Voriconazole

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Hepatic Toxicity [see Warnings and Precautions (5.1) ] Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2) ] Infusion Related Reactions [see Warnings and Precautions (5.3) ] Visual Disturbances [see Warnings and Precautions (5.4) ] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5) ] Photosensitivity [see Warnings and Precautions (5.6) ] Renal Toxicity [see Warnings and Precautions (5.7) ] Adult patients : The most common adverse reactions (incidence ≥2%): were visual disturbances, fever, nausea, rash, vomiting, chills, headache, liver function test abnormal, tachycardia, hallucinations ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Xellia Pharmaceuticals USA, LLC at 1-833-295-6953, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience in Adults Overview The most frequently reported adverse reactions (see Table 3 ) in the adult therapeutic trials were visual disturbances (18.7%), fever (5.7%), nausea (5.4%), rash (5.3%), vomiting (4.4%), chills (3.7%), headache (3.0%), liver function test increased (2.7%), tachycardia (2.4%), hallucinations (2.4%). The adverse reactions which most often led to discontinuation of voriconazole therapy were elevated liver function tests, rash, and visual disturbances [see Warning and Precautions (5.1 , 5.4) , and Adverse Reactions (6.1) ] . The data described in Table 3 reflect exposure to voriconazole in 1655 patients in the nine therapeutic studies. This represents a heterogeneous population, including immunocompromised patients, e.g., patients with hematological malignancy or HIV and non-neutropenic patients. This subgroup does not include healthy subjects and patients treated in the compassionate use and non-therapeutic studies. This patient population was 62% male, had a mean age of 46 years (range 11–90, including 51 patients aged 12–18 years), and was 78% White and 10% Black. Five hundred sixty one patients had a duration of voriconazole therapy of greater than 12 weeks, with 136 patients receiving voriconazole for over six months. Table 3 includes all adverse reactions which were reported at an incidence of ≥2% during voriconazole therapy in the all therapeutic studies population, studies 307/602 and 608 combined, as well as events of concern which occurred at an incidence of <2%. In study 307/602, 381 patients (196 on voriconazole, 185 on amphotericin B) were treated to compare voriconazole to amphotericin B followed by other licensed antifungal therapy (OLAT) in the primary treatment of patients with acute IA. The rate of discontinuation from voriconazole study medication due to adverse reactions was 21.4% (42/196 patients). In study 608, 403 patients with candidemia were treated to compare voriconazole (272 patients) to the regimen of amphotericin B followed by fluconazole (131 patients). The rate of discontinuation from voriconazole study medication due to adverse reactions was 19.5% out of 272 patients. Laboratory test abnormalities for these studies are discussed under Clinical Laboratory Values below. Table 3: Adverse Reactions Rate ≥ 2% on Voriconazole or Adverse Reactions of Concern in Therapeutic Studies Population, Studies 307/602-608 Combined, Possibly Related to Therapy or Causality Unknown Study 307/602: IA; Study 608: candidemia Therapeutic Studies Studies 303, 304, 307, 309, 602, 603, 604, 608 Studies 307/602 and 608 Voriconazole N=1655 Voriconazole N=468 Ampho B Amphotericin B followed by other licensed antifungal therapy N=185 Ampho B→ Fluconazole N=131 N (%) N (%) N (%) N (%) Special Senses See Warnings and Precautions (5.4) Abnormal vision 310 (18.7) 63 (13.5) 1 (0.5) 0 Photophobia 37 (2.2) 8 (1.7) 0 0 Chromatopsia 20 (1.2) 2 (0.4) 0 0 Body as a Whole Fever 94 (5.7) 8 (1.7) 25 (13.5) 5 (3.8) Chills 61 (3.7) 1 (0.2) 36 (19.5) 8 (6.1) Headache 49 (3.0) 9 (1.9) 8 (4.3) 1 (0.8) Cardiovascular System Tachycardia 39 (2.4) 6 (1.3) 5 (2.7) 0 Digestive System Nausea 89 (5.4) 18 (3.8) 29 (15.7) 2 (1.5) Vomiting 72 (4.4) 15 (3.2) 18 (9.7) 1 (0.8) Liver function tests abnormal 45 (2.7) 15 (3.2) 4 (2.2) 1 (0.8) Cholestatic jaundice 17 (1.0) 8 (1.7) 0 1 (0.8) Metabolic and Nutritional Systems Alkaline phosphatase increased 59 (3.6) 19 (4.1) 4 (2.2) 3 (2.3) Hepatic enzymes increased 30 (1.8) 11 (2.4) 5 (2.7) 1 (0.8) SGOT increased 31 (1.9) 9 (1.9) 0 1 (0.8) SGPT increased 29 (1.8) 9 (1.9) 1 (0.5) 2 (1.5) Hypokalemia 26 (1.6) 3 (0.6) 36 (19.5) 16 (12.2) Bilirubinemia 15 (0.9) 5 (1.1) 3 (1.6) 2 (1.5) Creatinine increased 4 (0.2) 0 59 (31.9) 10 (7.6) Nervous System Hallucinations 39 (2.4) 13 (2.8) 1 (0.5) 0 Skin and Appendages Rash 88 (5.3) 20 (4.3) 7 (3.8) 1 (0.8) Urogenital Kidney function abnormal 10 (0.6) 6 (1.3) 40 (21.6) 9 (6.9) Acute kidney failure 7 (0.4) 2 (0.4) 11 (5.9) 7 (5.3) Visual Disturbances Voriconazole for injection treatment-related visual disturbances are common. In therapeutic trials, approximately 21% of patients experienced abnormal vision, color vision change and/or photophobia. Visual disturbances may be associated with higher plasma concentrations and/or doses. The mechanism of action of the visual disturbance is unknown, although the site of action is most likely to be within the retina. In a study in healthy subjects investigating the effect of 28-day treatment with voriconazole on retinal function, Voriconazole for injection caused a decrease in the electroretinogram (ERG) waveform amplitude, a decrease in the visual field, and an alteration in color perception. The ERG measures electrical currents in the retina. These effects were noted early in administration of Voriconazole for injection and continued through the course of study drug treatment. Fourteen days after end of dosing, ERG, visual fields and color perception returned to normal [see Warnings and Precautions (5.4) ] . Dermatological Reactions Dermatological reactions were common in the patients treated with Voriconazole for injection. The mechanism underlying these dermatologic adverse reactions remains unknown. Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported during treatment with Voriconazole for injection. Erythema multiforme has also been reported during treatment with Voriconazole for injection [see Warnings and Precautions (5.5) and Adverse Reactions (6.2) ] . Voriconazole has also been associated with additional photosensitivity related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus [see Warnings and Precautions (5.6) and Adverse Reactions (6.2) ] . Less Common Adverse Reactions The following adverse reactions occurred in <2% of all voriconazole-treated patients in all therapeutic studies (N=1655). This listing includes events where a causal relationship to voriconazole cannot be ruled out or those which may help the physician in managing the risks to the patients. The list does not include events included in Table 3 above and does not include every event reported in the voriconazole clinical program. Body as a Whole: abdominal pain, abdomen enlarged, allergic reaction, anaphylactoid reaction [see Warnings and Precautions (5.3) ] , ascites, asthenia, back pain, chest pain, cellulitis, edema, face edema, flank pain, flu syndrome, graft versus host reaction, granuloma, infection, bacterial infection, fungal infection, injection site pain, injection site infection/inflammation, mucous membrane disorder, multi-organ failure, pain, pelvic pain, peritonitis, sepsis, substernal chest pain. Cardiovascular: atrial arrhythmia, atrial fibrillation, AV block complete, bigeminy, bradycardia, bundle branch block, cardiomegaly, cardiomyopathy, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident, congestive heart failure, deep thrombophlebitis, endocarditis, extrasystoles, heart arrest, hypertension, hypotension, myocardial infarction, nodal arrhythmia, palpitation, phlebitis, postural hypotension, pulmonary embolus, QT interval prolonged, supraventricular extrasystoles, supraventricular tachycardia, syncope, thrombophlebitis, vasodilatation, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia (including torsade de pointes ) [see Warnings and Precautions (5.2) ] . Digestive: anorexia, cheilitis, cholecystitis, cholelithiasis, constipation, diarrhea, duodenal ulcer perforation, duodenitis, dyspepsia, dysphagia, dry mouth, esophageal ulcer, esophagitis, flatulence, gastroenteritis, gastrointestinal hemorrhage, GGT/LDH elevated, gingivitis, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hepatic coma, hepatic failure, hepatitis, intestinal perforation, intestinal ulcer, jaundice, enlarged liver, melena, mouth ulceration, pancreatitis, parotid gland enlargement, periodontitis, proctitis, pseudomembranous colitis, rectal disorder, rectal hemorrhage, stomach ulcer, stomatitis, tongue edema. Endocrine: adrenal cortex insufficiency, diabetes insipidus, hyperthyroidism, hypothyroidism. Hemic and Lymphatic: agranulocytosis, anemia (macrocytic, megaloblastic, microcytic, normocytic), aplastic anemia, hemolytic anemia, bleeding time increased, cyanosis, DIC, ecchymosis, eosinophilia, hypervolemia, leukopenia, lymphadenopathy, lymphangitis, marrow depression, pancytopenia, petechia, purpura, enlarged spleen, thrombocytopenia, thrombotic thrombocytopenic purpura. Metabolic and Nutritional: albuminuria, BUN increased, creatine phosphokinase increased, edema, glucose tolerance decreased, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperuricemia, hypocalcemia, hypoglycemia, hypomagnesemia, hyponatremia, hypophosphatemia, peripheral edema, uremia. Musculoskeletal: arthralgia, arthritis, bone necrosis, bone pain, leg cramps, myalgia, myasthenia, myopathy, osteomalacia, osteoporosis. Nervous System: abnormal dreams, acute brain syndrome, agitation, akathisia, amnesia, anxiety, ataxia, brain edema, coma, confusion, convulsion, delirium, dementia, depersonalization, depression, diplopia, dizziness, encephalitis, encephalopathy, euphoria, Extrapyramidal Syndrome, grand mal convulsion, Guillain-Barré syndrome, hypertonia, hypesthesia, insomnia, intracranial hypertension, libido decreased, neuralgia, neuropathy, nystagmus, oculogyric crisis, paresthesia, psychosis, somnolence, suicidal ideation, tremor, vertigo. Respiratory System: cough increased, dyspnea, epistaxis, hemoptysis, hypoxia, lung edema, pharyngitis, pleural effusion, pneumonia, respiratory disorder, respiratory distress syndrome, respiratory tract infection, rhinitis, sinusitis, voice alteration. Skin and Appendages: alopecia, angioedema, contact dermatitis, discoid lupus erythematosis, eczema, erythema multiforme, exfoliative dermatitis, fixed drug eruption, furunculosis, herpes simplex, maculopapular rash, melanoma, melanosis, photosensitivity skin reaction, pruritus, pseudoporphyria, psoriasis, skin discoloration, skin disorder, skin dry, Stevens-Johnson syndrome, squamous cell carcinoma (including cutaneous SCC in situ , or Bowen's disease), sweating, toxic epidermal necrolysis, urticaria. Special Senses: abnormality of accommodation, blepharitis, color blindness, conjunctivitis, corneal opacity, deafness, ear pain, eye pain, eye hemorrhage, dry eyes, hypoacusis, keratitis, keratoconjunctivitis, mydriasis, night blindness, optic atrophy, optic neuritis, otitis externa, papilledema, retinal hemorrhage, retinitis, scleritis, taste loss, taste perversion, tinnitus, uveitis, visual field defect. Urogenital: anuria, blighted ovum, creatinine clearance decreased, dysmenorrhea, dysuria, epididymitis, glycosuria, hemorrhagic cystitis, hematuria, hydronephrosis, impotence, kidney pain, kidney tubular necrosis, metrorrhagia, nephritis, nephrosis, oliguria, scrotal edema, urinary incontinence, urinary retention, urinary tract infection, uterine hemorrhage, vaginal hemorrhage. Clinical Laboratory Values in Adults The overall incidence of transaminase increases >3× upper limit of normal (not necessarily comprising an adverse reaction) was 17.7% (268/1514) in adult subjects treated with Voriconazole for injection for therapeutic use in pooled clinical trials. Increased incidence of liver function test abnormalities may be associated with higher plasma concentrations and/or doses. The majority of abnormal liver function tests either resolved during treatment without dose adjustment or resolved following dose adjustment, including discontinuation of therapy. Voriconazole for injection 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 (5.1) ] . Acute renal failure has been observed in severely ill patients undergoing treatment with Voriconazole for injection. Patients being treated with Voriconazole for injection are likely to be treated concomitantly with nephrotoxic medications and have concurrent conditions that can result in decreased renal function. It is recommended that patients are monitored for the development of abnormal renal function. This should include laboratory evaluation of serum creatinine. Tables 4 to 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 IA 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. Table 4: Study 307/602 – Primary Treatment of Invasive Aspergillosis Clinically Significant Laboratory Test Abnormalities Criteria Without regard to baseline value Voriconazole Amphotericin B Amphotericin B followed by other licensed antifungal therapy n/N (%) n/N (%) n = number of patients with a clinically significant abnormality while on study therapy N = total number of patients with at least one observation of the given lab test while on study therapy AST = Aspartate aminotransferase; ALT = alanine aminotransferase ULN = upper limit of normal LLN = lower limit of normal T. Bilirubin >1.5× ULN 35/180 (19.4) 46/173 (26.6) AST >3.0× ULN 21/180 (11.7) 18/174 (10.3) ALT >3.0× ULN 34/180 (18.9) 40/173 (23.1) Alkaline Phosphatase >3.0× ULN 29/181 (16.0) 38/173 (22.0) Creatinine >1.3× ULN 39/182 (21.4) 102/177 (57.6) Potassium <0.9× LLN 30/181 (16.6) 70/178 (39.3) Table 5: Protocol 608 – Treatment of Candidemia Clinically Significant Laboratory Test Abnormalities Criteria Without regard to baseline value Voriconazole Amphotericin B followed by Fluconazole n/N (%) n/N (%) n = number of patients with a clinically significant abnormality while on study therapy N = total number of patients with at least one observation of the given lab test while on study therapy AST = Aspartate aminotransferase; ALT = alanine aminotransferase ULN = upper limit of normal LLN = lower limit of normal T. Bilirubin >1.5× ULN 50/261 (19.2) 31/115 (27.0) AST >3.0× ULN 40/261 (15.3) 16/116 (13.8) ALT >3.0× ULN 22/261 (8.4) 15/116 (12.9) Alkaline Phosphatase >3.0× ULN 59/261 (22.6) 26/115 (22.6) Creatinine >1.3× ULN 39/260 (15.0) 32/118 (27.1) Potassium <0.9× LLN 43/258 (16.7) 35/118 (29.7) Clinical Trials Experience in Pediatric Patients The safety of Voriconazole for injection was investigated in pediatric patients, including 51 pediatric patients aged 12 to less than 18 years of age who were enrolled in the adult therapeutic studies. Hepatic-Related Adverse Reactions in Pediatric Patients The frequency of hepatic-related adverse reactions in pediatric patients exposed to Voriconazole for injection in therapeutic studies was numerically higher than that of adults (28.6% compared to 24.1%, respectively). The higher frequency of hepatic adverse reactions in the pediatric population was mainly due to an increased frequency of liver enzyme elevations (21.9% in pediatric patients compared to 16.1% in adults), including transaminase elevations (ALT and AST combined) 7.6% in the pediatric patients compared to 5.1% in adults. Additional pediatric use information is approved for PF PRISM C.V.'s VFEND (voriconazole) for injection. However, due to PF PRISM C.V.'s marketing exclusivity rights, this drug product is not labeled with that information. 6.2 Postmarketing Experience in Adult and Pediatric Patients The following adverse reactions have been identified during post-approval use of Voriconazole for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Dermatological Reactions Increased risk of skin toxicity with concomitant use of methotrexate, a drug associated with UV reactivation, was observed in postmarketing reports [see Warnings and Precautions (5.6) and Adverse Reactions (6.1) ]. Adults Skeletal : fluorosis and periostitis have been reported during long-term voriconazole therapy [see Warnings and Precautions (5.11) ] . Eye disorders : prolonged visual adverse reactions, including optic neuritis and papilledema [see Warnings and Precautions (5.4) ]. Skin and Appendages : drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported [see Warnings and Precautions (5.5) and Adverse Reactions (6.1) ]. Endocrine disorders : adrenal insufficiency, Cushing's syndrome (when voriconazole has been used concomitantly with corticosteroids) [see Warnings and Precautions (5.8) ] . Pediatric Patients There have been postmarketing reports of pancreatitis in pediatric patients.

