Deferasirox Oral Granules

• Deferasirox oral granules can cause acute renal failure and death, particularly in patients with comorbidities and those who are in the advanced stages of their hematologic disorders.
• Evaluate baseline renal function prior to starting or increasing deferasirox oral granules dosing in all patients. Deferasirox oral granules is contraindicated in adult and pediatric patients with eGFR less than 40 mL/min/1.73 m
  
  ². Measure serum creatinine in duplicate prior to initiation of therapy. Monitor renal function at least monthly. For patients with baseline renal impairment or increased risk of acute renal failure, monitor renal function weekly for the first month, then at least monthly. Reduce the starting dose in patients with preexisting renal disease. During therapy, increase the frequency of monitoring and modify the dose for patients with an increased risk of renal impairment, including use of concomitant nephrotoxic drugs, and pediatric patients with volume depletion or overchelation [see Dosage and Administration (
  
  

  2.1 Transfusional Iron Overload

  Deferasirox oral granules therapy should only be considered when a patient has evidence of chronic transfusional iron overload. The evidence should include the transfusion of at least 100 mL/kg of packed red blood cells (e.g., at least 20 units of packed red blood cells for a 40 kg person or more in individuals weighing more than 40 kg), and a serum ferritin consistently greater than 1,000 mcg/L.

  Prior to starting therapy, or increasing dose, evaluate:

  • Serum ferritin level
  • Baseline renal function:
  • Obtain serum creatinine in duplicate (due to variations in measurements)
  • Calculate the estimated glomerular filtration rate (eGFR). Use a prediction equation appropriate for adult patients (e.g., CKD-EPI, MDRD method) and in pediatric patients (e.g., Schwartz equations).
  • Obtain urinalyses and serum electrolytes to evaluate renal tubular function [see Dosage and Administration (2.4), Warnings and Precautions (5.1)].
  • Serum transaminases and bilirubin [see Dosage and Administration (2.4), Warnings and Precautions (5.2)]
  • Baseline auditory and ophthalmic examinations [see Warnings and Precautions (5.10)]

  Initiating Therapy:

  The recommended initial dose of deferasirox oral granules for patients 2 years of age and older with eGFR greater than 60 mL/min/1.73 m²is 14 mg per kg body weight orally, once daily. Calculate doses (mg per kg per day) to the nearest whole sachet content for granules. Changes in weight of pediatric patients over time must be taken into account when calculating

  the dose.

  During Therapy:

  • Monitor serum ferritin monthly and adjust the dose of deferasirox oral granules, if necessary, every 3 to 6 months based on serum ferritin trends.
  • Use the minimum effective dose to achieve a trend of decreasing ferritin
  • Make dose adjustments in steps of 3.5 or 7 mg per kg and tailor adjustments to the individual patient’s response and therapeutic goals.
  • In patients not adequately controlled with doses of 21 mg per kg (e.g., serum ferritin levels persistently above 2,500 mcg/L and not showing a decreasing trend over time), doses of up to 28 mg per kg may be considered. Doses above 28 mg per kg are not recommended [see Warnings and Precautions (5.6)].
  • Adjust dose based on serum ferritin levels
    • If the serum ferritin falls below 1,000 mcg/L at 2 consecutive visits, consider dose reduction, especially if the deferasirox oral granules dose is greater than 17.5 mg/kg/day [see Adverse Reactions (6.1)].
    • If the serum ferritin falls below 500 mcg/L, interrupt deferasirox oral granules therapy to minimize the risk of overchelation, and continue monthly monitoring [ see Warnings and Precautions (5.6)].
    • Evaluate the need for ongoing chelation therapy for patients whose conditions no longer require regular blood transfusions.
    • Use the minimum effective dose to maintain iron burden in the target range [see Warnings and Precautions (5.6)].
  • Monitor blood counts, liver function, renal function and ferritin monthly [see Warnings and Precautions (5.1, 5.2, 5.4)].
  • Interrupt deferasirox oral granules for pediatric patients who have acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor more frequently. Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal [see Dosage and Administration (2.4, 2.5), Warnings and Precautions (5.1), Use in Specific Populations (8.4), Clinical Pharmacology (12.3)].

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  2.4 Use in Patients with Baseline Hepatic or Renal Impairment

  Patients with Baseline Hepatic Impairment

  Mild (Child-Pugh A) Hepatic Impairment: No dose adjustment is necessary.

  Moderate (Child-Pugh B) Hepatic Impairment: Reduce the starting dose by 50%.

  Severe (Child-Pugh C) Hepatic Impairment: Avoid deferasirox oral granules [see Warnings and Precautions (5.2), Use in Specific Populations (8.7)].

  Patients with Baseline Renal Impairment

  Do not use deferasirox oral granules in adult or pediatric patients with eGFR less than 40 mL/min/1.73 m²[see Dosage and Administration (2.5), Contraindications (4)].

  For patients with renal impairment (eGFR 40-60 mL/min/1.73 m²), reduce the starting dose by 50% [see Use in Specific Populations (8.6)].

