP3A4 is recommended [see Warnings and Precautions (5.1)].

Cyclosporine (CYP3A4 substrate) - In stable renal transplant recipients receiving chronic cyclosporine therapy, concomitant administration of oral voriconazole (200 mg every 12h for 8 days) increased cyclosporine C_max and AUC_Τ an average of 1.1 times (90% CI: 0.9, 1.41) and 1.7 times (90% CI: 1.5, 2.0), respectively, as compared to when cyclosporine was administered without voriconazole. When initiating therapy with voriconazole in patients already receiving cyclosporine, it is recommended that the cyclosporine dose be reduced to one-half of the original dose and followed with frequent monitoring of the cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine levels should be frequently monitored and the dose increased as necessary [see Warnings and Precautions (5.1)].

Methadone (CYP3A4, CYP2C19, CYP2C9 substrate) - Repeat dose administration of oral voriconazole (400 mg every 12h for 1 day, then 200 mg every 12h for 4 days) increased the C_max and AUC_Τ of pharmacologically active Rmethadone by 31% (90% CI: 22%, 40%) and 47% (90% CI: 38%, 57%), respectively, in subjects receiving a methadone maintenance dose (30-100 mg every 24h). The C_max and AUC_Τ of (S)-methadone increased by 65% (90% CI: 53%, 79%) and 103% (90% CI: 85%, 124%), respectively. Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed [see Warnings and Precautions (5.1)].

Tacrolimus (CYP3A4 substrate) - Repeat oral dose administration of voriconazole (400 mg every 12h × 1 day, then 200 mg every 12h × 6 days) increased tacrolimus (0.1 mg/kg single dose) C_max and AUC_Τ in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively. When initiating therapy with voriconazole in patients already receiving tacrolimus, it is recommended that the tacrolimus dose be reduced to one-third of the original dose and followed with frequent monitoring of the tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus levels should be carefully monitored and the dose increased as necessary [see Warnings and Precautions (5.1)].

Warfarin (CYP2C9 substrate) - Coadministration of voriconazole (300 mg every 12h × 12 days) with warfarin (30 mg single dose) significantly increased maximum prothrombin time by approximately 2 times that of placebo in healthy subjects. Close monitoring of prothrombin time or other suitable anticoagulation tests is recommended if warfarin and voriconazole are coadministered and the warfarin dose adjusted accordingly [see Warnings and Precautions (5.1)].

Oral Coumarin Anticoagulants (CYP2C9, CYP3A4 substrates) - Although not studied in vitro or in vivo, voriconazole may increase the plasma concentrations of coumarin anticoagulants and therefore may cause an increase in prothrombin time. If patients receiving coumarin preparations are treated simultaneously with voriconazole, the prothrombin time or other suitable anti-coagulation tests should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly [see Warnings and Precautions (5.1)].

Statins (CYP3A4 substrates) - Although not studied clinically, voriconazole has been shown to inhibit lovastatin metabolism in vitro (human liver microsomes). Therefore, voriconazole is likely to increase the plasma concentrations of statins that are metabolized by CYP3A4. It is recommended that dose adjustment of the statin be considered during coadministration. Increased statin concentrations in plasma have been associated with rhabdomyolysis [see Warnings and Precautions (5.1)].

Benzodiazepines (CYP3A4 substrates) - Although not studied clinically, voriconazole has been shown to inhibit midazolam metabolism in vitro (human liver microsomes). Therefore, voriconazole is likely to increase the plasma concentrations of benzodiazepines that are metabolized by CYP3A4 (e.g., midazolam, triazolam, and alprazolam) and lead to a prolonged sedative effect. It is recommended that dose adjustment of the benzodiazepine be considered during coadministration [see Warnings and Precautions (5.1)].

Calcium Channel Blockers (CYP3A4 substrates) - Although not studied clinically, voriconazole has been shown to inhibit felodipine metabolism in vitro (human liver microsomes). Therefore, voriconazole may increase the plasma concentrations of calcium channel blockers that are metabolized by CYP3A4. Frequent monitoring for adverse events and toxicity related to calcium channel blockers is recommended during coadministration. Dose adjustment of the calcium channel blocker may be needed [see Warnings and Precautions (5.1)].

