Voriconazole

5 WARNINGS AND PRECAUTIONS Hepatic Toxicity: Serious hepatic reactions reported. Evaluate liver function tests at start of and during voriconazole therapy ( 5.1 ) Arrhythmias and QT Prolongation : Correct potassium, magnesium and calcium prior to use; caution patients with proarrhythmic conditions ( 5.2 ) Infusion Related Reactions (including anaphylaxis) : Stop the infusion ( 5.3 ) Visual Disturbances (including optic neuritis and papilledema): Monitor visual function if treatment continues beyond 28 days ( 5.4 ) Severe Cutaneous Adverse Reactions: Discontinue for exfoliative cutaneous reactions ( 5.5 ) Photosensitivity: Avoid sunlight due to risk of photosensitivity ( 5.6 ) Adrenal Dysfunction: Carefully monitor patients receiving voriconazole tablets and corticosteroids (via all routes of administration) for adrenal dysfunction both during and after voriconazole tablets treatment. Instruct patients to seek immediate medical care if they develop signs and symptoms of Cushing’s syndrome or adrenal insufficiency ( 5.8 ) Embryo-Fetal Toxicity: Voriconazole can cause fetal harm when administered to a pregnant woman. Inform pregnant patients of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during treatment with voriconazole ( 5.9 , 8.1 , 8.3 ) Skeletal Adverse Reactions: Fluorosis and periostitis with long-term voriconazole therapy. Discontinue if these adverse reactions occur ( 5.12 ) Clinically Significant Drug Interactions: Review patient’s concomitant medications ( 5.13 , 7 ) Patients with Hereditary Galactose Intolerance, Lapp Lactase Deficiency or Glucose-Galactose Malabsorption: voriconazole tablets should not be given to these patients because it contains lactose ( 5.14 ) 5.1 Hepatic Toxicity In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with voriconazole (including clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities). Instances of hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly hematological malignancy). Hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. Liver dysfunction has usually been reversible on discontinuation of therapy [ see Adverse Reactions (6.1) ]. A higher frequency of liver enzyme elevations was observed in the pediatric population [see Adverse Reactions (6.1) ] . Hepatic function should be monitored in both adult and pediatric patients. Measure serum transaminase levels and bilirubin at the initiation of voriconazole therapy and monitor at least weekly for the first month of treatment. Monitoring frequency can be reduced to monthly during continued use if no clinically significant changes are noted. If liver function tests become markedly elevated compared to baseline, voriconazole should be discontinued unless the medical judgment of the benefit/risk of the treatment for the patient justifies continued use [ see Dosage and Administration ( 2.5 ) and Adverse Reactions (6.1) ]. 5.2 Arrhythmias and QT Prolongation Some azoles, including voriconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During clinical development and post-marketing surveillance, there have been rare cases of arrhythmias, (including ventricular arrhythmias such as torsade de pointes ), cardiac arrests and sudden deaths in patients taking voriconazole. These cases usually involved seriously ill patients with multiple confounding risk factors, such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant medications that may have been contributory. Voriconazole should be administered with caution to patients with potentially proarrhythmic conditions, such as: Congenital or acquired QT prolongation Cardiomyopathy, in particular when heart failure is present Sinus bradycardia Existing symptomatic arrhythmias Concomitant medicinal product that is known to prolong QT interval [ see Contraindications (4) , Drug Interactions (7) , and Clinical Pharmacology (12.3) ] Rigorous attempts to correct potassium, magnesium and calcium should be made before starting and during voriconazole therapy [ see Clinical Pharmacology (12.3) ]. 5.3 Infusion Related Reactions During infusion of the intravenous formulation of voriconazole in healthy subjects, anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus and rash, have occurred uncommonly. Symptoms appeared immediately upon initiating the infusion. Consideration should be given to stopping the infusion should these reactions occur. 5.4 Visual Disturbances The effect of voriconazole on visual function is not known if treatment continues beyond 28 days. There have been post-marketing reports of prolonged visual adverse events, including optic neuritis and papilledema. If treatment continues beyond 28 days, visual function including visual acuity, visual field, and color perception should be monitored [ see Adverse Reactions (6.2)] . 5.5 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with voriconazole. If a patient develops a severe cutaneous adverse reaction, voriconazole should be discontinued [see Adverse Reactions ( 6.1 , 6.2 )] . 