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 for injection (voriconazole) and other azole antifungal agents. Caution should be used when prescribing Voriconazole for injection to patients with hypersensitivity to other azoles. Coadministration of pimozide, quinidine or ivabradine 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) ] . Coadministration of Voriconazole for injection with sirolimus is contraindicated because Voriconazole for injection significantly increases sirolimus concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] . Coadministration of Voriconazole for injection with rifampin, carbamazepine, long-acting barbiturates and St. John's Wort is contraindicated because these drugs are likely to decrease plasma voriconazole concentrations significantly [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] . Coadministration of standard doses of voriconazole with efavirenz doses of 400 mg every 24 hours or higher is contraindicated, because efavirenz significantly decreases plasma voriconazole concentrations in healthy subjects at these doses. Voriconazole also significantly increases efavirenz plasma concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] . Coadministration of Voriconazole for injection with high-dose ritonavir (400 mg every 12 hours) is contraindicated because ritonavir (400 mg every 12 hours) significantly decreases plasma voriconazole concentrations. Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] . Coadministration of Voriconazole for injection with rifabutin is contraindicated since Voriconazole for injection 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 for injection may increase the plasma concentration of ergot alkaloids, which may lead to ergotism [see Drug Interactions (7) ] . Coadministration of Voriconazole for injection with naloxegol is contraindicated because Voriconazole for injection may increase plasma concentrations of naloxegol which may precipitate opioid withdrawal symptoms [see Drug Interactions (7) ]. Coadministration of Voriconazole for injection with tolvaptan is contraindicated because Voriconazole for injection may increase tolvaptan plasma concentrations and increase risk of adverse reactions [see Drug Interactions (7) ]. Coadministration of Voriconazole for injection with venetoclax at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome [see Drug Interactions (7) ]. Coadministration of Voriconazole for injection with lurasidone is contraindicated since it may result in significant increases in lurasidone exposure and the potential for serious adverse reactions [see Drug Interactions (7) ] . Hypersensitivity to voriconazole or its excipients ( 4 ) Coadministration with pimozide, quinidine, sirolimus or ivabradine due to risk of serious adverse reactions ( 4 , 7 ) Coadministration with rifampin, carbamazepine, long-acting barbiturates, efavirenz, ritonavir, rifabutin, ergot alkaloids, and St. John's Wort due to risk of loss of efficacy ( 4 , 7 ) Coadministration with naloxegol, tolvaptan, and lurasidone due to risk of adverse reactions ( 4 , 7 ) Coadministration of Voriconazole for injection with venetoclax at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to increased risk of adverse reactions ( 4 , 7 )

11 DESCRIPTION Voriconazole for injection, an azole antifungal is available as a sterile 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-(1 H -1,2,4-triazol-1-yl)-2-butanol with an empirical formula of C 16 H 14 F 3 N 5 O 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 β-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 β-cyclodextrin (HPβCD). The resultant solution is further diluted prior to administration as an intravenous infusion [see Dosage and Administration (2) ] . Chemical Structure