  Exercise caution in pediatric patients with eGFR between 40 and 60 mL/minute/1.73 m². If treatment is needed, use the minimum effective dose and monitor renal function frequently. Individualize dose titration based on improvement in renal injury [see Use in Specific Populations (8.6)].

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  2.5 Dose Modifications for Decreases in Renal Function while on deferasirox oral granules

  Deferasirox oral granules are contraindicated in patients with eGFR less than 40 mL/min/1.73 m²[see Contraindications (4)].

  For decreases in renal function while receiving deferasirox oral granules [see Warnings and Precautions (5.1)], modify the dose as follows:

  Transfusional Iron Overload

  Adults:

  • If the serum creatinine increases by 33% or more above the average baseline measurement, repeat the serum creatinine within 1 week, and if still elevated by 33% or more, reduce the dose by 7 mg per kg.

  Pediatric Patients (ages 2 years–17 years):

  • Reduce the dose by 7 mg per kg if eGFR decreases by greater than 33% below the average baseline measurement and repeat eGFR within 1 week.
  • Interrupt deferasirox oral granules for acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor more frequently. Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal. Avoid use of other nephrotoxic drugs [see Warnings and Precautions (5.1)].
  • In the setting of decreased renal function, evaluate the risk benefit profile of continued deferasirox oral granules use. Use the minimum effective deferasirox oral granules dose and monitor renal function more frequently, by evaluating tubular and glomerular function. Titrate dosing based on renal injury. Consider dose reduction or interruption and less nephrotoxic therapies until improvement of renal function. If signs of renal tubular or glomerular injury occur in the presence of other risk factors such as volume depletion, reduce or interrupt deferasirox oral granules to prevent severe and irreversible renal injury [see Warnings and Precautions (5.1)].

  All Patients (regardless of age):

  • Discontinue therapy for eGFR less than 40 mL/min/1.73 m²[see Contraindications (4)].

  Non-Transfusion-Dependent Thalassemia Syndromes

  Adults:

  • If the serum creatinine increases by 33% or more above the average baseline measurement, repeat the serum creatinine within 1 week, and if still elevated by 33% or more, interrupt therapy if the dose is 3.5 mg per kg, or reduce by 50% if the dose is 7 or 14 mg per kg.

  Pediatric Patients (ages 10 years–17 years):

  • Reduce the dose by 3.5 mg per kg if eGFR decreases by greater than 33% below the average baseline measurement and repeat the eGFR within 1 week.
  • Increase monitoring frequency for pediatric patients who have acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake. Consider dose interruption until oral intake and volume status are normal. Avoid use of other nephrotoxic drugs [see Warnings and Precautions (5.1)].
  • In the setting of decreased renal function, evaluate the risk benefit profile of continued deferasirox oral granules use. Use the minimum effective deferasirox oral granules dose and monitor renal function more frequently, by evaluating tubular and glomerular function. Titrate dosing based on renal injury. Consider dose reduction or interruption and less nephrotoxic therapies until improvement of renal function. If signs of renal tubular or glomerular injury occur in the presence of other risk factors such as volume depletion, reduce or interrupt deferasirox oral granules to prevent severe and irreversible renal injury [see Warnings and Precautions (5.1)].

  All Patients (regardless of age):

  • Discontinue therapy for eGFR less than 40 mL/min/1.73 m²[see Contraindications (4)].

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  5.1 Acute Kidney Injury, Including Acute Renal Failure Requiring Dialysis and Renal Tubular Toxicity Including Fanconi Syndrome

  Deferasirox oral granules are contraindicated in patients with eGFR less than 40 mL/min/1.73 m². Exercise caution in pediatric patients with eGFR between 40 and 60 mL/min/1.73 m². If treatment is needed, use the minimum effective dose and monitor renal function frequently. Individualize dose titration based on improvement in renal injury [see Use in Specific Populations (8.6)]. For patients with renal impairment (eGFR 40-60 mL/min/1.73 m²) reduce the starting dose by 50% [see Dosage and Administration (2.4, 2.5), Use in Specific Populations (8.6)].

  Deferasirox oral granules can cause acute kidney injury including renal failure requiring dialysis that has resulted in fatal outcomes. Based on postmarketing experience, most fatalities have occurred in patients with multiple comorbidities and who were in advanced stages of their hematological disorders. In the clinical trials, adults and pediatric deferasirox-treated patients with no preexisting renal disease experienced dose-dependent mild, non-progressive increases in serum creatinine and proteinuria. Preexisting renal disease and concomitant use of other nephrotoxic drugs may increase the risk of acute kidney injury in adult and pediatric patients. Acute illnesses associated with volume depletion and overchelation may increase the risk of acute kidney injury in pediatric patients. In pediatric patients, small decreases in eGFR can result in increases in deferasirox exposure, particularly in younger patients with body surface area typical of patients less than age 7 years. This can lead to a cycle of worsening renal function and further increases in deferasirox tablets for oral suspension exposure, unless the dose is reduced or interrupted. Renal tubular toxicity, including acquired Fanconi syndrome, has been reported in patients treated with deferasirox, most commonly in pediatric patients with beta-thalassemia and serum ferritin levels less than 1,500 mcg/L [see Warnings and Precautions (5.6), Adverse Reactions (6.1, 6.2), Use in Specific Populations (8.4), Clinical Pharmacology (12.3)].

