1 INDICATIONS AND USAGE Voriconazole tablets are an azole antifungal indicated for 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 ) • Esophageal candidiasis ( 1.3 ) • Serious fungal infections caused by Scedosporium apiospermum and Fusarium species including Fusarium solani , in patients intolerant of, or refractory to, other therapy ( 1.4 ) 1.1 Invasive Aspergillosis Voriconazole tablets are 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 , 14.5) and Microbiology (12.4) ] .

1.2 Candidemia in Non-neutropenic Patients and Other Deep Tissue Candida Infections Voriconazole tablets are 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 candidemia in non-neutropenic patients and the following Candida infections: disseminated infections in skin and infections in abdomen, kidney, bladder wall, and wounds [see Clinical Studies (14.2 , 14.5) and Microbiology (12.4) ].

1.3 Esophageal Candidiasis Voriconazole tablets are 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 esophageal candidiasis (EC) 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 [see Clinical Studies (14.3 , 14.5) and Microbiology (12.4) ].

1.4 Scedosporiosis and Fusariosis Voriconazole tablets are indicated for the treatment of serious fungal infections caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii ) and Fusarium spp.

including Fusarium solani , in adults and pediatric patients (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 (14.4) and Microbiology (12.4) ].

1.5 Usage Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s).

Therapy may be instituted before the results of the cultures and other laboratory studies are known.

However, once these results become available, antifungal therapy should be adjusted accordingly.

Additional pediatric use information is approved for PF PRISM C.V.'s VFEND (voriconazole).

However, due to PF PRISM C.V.'s marketing exclusivity rights, this drug product is not labeled with that information.

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 Sandoz Inc.

at 1-800-525-8747 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%), 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 1,655 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 to 90, including 51 patients aged 12 to 18 years), and was 78% White and 10% Black.

Five hundred sixty one patients had a duration of voriconazole therapy of greater than 12 weeks, with 136 patients receiving voriconazole for over six months.

Table 4 includes all adverse reactions which were reported at an incidence of ≥2% during voriconazole therapy in the all therapeutic studies population, studies 307/602 and 608 combined, or study 305, as well as events of concern which occurred at an incidence of <2%.

In study 307/602, 381 patients (196 on voriconazole, 185 on amphotericin B) were treated to compare voriconazole to amphotericin B followed by other licensed antifungal therapy (OLAT) in the primary treatment of patients with acute IA.

The rate of discontinuation from voriconazole study medication due to adverse reactions was 21.4% (42/196 patients).

In study 608, 403 patients with candidemia were treated to compare voriconazole (272 patients) to the regimen of amphotericin B followed by fluconazole (131 patients).

The rate of discontinuation from voriconazole study medication due to adverse reactions was 19.5% out of 272 patients.

Study 305 evaluated the effects of oral voriconazole (200 patients) and oral fluconazole (191 patients) in the treatment of EC.

The rate of discontinuation from voriconazole study medication in Study 305 due to adverse reactions was 7% (14/200 patients).

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

Table 4: Adverse Reactions Rate ≥ 2% on Voriconazole or Adverse Reactions of Concern in Therapeutic Studies Population, Studies 307/602-608 Combined, or Study 305.

Possibly Related to Therapy or Causality 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) Chromatopsia 20 (1.2) 2 (0.4) 0 0 2 (1) 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) 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) 3 (1.6) Vomiting 72 (4.4) 15 (3.2) 18 (9.7) 1 (0.8) 2 (1) 1 (0.5) Liver function tests abnormal 45 (2.7) 15 (3.2) 4 (2.2) 1 (0.8) 6 (3) 2 (1) Cholestatic jaundice 17 (1) 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) 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) 2 (1) SGPT increased 29 (1.8) 9 (1.9) 1 (0.5) 2 (1.5) 6 (3) 2 (1) 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 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.

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=1,655).

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 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% (268/1,514) in adult subjects treated with voriconazole 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 therapy.

Patients who develop abnormal liver function tests during voriconazole 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.

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 of serum creatinine.

Tables 5 to 7 show the number of patients with hypokalemia and clinically significant changes in renal and liver function tests in three randomized, comparative multicenter studies.

In study 305, patients with EC were randomized to either oral 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 >1.5× ULN 8/185 (4.3) 7/186 (3.8) AST >3× ULN 38/187 (20.3) 15/186 (8.1) ALT >3× ULN 20/187 (10.7) 12/186 (6.5) Alkaline Phosphatase >3× 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 >1.5× ULN 35/180 (19.4) 46/173 (26.6) AST >3× ULN 21/180 (11.7) 18/174 (10.3) ALT >3× ULN 34/180 (18.9) 40/173 (23.1) Alkaline Phosphatase >3× ULN 29/181 (16) 38/173 (22) Creatinine >1.3× ULN 39/182 (21.4) 102/177 (57.6) Potassium <0.9× 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 >1.5× ULN 50/261 (19.2) 31/115 (27) AST >3× ULN 40/261 (15.3) 16/116 (13.8) ALT >3× ULN 22/261 (8.4) 15/116 (12.9) Alkaline Phosphatase >3× ULN 59/261 (22.6) 26/115 (22.6) Creatinine >1.3× ULN 39/260 (15) 32/118 (27.1) Potassium <0.9× 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 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 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 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.

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.