2 DOSAGE AND ADMINISTRATION Dosage in Adults ( 2.3 ) Infection Loading dose Maintenance Dose Intravenous infusion Intravenous infusion Invasive Aspergillosis 6 mg/kg every 12 hours for the first 24 hours 4 mg/kg every 12 hours Candidemia in nonneutropenics and other deep tissue Candida infections 3–4 mg/kg every 12 hours Scedosporiosis and Fusariosis 4 mg/kg every 12 hours Hepatic Impairment : Use half the maintenance dose in adult patients with mild to moderate hepatic impairment (Child-Pugh Class A and B) ( 2.5 ) Renal Impairment : Avoid intravenous administration in adult patients with moderate to severe renal impairment (creatinine clearance <50 mL/min) ( 2.6 ) Dosage in Pediatric Patients ( 2.4 ) For pediatric patients aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight use adult dosage. ( 2.4 ) Dosage adjustment of Voriconazole for injection in pediatric patients with renal or hepatic impairment has not been established. ( 2.5 , 2.6 ) See full prescribing information for instructions on reconstitution of Voriconazole for injection lyophilized powder for intravenous use ( 2.8 ) 2.1 Important Administration 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 3 hours. Administer diluted Voriconazole for injection by intravenous infusion over 1 to 3 hours only. Do not administer as an IV 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 (5.10) ] . 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 Regimen in Adults Invasive aspergillosis and serious fungal infections due to Fusarium spp. and Scedosporium apiospermum See Table 1 . Therapy must be initiated with the specified loading dose regimen of intravenous 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 [see Clinical Pharmacology (12.3) ] . Candidemia in non-neutropenic patients and other deep tissue Candida infections See Table 1 . Patients should be treated for at least 14 days following resolution of symptoms or following last positive culture, whichever is longer. Table 1: Recommended Dosing Regimen (Adults) Infection Loading Dose Maintenance Dose Increase dose when Voriconazole for injection is co-administered with phenytoin or efavirenz (7); Decrease dose in patients with hepatic impairment (2.5) Intravenous infusion Intravenous infusion Invasive Aspergillosis In a clinical study of IA, the median duration of intravenous Voriconazole for injection therapy was 10 days (range 2 to 85 days) (14.1). 6 mg/kg every 12 hours for the first 24 hours 4 mg/kg every 12 hours Candidemia in nonneutropenic patients and other deep tissue Candida infections 6 mg/kg every 12 hours for the first 24 hours 3–4 mg/kg every 12 hours In clinical trials, patients with candidemia received 3 mg/kg intravenous infusion every 12 hours as primary therapy, while patients with other deep tissue Candida infections received 4 mg/kg every 12 hours as salvage therapy. Appropriate dose should be based on the severity and nature of the infection. Scedosporiosis and Fusariosis 6 mg/kg every 12 hours for the first 24 hours 4 mg/kg every 12 hours Method for Adjusting the Dosing Regimen in Adults If patient is unable to tolerate 4 mg/kg intravenously every 12 hours, reduce the intravenous maintenance dose to 3 mg/kg every 12 hours. 2.4 Recommended Dosing Regimen in Pediatric Patients For pediatric patients 12 to 14 years of age with a body weight greater than or equal to 50 kg and those 15 years of age and above regardless of body weight, administer the adult dosing regimen of Voriconazole for injection [see Dosage and Administration (2.3) ] . Initiate therapy with an intravenous infusion regimen. Consider an oral regimen only after there is a significant clinical improvement. Method for Adjusting the Dosing Regimen in Pediatric Patients Pediatric patients 12 to 14 years of age weighing greater than or equal to 50 kg and 15 years of age and older regardless of body weight: Use the optimal method for titrating dosage recommended for adults [see Dosage and Administration (2.3) ] . Additional pediatric use information is approved for PF PRISM C.V.'s VFEND (voriconazole) for injection. However, due to PF PRISM C.V.'s marketing exclusivity rights, this drug product is not labeled with that information. 2.5 Dosage Modifications in Patients With Hepatic Impairment Adults The maintenance dose of Voriconazole for injection should be reduced in adult patients with mild to moderate hepatic impairment, Child-Pugh Class A and B. There are no PK data to allow for dosage adjustment recommendations in patients with severe hepatic impairment (Child-Pugh Class C). Duration of therapy should be based on the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response. Adult patients with baseline liver function tests (ALT, AST) up to 5 times the upper limit of normal (ULN) were included in the clinical program. Dose adjustments are not necessary for adult patients with this degree of abnormal liver function, but continued monitoring of liver function tests for further elevations is recommended [see Warnings and Precautions (5.1) ] . It is recommended that the recommended Voriconazole for injection loading dose regimens be used, but that the maintenance dose be halved in adult patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) [see Clinical Pharmacology (12.3) ] . Voriconazole for injection has not been studied in adult patients with severe hepatic cirrhosis (Child-Pugh Class C) or in patients with chronic hepatitis B or chronic hepatitis C disease. Voriconazole for injection has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice. Voriconazole for injection should only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with hepatic impairment must be carefully monitored for drug toxicity. Pediatric Patients Dosage adjustment of Voriconazole for injection in pediatric patients with hepatic impairment has not been established [see Use in Specific Populations (8.4) ] . 2.6 Dosage Modifications in Patients With Renal Impairment Adult Patients In patients with moderate or severe renal impairment (creatinine clearance <50 mL/min) who are receiving an intravenous infusion of Voriconazole for injection, accumulation of the intravenous vehicle, hydroxypropyl β-cyclodextrin (HPβCD), occurs. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral voriconazole therapy. [see Warnings and Precautions (5.7) ] . Voriconazole and the intravenous vehicle, HPβCD, are dialyzable. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment [see Clinical Pharmacology (12.3) ] . Pediatric Patients Dosage adjustment of Voriconazole for injection in pediatric patients with renal impairment has not been established [see Use in Specific Populations (8.4) ] . 2.7 Dosage Adjustment When Co-Administered With Phenytoin or Efavirenz The maintenance dose of voriconazole should be increased when co-administered with phenytoin or efavirenz. Use the optimal method for titrating dosage [see Drug Interactions (7) and Dosage and Administration (2.3) ]. 2.8 Preparation and Intravenous Administration of Voriconazole for Injection Reconstitution The powder is reconstituted with 19 mL of Water for Injection to obtain an extractable volume of 20 mL of clear concentrate containing 10 mg/mL of voriconazole. It is recommended that a standard 20 mL (non-automated) syringe be used to ensure that the exact amount (19.0 mL) of Water for Injection is dispensed. Discard the vial if a vacuum does not pull the diluent into the vial. Shake the vial until all the powder is dissolved. 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 to 3 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 Partially Used Vials . The final Voriconazole for injection solution must be infused over 1 to 3 hours at a maximum rate of 3 mg/kg per hour. 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 mL (1) 12 mL (1) 18 mL (1) 35 10.5 mL (1) 14 mL (1) 21 mL (2) 40 12 mL (1) 16 mL (1) 24 mL (2) 45 13.5 mL (1) 18 mL (1) 27 mL (2) 50 15 mL (1) 20 mL (1) 30 mL (2) 55 16.5 mL (1) 22 mL (2) 33 mL (2) 60 18 mL (1) 24 mL (2) 36 mL (2) 65 19.5 mL (1) 26 mL (2) 39 mL (2) 70 21 mL (2) 28 mL (2) 42 mL (3) 75 22.5 mL (2) 30 mL (2) 45 mL (3) 80 24 mL (2) 32 mL (2) 48 mL (3) 85 25.5 mL (2) 34 mL (2) 51 mL (3) 90 27 mL (2) 36 mL (2) 54 mL (3) 95 28.5 mL (2) 38 mL (2) 57 mL (3) 100 30 mL (2) 40 mL (2) 60 mL (3) Voriconazole for injection is a single-dose unpreserved sterile lyophile. Therefore, from a microbiological point of view, once reconstituted, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2°C to 8°C (36°F to 46°F). This medicinal product is for single use only and any unused solution should be discarded. Only clear solutions without particles should be used. The reconstituted solution can be diluted with: 0.9% Sodium Chloride USP Lactated Ringers USP 5% Dextrose and Lactated Ringers USP 5% Dextrose and 0.45% Sodium Chloride USP 5% Dextrose USP 5% Dextrose and 20 mEq Potassium Chloride USP 0.45% Sodium Chloride USP 5% Dextrose and 0.9% Sodium Chloride USP The compatibility of Voriconazole for injection with diluents other than those described above is unknown (see Incompatibilities below). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Incompatibilities 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 for injection 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. Additional pediatric use information is approved for PF PRISM C.V.'s VFEND (voriconazole) for injection. However, due to PF PRISM C.V.'s marketing exclusivity rights, this drug product is not labeled with that information.

1 INDICATIONS AND USAGE Voriconazole for injection is an azole antifungal indicated for use in the treatment of adults and pediatric patients aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight with: Invasive aspergillosis ( 1.1 ) Candidemia in non-neutropenics and other deep tissue Candida infections ( 1.2 ) Serious fungal infections caused by Scedosporium apiospermum and Fusarium species including Fusarium solani , in patients intolerant of, or refractory to, other therapy ( 1.3 ) 1.1 Invasive Aspergillosis Voriconazole for injection is indicated in adults and pediatric patients (aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight) for the treatment of invasive aspergillosis (IA). In clinical trials, the majority of isolates recovered were Aspergillus fumigatus . There was a small number of cases of culture-proven disease due to species of Aspergillus other than A. fumigatus [see Clinical Studies (14.1) and Microbiology (12.4) ]. 1.2 Candidemia in Non-neutropenic Patients and Other Deep Tissue Candida Infections Voriconazole for injection is indicated in adult and pediatric patients (aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight) for the treatment of candidemia in non-neutropenic patients and the following Candida infections: disseminated infections in skin and infections in abdomen, kidney, bladder wall, and wounds [see Clinical Studies (14.2) and Microbiology (12.4) ]. 1.3 Scedosporiosis and Fusariosis Voriconazole for injection is indicated for the treatment of serious fungal infections caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii ) and Fusarium spp . including Fusarium solani , in adult and pediatric patients (aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight) intolerant of, or refractory to, other therapy [see Clinical Studies (14.3) and Microbiology (12.4) ] . 1.4 Usage Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly. Additional pediatric use information is approved for PF PRISM C.V.'s VFEND (voriconazole) for injection. However, due to PF PRISM C.V.'s marketing exclusivity rights, this drug product is not labeled with that information.

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.