5.6 Photosensitivity Voriconazole has been associated with photosensitivity skin reaction. Patients, including pediatric patients, should avoid exposure to direct sunlight during voriconazole treatment and should use measures such as protective clothing and sunscreen with high sun protection factor (SPF). If phototoxic reactions occur, the patient should be referred to a dermatologist and voriconazole discontinuation should be considered. If voriconazole is continued despite the occurrence of phototoxicity-related lesions, dermatologic evaluation should be performed on a systematic and regular basis to allow early detection and management of premalignant lesions. Squamous cell carcinoma of the skin and melanoma have been reported during long-term voriconazole therapy in patients with photosensitivity skin reactions. If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, voriconazole should be discontinued. In addition, voriconazole has been associated with photosensitivity related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus. Patients should avoid strong, direct sunlight during voriconazole therapy. The frequency of phototoxicity reactions is higher in the pediatric population. Because squamous cell carcinoma has been reported in patients who experience photosensitivity reactions, stringent measures for photoprotection are warranted in children. In children experiencing photoaging injuries such as lentigines or ephelides, sun avoidance and dermatologic follow-up are recommended even after treatment discontinuation. 5.7 Renal Toxicity Acute renal failure has been observed in patients undergoing treatment with voriconazole. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and may have concurrent conditions that may result in decreased renal function. Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation of serum creatinine [see Clinical Pharmacology (12.3) and Dosage and Administration (2.6) ] . 5.8 Adrenal Dysfunction Reversible cases of azole-induced adrenal insufficiency have been reported in patients receiving azoles, including voriconazole tablets. Adrenal insufficiency has been reported in patients receiving azoles with or without concomitant corticosteroids. In patients receiving azoles without corticosteroids adrenal insufficiency is related to direct inhibition of steroidogenesis by azoles. In patients taking corticosteroids, voriconazole associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression [see Drug Interactions (7) and Clinical Pharmacology (12.3) ]. Cushing’s syndrome with and without subsequent adrenal insufficiency has also been reported in patients receiving voriconazole tablets concomitantly with corticosteroids. Patients receiving voriconazole tablets and corticosteroids (via all routes of administration) should be carefully monitored for adrenal dysfunction both during and after voriconazole tablets treatment. Patients should be instructed to seek immediate medical care if they develop signs and symptoms of Cushing’s syndrome or adrenal insufficiency. 5.9 Embryo-Fetal Toxicity Voriconazole can cause fetal harm when administered to a pregnant woman. In animals, voriconazole administration was associated with fetal malformations, embryotoxicity, increased gestational length, dystocia and embryomortality [ see Use in Specific Populations (8.1) ]. If voriconazole is used during pregnancy, or if the patient becomes pregnant while taking voriconazole, inform the patient of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during treatment with voriconazole [see Use in Specific Populations (8.3) ] . 5.10 Laboratory Tests Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of and during voriconazole therapy. Patient management should include laboratory evaluation of renal (particularly serum creatinine) and hepatic function (particularly liver function tests and bilirubin). 5.11 Pancreatitis Pancreatitis has been observed in patients undergoing treatment with voriconazole [see Adverse Reactions (6.1, 6.2) ] Patients with risk factors for acute pancreatitis (e.g., recent chemotherapy, hematopoietic stem cell transplantation [HSCT]) should be monitored for the development of pancreatitis during voriconazole treatment. 5.12 Skeletal Adverse Reactions Fluorosis and periostitis have been reported during long-term voriconazole therapy. If a patient develops skeletal pain and radiologic findings compatible with fluorosis or periostitis, voriconazole should be discontinued [ see Adverse Reactions (6.2) ]. 5.13 Clinically Significant Drug Interactions See Table 10 for a listing of drugs that may significantly alter voriconazole concentrations. Also, see Table 11 for a listing of drugs that may interact with voriconazole resulting in altered pharmacokinetics or pharmacodynamics of the other drug [ see Contraindications (4) and Drug Interactions (7) ]. 5.14 Galactose Intolerance Voriconazole tablets contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

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 AVKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience in Adults Overview The most frequently reported adverse reactions (see Table 4) in the adult therapeutic trials were visual disturbances (18.7%), fever (5.7%), nausea (5.4%), rash (5.3%), vomiting (4.4%), chills (3.7%), headache (3.0%), liver function test increased (2.7%), tachycardia (2.4%), hallucinations (2.4%). The adverse reactions which most often led to discontinuation of voriconazole therapy were elevated liver function tests, rash, and visual disturbances [ see Warning and Precautions (5.1, 5.4) and Adverse Reactions (6.1) ]. The data described in Table 4 reflect exposure to voriconazole in 1655 patients in nine therapeutic studies. This represents a heterogeneous population, including immunocompromised patients, e.g., patients with hematological malignancy or HIV and non-neutropenic patients. This subgroup does not include healthy subjects and patients treated in the compassionate use and non-therapeutic studies. This patient population was 62% male, had a mean age of 46 years (range 11-90, including 51 patients aged 12-18 years), and was 78% White and 10% Black. Five hundred sixty one patients had a duration of voriconazole therapy of greater than 12 weeks, with 136 patients receiving voriconazole for over six months. Table 4 includes all adverse reactions which were reported at an incidence of ≥2% during voriconazole therapy in the all therapeutic studies population, studies 307/602 and 608 