Deferasirox Prescribing Information
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Deferasirox 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) to establish accurate baseline
- 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 , Warnings and Precautions ].
- Serum transaminases and bilirubin [see Dosage and Administration , Warnings and Precautions ]
- Baseline auditory and ophthalmic examinations [see Warnings and Precautions ]
The recommended initial dose of deferasirox for patients 2 years of age and older with eGFR greater than 60 mL/min/1.73 m2is 20 mg per kg body weight orally, once daily. Calculate doses (mg per kg per day) to the nearest whole tablet.
Monitor serum ferritin monthly and adjust the dose of deferasirox, 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 5 or 10 mg per kg and tailor adjustments to the individual patient’s response and therapeutic goals.
In patients not adequately controlled with doses of 30 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 40 mg per kg may be considered. Doses above 40 mg per kg are not recommended
[see Warnings and Precautions ].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 dose is greater than 25 mg/kg/day
[see Adverse Reactions ].If the serum ferritin falls below 500 mcg/L, interrupt deferasirox to minimize the risk of overchelation, and continue monthly monitoring
[see Warnings and Precautions ].
Monitor blood counts, liver function, renal function and ferritin monthly
[see Warnings and Precautions ].Interrupt deferasirox 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 , Warnings and Precautions , Use in Specific Populations , Clinical Pharmacology ].
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
Do not use deferasirox in adult or pediatric patients with eGFR less than 40 mL/min/1.73m2
For patients with renal impairment (eGFR 40 to 60 mL/min/1.73m2), reduce the starting dose by 50%
Exercise caution in pediatric patients with eGFR between 40 and 60 mL/min/1.73m2. If treatment is needed, use the minimum effective dose and monitor renal function frequently. Individualize dose titration based on improvement in renal injury
Deferasirox is contraindicated in patients with eGFR less than 40 mL/min/1.73m2
For decreases in renal function while receiving deferasirox
- 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 10 mg per kg.Pediatric Patients (ages 2 yearsto17 years):
- Reduce the dose by 10 mg/kg/day if eGFR decreases by greater than 33% below the average baseline measurement and repeat the eGFR within 1 week.
- Interrupt deferasirox 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 ].
- In the setting of decreased renal function, evaluate the risk benefit profile of continued deferasirox use. Use the minimum effective deferasirox 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 to prevent severe and irreversible renal injury[see Warnings and Precautions ].All Patients (regardless of age):
- Discontinue therapy for eGFR less than 40 mL/min/1.73m2[see Contraindications ].
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 5 mg per kg, or reduce by 50% if the dose is 10 or 20 mg per kg.
Pediatric Patients (ages 10 years to 17 years):Reduce the dose by 5 mg/kg/day 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 ].In the setting of decreased renal function, evaluate the risk benefit profile of continued deferasirox use. Use the minimum effective deferasirox 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 to prevent severe and irreversible renal injury
[see Warnings and Precautions ].
- Discontinue therapy for eGFR less than 40 mL/min/1.73 m2[see Contraindications ].
Deferasirox is contraindicated in patients with eGFR less than 40 mL/min/1.73m2. Exercise caution in pediatric patients with eGFR between 40 and 60 mL/minute/1.73m2. If treatment is needed, use the minimum effective dose and monitor renal function frequently. Individualize dose titration based on improvement in renal injury
Deferasirox 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, adult 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 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
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
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.
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 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.
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 adverse events 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
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)
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
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. | |||||
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
Study 5 | Study 6 | Study 7 | ||
deferasirox N = 110 n (%) | Placebo N = 56 n (%) | deferasirox N = 130 n (%) | deferasirox N = 134 n (%) | |
Any adverse reaction | 31 (28) | 9 (16) | 27 (21) | 50 (37) |
| Nausea | 7 (6) | 4 (7) | 2 (2)a | 7 (5) |
| Rash | 7 (6) | 1 (2) | 2 (2)a | 3 (2)a |
| Diarrhea | 5 (5) | 1 (2) | 7 (5) | 8 (6) |
| Abbreviation: NTDT, non-transfusion-dependent thalassemia. aThe occurrence of nausea, and rash are included for Study 6 and rash for Study 7 for consistency. There were no additional adverse reactions with a suspected relationship to study drug occurring in greater than 5% of patients in Study 6 and Study 7. | ||||
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, Study 6, and Study 7 are presented in Table 4 below.
