Voriconazoleside effects

The following serious adverse reactions are described elsewhere in the labeling: Hepatic Toxicity Arrhythmias and QT Prolongation Visual Disturbances Severe Cutaneous Adverse Reactions Photosensitivity Renal Toxicity Adult Patients: The most common adverse reactions (incidence ≥2%) were visual disturbances, fever, nausea, rash, vomiting, chills, headache, liver function test abnormal, tachycardia, hallucinations Pediatric Patients: The most common adverse reactions (incidence ≥ 5%) were visual disturbances, pyrexia, vomiting, epistaxis, nausea, rash, abdominal pain, diarrhea, hypertension, hypokalemia, cough, headache, thrombocytopenia, ALT abnormal, hypotension, peripheral edema, hyperglycemia, tachycardia, dyspnea, hypocalcemia, hypophosphatemia, LFT abnormal, mucosal inflammation, photophobia, abdominal distention, constipation, dizziness, hallucinations, hemoptysis, hypoalbuminemia, hypomagnesemia, renal impairment, upper respiratory tract infection To report SUSPECTED ADVERSE REACTIONS, contact Ajanta Pharma USA Inc. at 855-664-7744 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. 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 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† † 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 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 63 1 0 31 8 Photophobia 37 8 0 0 5 2 Chromatopsia 20 2 0 0 2 0 Body as a Whole Fever 94 8 25 5 0 0 Chills 61 1 36 8 1 0 Headache 49 9 8 1 0 1 Cardiovascular System Tachycardia 39 6 5 0 0 0 Digestive System Nausea 89 18 29 2 2 3 Vomiting 72 15 18 1 2 1 Liver function tests abnormal 45 15 4 1 6 2 Cholestatic jaundice 17 8 0 1 3 0 Metabolic and Nutritional Systems Alkaline phosphatase increased 59 19 4 3 10 3 Hepatic enzymes increased 30 11 5 1 3 0 SGOT increased 31 9 0 1 8 2 SGPT increased 29 9 1 2 6 2 Hypokalemia 26 3 36 16 0 0 Bilirubinemia 15 5 3 2 1 0 Creatinine increased 4 0 59 10 1 0 Nervous System Hallucinations 39 13 1 0 0 0 Skin and Appendages Rash 88 20 7 1 3 1 Urogenital Kidney function abnormal 10 6 40 9 1 1 Acute kidney failure 7 2 11 7 0 0 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. 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 tablets. Erythema multiforme has also been reported during treatment with voriconazole tablets.. Voriconazole tablets have also been associated with additional photosensitivity related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus. 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, 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 ).

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 >3x upper limit of normal (not necessarily comprising an adverse reaction) was 17.7% (268/1514) 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 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. 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 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 CandidiasisClinically Significant Laboratory Test Abnormalities * 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 Criteria* Voriconazole Fluconazole n/N (%) n /N (%) T. Bilirubin >1.5x ULN 8/185 7/186 AST >3.0x ULN 38/187 15/186 ALT >3.0x ULN 20/187 12/186 Alkaline Phosphatase >3.0x ULN 19/187 14/186 Table 6: Protocol 307/602 – Primary Treatment of Invasive Aspergillosis Clinically Significant Laboratory Test Abnormalities * 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 Criteria* Voriconazole Amphotericin B** n/N (%) n/N (%) T. Bilirubin >1.5x ULN 35/180 46/173 AST >3.0x ULN 21/180 18/174 ALT >3.0x ULN 34/180 40/173 Alkaline Phosphatase >3.0x ULN 29/181 38/173 Creatinine >1.3x ULN 39/182 102/177 Potassium <0.9x LLN 30/181 70/178 Table 7: Protocol 608 – Treatment of Candidemia Clinically Significant Laboratory Test Abnormalities * 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 Criteria* Voriconazole Amphotericin B followed by Fluconazole n/N (%) n/N (%) T. Bilirubin >1.5x ULN 50/261 31/115 AST >3.0x ULN 40/261 16/116 ALT >3.0x ULN 22/261 15/116 Alkaline Phosphatase >3.0x ULN 59/261 26/115 Creatinine >1.3x ULN 39/260 32/118 Potassium <0.9x LLN 43/258 35/118 Clinical Trials Experience in Pediatric Patients The safety of voriconazole was investigated in 105 pediatric patients aged 2 to less than 18 years, including 52 pediatric patients less than 18 years of age who were enrolled in the adult therapeutic studies. Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In clinical studies, serious adverse reactions occurred in 46% (48/105) of voriconazole treated pediatric patients. Treatment discontinuations due to adverse reactions occurred in 12 /105 (11%) of all patients. Hepatic adverse reactions (i.e. ALT increased; liver function test abnormal; jaundice) 6% (6/105) accounted for the majority of voriconazole treatment discontinuations. Most Common Adverse Reactions The most common adverse reactions occurring in ≥5% of pediatric patients receiving voriconazole tablets in the pooled pediatric clinical trials are displayed by body system, in Table 8.