7 DRUG INTERACTIONS Voriconazole is metabolized by cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Therefore, inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively. Voriconazole is a strong inhibitor of CYP3A4, and also inhibits CYP2C19 and CYP2C9. Therefore, voriconazole may increase the plasma concentrations of substances metabolized by these CYP450 isoenzymes. Tables 6 and 7 provide the clinically significant interactions between voriconazole and other medical products. Table 6: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3) ] Drug/Drug Class (Mechanism of Interaction by the Drug) Voriconazole Plasma Exposure (C max and AUC τ after 200 mg every 12 hours) Recommendations for Voriconazole Dosage Adjustment/Comments Rifampin and Rifabutin (CYP450 Induction) Significantly Reduced Contraindicated Efavirenz (400 mg every 24 hours) (CYP450 Induction) Significantly Reduced Contraindicated High-dose Ritonavir (400 mg every 12 hours) (CYP450 Induction) Significantly Reduced Contraindicated Low-dose Ritonavir (100 mg every 12 hours) (CYP450 Induction) Reduced Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole Carbamazepine (CYP450 Induction) Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction Contraindicated Long Acting Barbiturates (e.g., phenobarbital, mephobarbital) (CYP450 Induction) Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction Contraindicated Phenytoin (CYP450 Induction) Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every12 hours Letermovir (CYP2C9/2C19 Induction) Reduced If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole. St. John's Wort (CYP450 inducer; P-gp inducer) Significantly Reduced Contraindicated Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) Increased Monitoring for adverse reactions and toxicity related to voriconazole is recommended when coadministered with oral contraceptives Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse reactions and toxicity related to voriconazole is started within 24 hours after the last dose of fluconazole Other HIV Protease Inhibitors (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir. In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse reactions and toxicity related to voriconazole when coadministered with other HIV protease inhibitors Other NNRTIs Non-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction) In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure). Frequent monitoring for adverse reactions and toxicity related to voriconazole A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) Careful assessment of voriconazole effectiveness Table 7: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3) ] Drug/Drug Class (Mechanism of Interaction by Voriconazole) Drug Plasma Exposure (C max and AUC τ ) Recommendations for Drug Dosage Adjustment/Comments Sirolimus (CYP3A4 Inhibition) Significantly Increased Contraindicated Rifabutin (CYP3A4 Inhibition) Significantly Increased Contraindicated Efavirenz (400 mg every 24 hours) (CYP3A4 Inhibition) Significantly Increased Contraindicated High-dose Ritonavir (400 mg every 12 hours) (CYP3A4 Inhibition) No Significant Effect of Voriconazole on Ritonavir C max or AUC τ Contraindicated because of significant reduction of voriconazole C max and AUC τ Low-dose Ritonavir (100 mg every 12 hours) Slight Decrease in Ritonavir C max and AUC τ Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided (due to the reduction in voriconazole C max and AUC τ ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole Pimozide, Quinidine, Ivabradine (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes Ergot Alkaloids (CYP450 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Contraindicated Naloxegol (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions Contraindicated Tolvaptan (CYP3A4 Inhibition) Although Not Studied Clinically, Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Tolvaptan Contraindicated Venetoclax (CYP3A4 Inhibition) Not studied In Vivo or In Vitro , but Venetoclax Plasma Exposure Likely to be Significantly Increased Coadministration of voriconazole is contraindicated at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering Voriconazole for injection with venetoclax. Refer to the venetoclax prescribing information for dosing instructions. Lemborexant (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Avoid concomitant use of Voriconazole for injection with lemborexant. Glasdegib (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Consider alternative therapies. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions including QTc interval prolongation. Tyrosine kinase inhibitors (including but not limited to axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Avoid concomitant use of Voriconazole for injection. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor is recommended. Refer to the prescribing information for the relevant product. Lurasidone (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Lurasidone Contraindicated Cyclosporine (CYP3A4 Inhibition) AUC τ Significantly Increased; No Significant Effect on C max When initiating therapy with Voriconazole for injection in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When Voriconazole for injection is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. Methadone (CYP3A4 Inhibition) Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse reactions and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed. Fentanyl (CYP3A4 Inhibition) Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with Voriconazole for injection. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary. Alfentanil (CYP3A4 Inhibition) Significantly Increased An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting were observed when coadministered with Voriconazole for injection. Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with Voriconazole for injection. A longer period for monitoring respiratory and other opiate-associated adverse reactions may be necessary. Oxycodone (CYP3A4 Inhibition) Significantly Increased Increased visual effects (heterophoria and miosis) of oxycodone were observed when coadministered with Voriconazole for injection. Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with Voriconazole for injection. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary. NSAIDs Non-Steroidal Anti-Inflammatory Drug including ibuprofen and diclofenac (CYP2C9 Inhibition) Increased Frequent monitoring for adverse reactions and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. Tacrolimus (CYP3A4 Inhibition) Significantly Increased When initiating therapy with Voriconazole for injection in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When Voriconazole for injection is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. Phenytoin (CYP2C9 Inhibition) Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) Increased Monitoring for adverse reactions related to oral contraceptives is recommended during coadministration. Prednisolone and other corticosteroids (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects of Voriconazole for injection on Prednisolone Exposure No dosage adjustment for prednisolone when coadministered with Voriconazole for injection [see Clinical Pharmacology (12.3) ] . Not Studied In vitro or In vivo for Other Corticosteroids, but Drug Exposure Likely to be Increased Monitor for potential adrenal dysfunction when Voriconazole for injection is administered with other corticosteroids [see Warnings and Precautions (5.8) ] . Warfarin (CYP2C9 Inhibition) Prothrombin Time Significantly Increased If patients receiving coumarin preparations are treated simultaneously with voriconazole, the prothrombin time or other suitable anticoagulation tests should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly. Other Oral Coumarin Anticoagulants (CYP2C9/3A4 Inhibition) Not Studied In Vivo or In Vitro for other Oral Coumarin Anticoagulants, but Drug Plasma Exposure Likely to be Increased Ivacaftor (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions Dose reduction of ivacaftor is recommended. Refer to the prescribing information for ivacaftor Eszopiclone (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Sedative Effect of Eszopiclone Dose reduction of eszopiclone is recommended. Refer to the prescribing information for eszopiclone. Omeprazole (CYP2C19/3A4 Inhibition) Significantly Increased When initiating therapy with Voriconazole for injection in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors. Other HIV Protease Inhibitors (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects on Indinavir Exposure No dosage adjustment for indinavir when coadministered with Voriconazole for injection In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse reactions and toxicity related to other HIV protease inhibitors Other NNRTIs Non-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse reactions and toxicity related to NNRTI. Tretinoin (CYP3A4 Inhibition) Although Not Studied, Voriconazole may Increase Tretinoin Concentrations and Increase the Risk of Adverse Reactions Frequent monitoring for signs and symptoms of pseudotumor cerebri or hypercalcemia. Midazolam (CYP3A4 Inhibition) Significantly Increased Increased plasma exposures may increase the risk of adverse reactions and toxicities related to benzodiazepines. Other benzodiazepines including triazolam and alprazolam (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Refer to drug-specific labeling for details. HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse reactions and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed. Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed. Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed. Vinca Alkaloids (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse reactions and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Reserve azole antifungals, including Voriconazole for injection, for patients receiving a vinca alkaloid who have no alternative antifungal treatment options. Everolimus (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Concomitant administration of Voriconazole for injection and everolimus is not recommended. CYP3A4, CYP2C9, and CYP2C19 inhibitors and inducers: Adjust Voriconazole for injection dosage and monitor for adverse reactions or lack of efficacy ( 4 , 7 ) Voriconazole for injection may increase the concentrations and activity of drugs that are CYP3A4, CYP2C9 and CYP2C19 substrates. Reduce dosage of these other drugs and monitor for adverse reactions ( 4 , 7 ) Phenytoin or Efavirenz: With co-administration, increase maintenance intravenous dosage of Voriconazole for injection ( 2.3 , 2.7 , 7 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Voriconazole is an antifungal drug [see Microbiology (12.4) ] . 12.2 Pharmacodynamics Exposure-Response Relationship For Efficacy and Safety In 10 clinical trials (N=1121), the median values for the average and maximum voriconazole plasma concentrations in individual patients across these studies was 2.51 µg/mL (inter-quartile range 1.21 to 4.44 µg/mL) and 3.79 µg/mL (inter-quartile range 2.06 to 6.31 µg/mL), respectively. A pharmacokinetic-pharmacodynamic analysis of patient data from 6 of these 10 clinical trials (N=280) could not detect a positive association between mean, maximum or minimum plasma voriconazole concentration and efficacy. However, pharmacokinetic/pharmacodynamic analyses of the data from all 10 clinical trials identified positive associations between plasma voriconazole concentrations and rate of both liver function test abnormalities and visual disturbances [see Adverse Reactions (6) ] . Cardiac Electrophysiology A placebo-controlled, randomized, crossover study to evaluate the effect on the QT interval of healthy male and female subjects was conducted with three single oral doses of voriconazole and ketoconazole. Serial ECGs and plasma samples were obtained at specified intervals over a 24-hour post dose observation period. The placebo-adjusted mean maximum increases in QTc from baseline after 800, 1200, and 1600 mg of voriconazole and after ketoconazole 800 mg were all <10 msec. Females exhibited a greater increase in QTc than males, although all mean changes were <10 msec. Age was not found to affect the magnitude of increase in QTc. No subject in any group had an increase in QTc of ≥60 msec from baseline. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec. However, the QT effect of voriconazole combined with drugs known to prolong the QT interval is unknown [see Contraindications (4) and Drug Interactions (7) ] . 12.3 Pharmacokinetics The pharmacokinetics of voriconazole have been characterized in healthy subjects, special populations and patients. The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. The interindividual variability of voriconazole pharmacokinetics is high. Greater than proportional increase in exposure is observed with increasing dose. It is estimated that, on average, increasing the intravenous dose from 3 mg/kg every 12 hours to 4 mg/kg every 12 hours produces an approximately 2.5-fold increase in exposure (Table 8). Table 8: Geometric Mean (%CV) Plasma Voriconazole Pharmacokinetic Parameters in Adults Receiving Different Dosing Regimens 6 mg/kg IV (loading dose) 3 mg/kg IV every 12 hours 4 mg/kg IV every 12 hours Note: Parameters were estimated based on non-compartmental analysis from 5 pharmacokinetic studies. AUC 12 = area under the curve over 12 hour dosing interval, C max = maximum plasma concentration, C min = minimum plasma concentration. CV = coefficient of variation. N 35 23 40 AUC 12 (μg∙h/mL) 13.9 (32) 13.7 (53) 33.9 (54) C max (μg/mL) 3.13 (20) 3.03 (25) 4.77 (36) C min (μg/mL) -- 0.46 (97) 1.73 (74) When the recommended intravenous loading dose regimen is administered to healthy subjects, plasma concentrations close to steady state are achieved within the first 24 hours of dosing (e.g., 6 mg/kg IV every 12 hours on day 1 followed by 3 mg/kg IV every 12 hours). Without the loading dose, accumulation occurs during twice daily multiple dosing with steady state plasma voriconazole concentrations being achieved by day 6 in the majority of subjects. 