6 ADVERSE REACTIONS The following clinically significant adverse reactions are also discussed in other sections of the labeling: Acute Kidney Injury, Including Acute Renal Failure Requiring Dialysis, and Renal Tubular Toxicity Including Fanconi Syndrome [see Warnings and Precautions (5.1)] Hepatic Toxicity and Failure [see Warnings and Precautions (5.2)] Gastrointestinal (GI) Hemorrhage [see Warnings and Precautions (5.3)] Bone Marrow Suppression [see Warnings and Precautions (5.4)] Hypersensitivity [see Warnings and Precautions (5.7)] Severe Skin Reactions [see Warnings and Precautions (5.8)] Skin Rash [see Warnings and Precautions (5.9)] Auditory and Ocular Abnormities [see Warnings and Precautions (5.10)] In patients with transfusional iron overload, the most frequently occurring (greater than 5%) adverse reactions are diarrhea, vomiting, nausea, abdominal pain, skin rashes, and increases in serum creatinine. In Exjade-treated patients with NTDT syndromes, the most frequently occurring (greater than 5%) adverse reactions are diarrhea, rash, and nausea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 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 the 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. Transfusional Iron Overload A total of 700 adult and pediatric patients were treated with Exjade (deferasirox) for 48 weeks in premarketing studies. These included 469 patients with beta-thalassemia, 99 with rare anemias, and 132 with sickle cell disease. Of these patients, 45% were male, 70% were Caucasian, and 292 patients were less than 16 years of age. In the sickle cell disease population, 89% of patients were black. Median treatment duration among the sickle cell patients was 51 weeks. Of the 700 patients treated, 469 (403 beta-thalassemia and 66 rare anemias) were entered into extensions of the original clinical protocols. In ongoing extension studies, median durations of treatment were 88-205 weeks. Six hundred twenty-seven (627) patients with MDS were enrolled across 5 uncontrolled trials. These studies varied in duration from 1 to 5 years. The discontinuation rate across studies in the first year was 46% (AEs 20%, withdrawal of consent 10%, death 8%, other 4%, lab abnormalities 3%, and lack of efficacy 1%). Among 47 patients enrolled in the study of 5-year duration, 10 remained on Exjade at the completion of the study. Table 1 displays adverse reactions occurring in greater than 5% of Exjade-treated beta-thalassemia patients (Study 1), sickle cell disease patients (Study 3), and patients with MDS (MDS pool). Abdominal pain, nausea, vomiting, diarrhea, skin rashes, and increases in serum creatinine were the most frequent adverse reactions reported with a suspected relationship to Exjade. Gastrointestinal symptoms, increases in serum creatinine, and skin rash were dose related. Table 1. Adverse Reactions *Occurring in Greater Than 5% of Exjade-treated Patients in Study 1, Study 3, and MDS Pool *Adverse reaction frequencies are based on adverse events reported regardless of relationship to study drug. **Includes ‘abdominal pain’, ‘abdominal pain lower’, and ‘abdominal pain upper’, which were reported as adverse events. ***Includes ‘blood creatinine increased’ and ‘blood creatinine abnormal’, which were reported as adverse events. See also Table 2. Study 1 (Beta-thalassemia) Study 3 (Sickle Cell Disease) MDS Pool Adverse Reactions Exjade N = 296 n (%) Deferoxamine N = 290 n (%) Exjade N = 132 n (%) Deferoxamine N = 63 n (%) Exjade N = 627 n (%) Abdominal Pain** 63 (21) 41 (14) 37 (28) 9 (14) 145 (23) Diarrhea 35 (12) 21 (7) 26 (20) 3 (5) 297 (47) Creatinine Increased*** 33 (11) 0 (0) 9 (7) 0 89 (14) Nausea 31 (11) 14 (5) 30 (23) 7 (11) 161 (26) Vomiting 30 (10) 28 (10) 28 (21) 10 (16) 83 (13) Rash 25 (8) 9 (3) 14 (11) 3 (5) 83 (13) In Study 1, a total of 113 (38%) patients treated with Exjade had increases in serum creatinine greater than 33% above baseline on 2 separate occasions (Table 2) and 25 (8%) patients required dose reductions. Increases in serum creatinine appeared to be dose related [see Warnings and Precautions (5.1)]. In this study, 17 (6%) patients treated with Exjade developed elevations in SGPT/ALT levels greater than 5 times the ULN at 2 consecutive visits. Of these, 2 patients had liver biopsy proven drug-induced hepatitis and both discontinued Exjade therapy [see Warnings and Precautions (5.2)]. An additional 2 patients, who did not have elevations in