Table 8: Adverse Reactions Occurring in ≥5% of Pediatric Patients ReceivingVoriconazole tablets in the Pooled Pediatric Clinical Trials a Reflects all adverse reactions and not treatment-related only. b Pooled reports include such terms as: amaurosis (partial or total blindness without visible change in the eye); asthenopia (eye strain); chromatopsia (abnormally colored vision); color blindness; diplopia; photopsia; retinal disorder; vision blurred, visual acuity decreased, visual brightness; visual impairment. Several patients had more than one visual disturbance. c Pooled reports include such terms as: abdominal pain and abdominal pain, upper. d Pooled reports include such terms as: ALT abnormal and ALT increased. e Pooled reports include such terms as: hallucination; hallucination, auditory; hallucination, visual. Several patients had both visual and auditory hallucinations. f Pooled reports include such terms as: renal failure and a single patient with renal impairment. g Pooled reports include such terms as: rash; rash generalized; rash macular; rash maculopapular; rash pruritic.

Abbreviations: ALT = alanine aminotransferase; LFT = liver function test Body System Adverse Reaction Pooled Pediatric Data a N=105 n (%) Blood and Lymphatic Systems Disorders Thrombocytopenia 10 Cardiac Disorders Tachycardia 7 Eye Disorders Visual Disturbances b 27 Photophobia 6 Gastrointestinal Disorders Vomiting 21 Nausea 14 Abdominal pain c 13 Diarrhea 12 Abdominal distention 5 Constipation 5 General Disorders and Administration Site Conditions Pyrexia 25 Peripheral edema 9 Mucosal inflammation 6 Infections and Infestations Upper respiratory tract infection 5 Investigations ALT abnormal d 9 LFT abnormal 6 Metabolism and Nutrition Disorders Hypokalemia 11 Hyperglycemia 7 Hypocalcemia 6 Hypophosphotemia 6 Hypoalbuminemia 5 Hypomagnesemia 5 Nervous System Disorders Headache 10 Dizziness 5 Psychiatric Disorders Hallucinations e 5 Renal and Urinary Disorders Renal impairment f 5 Respiratory Disorders Epistaxis 17 Cough 10 Dyspnea 6 Hemoptysis 5 Skin and Subcutaneous Tissue Disorders Rash g 14 Vascular Disorders Hypertension 12 Hypotension 9 The following adverse reactions with incidence less than 5% were reported in 105 pediatric patients treated with voriconazole: Blood and Lymphatic System Disorders: anemia, leukopenia, pancytopenia Cardiac Disorders: bradycardia, palpitations, supraventricular tachycardia Eye Disorders: dry eye, keratitis Ear and Labyrinth Disorders: tinnitus, vertigo Gastrointestinal Disorders: abdominal tenderness, dyspepsia General Disorders and Administration Site Conditions: asthenia, catheter site pain, chills, hypothermia, lethargy Hepatobiliary Disorders: cholestasis, hyperbilirubinemia, jaundice Immune System Disorders: hypersensitivity, urticaria Infections and Infestations: conjunctivitis Laboratory Investigations: AST increased, blood creatinine increased, gamma-glutamyl transferase increased Metabolism and Nutrition Disorders: hypercalcemia, hypermagnesemia, hyperphosphatemia, hypoglycemia Musculoskeletal and Connective Tissue Disorders: arthralgia, myalgia Nervous System Disorders: ataxia, convulsion, dizziness, nystagmus, paresthesia, syncope Psychiatric Disorders: affect lability, agitation, anxiety, depression, insomnia Respiratory Disorders: bronchospasm, nasal congestion, respiratory failure, tachypnea Skin and Subcutaneous Tissue Disorders: alopecia, dermatitis (allergic, contact, and exfoliative), pruritus Vascular Disorders: flushing, phlebitis 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. Clinical Laboratory Values in Pediatric Patients The overall incidence of transaminase increases >3x upper limit of normal was 27.2% (28/103) in pediatric and 17.7% (268/1514) in adult patients treated with voriconazole in pooled clinical trials. The majority of abnormal liver function tests either resolved on treatment with or without dose adjustment or after voriconazole discontinuation. A higher frequency of clinically significant liver laboratory abnormalities, irrespective of baseline laboratory values (>3x ULN ALT or AST), was consistently observed in the combined therapeutic pediatric population (15.5% AST and 22.5% ALT) when compared to adults (12.9% AST and 11.6% ALT). The incidence of bilirubin elevation was comparable between adult and pediatric patients. The incidence of hepatic abnormalities in pediatric patients is shown in Table 9.

Table 9: Incidence of Hepatic Abnormalities among Pediatric Subjects n = number of patients with a clinically significant abnormality while on study therapyN = 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 Criteria n/N (%) Total bilirubin >1.5x ULN 19/102 AST >3.0x ULN 16/103 ALT >3.0x ULN 23/102 Alkaline Phosphatase >3.0x ULN 8/97

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. Dermatological Reactions Increased risk of skin toxicity with concomitant use of methotrexate, a drug associated with UV reactivation, was observed in postmarketing reports.

Adults Skeletal: fluorosis and periostitis have been reported during long-term voriconazole therapy.

Eye disorders: prolonged visual adverse reactions, including optic neuritis and papilledema.

Skin and Appendages: drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported.

Endocrine disorders: adrenal insufficiency, Cushing’s syndrome (when voriconazole has been used concomitantly with corticosteroids). Pediatric Patients There have been postmarketing reports of pancreatitis in pediatric patients.