Sulfonylureas (CYP2C9 substrates) - Although not studied in vitro or in vivo, voriconazole may increase plasma concentrations of sulfonylureas (e.g., tolbutamide, glipizide, and glyburide) and therefore cause hypoglycemia. Frequent monitoring of blood glucose and appropriate adjustment (i.e., reduction) of the sulfonylurea dosage is recommended during coadministration [see Warnings and Precautions (5.1)].

Vinca Alkaloids (CYP3A4 substrates) - Although not studied in vitro or in vivo, voriconazole may increase the plasma concentrations of the vinca alkaloids (e.g., vincristine and vinblastine) and lead to neurotoxicity. Therefore, reserve azole antifungals, including voriconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options [see Warnings and Precautions (5.1)].

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs; CYP2C9 substrates): In two independent published studies, single doses of ibuprofen (400 mg) and diclofenac (50 mg) were coadministered with the last dose of voriconazole (400 mg every 12h on Day 1, followed by 200 mg every 12h on Day 2). Voriconazole increased the mean C_max and AUC of the pharmacologically active isomer, S (+)-ibuprofen by 20% and 100%, respectively. Voriconazole increased the mean C_max and AUC of diclofenac by 114% and 78%, respectively.

A reduction in ibuprofen and diclofenac dosage may be needed during concomitant administration with voriconazole. Patients receiving voriconazole concomitantly with other NSAIDs (e.g., celecoxib, naproxen, lornoxicam, meloxicam) that are also metabolized by CYP2C9 should be carefully monitored for NSAID-related adverse events and toxicity, and dosage reduction should be made if warranted [see Warnings and Precautions (5.1)].

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

Prednisolone (CYP3A4 substrate) - Voriconazole (200 mg every 12h × 30 days) increased C_max and AUC of prednisolone (60 mg single dose) by an average of 11% and 34%, respectively, in healthy subjects.

Digoxin (P-glycoprotein mediated transport) - Voriconazole (200 mg every 12h × 12 days) had no significant effect on steady state C_max and AUC_Τ of digoxin (0.25 mg once daily for 10 days) in healthy subjects.

Mycophenolic acid (UDP-glucuronyl transferase substrate) - Voriconazole (200 mg every 12h × 5 days) had no significant effect on the C_max and AUC_Τ of mycophenolic acid and its major metabolite, mycophenolic acid glucuronide after administration of a 1 g single oral dose of mycophenolate mofetil.

Two-Way Interactions

Concomitant use of the following agents with voriconazole is contraindicated:

Rifabutin (potent CYP450 inducer) - Rifabutin (300 mg once daily) decreased the C_max and AUC_Τ of voriconazole at 200 mg twice daily by an average of 67% (90% CI: 58%, 73%) and 79% (90% CI: 71%, 84%), respectively, in healthy subjects. During coadministration with rifabutin (300 mg once daily), the steady state C_max and AUC_Τ of voriconazole following an increased dose of 400 mg twice daily were on average approximately 2 times higher, compared with voriconazole alone at 200 mg twice daily. Coadministration of voriconazole at 400 mg twice daily with rifabutin 300 mg twice daily increased the C_max and AUC_Τ of rifabutin by an average of 3-times (90% CI: 2.2, 4.0) and 4 times (90% CI: 3.5, 5.4), respectively, compared to rifabutin given alone. Coadministration of voriconazole and rifabutin is contraindicated [see Contraindications (4)].