SGPT/ALT greater than 5 times the ULN, discontinued Exjade because of increased SGPT/ALT. Increases in transaminases did not appear to be dose related. Adverse reactions that led to discontinuations included abnormal liver function tests (2 patients) and drug-induced hepatitis (2 patients), skin rash, glycosuria/proteinuria, Henoch Schönlein purpura, hyperactivity/insomnia, drug fever, and cataract (1 patient each). In Study 3, a total of 48 (36%) patients treated with Exjade had increases in serum creatinine greater than 33% above baseline on 2 separate occasions (Table 2) [see Warnings and Precautions (5.1)]. Of the patients who experienced creatinine increases in Study 3, 8 Exjade-treated patients required dose reductions. In this study, 5 patients in the Exjade group developed elevations in SGPT/ALT levels greater than 5 times the ULN at 2 consecutive visits and 1 patient subsequently had Exjade permanently discontinued. Four additional patients discontinued Exjade due to adverse reactions with a suspected relationship to study drug, including diarrhea, pancreatitis associated with gallstones, atypical tuberculosis, and skin rash. In the MDS pool, in the first year, a total of 229 (37%) patients treated with Exjade had increases in serum creatinine greater than 33% above baseline on 2 consecutive occasions (Table 2) and 8 (3.5%) patients permanently discontinued [see Warnings and Precautions (5.1)]. A total of 5 (0.8%) patients developed SGPT/ALT levels greater than 5 times the ULN at 2 consecutive visits. The most frequent adverse reactions that led to discontinuation included increases in serum creatinine, diarrhea, nausea, rash, and vomiting. Death was reported in the first year in 52 (8%) of patients [see Clinical Studies (14)]. Table 2. Number (%) of Patients with Increases in Serum Creatinine or SGPT/ALT in Study 1, Study 3, and MDS Pool Study 1 (Beta-thalassemia) Study 3 (Sickle Cell Disease) MDS Pool Laboratory Parameter Exjade N = 296 n (%) Deferoxamine N = 290 n (%) Exjade N = 132 n (%) Deferoxamine N = 63 n (%) Exjade N = 627 n (%) Serum Creatinine Creatinine increase > 33% at 2 consecutive post-baseline visits 113 (38) 41 (14) 48 (36) 14 (22) 229 (37) Creatinine increase > 33% and > ULN at 2 consecutive post-baseline visits 7 (2) 1 (0) 3 (2) 2 (3) 126 (20) SGPT/ALT SGPT/ALT > 5 x ULN at 2 postbaseline visits 25 (8) 7 (2) 2 (2) 0 9 (1) SGPT/ALT > 5 x ULN at 2 consecutive post-baseline visits 17 (6) 5 (2) 5 (4) 0 5 (1) Non-Transfusion-Dependent Thalassemia Syndromes In Study 5, 110 patients with NTDT received 1 year of treatment with Exjade 5 or 10 mg/kg/day and 56 patients received placebo in a double-blind, randomized trial. In Study 6, 130 of the patients who completed Study 5 were treated with open-label Exjade at 5, 10, or 20 mg/kg/day (depending on the baseline LIC) for 1 year [see Clinical Studies (14)]. Table 3 displays adverse reactions occurring in greater than 5% in any group. The most frequent adverse reactions with a suspected relationship to study drug were nausea, rash, and diarrhea. Table 3. Adverse Reactions Occurring in Greater Than 5% in NTDT Patients Study 5 Study 6 Exjade Placebo Exjade N = 110 N = 56 N = 130 n (%) n (%) n (%) Any adverse reaction 31 (28) 9 (16) 27 (21) Nausea 7 (6) 4 (7) 2 (2) Rash 7 (6) 1 (2) 2 (2) Diarrhea 5 (5) 1 (2) 7 (5) In Study 5, 1 patient in the placebo 10 mg/kg/day group experienced an ALT increase to greater than 5 times ULN and greater than 2 times baseline (Table 4). Three Exjade-treated patients (all in the 10 mg/kg/day group) had 2 consecutive serum creatinine level increases greater than 33% from baseline and greater than ULN. Serum creatinine returned to normal in all 3 patients (in 1 spontaneously and in the other 2 after drug interruption). Two additional cases of ALT increase and 2 additional cases of serum creatinine increase were observed in the 1-year extension of Study 5. Table 4. Number (%) of NTDT Patients with Increases in Serum Creatinine or SGPT/ALT Study 5 Study 6 Exjade Placebo Exjade N = 110 N = 56 N = 130 Laboratory Parameter n (%) n (%) n (%) Serum creatinine (> 33% increase from baseline and > ULN at ≥ 2 consecutive post-baseline values) 3 (3) 0 2 (2) SGPT/ALT (> 5 x ULN and > 2 x baseline) 1 (1) 1 (2) 2 (2) Proteinuria In clinical studies, urine protein was measured monthly. Intermittent proteinuria (urine protein/creatinine ratio greater than 0.6 mg/mg) occurred in 18.6% of Exjade-treated patients compared