combined, or study 305, as well as events of concern which occurred at an incidence of <2%. In study 307/602, 381 patients (196 on voriconazole, 185 on amphotericin B) were treated to compare voriconazole to amphotericin B followed by other licensed antifungal therapy (OLAT) in the primary treatment of patients with acute IA. The rate of discontinuation from voriconazole study medication due to adverse events was 21.4% (42/196 patients). In study 608, 403 patients with candidemia were treated to compare voriconazole (272 patients) to the regimen of amphotericin B followed by fluconazole (131 patients). The rate of discontinuation from voriconazole study medication due to adverse events was 19.5% out of 272 patients. Study 305 evaluated the effects of oral voriconazole (200 patients) and oral fluconazole (191 patients) in the treatment of EC. The rate of discontinuation from voriconazole study medication in Study 305 due to adverse events was 7% (14/200 patients). Laboratory test abnormalities for these studies are discussed under Clinical Laboratory Values below. Table 4: Treatment Emergent Adverse Events Rate ≥ 2% on Voriconazole or Adverse Events of Concern in Therapeutic Studies Population, Studies 307/602-608 Combined, or Study 305. Possibly Related to Therapy or Causality Unknown † Therapeutic Studies* Studies 307/602 and 608 (IV/ oral therapy) Study 305 (oral therapy) Voriconazole N=1655 Voriconazole N=468 Ampho B** N=185 Ampho B→ Fluconazole N=131 Voriconazole N=200 Fluconazole N=191 N (%) N (%) N (%) N (%) N (%) N (%) Special Senses*** Abnormal vision 310 (18.7) 63 (13.5) 1 (0.5) 0 31 (15.5) 8 (4.2) Photophobia 37 (2.2) 8 (1.7) 0 0 5 (2.5) 2 (1.0) Chromatopsia 20 (1.2) 2 (0.4) 0 0 2 (1.0) 0 Body as a Whole Fever 94 (5.7) 8 (1.7) 25 (13.5) 5 (3.8) 0 0 Chills 61 (3.7) 1 (0.2) 36 (19.5) 8 (6.1) 1 (0.5) 0 Headache 49 (3.0) 9 (1.9) 8 (4.3) 1 (0.8) 0 1 (0.5) Cardiovascular System Tachycardia 39 (2.4) 6 (1.3) 5 (2.7) 0 0 0 Digestive System Nausea 89 (5.4) 18 (3.8) 29 (15.7) 2 (1.5) 2 (1.0) 3 (1.6) Vomiting 72 (4.4) 15 (3.2) 18 (9.7) 1 (0.8) 2 (1.0) 1 (0.5) Liver function tests abnormal 45 (2.7) 15 (3.2) 4 (2.2) 1 (0.8) 6 (3.0) 2 (1.0) Cholestatic jaundice 17 (1.0) 8 (1.7) 0 1 (0.8) 3 (1.5) 0 Metabolic and Nutritional Systems Alkaline phosphatase increased 59 (3.6) 19 (4.1) 4 (2.2) 3 (2.3) 10 (5.0) 3 (1.6) Hepatic enzymes increased 30 (1.8) 11 (2.4) 5 (2.7) 1 (0.8) 3 (1.5) 0 SGOT increased 31 (1.9) 9 (1.9) 0 1 (0.8) 8 (4.0) 2 (1.0) SGPT increased 29 (1.8) 9 (1.9) 1 (0.5) 2 (1.5) 6 (3.0) 2 (1.0) Hypokalemia 26 (1.6) 3 (0.6) 36 (19.5) 16 (12.2) 0 0 Bilirubinemia 15 (0.9) 5 (1.1) 3 (1.6) 2 (1.5) 1 (0.5) 0 Creatinine increased 4 (0.2) 0 59 (31.9) 10 (7.6) 1 (0.5) 0 Nervous System Hallucinations 39 (2.4) 13 (2.8) 1 (0.5) 0 0 0 Skin and Appendages Rash 88 (5.3) 20 (4.3) 7 (3.8) 1 (0.8) 3 (1.5) 1 (0.5) Urogenital Kidney function abnormal 10 (0.6) 6 (1.3) 40 (21.6) 9 (6.9) 1 (0.5) 1 (0.5) Acute kidney failure 7 (0.4) 2 (0.4) 11 (5.9) 7 (5.3) 0 0 † Study 307/602: IA; Study 608: candidemia; Study 305: EC * Studies 303, 304, 305, 307, 309, 602, 603, 604, 608 ** Amphotericin B followed by other licensed antifungal therapy *** See Warnings and Precautions ( 5.4 ) Visual Disturbances Voriconazole treatment-related visual disturbances are common. In therapeutic trials, approximately 21% of patients experienced abnormal vision, color vision change and/or photophobia. Visual disturbances may be associated with higher plasma concentrations and/or doses. The mechanism of action of the visual disturbance is unknown, although the site of action is most likely to be within the retina. In a study in healthy subjects investigating the effect of 28-day treatment with voriconazole on retinal function, voriconazole caused a decrease in the electroretinogram (ERG) waveform amplitude, a decrease in the visual field, and an alteration in color perception. The ERG measures electrical currents in the retina. These effects were noted early in administration of voriconazole and continued through the course of study drug treatment. Fourteen days after the end of dosing, ERG, visual fields and color perception returned to normal [ see Warnings and Precautions (5.4) ]. Dermatological Reactions Dermatological reactions were common in patients treated with voriconazole. The mechanism underlying these dermatologic adverse events 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. Erythema multiforme has also been reported during treatment with voriconazole [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) ] . Less Common Adverse Reactions The following adverse reactions occurred in <2% of all voriconazole-treated patients in all therapeutic studies (N=1655). This listing includes events where a causal relationship to voriconazole cannot be ruled out or those which may help the physician in managing the risks to the patients. The list does not include events included in Table 4 above and does not include every event reported in the voriconazole clinical program. Body as a Whole: abdominal pain, abdomen enlarged, allergic reaction, anaphylactoid reaction [ see Warnings and Precautions (5.3) ], ascites, asthenia, back pain, chest pain, cellulitis, edema, face edema, flank pain, flu syndrome, graft versus host reaction, granuloma, infection, bacterial infection, fungal infection, injection site pain, injection site infection/inflammation, mucous membrane disorder, multi-organ failure, pain, pelvic pain, peritonitis, sepsis, substernal chest pain. Cardiovascular: atrial arrhythmia, atrial fibrillation, AV block complete, bigeminy, bradycardia, bundle branch block, cardiomegaly, cardiomyopathy, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident, congestive heart failure, deep