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

Efavirenz, a non-nucleoside reverse transcriptase inhibitor (CYP450 inducer; CYP3A4 inhibitor and substrate) - Standard doses of voriconazole and efavirenz (400 mg every 24h or higher) must not be coadministered [see Drug Interactions (7)]. Steady state efavirenz (400 mg PO every 24h) decreased the steady state C_max and AUC_Τ of voriconazole (400 mg PO every 12h for 1 day, then 200 mg PO every 12h for 8 days) by an average of 61% and 77%, respectively, in healthy male subjects. Voriconazole at steady state (400 mg PO every 12h for 1 day, then 200 mg every 12h for 8 days) increased the steady state C_max and AUC_Τ of efavirenz (400 mg PO every 24h for 9 days) by an average of 38% and 44%, respectively, in healthy subjects.

Coadministration of standard doses of voriconazole and efavirenz (400 mg every 24h or higher) is contraindicated. [see  Contraindications (4) and Drug Interactions (7)].

Phenytoin (CYP2C9 substrate and potent CYP450 inducer) - Repeat dose administration of phenytoin (300 mg once daily) decreased the steady state C_max and AUC_Τ of orally administered voriconazole (200 mg every 12h × 14 days) by an average of 50% and 70%, respectively, in healthy subjects.

Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased from 4 mg/kg to 5 mg/kg intravenously every 12 hours [see Dosage and Administration (2.4) and Drug Interactions (7)].

Repeat dose administration of voriconazole (400 mg every 12h × 10 days) increased the steady state C_max and AUC_Τ of phenytoin (300 mg once daily) by an average of 70% and 80%, respectively, in healthy subjects. The increase in phenytoin C_max and AUC_Τ when coadministered with voriconazole may be expected to be as high as 2 times the C_max and AUC_Τ estimates when phenytoin is given without voriconazole. Therefore, frequent monitoring of plasma phenytoin concentrations and phenytoin-related adverse effects is recommended when phenytoin is coadministered with voriconazole [see Warnings and Precautions (5.1)].

Omeprazole (CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate) - Coadministration of omeprazole (40 mg once daily × 10 days) with oral voriconazole (400 mg every 12h × 1 day, then 200 mg every 12h × 9 days) increased the steady state C_max and AUC_Τ of voriconazole by an average of 15% (90% CI: 5%, 25%) and 40% (90% CI: 29%, 55%), respectively, in healthy subjects. No dosage adjustment of voriconazole is recommended.

Coadministration of voriconazole (400 mg every 12h × 1 day, then 200 mg × 6 days) with omeprazole (40 mg once daily × 7 days) to healthy subjects significantly increased the steady state C_max and AUC_Τ of omeprazole an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4), respectively, as compared to when omeprazole is given without voriconazole. When initiating voriconazole in patients already receiving omeprazole doses of 40 mg or greater, it is recommended that the omeprazole dose be reduced by one-half [see Warnings and Precautions (5.1)].

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 these drugs.

Oral Contraceptives (CYP3A4 substrate; CYP2C19 inhibitor) - Coadministration of oral voriconazole (400 mg every 12h for 1 day, then 200 mg every 12h for 3 days) and oral contraceptive (Ortho-Novum1/35® consisting of 35 mcg ethinyl estradiol and 1 mg norethindrone, every 24h) to healthy female subjects at steady state increased the C_max and AUC_Τ of ethinyl estradiol by an average of 36% (90% CI: 28%, 45%) and 61% (90% CI: 50%, 72%), respectively, and that of norethindrone by 15% (90% CI: 3%, 28%) and 53% (90% CI: 44%, 63%), respectively in healthy subjects. Voriconazole C_max and AUC_Τ increased by an average of 14% (90% CI: 3%, 27%) and 46% (90% CI: 32%, 61%), respectively. Monitoring for adverse events related to oral contraceptives, in addition to those for voriconazole, is recommended during coadministration [see Warnings and Precautions (5.1)].

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

Indinavir (CYP3A4 inhibitor and substrate) - Repeat dose administration of indinavir (800 mg TID for 10 days) had no significant effect on voriconazole C_max and AUC following repeat dose administration (200 mg every 12h for 17 days) in healthy subjects.

