deferasirox
Brand names: Jadenu, DEFERASIROX, Deferasirox, deferasirox, Exjade, Deferasirox Oral Granules, Deferasorox
Boxed warning
WARNING:RENAL FAILURE, HEPATIC FAILURE, AND GASTROINTESTINAL HEMORRHAGE Renal Failure Deferasirox 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 dosing in all patients. Deferasirox 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 pre-existing 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 , 2.4 , 2.5 ), Warnings and Precautions (5.1) , Adverse Reactions (6.1 , 6.2 )]. Hepatic Failure Deferasirox 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 in patients with severe (Child-Pugh C) hepatic impairment and reduce the dose in patients with moderate (Child-Pugh B) hepatic impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.2)]. Gastrointestinal Hemorrhage Deferasirox 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 for suspected GI ulceration or hemorrhage [see Warnings and Precautions (5.3)]. WARNING: RENAL FAILURE, HEPATIC FAILURE, AND GASTROINTESTINAL HEMORRHAGE See full prescribing information for complete boxed warning. Deferasirox may cause: acute kidney injury, including acute renal failure requiring dialysis and renal tubular toxicity including Fanconi syndrome ( 5.1 ) hepatic toxicity, including failure ( 5.2 ) gastrointestinal hemorrhage ( 5.3 ) Deferasirox therapy requires close patient monitoring, including laboratory tests of renal and hepatic function. ( 5 )
Warnings
5 WARNINGS AND PRECAUTIONS Acute Kidney Injury : Measure serum creatinine in duplicate before starting therapy. Monitor renal function during deferasirox therapy and reduce dose or interrupt therapy for toxicity. ( 2.1 , 2.4 , 5.1 ) Hepatic Toxicity: Monitor hepatic function. Reduce dose or interrupt therapy for toxicity. ( 5.2 ) Fatal and Nonfatal Gastrointestinal Bleeding, Ulceration, and Irritation: Risk may be greater in patients who are taking deferasirox in combination with drugs that have known ulcerogenic or hemorrhagic potential. ( 5.3 ) Bone Marrow Suppression: Neutropenia, agranulocytosis, worsening anemia, and thrombocytopenia, including fatal events; monitor blood counts during deferasirox therapy. Interrupt therapy for toxicity. ( 5.4 ) Age-related Risk of Toxicity: Monitor elderly and pediatric patients closely for toxicity. ( 5.5 ) Hypersensitivity Reactions: Discontinue deferasirox for severe reaction and institute medical intervention. ( 5.7 ) Severe Skin Reactions including Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue deferasirox. ( 5.8 ) 5.1 Acute Kidney Injury, Including Acute Renal Failure Requiring Dialysis and Renal Tubular Toxicity Including Fanconi Syndrome Deferasirox is contraindicated in patients with eGFR less than 40 mL/min/1.73 m 2 . Exercise caution in pediatric patients with eGFR between 40 and 60 mL/minute/1.73 m 2 . 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 to 60 mL/min/1.73 m 2 ) reduce the starting dose by 50% [see Dosage and Administration (2.4, 2.5 ), Use in Specific Populations (8.6)]. 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 [ see Warnings and Precautions (5.6) , Adverse Reactions (6.1 , 6.2 ), Use in Special 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. 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 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 ), Use in Specific Populations (8.4 )]. 5.2 Hepatic Toxicity and Failure 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 multi-organ 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 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 in the 20 to 40 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 (AST and 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 [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. 5.3 Gastrointestinal (GI) Ulceration, Hemorrhage, and Perforation 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 [see Adverse Reactions (6.1) ]. Monitor for signs and symptoms of GI ulceration and hemorrhage during deferasirox therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. The risk of gastrointestinal hemorrhage may be increased when administering deferasirox 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 gastrointestinal perforation (including fatal outcome) [see Adverse Reactions (6.2) ]. 5.4 Bone Marrow Suppression 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 10 9 /L. 5.5 Age-Related Risk of Toxicity Elderly patients Deferasirox has been associated with serious and fatal adverse reactions in the postmarketing setting among adults, predominantly in elderly patients. Monitor elderly patients treated with deferasirox more frequently for toxicity [see Use in Specific Populations (8.5) ]. Pediatric Patients Deferasirox has been associated with serious and fatal adverse reactions in pediatric patients in the postmarketing setting. These events were frequently associated with volume depletion or with continued deferasirox doses in the 20 to 40 mg/kg/day range when body iron burden was approaching or in the normal range. Interrupt deferasirox in patients with volume depletion, and resume deferasirox when renal function and fluid volume have normalized. Monitor liver and renal function more frequently during volume depletion and in patients receiving deferasirox in the 20 to 40 mg/kg/day range when iron burden is approaching the normal range. Use the minimum effective dose to achieve and maintain a low iron burden. [see Dosage and Administration (2.4), Warnings and Precautions (5.6) , Use in Specific Populations (8.4)] 5.6 Overchelation For patients with transfusional iron overload, measure serum ferritin monthly to assess for possible overchelation of iron. An analysis of pediatric patients treated with deferasirox in pooled clinical trials (n=158) found a higher rate of renal adverse events among patients receiving doses greater than 25 mg/kg/day while their serum ferritin values were less than 1,000 mcg/L. Consider dose reduction or closer monitoring of renal and hepatic function, and serum ferritin levels during these periods. Use the minimum effective dose to maintain a low-iron burden [see Adverse Reactions (6.1), Use in Specific Populations (8.4 )]. 