to 7.2% of deferoxamine-treated patients in Study 1 [see Warnings and Precautions (5.1)]. Other Adverse Reactions In the population of more than 5000 patients with transfusional iron overload who have been treated with Exjade during clinical trials, adverse reactions occurring in 0.1% to 1% of patients included gastritis, edema, sleep disorder, pigmentation disorder, dizziness, anxiety, maculopathy, cholelithiasis, pyrexia, fatigue, laryngeal pain, cataract, hearing loss, gastrointestinal hemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, renal tubular disorder (Fanconi Syndrome), and acute pancreatitis (with and without underlying biliary conditions). Adverse reactions occurring in 0.01% to 0.1% of patients included optic neuritis, esophagitis, erythema multiforme, and drug reaction with eosinophilia and systemic symptoms (DRESS). Adverse reactions, which most frequently led to dose interruption or dose adjustment during clinical trials were rash, gastrointestinal disorders, infections, increased serum creatinine, and increased serum transaminases. Pooled Analysis of Pediatric Clinical Trial Data A nested case control analysis was conducted within a deferasirox pediatric pooled clinical trial dataset to evaluate the effects of dose and serum ferritin level, separately and combined, on kidney function. Among 1213 children (aged 2 to 15 years) with transfusion-dependent thalassemia, 162 cases of acute kidney injury (eGFR < 90 mL/min/1.73 m2) and 621 matched-controls with normal kidney function (eGFR > 120 mL/min/1.73 m2) were identified. The primary findings were: - A 26% increased risk of acute kidney injury was observed with each 5 mg/kg increase in daily Exjade dosage starting at 20 mg/kg/day (95% CI: 1.08-1.48). - A 25% increased risk for acute kidney injury was observed with each 250 mcg/L decrease in serum ferritin starting at 1250 mcg/L (95% CI: 1.01-1.56). - Among pediatric patients with a serum ferritin < 1000 mcg/L, those who received Exjade dosage > 30 mg/kg/day, compared to those who received lower dosages, had a higher risk for acute kidney injury (OR = 4.47, 95% CI: 1.25-15.95), consistent with overchelation. In addition, a cohort based analysis of adverse events was conducted in the deferasirox pediatric pooled clinical trial data. Pediatric patients who received Exjade dose > 25 mg/kg/day when their serum ferritin was < 1000 mcg/L (n = 158) had a 6-fold greater rate of renal adverse events (IRR = 6.00, 95% CI: 1.75-21.36) and a 2-fold greater rate of dose interruptions (IRR = 2.06, 95% CI: 1.33-3.17) compared to the time-period prior to meeting these simultaneous criteria. Adverse events of special interest (cytopenia, renal, hearing, and gastrointestinal disorders) occurred 1.9-fold more frequently when these simultaneous criteria were met, compared to preceding time-periods (IRR = 1.91, 95% CI: 1.05-3.48) [see Warnings and Precautions (5.6)]. 6.2 Postmarketing Experience The following adverse reactions have been spontaneously reported during postapproval use of Exjade in the transfusional-iron overload setting. Because these reactions are reported voluntarily from a population of uncertain size, in which patients may have received concomitant medication, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome (SJS), hypersensitivity vasculitis, urticaria, alopecia, toxic epidermal necrolysis (TEN) Immune System Disorders: hypersensitivity reactions (including anaphylactic reaction and angioedema) Renal and Urinary Disorders: acute renal failure, tubulointerstitial nephritis Hepatobiliary Disorders: hepatic failure Gastrointestinal Disorders: gastrointestinal perforation Blood and Lymphatic System Disorders: worsening anemia 5-Year Pediatric Registry In a 5-year observational study, 267 pediatric patients 2 to < 6 years of age (at enrollment) with transfusional hemosiderosis received deferasirox. Of the 242 patients who had pre- and post-baseline eGFR measurements, 116 (48%) patients had a decrease in eGFR of ≥ 33% observed at least once. Twenty-one (18%) of these 116 patients with decreased eGFR had a dose interruption, and 15 (13%) of these 116 patients had a dose decrease within 30 days. Adverse events leading to permanent discontinuation from the study included liver injury (n = 11), renal tubular disorder (n = 1), proteinuria (n = 1), hematuria (n = 1), upper gastrointestinal hemorrhage (n = 1), vomiting (n = 2), abdominal pain (n = 1), and hypokalemia (n = 1).