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

Other Two-Way Interactions Expected to be Significant Based on In Vitro and In Vivo Findings:

Other HIV Protease Inhibitors (CYP3A4 substrates and inhibitors) - In vitro studies (human liver microsomes) suggest that voriconazole may inhibit the metabolism of HIV protease inhibitors (e.g., saquinavir, amprenavir and nelfinavir). In vitro studies (human liver microsomes) also show that the metabolism of voriconazole may be inhibited by HIV protease inhibitors (e.g., saquinavir and amprenavir). Patients should be frequently monitored for drug toxicity during the coadministration of voriconazole and HIV protease inhibitors [see Warnings and Precautions (5.1)].

Other Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (CYP3A4 substrates, inhibitors or CYP450 inducers) - In vitro studies (human liver microsomes) show that the metabolism of voriconazole may be inhibited by a NNRTI (e.g., delavirdine). The findings of a clinical voriconazole-efavirenz drug interaction study in healthy male subjects suggest that the metabolism of voriconazole may be induced by a NNRTI. This in vivo study also showed that voriconazole may inhibit the metabolism of a NNRTI [see Drug Interactions (7) and Warnings and Precautions (5.8)]. Patients should be frequently monitored for drug toxicity during the coadministration of voriconazole and other NNRTIs (e.g., nevirapine and delavirdine) [see Warnings and Precautions (5.1)]. Dose adjustments are required when voriconazole is co-administered with efavirenz [see Drug Interactions (7) and Warnings and Precautions (5.1)].

12.4 Microbiology

Mechanism of Action

Voriconazole is an azole antifungal drug. The primary mode of action of voriconazole is the inhibition of fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell wall and may be responsible for the antifungal activity of voriconazole.

Resistance

A potential for development of resistance to voriconazole is well known. The mechanisms of resistance may include mutations in the gene ERG11 (encodes for the target enzyme, lanosterol 14-α-demethylase), upregulation of genes encoding the ATP-binding cassette efflux transporters i.e., Candida drug resistance (CDR) pumps and reduced access of the drug to the target, or some combination of those mechanisms. The frequency of drug resistance development for the various fungi for which this drug is indicated is not known.

Fungal isolates exhibiting reduced susceptibility to fluconazole or itraconazole may also show reduced susceptibility to voriconazole, suggesting cross-resistance can occur among these azoles. The relevance of cross-resistance and clinical outcome has not been fully characterized. Clinical cases where azole cross-resistance is demonstrated may require alternative antifungal therapy.

Antimicrobial Activity

Voriconazole has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections.

Aspergillus fumigatus
Aspergillus flavus
Aspergillus niger
Aspergillus terreus
Candida albicans
Candida glabrata (In clinical studies, the voriconazole MIC₉₀ was 4 µg/mL)^*
Candida krusei
Candida parapsilosis
Candida tropicalis
Fusarium spp. including Fusarium solani
Scedosporium apiospermum

___________

^*In clinical studies, voriconazole MIC₉₀ for C. glabrata baseline isolates was 4 µg/mL; 13/50 (26%) C. glabrata baseline isolates were resistant (MIC ≥4 µg/mL) to voriconazole. However, based on 1054 isolates tested in surveillance studies the MIC₉₀ was 1 µg/mL.

The following data are available, but their clinical significance is unknown. At least 90 percent of the following fungi exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for voriconazole against isolates of similar genus or organism group.  However, the efficacy of voriconazole in treating clinical infections due to these fungi has not been established in adequate and well-controlled clinical trials:

Candida lusitaniae
Candida guilliermondii

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

12.5 Pharmacogenomics

CYP2C19, significantly involved in the metabolism of voriconazole, exhibits genetic polymorphism. Approximately 15-20% of Asian populations may be expected to be poor metabolizers. For Caucasians and Blacks, the prevalence of poor metabolizers is 3-5%. Studies conducted in Caucasian and Japanese healthy subjects have shown that poor metabolizers have, on average, 4-fold higher voriconazole exposure (AUC_Τ) than their homozygous extensive metabolizer counterparts. Subjects who are heterozygous extensive metabolizers have, on average, 2-fold higher voriconazole exposure than their homozygous extensive metabolizer counterparts [see Clinical Pharmacology (12.3)].