thrombophlebitis, endocarditis, extrasystoles, heart arrest, hypertension, hypotension, myocardial infarction, nodal arrhythmia, palpitation, phlebitis, postural hypotension, pulmonary embolus, QT interval prolonged, supraventricular extrasystoles, supraventricular tachycardia, syncope, thrombophlebitis, vasodilatation, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia (including torsade de pointes) [ see Warnings and Precautions (5.2) ]. Digestive: anorexia, cheilitis, cholecystitis, cholelithiasis, constipation, diarrhea, duodenal ulcer perforation, duodenitis, dyspepsia, dysphagia, dry mouth, esophageal ulcer, esophagitis, flatulence, gastroenteritis, gastrointestinal hemorrhage, GGT/LDH elevated, gingivitis, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hepatic coma, hepatic failure, hepatitis, intestinal perforation, intestinal ulcer, jaundice, enlarged liver, melena, mouth ulceration, pancreatitis, parotid gland enlargement, periodontitis, proctitis, pseudomembranous colitis, rectal disorder, rectal hemorrhage, stomach ulcer, stomatitis, tongue edema. Endocrine: adrenal cortex insufficiency, diabetes insipidus, hyperthyroidism, hypothyroidism. Hemic and Lymphatic: agranulocytosis, anemia (macrocytic, megaloblastic, microcytic, normocytic), aplastic anemia, hemolytic anemia, bleeding time increased, cyanosis, DIC, ecchymosis, eosinophilia, hypervolemia, leukopenia, lymphadenopathy, lymphangitis, marrow depression, pancytopenia, petechia, purpura, enlarged spleen, thrombocytopenia, thrombotic thrombocytopenic purpura. Metabolic and Nutritional: albuminuria, BUN increased, creatine phosphokinase increased, edema, glucose tolerance decreased, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperuricemia, hypocalcemia, hypoglycemia, hypomagnesemia, hyponatremia, hypophosphatemia, peripheral edema, uremia. Musculoskeletal: arthralgia, arthritis, bone necrosis, bone pain, leg cramps, myalgia, myasthenia, myopathy, osteomalacia, osteoporosis. Nervous System: abnormal dreams, acute brain syndrome, agitation, akathisia, amnesia, anxiety, ataxia, brain edema, coma, confusion, convulsion, delirium, dementia, depersonalization, depression, diplopia, dizziness, encephalitis, encephalopathy, euphoria, Extrapyramidal Syndrome, grand mal convulsion, Guillain-Barré syndrome, hypertonia, hypesthesia, insomnia, intracranial hypertension, libido decreased, neuralgia, neuropathy, nystagmus, oculogyric crisis, paresthesia, psychosis, somnolence, suicidal ideation, tremor, vertigo. Respiratory System: cough increased, dyspnea, epistaxis, hemoptysis, hypoxia, lung edema, pharyngitis, pleural effusion, pneumonia, respiratory disorder, respiratory distress syndrome, respiratory tract infection, rhinitis, sinusitis, voice alteration. Skin and Appendages: alopecia, angioedema, contact dermatitis, discoid lupus erythematosis, eczema, erythema multiforme, exfoliative dermatitis, fixed drug eruption, furunculosis, herpes simplex, maculopapular rash, melanoma, melanosis, photosensitivity skin reaction, pruritus, pseudoporphyria, psoriasis, skin discoloration, skin disorder, skin dry, Stevens-Johnson syndrome, squamous cell carcinoma, sweating, toxic epidermal necrolysis, urticaria. Special Senses: a bnormality 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 >3x upper limit of normal (not necessarily comprising an adverse reaction) was 17.7% (268/1514) in adult subjects treated with voriconazole tablets 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 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 tablets therapy. Patients who develop abnormal liver function tests during voriconazole tablets 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 tablets must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to voriconazole tablets [ see Warnings and Precautions (5.1) ]. Acute renal failure has been observed in severely ill patients undergoing treatment with voriconazole tablets. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and may have concurrent conditions that can result in decreased renal function. It is recommended that patients are monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine. Tables 5 to 7 show the number of patients with hypokalemia and clinically significant changes in renal and liver function tests in three randomized, comparative multicenter studies. In study 305, patients with EC were randomized to either oral voriconazole or oral fluconazole. 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 5: Protocol 305 – Patients with Esophageal Candidiasis Clinically Significant Laboratory Test Abnormalities Criteria* Voriconazole Fluconazole n/N (%) n/N (%) T. Bilirubin >1.5x ULN 8/185 (4.3) 7/186 (3.8) AST >3.0x ULN 38/187 (20.3) 15/186 (8.1) ALT >3.0x ULN 20/187 (10.7) 12/186 (6.5) Alkaline Phosphatase >3.0x ULN 19/187 (10.2) 14/186 (7.5) * Without regard to baseline value 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 Table 6: Protocol 307/602 – Primary Treatment of Invasive Aspergillosis Clinically Significant Laboratory Test Abnormalities Criteria* Voriconazole Amphotericin B ** n/N (%) n/N (%) T. Bilirubin >1.5x ULN 35/180 (19.4) 46/173 (26.6) AST >3.0x ULN 21/180 (11.7) 18/174 (10.3) ALT >3.0x ULN 34/180 (18.9) 40/173 (23.1) Alkaline Phosphatase >3.0x ULN 29/181 (16.0) 38/173 (22.0) Creatinine >1.3x ULN 39/182 (21.4) 102/177 (57.6) Potassium <0.9x LLN 30/181 (16.6) 70/178 (39.3) * Without regard to baseline value ** Amphotericin B followed by other licensed antifungal therapy 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 Table 7: Protocol 608 – Treatment of Candidemia Clinically Significant Laboratory Test Abnormalities Criteria* Voriconazole Amphotericin B followed by Fluconazole n/N (%) n/N (%) T. Bilirubin >1.5x ULN 50/261 (19.2) 31/115 (27.0) AST >3.0x ULN 40/261 (15.3) 16/116 (13.8) ALT >3.0x ULN 22/261 (8.4) 15/116 (12.9) Alkaline Phosphatase >3.0x ULN 59/261 (22.6) 26/115 (22.6) Creatinine >1.3x ULN 39/260 (15.0) 32/118 (27.1) Potassium <0.9x LLN 43/258 (16.7) 35/118 (29.7) * Without regard to baseline value 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 Clinical Trials Experience in Pediatric Patients The safety of Voriconazole tablets was investigated in pediatric patients, including 52 pediatric patients 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 tablets 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). However, due to PF PRISMC.