  Evaluate renal glomerular and tubular function before initiating therapy or increasing the dose. Use prediction equations validated for use in adult and pediatric patients to estimate GFR. Obtain serum electrolytes and urinalysis in all patients to evaluate renal tubular function [see Dosage and Administration (2.1, 2.2)].

  Monitor all patients for changes in eGFR and for renal tubular toxicity weekly during the first month after initiation or modification of therapy and at least monthly thereafter. Dose reduction or interruption may be considered if abnormalities occur in levels of markers of renal tubular function and/or as clinically indicated. Monitor serum ferritin monthly to evaluate for overchelation. Use the minimum dose to establish and maintain a low iron burden. Monitor renal function more frequently in patients with preexisting renal disease or decreased renal function. In pediatric patients, interrupt deferasirox oral granules during acute illnesses, which can cause volume depletion such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor renal function more frequently. Promptly correct fluid deficits to prevent renal injury. Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal [see Dosage and Administration (2.5), Warnings and Precautions (5.6), Adverse Reactions (6.1, 6.2), U se in Specific Populations (8.4)].

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  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. Deferasirox oral granules was evaluated in healthy volunteer trials. Currently, there are no clinical data in patients with deferasirox oral granules. Deferasirox oral granules contain the same active ingredient as deferasirox tablets for oral suspension. The following adverse reactions have been reported with deferasirox tablets for oral suspension.

  Transfusional Iron Overload

  A total of 700 adult and pediatric patients were treated with 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 to 205 weeks.

  Six hundred twenty-seven (627) patients with myelodysplastic syndrome (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% (Adverse Events (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 deferasirox at the completion of the study.

  Table 1 displays adverse reactions occurring in greater than 5% of deferasirox-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 deferasirox. Gastrointestinal symptoms, increases in serum creatinine, and skin rash were dose related.

  Table 1. Adverse Reactions aOccurring in > 5% of Deferasirox-treated Patients in Study 1, Study 3, and MDS Pool

  	Study 1 (Beta-thalassemia)		Study 3 (Sickle Cell Disease)		MDS Pool
  Adverse Reactions	Deferasirox N = 296 n (%)	Deferoxamine N = 290 n (%)	Deferasirox N = 132 n (%)	Deferoxamine N = 63 n (%)	Deferasirox N = 627 n (%)
  Abdominal Painb	63 (21)	41 (14)	37 (28)	9 (14)	145 (23)
  Diarrhea	35 (12)	21 (7)	26 (20)	3 (5)	297 (47)
  Creatinine Increasedc	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)
  Abbreviation: MDS, myelodysplastic syndrome aAdverse reaction frequencies are based on AEs reported regardless of relationship to study drug. bIncludes ‘abdominal pain’, ‘abdominal pain lower’, and ‘abdominal pain upper’. cIncludes ‘blood creatinine increased’ and ‘blood creatinine abnormal’. See also Table 2.

  In Study 1, a total of 113 (38%) patients treated with deferasirox 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 deferasirox developed elevations in serum glutamic-pyruvic transaminase (SGPT)/ALT levels greater than 5 times the upper limit of normal (ULN) at 2 consecutive visits. Of these, 2 patients had liver biopsy proven drug-induced hepatitis and both discontinued deferasirox 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 deferasirox 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 deferasirox 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 deferasirox-treated patients required dose reductions. In this study, 5 patients in the deferasirox group developed elevations in SGPT/ALT levels greater than 5 times the ULN at 2 consecutive visits and 1 patient subsequently had deferasirox permanently discontinued. Four additional patients discontinued 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 deferasirox 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	Deferasirox N = 296 n (%)	Deferoxamine N = 290 n (%)	Deferasirox N = 132 n (%)	Deferoxamine N = 63 n (%)	Deferasirox 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 post-baseline 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)
  Abbreviations: ALT, alanine transaminase; MDS, myelodysplastic syndrome; SGPT, serum glutamic-pyruvic transaminase; ULN, upper limit of normal.

  Non-Transfusion-Dependent Thalassemia Syndromes

  In Study 5, 110 patients with NTDT received 1 year of treatment with deferasirox 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 deferasirox at 5, 10, or 20 mg/kg/day (depending on the baseline LIC) for 1 year [see Clinical Studies (14)]. Table 3 and 4 display the frequency of adverse reactions in patients with NTDT. Adverse reactions with a suspected relationship to study drug were included in Table 3 if they occurred at ≥ 5% of patients in Study 5.