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Two-year carcinogenicity studies were conducted in rats and mice. Rats were given oral doses of 6, 18 or 50 mg/kg voriconazole, or 0.2, 0.6, or 1.6 times the recommended maintenance dose (RMD) on a body surface areabasis. Hepatocellular adenomas were detected in females at 50 mg/kg and hepatocellular carcinomas were found in males at 6 and 50 mg/kg. Mice were given oral doses of 10, 30 or 100 mg/kg voriconazole, or 0.1, 0.4, or 1.4 times the RMD on a body surface areabasis. In mice, hepatocellular adenomas were detected in males and females and hepatocellular carcinomas were detected in males at 1.4 times the RMD of voriconazole.

Voriconazole demonstrated clastogenic activity (mostly chromosome breaks) in human lymphocyte cultures in vitro. Voriconazole was not genotoxic in the Ames assay, CHO HGPRT assay, the mouse micronucleus assay or the in vivo DNA repair test (Unscheduled DNA Synthesis assay).

Voriconazole administration induced no impairment of male or female fertility in rats dosed at 50 mg/kg, or 1.6 times the RMD (recommended maintenance dose).

14 Clinical Studies

Voriconazole, administered orally or parenterally, has been evaluated as primary or salvage therapy in 520 patients aged 12 years and older with infections caused by Aspergillus spp., Fusarium spp., and Scedosporium spp.

14.1 Invasive Aspergillosis

Voriconazole was studied in patients for primary therapy of invasive aspergillosis (randomized, controlled study 307/602), for primary and salvage therapy of aspergillosis (non-comparative study 304) and for treatment of patients with invasive aspergillosis who were refractory to, or intolerant of, other antifungal therapy (non-comparative study 309/604).

Study 307/602 - Primary Therapy of Invasive Aspergillosis

The efficacy of voriconazole compared to amphotericin B in the primary treatment of acute invasive aspergillosis was demonstrated in 277 patients treated for 12 weeks in a randomized, controlled study (Study 307/602). The majority of study patients had underlying hematologic malignancies, including bone marrow transplantation. The study also included patients with solid organ transplantation, solid tumors, and AIDS. The patients were mainly treated for definite or probable invasive aspergillosis of the lungs. Other aspergillosis infections included disseminated disease, CNS infections and sinus infections. Diagnosis of definite or probable invasive aspergillosis was made according to criteria modified from those established by the National Institute of Allergy and Infectious Diseases Mycoses Study Group/European Organisation for Research and Treatment of Cancer (NIAID MSG/EORTC).

Voriconazole was administered intravenously with a loading dose of 6 mg/kg every 12 hours for the first 24 hours followed by a maintenance dose of 4 mg/kg every 12 hours for a minimum of seven days. Therapy could then be switched to the oral formulation at a dose of 200 mg every 12h. Median duration of intravenous voriconazole therapy was 10 days (range 2-85 days). After intravenous voriconazole therapy, the median duration of PO voriconazole therapy was 76 days (range 22-32 days).

Patients in the comparator group received conventional amphotericin B as a slow infusion at a daily dose of 1.0-1.5 mg/kg/day. Median duration of intravenous amphotericin therapy was 12 days (range 1-85 days). Treatment was then continued with other licensed antifungal therapy (OLAT), including itraconazole and lipid amphotericin B formulations. Although initial therapy with conventional amphotericin B was to be continued for at least two weeks, actual duration of therapy was at the discretion of the investigator. Patients who discontinued initial randomized therapy due to toxicity or lack of efficacy were eligible to continue in the study with OLAT treatment.

A satisfactory global response at 12 weeks (complete or partial resolution of all attributable symptoms, signs, radiographic/bronchoscopic abnormalities present at baseline) was seen in 53% of voriconazole treated patients compared to 32% of amphotericin B treated patients (Table 12). A benefit of voriconazole compared to amphotericin B on patient survival at Day 84 was seen with a 71% survival rate on voriconazole compared to 58% on amphotericin B (Table 11).