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 IV voriconazole, preceded by multiple IV dosing, approximately 80% to 83% of the radioactivity is recovered in the urine. The majority (>94%) of the total radioactivity is excreted in the first 96 hours after 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 IV or oral administration. However, the safety profile of voriconazole in young and elderly subjects was similar and, therefore, no dosage adjustment is necessary for the elderly [see Use in Specific Populations (8.5) ] . Pediatric Patients Voriconazole exposures in the majority of pediatric patients aged 12 to less than 17 years were comparable to those in adults receiving the same dosing regimens. However, lower voriconazole exposure was observed in some pediatric patients aged 12 to less than 17 years with low body weight compared to adults [see Dosage and Administration (2.4) ] . Additional pediatric use information is approved for PF PRISM C.V.'s VFEND (voriconazole) for injection. However, due to PF PRISM C.V.'s marketing exclusivity rights, this drug product is not labeled with that information. Patients with Hepatic Impairment After a single oral dose (200 mg) of voriconazole in 8 patients with mild (Child-Pugh Class A) and 4 patients with moderate (Child-Pugh Class B) hepatic impairment, the mean systemic exposure (AUC) was 3.2-fold higher than in age and weight matched controls with normal hepatic function. There was no difference in mean peak plasma concentrations (C max ) between the groups. When only the patients with mild (Child-Pugh Class A) hepatic impairment were compared to controls, there was still a 2.3-fold increase in the mean AUC in the group with hepatic impairment compared to controls. In an oral multiple dose study, AUC 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 (2.5) ] . Patients with Renal Impairment In a multiple dose study of IV voriconazole (6 mg/kg IV loading dose × 2, then 3 mg/kg IV × 5.5 days) in 7 patients with moderate renal 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. However, in patients with moderate renal dysfunction, the pharmacokinetic profile of hydroxypropyl β-cyclodextrin (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-β-cyclodextrin was reduced in subjects with renal impairment, resulting in higher exposure to hydroxypropyl-β-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 hemodialyzed with a clearance of 37.5±24 mL/min. 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 [see Dosage and Administration (2.6) ] . Patients at Risk of Aspergillosis The observed voriconazole pharmacokinetics in patients at risk of aspergillosis (mainly patients with malignant neoplasms of lymphatic or hematopoietic tissue) were similar to healthy subjects. Drug Interaction Studies Effects of Other Drugs on Voriconazole Voriconazole is metabolized by the human hepatic cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. Results of in vitro metabolism studies indicate that the affinity of voriconazole is highest for CYP2C19, followed by CYP2C9, and is appreciably lower for CYP3A4. Inhibitors or inducers of these three enzymes may increase or decrease voriconazole systemic exposure (plasma concentrations), respectively. The systemic exposure to voriconazole is significantly reduced by the concomitant administration of the following agents and their use is contraindicated: Rifampin (potent CYP450 inducer) –Rifampin (600 mg once daily) decreased the steady state C max and AUC τ of voriconazole (200 mg every 12 hours × 7 days) by an average of 93% and 96%, respectively, in healthy subjects. Doubling the dose of voriconazole to 400 mg every 12 hours does not restore adequate exposure to voriconazole during coadministration with rifampin [see Contraindications (4) ] . Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate) –The effect of the coadministration of voriconazole and ritonavir (400 mg and 100 mg) was investigated in two separate studies. High-dose ritonavir (400 mg every 12 hours for 9 days) decreased the steady state C max and AUC τ of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) by an average of 66% and 82%, respectively, in healthy subjects. Low-dose ritonavir (100 mg every 12 hours for 9 days) decreased the steady state C max and AUC τ of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) by an average of 24% and 39%, respectively , in healthy subjects. Although repeat oral administration of voriconazole did not have a significant effect on steady state 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 [see Contraindications (4) ] . St. John's Wort (CYP450 inducer; P-gp inducer) –In an independent published study in healthy volunteers who were given multiple oral doses of St. John's Wort (300 mg LI 160 extract three times daily for 15 days) followed by a single 400 mg oral dose of voriconazole, a 59% decrease in mean voriconazole AUC 0 –∞ was observed. In contrast, coadministration of single oral doses of St. John's Wort and voriconazole had no appreciable effect on voriconazole AUC 0 –∞. Long-term use of St. John's Wort could lead to reduced voriconazole exposure [see Contraindications (4) ] . Significant drug interactions that may require voriconazole dosage adjustment, or frequent monitoring of voriconazole-related adverse reactions/toxicity: Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor): Concurrent administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) to 6 healthy male subjects resulted in an increase in C 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 [see Drug Interactions (7) ] . Letermovir (CYP2C9/2C19 inducer) –Coadministration of oral letermovir with oral voriconazole decreased the steady state C max and AUC 0-12 of voriconazole by an average of 39% and 44%, respectively [see Drug Interactions (7) ] . Minor or no significant pharmacokinetic interactions that do not require dosage adjustment: Cimetidine (non-specific CYP450 inhibitor and increases gastric pH) –Cimetidine (400 mg every 12 hours × 8 days) increased voriconazole steady state C 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 12 hours × 7 days to healthy subjects. Ranitidine (increases gastric pH) –Ranitidine (150 mg every 12 hours) had no significant effect on voriconazole C max and AUC τ following oral doses of 200 mg every 12 hours × 7 days to healthy subjects. Macrolide antibiotics –Coadministration of erythromycin (CYP3A4 inhibitor; 1gram every 12 hours for 7 days) or azithromycin (500 mg every 24 hours for 3 days) with voriconazole 200 mg every 12 hours for 14 days had no significant effect on voriconazole steady state C 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 by coadministration of voriconazole and their use is contraindicated: Sirolimus (CYP3A4 substrate) –Repeat dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) increased the C 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 [see Contraindications (4) ] . Coadministration of voriconazole with the following agents results in increased exposure to these drugs. Therefore, careful monitoring and/or dosage adjustment of these drugs is needed: Alfentanil (CYP3A4 substrate) –Coadministration of multiple doses of oral voriconazole (400 mg every 12 hours on day 1, 200 mg every 12 hours on day 2) with a single 20 mcg/kg intravenous dose of alfentanil with concomitant naloxone resulted in a 6-fold increase in mean alfentanil AUC 0 –∞ and a 4-fold prolongation of mean alfentanil elimination half-life, compared to when alfentanil was given alone [see Drug Interactions (7) ] . Fentanyl (CYP3A4 substrate): In an independent published study, concomitant use of voriconazole (400 mg every 12 hours on Day 1, then 200 mg every 12 hours on Day 2) with a single intravenous dose of fentanyl (5 µg/kg) resulted in an increase in the mean AUC 0 –∞ of fentanyl by 1.4-fold (range 0.81- to 2.04-fold) [see Drug Interactions (7) ] . Oxycodone (CYP3A4 substrate): In an independent published study, coadministration of multiple doses of oral voriconazole (400 mg every 12 hours, on Day 1 followed by five doses of 200 mg every 12 hours on Days 2 to 4) with a single 10 mg oral dose of oxycodone on Day 3 resulted in an increase in the mean C 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) [see Drug Interactions (7) ] . Cyclosporine (CYP3A4 substrate) –In stable renal transplant recipients receiving chronic cyclosporine therapy, concomitant administration of oral voriconazole (200 mg every 12 hours for 8 days) increased cyclosporine C 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 [see Drug Interactions (7) ] . Methadone (CYP3A4, CYP2C19, CYP2C9 substrate) –Repeat dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days) increased the C 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 24 hours). The C max and AUC of (S)-methadone increased by 65% (90% CI: 53%, 79%) and 103% (90% CI: 85%, 124%), respectively [see Drug Interactions (7) ] . Tacrolimus (CYP3A4 substrate) –Repeat oral dose administration of voriconazole (400 mg every 12 hours × 1 day, then 200 mg every 12 hours × 6 days) increased tacrolimus (0.1 mg/kg single dose) C 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 [see Drug Interactions (7) ] . Warfarin (CYP2C9 substrate) –Coadministration of voriconazole (300 mg every 12 hours × 12 days) with warfarin (30 mg single dose) significantly increased maximum prothrombin time by approximately 2 times that of placebo in healthy subjects [see Drug Interactions (7) ] . Non-Steroidal Anti-Inflammatory Drugs (NSAIDs; CYP2C9 substrates): In two independent published studies, single doses of ibuprofen (400 mg) and diclofenac (50 mg) were coadministered with the last dose of voriconazole (400 mg every 12 hours on Day 1, followed by 200 mg every 12 hours on Day 2). Voriconazole increased the mean C 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 [see Drug Interactions (7) ]. No significant pharmacokinetic interactions were observed when voriconazole was coadministered with the following agents. Therefore, no dosage adjustment for these agents is recommended: Prednisolone (CYP3A4 substrate) –Voriconazole (200 mg every 12 hours × 30 days) increased C max and AUC of prednisolone (60 mg single dose) by an average of 11% and 34%, respectively, in healthy subjects [see Warnings and Precautions (5.8) ] . Digoxin (P-glycoprotein mediated transport) –Voriconazole (200 mg every 12 hours × 12 days) had no significant effect on steady state C 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 12 hours × 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 1gram 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 [see Contraindications (4) ] . Significant drug interactions that may require dosage adjustment, frequent monitoring of drug levels and/or frequent monitoring of drug-related adverse reactions/toxicity: Efavirenz, a non-nucleoside reverse transcriptase inhibitor (CYP450 inducer; CYP3A4 inhibitor and substrate) –Standard doses of voriconazole and efavirenz (400 mg every 24 hours or higher) must not be coadministered [see Drug Interactions (7) ] . Steady state efavirenz (400 mg PO every 24 hours) decreased the steady state C max and AUC τ of voriconazole (400 mg PO every 12 hours for 1 day, then 200 mg PO every 12 hours for 8 days) by an average of 61% and 77%, respectively, in healthy male subjects. Voriconazole at steady state (400 mg PO every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) increased the steady state C max and AUC τ of efavirenz (400 mg PO every 24 hours for 9 days) by an average of 38% and 44%, respectively, in healthy subjects. 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 12 hours × 14 days) by an average of 50% and 70%, respectively, in healthy subjects. Administration of a higher voriconazole dose (400 mg every 12 hours × 7 days) with phenytoin (300 mg once daily) resulted in comparable steady state voriconazole C max and AUC τ estimates as compared to when voriconazole was given at 200 mg every 12 hours without phenytoin [see Dosage and Administration (2.7) and Drug Interactions (7) ]. Repeat dose administration of voriconazole (400 mg every 12 hours × 10 days) increased the steady state C 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 when coadministered with voriconazole may be expected to be as high as 2 times the C max and AUC 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 Drug Interactions (7) ] . Omeprazole (CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate) –Coadministration of omeprazole (40 mg once daily × 10 days) with oral voriconazole (400 mg every 12 hours × 1 day, then 200 mg every 12 hours × 9 days) increased the steady state C 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 12 hours × 1 day, then 200 mg × 6 days) with omeprazole (40 mg once daily × 7 days) to healthy subjects significantly increased the steady state C 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 [see Drug Interactions (7) ] . Oral Contraceptives (CYP3A4 substrate; CYP2C19 inhibitor) –Coadministration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 3 days) and oral contraceptive (Ortho-Novum1/35 ® consisting of 35 mcg ethinyl estradiol and 1 mg norethindrone, every 24 hours) to healthy female subjects at steady state increased the C 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 [see Drug Interactions (7) ] . No significant pharmacokinetic interaction was seen and no dosage adjustment of these drugs is recommended: Indinavir (CYP3A4 inhibitor and substrate) –Repeat dose administration of indinavir (800 mg TID for 10 days) had no significant effect on voriconazole C max and AUC following repeat dose administration (200 mg every 12 hours for 17 days) in healthy subjects. Repeat dose administration of voriconazole (200 mg every 12 hours for 7 days) did not have a significant effect on steady state C max and AUC τ of indinavir following repeat dose administration (800 mg TID for 7 days) in healthy subjects. 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 MIC 90 was 4 µg/mL) In clinical studies, voriconazole MIC 90 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 MIC 90 was 1 µg/mL. Candida krusei Candida parapsilosis Candida tropicalis Fusarium spp. including Fusarium solani Scedosporium apiospermum 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 effectiveness 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) ] .