Study 5 | Study 6 | Study 7 | ||
D eferasirox N = 110 | Placebo N = 56 | D eferasirox N = 130 | D eferasirox N = 134 | |
Laboratory Parameter | n (%) | n (%) | n (%) | n (%) |
| Serum creatinine (> 33% increase from baseline and > ULN at ≥ 2 consecutive post-baseline values) | 3 (3) | 0 | 2 (2) | 2 (2) |
| SGPT/ALT (> 5 x ULN and > 2 x baseline) | 1 (1) | 1 (2) | 2 (2) | 1 (1) |
| Abbreviations: ALT, alanine transaminase; NTDT, non-transfusion-dependent thalassemia; SGPT, serum glutamic-pyruvic transaminase; ULN, upper limit of normal. | ||||
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
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/1.73m2) and 621 matched-controls with normal kidney function (eGFR ≥120 mL/min/1.73m2) 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 dosage starting at 20 mg/kg/day (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 dosage > 30 mg/kg/day, 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 dose > 25 mg/kg/day when their serum ferritin was <1,000 mcg/L (n=158) had a 6-fold greater rate of renal adverse reactions (incidence rate ration (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 reaction 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)
The following adverse reactions have been spontaneously reported during postapproval 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), 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: GI perforation
Blood and Lymphatic System Disorders: worsening anemia
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), renal tubular disorder (n=1), proteinuria (n=1), hematuria (n=1), upper GI hemorrhage (n=1), vomiting (n=2), abdominal pain (n=1), and hypokalemia (n=1).
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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
Do not use deferasirox in adult or pediatric patients with eGFR less than 40 mL/min/1.73m2
For patients with renal impairment (eGFR 40 to 60 mL/min/1.73m2), reduce the starting dose by 50%
Exercise caution in pediatric patients with eGFR between 40 and 60 mL/min/1.73m2. If treatment is needed, use the minimum effective dose and monitor renal function frequently. Individualize dose titration based on improvement in renal injury
Deferasirox 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
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 in patients with severe (Child-Pugh C) hepatic impairment. Reduce the starting dose in patients with moderate (Child-Pugh B) hepatic impairment
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GI hemorrhage, including deaths, has been reported in deferasirox-treated patients, 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
Deferasirox tablets for oral suspension are an iron chelator indicated for the treatment of chronic iron overload due to blood transfusions in patients 2 years of age and older.
Deferasirox tablets for oral suspension 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 and a serum ferritin greater than 300 mcg/L. (
Deferasirox 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 concentration (LIC) of at least 5 milligrams of iron per gram of liver dry weight (mg Fe/g dw) and a serum ferritin greater than 300 mcg/L.
- Transfusional Iron Overload: Initial dose for patients with estimated glomerular filtration rate (eGFR) greater than 60 mL/min/1.73 m2 is 20 mg per kg body weight once daily, as oral suspension. Calculate dose to the nearest whole tablet. ()
2.1 Transfusional Iron OverloadDeferasirox 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) to establish accurate baseline
- 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 , Warnings and Precautions ].
- Serum transaminases and bilirubin [see Dosage and Administration , Warnings and Precautions ]
- Baseline auditory and ophthalmic examinations [see Warnings and Precautions ]
Initiating Therapy:The recommended initial dose of deferasirox for patients 2 years of age and older with eGFR greater than 60 mL/min/1.73 m2is 20 mg per kg body weight orally, once daily. Calculate doses (mg per kg per day) to the nearest whole tablet.
During Therapy:Monitor serum ferritin monthly and adjust the dose of deferasirox, 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 5 or 10 mg per kg and tailor adjustments to the individual patient’s response and therapeutic goals.
In patients not adequately controlled with doses of 30 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 40 mg per kg may be considered. Doses above 40 mg per kg are not recommended
[see Warnings and Precautions ].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 dose is greater than 25 mg/kg/day
[see Adverse Reactions ].If the serum ferritin falls below 500 mcg/L, interrupt deferasirox to minimize the risk of overchelation, and continue monthly monitoring
[see Warnings and Precautions ].
Monitor blood counts, liver function, renal function and ferritin monthly
[see Warnings and Precautions ].Interrupt deferasirox 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 , Warnings and Precautions , Use in Specific Populations , Clinical Pharmacology ].
- NTDT Syndromes: Initial dose for patients with eGFR greater than 60 mL/min/1.73 m2 is 10 mg per kg body weight once daily, as oral suspension. Calculate dose to the nearest whole tablet. ()
2.2 Iron Overload in Non-Transfusion-Dependent Thalassemia SyndromesDeferasirox 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 ]
- Baseline renal function:
- Obtain serum creatinine in duplicate (due to variations in measurements) to establish accurate baseline
- Calculate 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 , Warnings and Precautions ]
- Baseline auditory and ophthalmic examinations [see Warnings and Precautions ]
Initiating Therapy:
- The recommended initial dose of deferasirox for patients with eGFR greater than 60 mL/min/1.73 m2 is 10 mg per kg body weight orally once daily. Calculate doses (mg per kg per day) to the nearest whole tablet.
- If the baseline LIC is greater than 15 mg Fe/g dw, consider increasing the dose to 20 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 ]. 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 20 mg/kg/day. Do not exceed a maximum of 20 mg/kg/day.