Table 11 also summarizes the response (success) based on mycological confirmation and species.

Study 304 - Primary and Salvage Therapy of Aspergillosis

In this non-comparative study, an overall success rate of 52% (26/50) was seen in patients treated with voriconazole for primary therapy. Success was seen in 17/29 (59%) with Aspergillus fumigatus infections and 3/6 (50%) patients with infections due to non-fumigatus species [A. flavus (1/1); A. nidulans (0/2); A. niger (2/2); A. terreus (0/1)]. Success in patients who received voriconazole as salvage therapy is presented in Table 12.

Study 309/604 - Treatment of Patients with Invasive Aspergillosis who were Refractory to, or Intolerant of, other Antifungal Therapy

Additional data regarding response rates in patients who were refractory to, or intolerant of, other antifungal agents are also provided in Table 13. In this non-comparative study, overall mycological eradication for culture-documented infections due to fumigatus and non-fumigatus species of Aspergillus was 36/82 (44%) and 12/30 (40%), respectively, in voriconazole treated patients. Patients had various underlying diseases and species other than A. fumigatus contributed to mixed infections in some cases.

For patients who were infected with a single pathogen and were refractory to, or intolerant of, other antifungal agents, the satisfactory response rates for voriconazole in studies 304 and 309/604 are presented in Table 12.

Nineteen patients had more than one species of Aspergillus isolated. Success was seen in 4/17 (24%) of these patients.

14.2 Candidemia In Non-Neutropenic Patients And Other Deep Tissue Candida Infections

Voriconazole was compared to the regimen of amphotericin B followed by fluconazole in Study 608, an open label, comparative study in nonneutropenic patients with candidemia associated with clinical signs of infection. Patients were randomized in 2:1 ratio to receive either voriconazole (n=283) or the regimen of amphotericin B followed by fluconazole (n=139). Patients were treated with randomized study drug for a median of 15 days. Most of the candidemia in patients evaluated for efficacy was caused by C. albicans (46%), followed by C. tropicalis (19%), C. parapsilosis (17%), C. glabrata (15%), and C. krusei (1%).

An independent Data Review Committee (DRC), blinded to study treatment, reviewed the clinical and mycological data from this study, and generated one assessment of response for each patient. A successful response required all of the following: resolution or improvement in all clinical signs and symptoms of infection, blood cultures negative for Candida, infected deep tissue sites negative for Candida or resolution of all local signs of infection, and no systemic antifungal therapy other than study drug. The primary analysis, which counted DRC-assessed successes at the fixed time point (12 weeks after End of Therapy [EOT]), demonstrated that voriconazole was comparable to the regimen of amphotericin B followed by fluconazole (response rates of 41% and 41%, respectively) in the treatment of candidemia. Patients who did not have a 12-week assessment for any reason were considered a treatment failure.

The overall clinical and mycological success rates by Candida species in Study 150-608 are presented in Table 13.

In a secondary analysis, which counted DRC-assessed successes at any time point (EOT, or 2, 6, or 12 weeks after EOT), the response rates were 65% for voriconazole and 71% for the regimen of amphotericin B followed by fluconazole.

In Studies 608 and 309/604 (non-comparative study in patients with invasive fungal infections who were refractory to, or intolerant of, other antifungal agents), voriconazole was evaluated in 35 patients with deep tissue Candida infections. A favorable response was seen in 4 of 7 patients with intra-abdominal infections, 5 of 6 patients with kidney and bladder wall infections, 3 of 3 patients with deep tissue abscess or wound infection, 1 of 2 patients with pneumonia/pleural space infections, 2 of 4 patients with skin lesions, 1 of 1 patients with mixed intraabdominal and pulmonary infection, 1 of 2 patients with suppurative phlebitis, 1 of 3 patients with hepatosplenic infection, 1 of 5 patients with osteomyelitis, 0 of 1 with liver infection, and 0 of 1 with cervical lymph node infection.