12.1 Mechanism of Action Voriconazole is an antifungal drug [see Microbiology (12.4) ] .

12.2 Pharmacodynamics Exposure-Response Relationship For Efficacy and Safety In 10 clinical trials (N=1121), the median values for the average and maximum voriconazole plasma concentrations in individual patients across these studies was 2.51 µg/mL (inter-quartile range 1.21 to 4.44 µg/mL) and 3.79 µg/mL (inter-quartile range 2.06 to 6.31 µg/mL), respectively. A pharmacokinetic-pharmacodynamic analysis of patient data from 6 of these 10 clinical trials (N=280) could not detect a positive association between mean, maximum or minimum plasma voriconazole concentration and efficacy. However, pharmacokinetic/pharmacodynamic analyses of the data from all 10 clinical trials identified positive associations between plasma voriconazole concentrations and rate of both liver function test abnormalities and visual disturbances [see Adverse Reactions (6) ] . Cardiac Electrophysiology A placebo-controlled, randomized, crossover study to evaluate the effect on the QT interval of healthy male and female subjects was conducted with three single oral doses of voriconazole and ketoconazole. Serial ECGs and plasma samples were obtained at specified intervals over a 24-hour post dose observation period. The placebo-adjusted mean maximum increases in QTc from baseline after 800, 1200, and 1600 mg of voriconazole and after ketoconazole 800 mg were all <10 msec. Females exhibited a greater increase in QTc than males, although all mean changes were <10 msec. Age was not found to affect the magnitude of increase in QTc. No subject in any group had an increase in QTc of ≥60 msec from baseline. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec. However, the QT effect of voriconazole combined with drugs known to prolong the QT interval is unknown [see Contraindications (4) and Drug Interactions (7) ] .

12.3 Pharmacokinetics The pharmacokinetics of voriconazole have been characterized in healthy subjects, special populations and patients. The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. The interindividual variability of voriconazole pharmacokinetics is high. Greater than proportional increase in exposure is observed with increasing dose. It is estimated that, on average, increasing the intravenous dose from 3 mg/kg every 12 hours to 4 mg/kg every 12 hours produces an approximately 2.5-fold increase in exposure (Table 8). Table 8: Geometric Mean (%CV) Plasma Voriconazole Pharmacokinetic Parameters in Adults Receiving Different Dosing Regimens 6 mg/kg IV (loading dose) 3 mg/kg IV every 12 hours 4 mg/kg IV every 12 hours Note: Parameters were estimated based on non-compartmental analysis from 5 pharmacokinetic studies. AUC 12 = area under the curve over 12 hour dosing interval, C max = maximum plasma concentration, C min = minimum plasma concentration. CV = coefficient of variation. N 35 23 40 AUC 12 (μg∙h/mL) 13.9 (32) 13.7 (53) 33.9 (54) C max (μg/mL) 3.13 (20) 3.03 (25) 4.77 (36) C min (μg/mL) -- 0.46 (97) 1.73 (74) When the recommended intravenous loading dose regimen is administered to healthy subjects, plasma concentrations close to steady state are achieved within the first 24 hours of dosing (e.g., 6 mg/kg IV every 12 hours on day 1 followed by 3 mg/kg IV every 12 hours). Without the loading dose, accumulation occurs during twice daily multiple dosing with steady state plasma voriconazole concentrations being achieved by day 6 in the majority of subjects. 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 IV voriconazole, preceded by multiple IV dosing, approximately 80% to 83% of the radioactivity is recovered in the urine. The majority (>94%) of the total radioactivity is excreted in the first 96 hours after 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 IV or oral administration. However, the safety profile of voriconazole in young and elderly subjects was similar and, therefore, no dosage adjustment is necessary for the elderly [see Use in Specific Populations (8.5) ] . Pediatric Patients Voriconazole exposures in the majority of pediatric patients aged 12 to less than 17 years were comparable to those in adults receiving the same dosing regimens. However, lower voriconazole exposure was observed in some pediatric patients aged 12 to less than 17 years with low body weight compared to adults [see Dosage and Administration (2.4) ] . Additional pediatric use information is approved for PF PRISM C.V.'s VFEND (voriconazole) for injection. However, due to PF PRISM C.V.'s marketing exclusivity rights, this drug product is not labeled with that information. Patients with Hepatic Impairment After a single oral dose (200 mg) of voriconazole in 8 patients with mild (Child-Pugh Class A) and 4 patients with moderate (Child-Pugh Class B) hepatic impairment, the mean systemic exposure (AUC) was 3.2-fold higher than in age and weight matched controls with normal hepatic function. There was no difference in mean peak plasma concentrations (C max ) between the groups. When only the patients with mild (Child-Pugh Class A) hepatic impairment were compared to controls, there was still a 2.3-fold increase in the mean AUC in the group with hepatic impairment compared to controls. In an oral multiple dose study, AUC 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 (2.5) ] . Patients with Renal Impairment In a multiple dose study of IV voriconazole (6 mg/kg IV loading dose × 2, then 3 mg/kg IV × 5.5 days) in 7 patients with moderate renal 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. However, in patients with moderate renal dysfunction, the pharmacokinetic profile of hydroxypropyl β-cyclodextrin (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-β-cyclodextrin was reduced in subjects with renal impairment, resulting in higher exposure to hydroxypropyl-β-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 hemodialyzed with a clearance of 37.5±24 mL/min. 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 [see Dosage and Administration (2.6) ] . Patients at Risk of Aspergillosis The observed voriconazole pharmacokinetics in patients at risk of aspergillosis (mainly patients with malignant neoplasms of lymphatic or hematopoietic tissue) were similar to healthy subjects. Drug Interaction Studies Effects of Other Drugs on Voriconazole Voriconazole is metabolized by the human hepatic cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. Results of in vitro metabolism studies indicate that the affinity of voriconazole is highest for CYP2C19, followed by CYP2C9, and is appreciably lower for CYP3A4. Inhibitors or inducers of these three enzymes may increase or decrease voriconazole systemic exposure (plasma concentrations), respectively. The systemic exposure to voriconazole is significantly reduced by the concomitant administration of the following agents and their use is contraindicated: Rifampin (potent CYP450 inducer) –Rifampin (600 mg once daily) decreased the steady state C max and AUC τ of voriconazole (200 mg every 12 hours × 7 days) by an average of 93% and 96%, respectively, in healthy subjects. Doubling the dose of voriconazole to 400 mg every 12 hours does not restore adequate exposure to voriconazole during coadministration with rifampin [see Contraindications (4) ] . Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate) –The effect of the coadministration of voriconazole and ritonavir (400 mg and 100 mg) was investigated in two separate studies. High-dose ritonavir (400 mg every 12 hours for 9 days) decreased the steady state C max and AUC τ of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) by an average of 66% and 82%, respectively, in healthy subjects. Low-dose ritonavir (100 mg every 12 hours for 9 days) decreased the steady state C max and AUC τ of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) by an average of 24% and 39%, respectively , in healthy subjects. Although repeat oral administration of voriconazole did not have a significant effect on steady state 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 [see Contraindications (4) ] . St. John's Wort (CYP450 inducer; P-gp inducer) –In an independent published study in healthy volunteers who were given multiple oral doses of St. John's Wort (300 mg LI 160 extract three times daily for 15 days) followed by a single 400 mg oral dose of voriconazole, a 59% decrease in mean voriconazole AUC 0 –∞ was observed. In contrast, coadministration of single oral doses of St. John's Wort and voriconazole had no appreciable effect on voriconazole AUC 0 –∞. Long-term use of St. John's Wort could lead to reduced voriconazole exposure [see Contraindications (4) ] . Significant drug interactions that may require voriconazole dosage adjustment, or frequent monitoring of voriconazole-related adverse reactions/toxicity: Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor): Concurrent administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) to 6 healthy male subjects resulted in an increase in C 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 [see Drug Interactions (7) ] . Letermovir (CYP2C9/2C19 inducer) –Coadministration of oral letermovir with oral voriconazole decreased the steady state C max and AUC 0-12 of voriconazole by an average of 39% and 44%, respectively [see Drug Interactions (7) ] . Minor or no significant pharmacokinetic interactions that do not require dosage adjustment: Cimetidine (non-specific CYP450 inhibitor and increases gastric pH) –Cimetidine (400 mg every 12 hours × 8 days) increased voriconazole steady state C 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 12 hours × 7 days to healthy subjects. Ranitidine (increases gastric pH) –Ranitidine (150 mg every 12 hours) had no significant effect on voriconazole C max and AUC τ following oral doses of 200 mg every 12 hours × 7 days to healthy subjects. Macrolide antibiotics –Coadministration of erythromycin (CYP3A4 inhibitor; 1gram every 12 hours for 7 days) or azithromycin (500 mg every 24 hours for 3 days) with voriconazole 200 mg every 12 hours for 14 days had no significant effect on voriconazole steady state C 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 by coadministration of voriconazole and their use is contraindicated: Sirolimus (CYP3A4 substrate) –Repeat dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) increased the C 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 [see Contraindications (4) ] . Coadministration of voriconazole with the following agents results in increased exposure to these drugs. Therefore, careful monitoring and/or dosage adjustment of these drugs is needed: Alfentanil (CYP3A4 substrate) –Coadministration of multiple doses of oral voriconazole (400 mg every 12 hours on day 1, 200 mg every 12 hours on day 2) with a single 20 mcg/kg intravenous dose of alfentanil with concomitant naloxone resulted in a 6-fold increase in mean alfentanil AUC 0 –∞ and a 4-fold prolongation of mean alfentanil elimination half-life, compared to when alfentanil was given alone [see Drug Interactions (7) ] . Fentanyl (CYP3A4 substrate): In an independent published study, concomitant use of voriconazole (400 mg every 12 hours on Day 1, then 200 mg every 12 hours on Day 2) with a single intravenous dose of fentanyl (5 µg/kg) resulted in an increase in the mean AUC 0 –∞ of fentanyl by 1.4-fold (range 0.81- to 2.04-fold) [see Drug Interactions (7) ] . Oxycodone (CYP3A4 substrate): In an independent published study, coadministration of multiple doses of oral voriconazole (400 mg every 12 hours, on Day 1 followed by five doses of 200 mg every 12 hours on Days 2 to 4) with a single 10 mg oral dose of oxycodone on Day 3 resulted in an increase in the mean C 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) [see Drug Interactions (7) ] . Cyclosporine (CYP3A4 substrate) –In stable renal transplant recipients receiving chronic cyclosporine therapy, concomitant administration of oral voriconazole (200 mg every 12 hours for 8 days) increased cyclosporine C 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 [see Drug Interactions (7) ] . Methadone (CYP3A4, CYP2C19, CYP2C9 substrate) –Repeat dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days) increased the C 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 24 hours). The C max and AUC of (S)-methadone increased by 65% (90% CI: 53%, 79%) and 103% (90% CI: 85%, 124%), respectively [see Drug Interactions (7) ] . Tacrolimus (CYP3A4 substrate) –Repeat oral dose administration of voriconazole (400 mg every 12 hours × 1 day, then 200 mg every 12 hours × 6 days) increased tacrolimus (0.1 mg/kg single dose) C 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 [see Drug Interactions (7) ] . Warfarin (CYP2C9 substrate) –Coadministration of voriconazole (300 mg every 12 hours × 12 days) with warfarin (30 mg single dose) significantly increased maximum prothrombin time by approximately 2 times that of placebo in healthy subjects [see Drug Interactions (7) ] . Non-Steroidal Anti-Inflammatory Drugs (NSAIDs; CYP2C9 substrates): In two independent published studies, single doses of ibuprofen (400 mg) and diclofenac (50 mg) were coadministered with the last dose of voriconazole (400 mg every 12 hours on Day 1, followed by 200 mg every 12 hours on Day 2). Voriconazole increased the mean C 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 [see Drug Interactions (7) ]. No significant pharmacokinetic interactions were observed when voriconazole was coadministered with the following agents. Therefore, no dosage adjustment for these agents is recommended: Prednisolone (CYP3A4 substrate) –Voriconazole (200 mg every 12 hours × 30 days) increased C max and AUC of prednisolone (60 mg single dose) by an average of 11% and 34%, respectively, in healthy subjects [see Warnings and Precautions (5.8) ] . Digoxin (P-glycoprotein mediated transport) –Voriconazole (200 mg every 12 hours × 12 days) had no significant effect on steady state C 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 12 hours × 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 1gram 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 [see Contraindications (4) ] . Significant drug interactions that may require dosage adjustment, frequent monitoring of drug levels and/or frequent monitoring of drug-related adverse reactions/toxicity: Efavirenz, a non-nucleoside reverse transcriptase inhibitor (CYP450 inducer; CYP3A4 inhibitor and substrate) –Standard doses of voriconazole and efavirenz (400 mg every 24 hours or higher) must not be coadministered [see Drug Interactions (7) ] . Steady state efavirenz (400 mg PO every 24 hours) decreased the steady state C max and AUC τ of voriconazole (400 mg PO every 12 hours for 1 day, then 200 mg PO every 12 hours for 8 days) by an average of 61% and 77%, respectively, in healthy male subjects. Voriconazole at steady state (400 mg PO every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) increased the steady state C max and AUC τ of efavirenz (400 mg PO every 24 hours for 9 days) by an average of 38% and 44%, respectively, in healthy subjects. 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 12 hours × 14 days) by an average of 50% and 70%, respectively, in healthy subjects. Administration of a higher voriconazole dose (400 mg every 12 hours × 7 days) with phenytoin (300 mg once daily) resulted in comparable steady state voriconazole C max and AUC τ estimates as compared to when voriconazole was given at 200 mg every 12 hours without phenytoin [see Dosage and Administration (2.7) and Drug Interactions (7) ]. Repeat dose administration of voriconazole (400 mg every 12 hours × 10 days) increased the steady state C 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 when coadministered with voriconazole may be expected to be as high as 2 times the C max and AUC 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 Drug Interactions (7) ] . Omeprazole (CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate) –Coadministration of omeprazole (40 mg once daily × 10 days) with oral voriconazole (400 mg every 12 hours × 1 day, then 200 mg every 12 hours × 9 days) increased the steady state C 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 12 hours × 1 day, then 200 mg × 6 days) with omeprazole (40 mg once daily × 7 days) to healthy subjects significantly increased the steady state C 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 [see Drug Interactions (7) ] . Oral Contraceptives (CYP3A4 substrate; CYP2C19 inhibitor) –Coadministration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 3 days) and oral contraceptive (Ortho-Novum1/35 ® consisting of 35 mcg ethinyl estradiol and 1 mg norethindrone, every 24 hours) to healthy female subjects at steady state increased the C 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 [see Drug Interactions (7) ] . No significant pharmacokinetic interaction was seen and no dosage adjustment of these drugs is recommended: Indinavir (CYP3A4 inhibitor and substrate) –Repeat dose administration of indinavir (800 mg TID for 10 days) had no significant effect on voriconazole C max and AUC following repeat dose administration (200 mg every 12 hours for 17 days) in healthy subjects. Repeat dose administration of voriconazole (200 mg every 12 hours for 7 days) did not have a significant effect on steady state C max and AUC τ of indinavir following repeat dose administration (800 mg TID for 7 days) in healthy subjects.