  Table 3. Adverse Reactions Occurring in Greater Than 5% Patients with NTDT

  Any adverse reaction	Study 5		Study 6
  	Deferasirox N = 110 n (%) 31 (28)	Placebo N = 56 n (%) 9 (16)	Deferasirox N = 130 n (%) 27 (21)
  Nausea	7 (6)	4 (7)	2 (2)a
  Rash	7 (6)	1 (2)	2 (2)a
  Diarrhea	5 (5)	1 (2)	7 (5)
  Abbreviation: NTDT, non-transfusion-dependent thalassemia. aThe occurrence of nausea, and rash are included for Study 6. There were no additional adverse reactions with a suspected relationship to study drug occurring in >5% of patients in Study 6.

  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 deferasirox-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. The number (%) of patients with NTDT with increase in serum creatinine or SGPT/ALT in Study 5 and Study 6 are presented in Table 4 below.

  Table 4. Number (%) of Patients with NTDT with Increases in Serum Creatinine or SGPT/ALT

  Laboratory Parameter	Study 5		Study 6
  	Deferasirox N = 110 n (%)	Placebo N = 56 n (%)	Deferasirox N = 130 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)
  Abbreviations: ALT, alanine transaminase; NTDT, non-transfusion-dependent thalassemia; SGPT, serum glutamic-pyruvic transaminase; ULN, upper limit of normal.

  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 deferasirox-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 5,000 patients with transfusional iron overload, who have been treated with deferasirox 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, GI 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, GI 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 tablets for oral suspension 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 deferasirox tablets for oral suspension dosage equivalent to 3.5 mg/kg deferasirox oral granules, starting at 20 mg/kg/day equivalent to 14 mg/kg/day deferasirox oral granules (95% confidence interval (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 < 1,000 mcg/L, those who received deferasirox tablets for oral suspension dosage > 30 mg/kg/day, equivalent to 21 mg/kg/day deferasirox oral granules compared to those who received lower dosages, had a higher risk for acute kidney injury (Odds ratio (OR) = 4.47, 95% CI: 1.25-15.95), consistent with overchelation.

  In addition, a cohort-based analysis of ARs was conducted in the deferasirox tablets for oral suspension pediatric pooled clinical trial data. Pediatric patients who received deferasirox tablets for oral suspension dose > 25 mg/kg/day equivalent to 17.5 mg/kg/day deferasirox oral granules when their serum ferritin was < 1,000 mcg/L (n = 158), had a 6-fold greater rate of renal adverse events (Incident Rate Ratio (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 reactions of special interest (cytopenia, renal, hearing, and GI 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)].

  Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's JADENU (deferasirox) tablets and granules. However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that information.

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  6.2 Postmarketing Experience

  The following adverse reactions have been spontaneously reported during post-approval use of deferasirox 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), leukocytoclastic 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

  GI Disorders: GI 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 reactions leading to permanent discontinuation from the study included liver injury (n = 11), vomiting (n = 2), renal tubular disorder (n = 1), proteinuria (n = 1), hematuria (n = 1), upper gastrointestinal hemorrhage (n = 1), abdominal pain (n = 1), and hypokalemia (n = 1).

  ].
  
  

• Deferasirox oral granules can cause hepatic injury including hepatic failure and death.
• Measure serum transaminases and bilirubin in all patients prior to initiating treatment, every 2 weeks during the first month, and at least monthly thereafter.
• Avoid use of deferasirox oral granules in patients with severe (Child-Pugh C) hepatic impairment and reduce the dose in patients with moderate (Child-Pugh B) hepatic impairment [see
  
  

  2.4 Use in Patients with Baseline Hepatic or Renal Impairment

  Patients with Baseline Hepatic Impairment

  Mild (Child-Pugh A) Hepatic Impairment: No dose adjustment is necessary.

  Moderate (Child-Pugh B) Hepatic Impairment: Reduce the starting dose by 50%.

  Severe (Child-Pugh C) Hepatic Impairment: Avoid deferasirox oral granules [see Warnings and Precautions (5.2), Use in Specific Populations (8.7)].

  Patients with Baseline Renal Impairment

  Do not use deferasirox oral granules in adult or pediatric patients with eGFR less than 40 mL/min/1.73 m²[see Dosage and Administration (2.5), Contraindications (4)].

  For patients with renal impairment (eGFR 40-60 mL/min/1.73 m²), reduce the starting dose by 50% [see Use in Specific Populations (8.6)].

  Exercise caution in pediatric patients with eGFR between 40 and 60 mL/minute/1.73 m². If treatment is needed, use the minimum effective dose and monitor renal function frequently. Individualize dose titration based on improvement in renal injury [see Use in Specific Populations (8.6)].

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  5.2 Hepatic Toxicity and Failure

  Deferasirox oral granules can cause hepatic injury, fatal in some patients. In Study 1, 4 patients (1.3%) discontinued deferasirox because of hepatic toxicity (drug-induced hepatitis in 2 patients and increased serum transaminases in 2 additional patients). Hepatic toxicity appears to be more common in patients greater than 55 years of age. Hepatic failure was more common in patients with significant comorbidities, including liver cirrhosis and multiorgan failure [see Adverse Reactions (6.1)].