- If after 6 months of therapy, the LIC is 3-7 mg Fe/g dw, continue treatment with deferasirox at no more than 10 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 ].
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 , Warnings and Precautions , Use in Specific Populations , Clinical Pharmacology ].
Restart treatment when the LIC rises again to more than 5 mg Fe/g dw.
Deferasirox is provided as 125 mg, 250 mg and 500 mg tablets for oral suspension.
• 125 mg - White to off white, round, flat tablet with beveled edge and debossed with 'DS' on the one side and '125' on other side.
• 250 mg - White to off white, round, flat tablet with beveled edge and debossed with 'DS' on the one side and '250' on other side.
• 500 mg - White to off white, round, flat tablet with beveled edge and debossed with 'DS' on the one side and '500' on other side.
Lactation: Advise women not to breastfeed. (
No data are available regarding the presence of deferasirox 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.
Deferasirox
· Estimated GFR less than 40 mL/min/1.73 m2
Deferasirox is contraindicated in patients with eGFR less than 40 mL/min/1.73m2
For decreases in renal function while receiving deferasirox
- 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 10 mg per kg.Pediatric Patients (ages 2 yearsto17 years):
- Reduce the dose by 10 mg/kg/day if eGFR decreases by greater than 33% below the average baseline measurement and repeat the eGFR within 1 week.
- Interrupt deferasirox 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 ].
- In the setting of decreased renal function, evaluate the risk benefit profile of continued deferasirox use. Use the minimum effective deferasirox 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 to prevent severe and irreversible renal injury[see Warnings and Precautions ].All Patients (regardless of age):
- Discontinue therapy for eGFR less than 40 mL/min/1.73m2[see Contraindications ].
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 5 mg per kg, or reduce by 50% if the dose is 10 or 20 mg per kg.
Pediatric Patients (ages 10 years to 17 years):Reduce the dose by 5 mg/kg/day 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 ].In the setting of decreased renal function, evaluate the risk benefit profile of continued deferasirox use. Use the minimum effective deferasirox 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 to prevent severe and irreversible renal injury
[see Warnings and Precautions ].
- Discontinue therapy for eGFR less than 40 mL/min/1.73 m2[see Contraindications ].
Deferasirox is contraindicated in patients with eGFR less than 40 mL/min/1.73m2. Exercise caution in pediatric patients with eGFR between 40 and 60 mL/minute/1.73m2. If treatment is needed, use the minimum effective dose and monitor renal function frequently. Individualize dose titration based on improvement in renal injury
Deferasirox 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, adult 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 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
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
· Poor performance status;
Deferasirox is contraindicated in patients with eGFR less than 40 mL/min/1.73m2. Exercise caution in pediatric patients with eGFR between 40 and 60 mL/minute/1.73m2. If treatment is needed, use the minimum effective dose and monitor renal function frequently. Individualize dose titration based on improvement in renal injury
Deferasirox 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, adult 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 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
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
GI hemorrhage, including deaths, has been reported in deferasirox-treated patients, 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
· High-risk myelodysplastic syndromes; (this patient population was not studied and is not expected to benefit from chelation therapy)
· Advanced malignancies.
Deferasirox is contraindicated in patients with eGFR less than 40 mL/min/1.73m2. Exercise caution in pediatric patients with eGFR between 40 and 60 mL/minute/1.73m2. If treatment is needed, use the minimum effective dose and monitor renal function frequently. Individualize dose titration based on improvement in renal injury
Deferasirox 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, adult 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 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
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
GI hemorrhage, including deaths, has been reported in deferasirox-treated patients, 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
· Platelet counts less than 50 x 109/L
GI hemorrhage, including deaths, has been reported in deferasirox-treated patients, 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
Neutropenia, agranulocytosis, worsening anemia, and thrombocytopenia, including fatal events, have been reported in patients treated with deferasirox. Preexisting hematologic disorders may increase this risk. Monitor blood counts in all patients. Interrupt treatment with deferasirox in patients who develop cytopenias until the cause of the cytopenia has been determined. Deferasirox is contraindicated in patients with platelet counts below 50 x 109/L.
· Known hypersensitivity to deferasirox or any component of deferasirox tablets for oral suspension
Deferasirox may cause serious hypersensitivity reactions (such as anaphylaxis and angioedema), with the onset of the reaction usually occurring within the first month of treatment
The following adverse reactions have been spontaneously reported during postapproval 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), 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: GI perforation
Blood and Lymphatic System Disorders: worsening anemia
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), renal tubular disorder (n=1), proteinuria (n=1), hematuria (n=1), upper GI hemorrhage (n=1), vomiting (n=2), abdominal pain (n=1), and hypokalemia (n=1).