20230112

7

3 DOSAGE FORMS AND STRENGTHS For Injection : Lyophilized white to off white cake or powder containing 200 mg voriconazole and 3,200 mg of hydroxypropyl β-cyclodextrin (HPβCD); after reconstitution 10 mg/mL of voriconazole and 160 mg/mL of HPβCD ( 3 ) 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 3,200 mg hydroxypropyl β-cyclodextrin (HPβCD).

Voriconazole Voriconazole VORICONAZOLE VORICONAZOLE HYDROXYPROPYL BETADEX

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 RMD on a body surface area basis. 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 area basis. 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.

13 NONCLINICAL TOXICOLOGY 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 RMD on a body surface area basis. 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 area basis. 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.

NDA208562

Voriconazole

Voriconazole

70594-067

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

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 MIC 90 was 4 µg/mL) In clinical studies, voriconazole MIC 90 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 MIC 90 was 1 µg/mL. Candida krusei Candida parapsilosis Candida tropicalis Fusarium spp. including Fusarium solani Scedosporium apiospermum 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 effectiveness 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.

PRINCIPAL DISPLAY PANEL - 200 MG Vial Label NDC 70594-067-01 Rx Only 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 PRINCIPAL DISPLAY PANEL - 200 MG Vial Label

Contraindications ( 4 ) 1/2023 Warnings and Precautions, Photosensitivity ( 5.6 ) 1/2023

Manufactured for: Xellia Pharmaceuticals USA, LLC Buffalo Grove, IL 60089 United States of America Made in India 1313000874-00

17 PATIENT COUNSELING INFORMATION Visual Disturbances Patients should be instructed that visual disturbances such as blurring and sensitivity to light may occur with the use of voriconazole. Photosensitivity Advise patients of the risk of photosensitivity (with or without concomitant methotrexate), accelerated photoaging, and skin cancer. Advise patients that Voriconazole for injection can cause serious photosensitivity and to immediately contact their healthcare provider for new or worsening skin rash. Advise patients to avoid exposure to direct sun light and to use measures such as protective clothing and sunscreen with high sun protection factor (SPF). 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.

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 (IA) Voriconazole was studied in patients for primary therapy of IA (randomized, controlled study 307/602), for primary and salvage therapy of aspergillosis (non-comparative study 304) and for treatment of patients with IA 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 IA 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 IA of the lungs. Other aspergillosis infections included disseminated disease, CNS infections and sinus infections. Diagnosis of definite or probable IA 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 7 days. Therapy could then be switched to the oral formulation at a dose of 200 mg every 12 hours. Median duration of IV voriconazole therapy was 10 days (range 2–85 days). After IV voriconazole therapy, the median duration of PO voriconazole therapy was 76 days (range 2–232 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 IV amphotericin therapy was 12 days (range 1–85 days). Treatment was then continued with 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 11). 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 9). Table 9 also summarizes the response (success) based on mycological confirmation and species. Table 9: Overall Efficacy and Success by Species in the Primary Treatment of Acute Invasive Aspergillosis Study 307/602 Voriconazole Ampho B Amphotericin B followed by other licensed antifungal therapy Stratified Difference (95% CI) Difference and corresponding 95% confidence interval are stratified by protocol n/N (%) n/N (%) Efficacy as Primary Therapy Satisfactory Global Response Assessed by independent Data Review Committee (DRC) 76/144 (53) 42/133 (32) 21.8% (10.5%, 33.0%) p<0.0001 Survival at Day 84 Proportion of subjects alive 102/144 (71) 77/133 (58) 13.1% (2.1%, 24.2%) Success by Species Success n/N (%) Overall success 76/144 (53) 42/133 (32) Mycologically confirmed Not all mycologically confirmed specimens were speciated 37/84 (44) 16/67 (24) Aspergillus spp. Some patients had more than one species isolated at baseline A. fumigatus 28/63 (44) 12/47 (26) A. flavus 3/6 4/9 A. terreus 2/3 0/3 A. niger 1/4 0/9 A. nidulans 1/1 0/0 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 10. 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 11. 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 10. Table 10: Combined Response Data in Salvage Patients with Single Aspergillus Species (Studies 304 and 309/604) Success n/N A. fumigatus 43/97 (44%) A. flavus 5/12 A. nidulans 1/3 A. niger 4/5 A. terreus 3/8 A. versicolor 0/1 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 11. Table 11: Overall Success Rates Sustained From EOT To The Fixed 12-Week Follow-Up Time Point By Baseline Pathogen A few patients had more than one pathogen at baseline. , Patients who did not have a 12-week assessment for any reason were considered a treatment failure. Baseline Pathogen Clinical and Mycological Success (%) Voriconazole Amphotericin B --> Fluconazole C. albicans 46/107 (43%) 30/63 (48%) C. tropicalis 17/53 (32%) 1/16 (6%) C. parapsilosis 24/45 (53%) 10/19 (53%) C. glabrata 12/36 (33%) 7/21 (33%) C. krusei 1/4 0/1 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 intra-abdominal 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. 14.4 Pediatric Studies A total of 22 patients aged 12 to 18 years with IA were included in the adult therapeutic studies. Twelve out of 22 (55%) patients had successful response after treatment with a maintenance dose of voriconazole 4 mg/kg every 12 hours. Additional pediatric use information is approved for PF PRISM C.V.'s VFEND (voriconazole) for injection. However, due to PF PRISM C.V.'s marketing exclusivity rights, this drug product is not labeled with that information.