  Acute liver injury and failure, including fatal outcomes, have occurred in pediatric deferasirox-treated patients. Liver failure occurred in association with acute kidney injury in pediatric patients at risk for overchelation during a volume-depleting event. Interrupt deferasirox oral granules therapy when acute liver injury or acute kidney injury is suspected and during volume depletion. Monitor liver and renal function more frequently in pediatric patients who are receiving deferasirox oral granules in the 14-28 mg/kg/day range and when iron burden is approaching normal. Use the minimum effective dose to achieve and maintain a low iron burden [see Dosage and Administration (2.5), Warnings and Precautions (5.6), Adverse Reactions (6.1)].

  Measure transaminases [aspartate transaminase (AST) and alanine transaminase (ALT)] and bilirubin in all patients before the initiation of treatment and every 2 weeks during the first month and at least monthly thereafter. Consider dose modifications or interruption of treatment for severe or persistent elevations.

  Avoid the use of deferasirox oral granules in patients with severe (Child-Pugh C) hepatic impairment. Reduce the starting dose in patients with moderate (Child-Pugh B) hepatic impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.7)]. Patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment may be at higher risk for hepatic toxicity.

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• Deferasirox oral granules can cause gastrointestinal (GI) hemorrhages, which may be fatal, especially in elderly patients who have advanced hematologic malignancies and/or low platelet counts.
• Monitor patients and discontinue deferasirox oral granules for suspected GI ulceration or hemorrhage [see
  
  

  5.3 Gastrointestinal (GI) Ulceration, Hemorrhage, and Perforation

  GI hemorrhage, including deaths, has been reported, especially in elderly patients who had advanced hematologic malignancies and/or low platelet counts. Nonfatal upper GI irritation, ulceration and hemorrhage have been reported in patients, including children and adolescents, receiving deferasirox [see Adverse Reactions (6.1)]. Monitor for signs and symptoms of GI ulceration and hemorrhage during deferasirox oral granules therapy, and promptly initiate additional evaluation and treatment if a serious GI adverse reaction is suspected. The risk of gastrointestinal hemorrhage may be increased when administering deferasirox oral granules in combination with drugs that have ulcerogenic or hemorrhagic potential, such as nonsteroidal anti- inflammatory drugs (NSAIDs), corticosteroids, oral bisphosphonates, or anticoagulants. There have been reports of ulcers complicated with GI perforation (including fatal outcome) [see Adverse Reactions (6.2)].

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Deferasirox oral granules is an iron chelator indicated for the treatment of chronic iron overload due to blood transfusions in patients 2 years of age and older. (

Deferasirox oral granules is indicated for the treatment of chronic iron overload in patients 10 years of age and older with non-transfusion- dependent thalassemia (NTDT) syndromes, and with a liver iron (Fe) concentration (LIC) of at least 5 mg Fe per gram of dry weight (Fe/g dw) and a serum ferritin greater than 300 mcg/L. (

The safety and efficacy of deferasirox oral granules when administered with other iron chelation therapy have not been established. (

• Transfusional Iron Overload: Initial dose for patients with estimated glomerular filtration rate (e GFR) greater than 60 mL/min/1.73 m
  
  ²is 14 mg per kg (calculated to nearest whole sachet content for granules) once daily. (
  
  
  2.1 Transfusional Iron Overload

  Deferasirox oral granules therapy should only be considered when a patient has evidence of chronic transfusional iron overload. The evidence should include the transfusion of at least 100 mL/kg of packed red blood cells (e.g., at least 20 units of packed red blood cells for a 40 kg person or more in individuals weighing more than 40 kg), and a serum ferritin consistently greater than 1,000 mcg/L.

  Prior to starting therapy, or increasing dose, evaluate:

  • Serum ferritin level
  • Baseline renal function:
  • Obtain serum creatinine in duplicate (due to variations in measurements)
  • Calculate the estimated glomerular filtration rate (eGFR). Use a prediction equation appropriate for adult patients (e.g., CKD-EPI, MDRD method) and in pediatric patients (e.g., Schwartz equations).
  • Obtain urinalyses and serum electrolytes to evaluate renal tubular function [see Dosage and Administration (2.4), Warnings and Precautions (5.1)].
  • Serum transaminases and bilirubin [see Dosage and Administration (2.4), Warnings and Precautions (5.2)]
  • Baseline auditory and ophthalmic examinations [see Warnings and Precautions (5.10)]

  Initiating Therapy:

  The recommended initial dose of deferasirox oral granules for patients 2 years of age and older with eGFR greater than 60 mL/min/1.73 m²is 14 mg per kg body weight orally, once daily. Calculate doses (mg per kg per day) to the nearest whole sachet content for granules. Changes in weight of pediatric patients over time must be taken into account when calculating

  the dose.