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. 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. Adults Skeletal: fluorosis and periostitis have been reported during long-term voriconazole therapy [ see Warnings and Precautions (5.12) ]. Eye disorders : prolonged visual adverse reactions, including optic neuritis and papilledema [see Warnings and Precautions (5.4) ] . Skin and Appendages: drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)] Endocrine disorders: adrenal insufficiency, Cushing’s syndrome (when voriconazole has been used concomitantly with corticosteroids) [see Warnings and Precautions (5.8) ]. Pediatric Patients There have been postmarketing reports of pancreatitis in pediatric patients. To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

<table width="97%"><col width="16%"/><col width="16%"/><col width="14%"/><col width="14%"/><col width="13%"/><col width="14%"/><col width="13%"/><thead><tr><th align="left" rowspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Therapeutic Studies*</content></th><th align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Studies 307/602 and 608</content> <content styleCode="bold">(IV/ oral therapy)</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Study 305</content> <content styleCode="bold">(oral therapy)</content></th></tr><tr><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">Voriconazole N=1655</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">Voriconazole N=468</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">Ampho B** N=185</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">Ampho B&#x2192; Fluconazole N=131</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">Voriconazole N=200</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">Fluconazole N=191</content></th></tr><tr><th align="center" styleCode="Rrule Lrule Botrule " valign="middle"><content styleCode="bold">N (%)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="middle"><content styleCode="bold">N (%)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="middle"><content styleCode="bold">N (%)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="middle"><content styleCode="bold">N (%)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="middle"><content styleCode="bold">N (%)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="middle"><content styleCode="bold">N (%)</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Special Senses***</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Abnormal vision</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>310 (18.7)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>63 (13.5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (0.5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>31 (15.5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8 (4.2)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Photophobia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>37 (2.2)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8 (1.7)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5 (2.5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (1.0)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Chromatopsia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20 (1.2)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (0.4)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (1.0)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Body as a Whole</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Fever</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>94 (5.7)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8 (1.7)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25 (13.5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5 (3.8)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Chills</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>61 (3.7)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (0.2)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>36 (19.5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8 (6.1)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (0.5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Headache</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>49 (3.0)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9 (1.9)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8 (4.3)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (0.8)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (0.5)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cardiovascular System</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Tachycardia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>39 (2.4)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6 (1.3)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5 (2.7)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Digestive System</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>89 (5.4)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18 (3.8)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29 (15.7)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (1.5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (1.0)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (1.6)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Vomiting</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>72 (4.4)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15 (3.2)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18 (9.7)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (0.8)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (1.0)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (0.5)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Liver function tests abnormal</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>45 (2.7)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15 (3.2)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4 (2.2)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (0.8)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6 (3.0)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (1.0)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Cholestatic jaundice</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17 (1.0)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8 (1.7)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (0.8)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (1.5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolic and Nutritional Systems</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Alkaline phosphatase increased</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>59 (3.6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19 (4.1)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4 (2.2)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (2.3)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10 (5.0)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (1.6)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hepatic enzymes increased</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30 (1.8)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11 (2.4)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5 (2.7)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (0.8)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (1.5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>SGOT increased</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>31 (1.9)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9 (1.9)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (0.8)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8 (4.0)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (1.0)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>SGPT increased</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29 (1.8)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9 (1.9)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (0.5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (1.5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6 (3.0)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (1.0)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hypokalemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26 (1.6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (0.6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>36 (19.5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16 (12.2)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Bilirubinemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15 (0.9)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5 (1.1)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (1.6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (1.5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (0.5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Creatinine increased</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4 (0.2)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>59 (31.9)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10 (7.6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (0.5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous System</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hallucinations</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>39 (2.4)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13 (2.8)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (0.5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Skin and Appendages</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Rash</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>88 (5.3)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20 (4.3)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7 (3.8)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (0.8)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (1.5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (0.5)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Urogenital</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Kidney function abnormal</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10 (0.6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6 (1.3)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>40 (21.6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9 (6.9)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (0.5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (0.5)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Acute kidney failure</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7 (0.4)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (0.4)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11 (5.9)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7 (5.3)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td colspan="7" styleCode="Botrule " valign="top"><paragraph>^&#x2020;Study 307/602: IA; Study 608: candidemia; Study 305: EC </paragraph><paragraph>^*Studies 303, 304, 305, 307, 309, 602, 603, 604, 608 </paragraph><paragraph>^**Amphotericin B followed by other licensed antifungal therapy </paragraph><paragraph>^***See Warnings and Precautions ( <linkHtml href="#L888ef50c-1611-45ac-8884-2ea7058333cf">5.4</linkHtml>) </paragraph></td></tr></tbody></table>