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 IV or oral administration. However, the overall safety profile of the elderly patients was similar to that of the young so no dosage adjustment is recommended [see Clinical Pharmacology (12.3) ] .

8.4 Pediatric Use The safety and effectiveness of voriconazole have been established in pediatric patients aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight based on evidence from adequate and well-controlled studies in adult and pediatric patients and additional pediatric pharmacokinetic and safety data. A total of 51 pediatric patients aged 12 to less than 18 [N=51] from eight adult therapeutic trials provided safety information for voriconazole use in the pediatric population [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14) ] . Safety and effectiveness in pediatric patients below the age of 2 years has not been established. Therefore, Voriconazole for injection is not recommended for pediatric patients less than 2 years of age. A higher frequency of liver enzyme elevations was observed in the pediatric patients [see Dosage and Administration (2.5) , Warnings and Precautions (5.1) , and Adverse Reactions (6.1) ] . The frequency of phototoxicity reactions is higher in the pediatric population. Squamous cell carcinoma has been reported in patients who experience photosensitivity reactions. Stringent measures for photoprotection are warranted. Sun avoidance and dermatologic follow-up are recommended in pediatric patients experiencing photoaging injuries, such as lentigines or ephelides, even after treatment discontinuation [see Warnings and Precautions (5.6) ]. Voriconazole for injection has not been studied in pediatric patients with hepatic or renal impairment [see Dosage and Administration (2.5 , 2.6) ] . Hepatic function and serum creatinine levels should be closely monitored in pediatric patients [see Dosage and Administration (2.6) and Warnings and Precautions (5.1 , 5.10) ] . Additional pediatric use information is approved for PF PRISM C.V.'s VFEND (voriconazole) for injection. However, due to PF PRISM C.V.'s marketing exclusivity rights, this drug product is not labeled with that information.

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 associated with fetal malformations in rats and fetal toxicity in rabbits. Cleft palates and hydronephrosis/hydroureter were observed in rat pups exposed to voriconazole during organogenesis at and above 10 mg/kg (0.3 times the RMD of 200 mg every 12 hours based on body surface area comparisons). In rabbits, embryomortality, reduced fetal weight and increased incidence of skeletal variations, cervical ribs and extrasternal ossification sites were observed in pups when pregnant rabbits were orally dosed at 100 mg/kg (6 times the RMD based on body surface area comparisons) during organogenesis. Rats exposed to voriconazole from implantation to weaning experienced increased gestational length and dystocia, which were associated with increased perinatal pup mortality at the 10 mg/kg dose [see Data ] . If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to the fetus [see Warnings and Precautions (5.9) ] . The background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20% respectively. Data Animal Data Voriconazole was administered orally to pregnant rats during organogenesis (gestation days 6-17) at 10, 30, and 60 mg/kg/day. Voriconazole was associated with increased incidences of the malformations in hydroureter and hydronephrosis at 10 mg/kg/day or greater, approximately 0.3 times the recommended human dose (RMD) based on body surface area comparisons, and cleft palate at 60 mg/kg, approximately 2 times the RMD based on body surface area comparisons. Reduced ossification of sacral and caudal vertebrae, skull, pubic, and hyoid bone, supernumerary ribs, anomalies of the sternebrae, and dilatation of the ureter/renal pelvis were also observed at doses of 10 mg/kg or greater. There was no evidence of maternal toxicity at any dose. Voriconazole was administered orally to pregnant rabbits during the period of organogenesis (gestation days 7-19) at 10, 40, and 100 mg/kg/day. Voriconazole was associated with increased post-implantation loss and decreased fetal body weight, in association with maternal toxicity (decreased body weight gain and food consumption) at 100 mg/kg/day (6 times the RMD based on body surface area comparisons). Fetal skeletal variations (increases in the incidence of cervical rib and extra sternebral ossification sites) were observed at 100 mg/kg/day. In a peri- and postnatal toxicity study in rats, voriconazole was administered orally to female rats from implantation through the end of lactation at 1, 3, and 10 mg/kg/day. Voriconazole prolonged the duration of gestation and labor and produced dystocia with related increases in maternal mortality and decreases in perinatal survival of F1 pups at 10 mg/kg/day, approximately 0.3 times the RMD.

8 USE IN SPECIFIC POPULATIONS Pediatrics : Safety and effectiveness in patients younger than 2 years has not been established ( 8.4 ) Additional pediatric use information is approved for PF PRISM C.V.'s VFEND (voriconazole) for injection. However, due to PF PRISM C.V.'s marketing exclusivity rights, this drug product is not labeled with that information . 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 associated with fetal malformations in rats and fetal toxicity in rabbits. Cleft palates and hydronephrosis/hydroureter were observed in rat pups exposed to voriconazole during organogenesis at and above 10 mg/kg (0.3 times the RMD of 200 mg every 12 hours based on body surface area comparisons). In rabbits, embryomortality, reduced fetal weight and increased incidence of skeletal variations, cervical ribs and extrasternal ossification sites were observed in pups when pregnant rabbits were orally dosed at 100 mg/kg (6 times the RMD based on body surface area comparisons) during organogenesis. Rats exposed to voriconazole from implantation to weaning experienced increased gestational length and dystocia, which were associated with increased perinatal pup mortality at the 10 mg/kg dose [see Data ] . If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to the fetus [see Warnings and Precautions (5.9) ] . The background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20% respectively. Data Animal Data Voriconazole was administered orally to pregnant rats during organogenesis (gestation days 6-17) at 10, 30, and 60 mg/kg/day. Voriconazole was associated with increased incidences of the malformations in hydroureter and hydronephrosis at 10 mg/kg/day or greater, approximately 0.3 times the recommended human dose (RMD) based on body surface area comparisons, and cleft palate at 60 mg/kg, approximately 2 times the RMD based on body surface area comparisons. Reduced ossification of sacral and caudal vertebrae, skull, pubic, and hyoid bone, supernumerary ribs, anomalies of the sternebrae, and dilatation of the ureter/renal pelvis were also observed at doses of 10 mg/kg or greater. There was no evidence of maternal toxicity at any dose. Voriconazole was administered orally to pregnant rabbits during the period of organogenesis (gestation days 7-19) at 10, 40, and 100 mg/kg/day. Voriconazole was associated with increased post-implantation loss and decreased fetal body weight, in association with maternal toxicity (decreased body weight gain and food consumption) at 100 mg/kg/day (6 times the RMD based on body surface area comparisons). Fetal skeletal variations (increases in the incidence of cervical rib and extra sternebral ossification sites) were observed at 100 mg/kg/day. In a peri- and postnatal toxicity study in rats, voriconazole was administered orally to female rats from implantation through the end of lactation at 1, 3, and 10 mg/kg/day. Voriconazole prolonged the duration of gestation and labor and produced dystocia with related increases in maternal mortality and decreases in perinatal survival of F1 pups at 10 mg/kg/day, approximately 0.3 times the RMD. 8.2 Lactation Risk Summary No data are available regarding the presence of voriconazole in human milk, the effects of voriconazole on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for 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 reactions associated with oral contraceptives and voriconazole is recommended [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] . 8.4 Pediatric Use The safety and effectiveness of voriconazole have been established in pediatric patients aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight based on evidence from adequate and well-controlled studies in adult and pediatric patients and additional pediatric pharmacokinetic and safety data. A total of 51 pediatric patients aged 12 to less than 18 [N=51] from eight adult therapeutic trials provided safety information for voriconazole use in the pediatric population [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14) ] . Safety and effectiveness in pediatric patients below the age of 2 years has not been established. Therefore, Voriconazole for injection is not recommended for pediatric patients less than 2 years of age. A higher frequency of liver enzyme elevations was observed in the pediatric patients [see Dosage and Administration (2.5) , Warnings and Precautions (5.1) , and Adverse Reactions (6.1) ] . The frequency of phototoxicity reactions is higher in the pediatric population. Squamous cell carcinoma has been reported in patients who experience photosensitivity reactions. Stringent measures for photoprotection are warranted. Sun avoidance and dermatologic follow-up are recommended in pediatric patients experiencing photoaging injuries, such as lentigines or ephelides, even after treatment discontinuation [see Warnings and Precautions (5.6) ]. Voriconazole for injection has not been studied in pediatric patients with hepatic or renal impairment [see Dosage and Administration (2.5 , 2.6) ] . Hepatic function and serum creatinine levels should be closely monitored in pediatric patients [see Dosage and Administration (2.6) and Warnings and Precautions (5.1 , 5.10) ] . Additional pediatric use information is approved for PF PRISM C.V.'s VFEND (voriconazole) for injection. However, due to PF PRISM C.V.'s marketing exclusivity rights, this drug product is not labeled with that information. 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 IV or oral administration. However, the overall safety profile of the elderly patients was similar to that of the young so no dosage adjustment is recommended [see Clinical Pharmacology (12.3) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Voriconazole for injection is supplied in a single dose-vial as a sterile white to off white lyophilized cake or powder equivalent to 200 mg voriconazole and 3,200 mg hydroxypropyl β-cyclodextrin (HPβCD). It does not contain preservatives and is not made with natural rubber latex. Individually packaged vials of Voriconazole for injection, 200 mg, NDC 70594-067-01. 16.2 Storage Powder for Injection: Voriconazole for injection unreconstituted vials should be stored at 20°C – 25°C (68°F – 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°C to 8°C (36° to 46°F). Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C to 8°C (36° to 46°F). Discard Unused Portion [see Dosage and Administration (2.8) ] . 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 (2.8) ] . 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 (2.8) ] .

16.2 Storage Powder for Injection: Voriconazole for injection unreconstituted vials should be stored at 20°C – 25°C (68°F – 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°C to 8°C (36° to 46°F). Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C to 8°C (36° to 46°F). Discard Unused Portion [see Dosage and Administration (2.8) ] . 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 (2.8) ] . 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 (2.8) ] .