  During Therapy:

  • Monitor serum ferritin monthly and adjust the dose of deferasirox oral granules, if necessary, every 3 to 6 months based on serum ferritin trends.
  • Use the minimum effective dose to achieve a trend of decreasing ferritin
  • Make dose adjustments in steps of 3.5 or 7 mg per kg and tailor adjustments to the individual patient’s response and therapeutic goals.
  • In patients not adequately controlled with doses of 21 mg per kg (e.g., serum ferritin levels persistently above 2,500 mcg/L and not showing a decreasing trend over time), doses of up to 28 mg per kg may be considered. Doses above 28 mg per kg are not recommended [see Warnings and Precautions (5.6)].
  • Adjust dose based on serum ferritin levels
    • If the serum ferritin falls below 1,000 mcg/L at 2 consecutive visits, consider dose reduction, especially if the deferasirox oral granules dose is greater than 17.5 mg/kg/day [see Adverse Reactions (6.1)].
    • If the serum ferritin falls below 500 mcg/L, interrupt deferasirox oral granules therapy to minimize the risk of overchelation, and continue monthly monitoring [ see Warnings and Precautions (5.6)].
    • Evaluate the need for ongoing chelation therapy for patients whose conditions no longer require regular blood transfusions.
    • Use the minimum effective dose to maintain iron burden in the target range [see Warnings and Precautions (5.6)].
  • Monitor blood counts, liver function, renal function and ferritin monthly [see Warnings and Precautions (5.1, 5.2, 5.4)].
  • Interrupt deferasirox oral granules for pediatric patients who have acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor more frequently. Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal [see Dosage and Administration (2.4, 2.5), Warnings and Precautions (5.1), Use in Specific Populations (8.4), Clinical Pharmacology (12.3)].
  )
  
• NTDT Syndromes: Initial dose for patients with eGFR greater than 60 mL/min/1.73 m
  
  ²is 7 mg per kg (calculated to nearest whole sachet content for granules) once daily. (
  
  
  2.2 Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes

  Deferasirox oral granules therapy should only be considered when a patient with NTDT syndrome has an LIC of at least 5 mg Fe/g dw and a serum ferritin greater than 300 mcg/L.

  Prior to starting therapy, obtain:

  • LIC by liver biopsy or by an FDA-cleared or approved method for identifying patients for treatment with deferasirox therapy
  • Serum ferritin level on at least 2 measurements 1-month apart [see Clinical Studies (14)]
  • Baseline renal function:
    • Obtain serum creatinine in duplicate (due to variations in measurements)
    • Calculate the estimated glomerular filtration rate (eGFR). Use a prediction equation appropriate for adult patients (e.g., CKD-EPI, MDRD method) and in pediatric patients (e.g., Schwartz equations).
    • Obtain urinalyses and serum electrolytes to evaluate renal tubular function [see Dosage and Administration (2.4), Warnings and Precautions (5.1)].
  • Serum transaminases and bilirubin [see Dosage and Administration (2.4), Warnings and Precautions (5.2)]
  • Baseline auditory and ophthalmic examinations [see Warnings and Precautions (5.10)]

  Initiating Therapy:

  • The recommended initial dose of deferasirox oral granules for patients with eGFR greater than 60 mL/min/1.73 m²is 7 mg per kg body weight orally once daily. Calculate doses (mg per kg per day) to the nearest whole sachet content for granules.
  • If the baseline LIC is greater than 15 mg Fe/g dw, consider increasing the dose to 14 mg/kg/day after 4 weeks.

  During Therapy:

  • Monitor serum ferritin monthly to assess the patient’s response to therapy and to minimize the risk of overchelation [see Warnings and Precautions (5.6)]. Interrupt treatment when serum ferritin is less than 300 mcg/L and obtain an LIC to determine whether the LIC has fallen to less than 3 mg Fe/g dw.
  • Use the minimum effective dose to achieve a trend of decreasing ferritin. Monitor LIC every 6 months.
  • After 6 months of therapy, if the LIC remains greater than 7 mg Fe/g dw, increase the dose of deferasirox to a maximum of 14 mg/kg/day. Do not exceed a maximum of 14 mg/kg/day.
  • If after 6 months of therapy, the LIC is 3 to 7 mg Fe/g dw, continue treatment with deferasirox at no more than 7 mg/kg/day.
  • When the LIC is less than 3 mg Fe/g dw, interrupt treatment with deferasirox and continue to monitor the LIC.
  • Monitor blood counts, liver function, renal function and ferritin monthly [see Warnings and Precautions (5.1, 5.2, 5.4)].
  • Increase monitoring frequency for pediatric patients who have acute illness, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake. Consider dose interruption until oral intake and volume status are normal [see Dosage and Administration (2.4, 2.5), Warnings and Precautions (5.1), Use in Specific Populations (8.4), Clinical Pharmacology (12.3)].