14.3 Other Serious Fungal Pathogens

In pooled analyses of patients, voriconazole was shown to be effective against the following additional fungal pathogens:

Scedosporium apiospermum - Successful response to voriconazole therapy was seen in 15 of 24 patients (63%). Three of these patients relapsed within 4 weeks, including 1 patient with pulmonary, skin and eye infections, 1 patient with cerebral disease, and 1 patient with skin infection. Ten patients had evidence of cerebral disease and 6 of these had a successful outcome (1 relapse). In addition, a successful response was seen in 1 of 3 patients with mixed organism infections.

Fusarium spp. - Nine of 21 (43%) patients were successfully treated with voriconazole. Of these 9 patients, 3 had eye infections, 1 had an eye and blood infection, 1 had a skin infection, 1 had a blood infection alone, 2 had sinus infections, and 1 had disseminated infection (pulmonary, skin, hepatosplenic). Three of these patients (1 with disseminated disease, 1 with an eye infection and 1 with a blood infection) had Fusarium solani and were complete successes. Two of these patients relapsed, 1 with a sinus infection and profound neutropenia and 1 post surgical patient with blood and eye infections.

16 How Supplied/Storage And Handling

16.1 How Supplied

Voriconazole for Injection is supplied in a single dose vial as an unpreserved, sterile white to off white lyophilized cake or powder equivalent to 200 mg voriconazole and 3200 mg hydroxypropyl ß-cyclodextrin (HPβCD).

Individually packaged vials of  Voriconazole for Injection, 200 mg, NDC 39822-1077-1.

16.2 Storage And Handling

Storage

Powder for Injection: Voriconazole for Injection unreconstituted vials should be stored at 20° – 25°C (68° – 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

Reconstituted Drug Solution: From a microbiological point of view, following reconstitution of the lyophile with Water for Injection, the reconstituted solution 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). Chemical and physical in-use stability has been demonstrated for 24 hours at 2° to 8°C (36° to 46°F). Discard Unused Portion. [see Dosage and Administration (2.5)].

Further Diluted Drug Solution for Infusion:  Once the reconstituted product is further diluted for infusion, it should be used immediately. Discard Unused Portion.  [see Dosage and Administration (2.5)].

This medicinal product is for single use only and any unused solution should be discarded. Only clear solutions without particles should be used [see Dosage and Administration (2.5)].

Handling

Not made with natural rubber latex.

17 Patient Counseling Information

• Patients should be instructed that visual disturbances such as blurring and sensitivity to light may occur with the use of voriconazole.
• Advise patients to avoid direct sunlight due to risk of phototoxicity. 
• Inform the patient of the potential hazard to the fetus, if the drug is used during pregnancy [see Warnings and Precautions (5)].

Embryo-Fetal Toxicity

• Advise female patients of the potential risks to a fetus.
• Advise females of reproductive potential to use effective contraception during treatment with Voriconazole for injection.

Distributed by:

X-GEN Pharmaceuticals, Inc.,

Big Flats, NY 14814

VOZE-PI-03

LEA-019800-03

Made in India

Package Label.Principal Display Panel

PRINCIPAL DISPLAY PANEL - 200 mg Vial Label
NDC 39822-1077-1

VORICONAZOLE FOR INJECTION

200 MG* per vial

Not made with natural rubber latex
No Preservatives

Sterile Single Dose Vial

Must be reconstituted then diluted

For Intravenous Infusion Only

Discard Unused Portion

XGen logo     Rx only

PRINCIPAL DISPLAY PANEL - 200 mg Vial Carton

NDC 39822-1077-1

VORICONAZOLE FOR INJECTION

200 MG* per vial

Sterile Single Dose Vial

Must be reconstituted then diluted

For Intravenous Infusion Only

Discard Unused Portion

Not made with natural rubber latex
No Preservatives

Rx Only

1 Vial      XGen logo