<table width="100%"><col width="21%"/><col width="15%"/><col width="16%"/><col width="19%"/><tbody><tr><td styleCode="Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Criteria*</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Voriconazole</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Fluconazole</content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="middle"/><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">n/N (%)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">n/N (%)</content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="middle"/><td styleCode="Rrule Lrule Botrule " valign="middle"/><td styleCode="Rrule Lrule Botrule " valign="middle"/></tr><tr><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>T. Bilirubin</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&gt;1.5x ULN</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8/185 (4.3)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7/186 (3.8)</paragraph></td></tr><tr><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>AST</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&gt;3.0x ULN</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>38/187 (20.3)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15/186 (8.1)</paragraph></td></tr><tr><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>ALT</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&gt;3.0x ULN</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20/187 (10.7)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12/186 (6.5)</paragraph></td></tr><tr><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>Alkaline Phosphatase</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>&gt;3.0x ULN</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>19/187 (10.2)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>14/186 (7.5)</paragraph></td></tr><tr><td colspan="4" styleCode="Botrule " valign="top"><paragraph>^*Without regard to baseline value </paragraph><paragraph>n = number of patients with a clinically significant abnormality while on study therapy </paragraph><paragraph>N = total number of patients with at least one observation of the given lab test while on study therapy </paragraph><paragraph>AST = Aspartate aminotransferase; ALT= alanine aminotransferase</paragraph><paragraph>ULN = upper limit of normal</paragraph></td></tr></tbody></table>

<table width="100%"><col width="21%"/><col width="13%"/><col width="18%"/><col width="21%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="middle"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Criteria*</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Voriconazole</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Amphotericin B ^**</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"/><td styleCode="Rrule Lrule Botrule " valign="middle"/><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">n/N (%)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">n/N (%)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"/><td styleCode="Rrule Lrule Botrule " valign="middle"/><td styleCode="Rrule Lrule Botrule " valign="middle"/><td styleCode="Rrule Lrule Botrule " valign="middle"/></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>T. Bilirubin</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>&gt;1.5x ULN</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>35/180 (19.4)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>46/173 (26.6)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>AST</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>&gt;3.0x ULN</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>21/180 (11.7)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>18/174 (10.3)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>ALT</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>&gt;3.0x ULN</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>34/180 (18.9)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>40/173 (23.1)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Alkaline Phosphatase</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>&gt;3.0x ULN</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>29/181 (16.0)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>38/173 (22.0)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Creatinine</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>&gt;1.3x ULN</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>39/182 (21.4)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>102/177 (57.6)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Potassium</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>&lt;0.9x LLN</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>30/181 (16.6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>70/178 (39.3)</paragraph></td></tr><tr><td colspan="4" styleCode="Botrule " valign="middle"><paragraph>^*Without regard to baseline value </paragraph><paragraph>^**Amphotericin B followed by other licensed antifungal therapy </paragraph><paragraph>n = number of patients with a clinically significant abnormality while on study therapy </paragraph><paragraph>N = total number of patients with at least one observation of the given lab test while on study therapy </paragraph><paragraph>AST = Aspartate aminotransferase; ALT= alanine aminotransferase</paragraph><paragraph>ULN = upper limit of normal </paragraph><paragraph>LLN = lower limit of normal</paragraph></td></tr></tbody></table>