  Restart treatment when the LIC rises again to more than 5 mg Fe/g dw.
  )
  
• See full prescribing information for information regarding monitoring, administration, and dose-reductions for organ impairment. (
  
  
  2.1 Transfusional Iron Overload

  Deferasirox oral granules therapy should only be considered when a patient has evidence of chronic transfusional iron overload. The evidence should include the transfusion of at least 100 mL/kg of packed red blood cells (e.g., at least 20 units of packed red blood cells for a 40 kg person or more in individuals weighing more than 40 kg), and a serum ferritin consistently greater than 1,000 mcg/L.

  Prior to starting therapy, or increasing dose, evaluate:

  • Serum ferritin level
  • Baseline renal function:
  • Obtain serum creatinine in duplicate (due to variations in measurements)
  • Calculate the estimated glomerular filtration rate (eGFR). Use a prediction equation appropriate for adult patients (e.g., CKD-EPI, MDRD method) and in pediatric patients (e.g., Schwartz equations).
  • Obtain urinalyses and serum electrolytes to evaluate renal tubular function [see Dosage and Administration (2.4), Warnings and Precautions (5.1)].
  • Serum transaminases and bilirubin [see Dosage and Administration (2.4), Warnings and Precautions (5.2)]
  • Baseline auditory and ophthalmic examinations [see Warnings and Precautions (5.10)]

  Initiating Therapy:

  The recommended initial dose of deferasirox oral granules for patients 2 years of age and older with eGFR greater than 60 mL/min/1.73 m²is 14 mg per kg body weight orally, once daily. Calculate doses (mg per kg per day) to the nearest whole sachet content for granules. Changes in weight of pediatric patients over time must be taken into account when calculating

  the dose.

  During Therapy:

  • Monitor serum ferritin monthly and adjust the dose of deferasirox oral granules, if necessary, every 3 to 6 months based on serum ferritin trends.
  • Use the minimum effective dose to achieve a trend of decreasing ferritin
  • Make dose adjustments in steps of 3.5 or 7 mg per kg and tailor adjustments to the individual patient’s response and therapeutic goals.
  • In patients not adequately controlled with doses of 21 mg per kg (e.g., serum ferritin levels persistently above 2,500 mcg/L and not showing a decreasing trend over time), doses of up to 28 mg per kg may be considered. Doses above 28 mg per kg are not recommended [see Warnings and Precautions (5.6)].
  • Adjust dose based on serum ferritin levels
    • If the serum ferritin falls below 1,000 mcg/L at 2 consecutive visits, consider dose reduction, especially if the deferasirox oral granules dose is greater than 17.5 mg/kg/day [see Adverse Reactions (6.1)].
    • If the serum ferritin falls below 500 mcg/L, interrupt deferasirox oral granules therapy to minimize the risk of overchelation, and continue monthly monitoring [ see Warnings and Precautions (5.6)].
    • Evaluate the need for ongoing chelation therapy for patients whose conditions no longer require regular blood transfusions.
    • Use the minimum effective dose to maintain iron burden in the target range [see Warnings and Precautions (5.6)].
  • Monitor blood counts, liver function, renal function and ferritin monthly [see Warnings and Precautions (5.1, 5.2, 5.4)].
  • Interrupt deferasirox oral granules for pediatric patients who have acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor more frequently. Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal [see Dosage and Administration (2.4, 2.5), Warnings and Precautions (5.1), Use in Specific Populations (8.4), Clinical Pharmacology (12.3)].
  ,
  
  
  2.2 Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes

  Deferasirox oral granules therapy should only be considered when a patient with NTDT syndrome has an LIC of at least 5 mg Fe/g dw and a serum ferritin greater than 300 mcg/L.

  Prior to starting therapy, obtain:

  • LIC by liver biopsy or by an FDA-cleared or approved method for identifying patients for treatment with deferasirox therapy
  • Serum ferritin level on at least 2 measurements 1-month apart [see Clinical Studies (14)]
  • Baseline renal function:
    • Obtain serum creatinine in duplicate (due to variations in measurements)
    • Calculate the estimated glomerular filtration rate (eGFR). Use a prediction equation appropriate for adult patients (e.g., CKD-EPI, MDRD method) and in pediatric patients (e.g., Schwartz equations).
    • Obtain urinalyses and serum electrolytes to evaluate renal tubular function [see Dosage and Administration (2.4), Warnings and Precautions (5.1)].
  • Serum transaminases and bilirubin [see Dosage and Administration (2.4), Warnings and Precautions (5.2)]
  • Baseline auditory and ophthalmic examinations [see Warnings and Precautions (5.10)]

  Initiating Therapy:

  • The recommended initial dose of deferasirox oral granules for patients with eGFR greater than 60 mL/min/1.73 m²is 7 mg per kg body weight orally once daily. Calculate doses (mg per kg per day) to the nearest whole sachet content for granules.
  • If the baseline LIC is greater than 15 mg Fe/g dw, consider increasing the dose to 14 mg/kg/day after 4 weeks.

  During Therapy:

  • Monitor serum ferritin monthly to assess the patient’s response to therapy and to minimize the risk of overchelation [see Warnings and Precautions (5.6)]. Interrupt treatment when serum ferritin is less than 300 mcg/L and obtain an LIC to determine whether the LIC has fallen to less than 3 mg Fe/g dw.
  • Use the minimum effective dose to achieve a trend of decreasing ferritin. Monitor LIC every 6 months.
  • After 6 months of therapy, if the LIC remains greater than 7 mg Fe/g dw, increase the dose of deferasirox to a maximum of 14 mg/kg/day. Do not exceed a maximum of 14 mg/kg/day.
  • If after 6 months of therapy, the LIC is 3 to 7 mg Fe/g dw, continue treatment with deferasirox at no more than 7 mg/kg/day.
  • When the LIC is less than 3 mg Fe/g dw, interrupt treatment with deferasirox and continue to monitor the LIC.
  • Monitor blood counts, liver function, renal function and ferritin monthly [see Warnings and Precautions (5.1, 5.2, 5.4)].
  • Increase monitoring frequency for pediatric patients who have acute illness, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake. Consider dose interruption until oral intake and volume status are normal [see Dosage and Administration (2.4, 2.5), Warnings and Precautions (5.1), Use in Specific Populations (8.4), Clinical Pharmacology (12.3)].

  Restart treatment when the LIC rises again to more than 5 mg Fe/g dw.
  ,
  
  
  2.3 Administration

  Take deferasirox oral granules on an empty stomach or with a light meal (contains less than 7% fat content and approximately 250 calories). Examples of light meals include 1 whole wheat English muffin, 1 packet jelly (0.5 ounces), and skim milk (8 fluid ounces) or a turkey sandwich (2 oz. turkey on whole wheat bread w/ lettuce, tomato, and 1 packet mustard) [

  see Clinical Pharmacology (12.3)

  ]. Administer deferasirox oral granules by sprinkling the full dose on soft food (e.g., yogurt or applesauce) immediately prior to use and administered orally. Deferasirox oral granules should be taken once a day, preferably at the same time each day. Do not take deferasirox oral granules with aluminum-containing antacid products [

  see Drug Interactions (7.1)

  ].

  For patients who are currently on chelation therapy with deferasirox tablets for oral suspension and converting to deferasirox oral granules, the dose should be about 30% lower, rounded to the nearest whole sachet content for granules. The table below provides additional information on dosing conversion to deferasirox oral granules.

  	Deferasirox Tablets for Oral Suspension	Deferasirox Oral Granules (white to off-white granules)
  Transfusion-Dependent Iron Overload
  Starting Dose	20 mg/kg/day	14 mg/kg/day
  Titration Increments	5 - 10 mg/kg	3.5 - 7 mg/kg
  Maximum Dose	40 mg/kg/day	28 mg/kg/day
  Non-Transfusion-Dependent Thalassemia Syndromes
  Starting Dose	10 mg/kg/day	7 mg/kg/day
  Titration Increments	5 - 10 mg/kg	3.5 - 7 mg/kg
  Maximum Dose	20 mg/kg/day	14 mg/kg/day
  ,
  
  
  2.4 Use in Patients with Baseline Hepatic or Renal Impairment

  Patients with Baseline Hepatic Impairment

  Mild (Child-Pugh A) Hepatic Impairment: No dose adjustment is necessary.

  Moderate (Child-Pugh B) Hepatic Impairment: Reduce the starting dose by 50%.

  Severe (Child-Pugh C) Hepatic Impairment: Avoid deferasirox oral granules [see Warnings and Precautions (5.2), Use in Specific Populations (8.7)].

  Patients with Baseline Renal Impairment

  Do not use deferasirox oral granules in adult or pediatric patients with eGFR less than 40 mL/min/1.73 m²[see Dosage and Administration (2.5), Contraindications (4)].

  For patients with renal impairment (eGFR 40-60 mL/min/1.73 m²), reduce the starting dose by 50% [see Use in Specific Populations (8.6)].

  Exercise caution in pediatric patients with eGFR between 40 and 60 mL/minute/1.73 m². If treatment is needed, use the minimum effective dose and monitor renal function frequently. Individualize dose titration based on improvement in renal injury [see Use in Specific Populations (8.6)].
  )
  

• 90 mg Deferasirox Oral Granules
• Supplied in cartons containing 30 child resistant foil sachets. Each sachet contains 162 mg of white to off white granules, equivalent to 90 mg deferasirox.
• 180 mg Deferasirox Oral Granules
• Supplied in cartons containing 30 child resistant foil sachets. Each sachet contains 324 mg of white to off white granules, equivalent to 180 mg deferasirox.
• 360 mg Deferasirox Oral Granules
• Supplied in cartons containing 30 child resistant foil sachets. Each sachet contains 648 mg of white to off white granules, equivalent to 360 mg deferasirox.

• Lactation: Advise women not to breastfeed. (
  
  
  8.2 Lactation

  Risk Summary

  No data are available regarding the presence of deferasirox oral granules or its metabolites in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production. Deferasirox and its metabolites were excreted in rat milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in a breastfeeding child from deferasirox and its metabolites, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of the drug to the mother.
  )