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 (6.1)] . If the serum ferritin falls below 500 mcg/L, interrupt therapy with deferasirox and continue monthly monitoring. Evaluate the need for ongoing chelation for patients whose conditions do not require regular blood transfusions. Use the minimum effective dose to maintain iron burden in the target range. Continued administration of deferasirox in the 20 to 40 mg/kg/day range when the body iron burden is approaching or within the normal range has resulted in life-threatening adverse events [see Dosage and Administration (2.1) ]. For patients with NTDT, measure LIC by liver biopsy or by using an FDA-cleared or approved method for monitoring patients receiving deferasirox therapy every 6 months on treatment. Interrupt deferasirox administration when the LIC is less than 3 mg Fe/g dw. Measure serum ferritin monthly, and if the serum ferritin falls below 300 mcg/L, interrupt deferasirox and obtain a confirmatory LIC [see Clinical Studies ( 14) ]. 5.7 Hypersensitivity 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 [see Adverse Reactions (6.2)]. If reactions are severe, discontinue deferasirox and institute appropriate medical intervention. Deferasirox is contraindicated in patients with known hypersensitivity to deferasirox products and should not be reintroduced in patients who have experienced previous hypersensitivity reactions on deferasirox products due to the risk of anaphylactic shock. 5.8 Severe Skin Reactions Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which could be life-threatening or fatal have been reported during deferasirox therapy [see Adverse Reactions (6.1, 6.2)]. Cases of erythema multiforme have been observed. Advise patients of the signs and symptoms of severe skin reactions, and closely monitor. If any severe skin reactions are suspected, discontinue deferasirox immediately and do not reintroduce deferasirox therapy. 5.9 Skin Rash Rashes may occur during deferasirox treatment [see Adverse Reactions (6.1)]. For rashes of mild to moderate severity, deferasirox may be continued without dose adjustment, since the rash often resolves spontaneously. In severe cases, interrupt treatment with deferasirox. Reintroduction at a lower dose with escalation may be considered after resolution of the rash. 5.10 Auditory and Ocular Abnormalities Auditory disturbances (high frequency hearing loss, decreased hearing), and ocular disturbances (lens opacities, cataracts, elevations in intraocular pressure, and retinal disorders) were reported at a frequency of less than 1% with deferasirox therapy in the clinical studies. The frequency of auditory adverse events irrespective of causality was increased among pediatric patients who received deferasirox doses greater than 25 mg/kg/day when serum ferritin was less than 1,000 mcg/L [see Warnings and Precautions (5.6)] . Perform auditory and ophthalmic testing (including slit-lamp examinations and dilated fundoscopy) before starting deferasirox treatment and thereafter at regular intervals (every 12 months). If disturbances are noted, monitor more frequently. Consider dose reduction or interruption.
Contraindications
4 CONTRAINDICATIONS Deferasirox is contraindicated in patients with: Estimated GFR less than 40 mL/min/1.73 m 2 [see Dosage and Administration (2.5) , Warnings and Precautions (5.1)]; Poor performance status; [ see Warnings and Precautions (5.1 , 5.3 )] High-risk myelodysplastic syndromes; (this patient population was not studied and is not expected to benefit from chelation therapy) Advanced malignancies. [ see Warnings and Precautions (5.1 , 5.3)] Platelet counts less than 50 x 10 9 /L [ see Warnings and Precautions (5.3 , 5.4)] Known hypersensitivity to deferasirox or any component of deferasirox [see Warnings and Precautions (5.7 ), Adverse Reactions (6.2) ]. • Estimated GFR less than 40 mL/min/1.73 m 2 . ( 4 ) • Patients with poor performance status. ( 4 ) • Patients with high-risk MDS. ( 4 ) • Patients with advanced malignancies. ( 4 ) • Patients with platelet counts less than 50 x 10 9 /L. ( 4 ) • Known hypersensitivity to deferasirox or any component of deferasirox. ( 4 )
Overdose
10 OVERDOSAGE Cases of overdose (2 - 3 times the prescribed dose for several weeks)have been reported. In one case, this resulted in hepatitis, which resolved without long-term consequences after a dose interruption. In one pediatric case, a dose of 2-3 times the prescribed dose for 6 days, resulted in acute renal failure requiring hemofiltration and acute liver injury/failure, which were reversible with intensive care support. Single doses up to 80 mg per kg per day in iron overloaded beta-thalassemic patients have been tolerated with nausea and diarrhea noted. In healthy volunteers, single doses of up to 40 mg per kg per day were tolerated. There is no specific antidote for deferasirox. In case of overdose, induce vomiting and employ gastric lavage. Early signs of acute overdose are digestive effects such as abdominal pain, diarrhea, nausea, and vomiting. Hepatic and renal disorders have been reported, including cases of liver enzyme and creatinine increased with recovery after treatment discontinuation. An erroneously administered single dose of 90 mg/kg led to Fanconi syndrome which resolved after treatment. There is no specific antidote for deferasirox. In case of overdose, it may be treated with induction of vomiting or gastric lavage, and by symptomatic treatment.
Drug interactions
7 DRUG INTERACTIONS Do not take deferasirox with aluminum-containing antacid preparations. (7.1) Deferasirox increases the exposure of the CYP2C8 substrate repaglinide. Consider repaglinide dose reduction and monitor blood glucose levels. (7.3) Avoid the use of deferasirox with CYP1A2 substrate theophylline. ( 7.4 ) Deferasirox increases exposure of busulfan. Monitor plasma concentrations of busulfan when coadministered with deferasirox to allow dose adjustment of busulfan as needed. (7 .7) 7.1 Aluminum-Containing Antacid Preparations The concomitant administration of deferasirox and aluminum-containing antacid preparations has not been formally studied. Although deferasirox has a lower affinity for aluminum than for iron, do not take deferasirox with aluminum-containing antacid preparations due to the mechanism of action of deferasirox. 7.2 Agents Metabolized by CYP3A4 Deferasirox may induce CYP3A4 resulting in a decrease in CYP3A4 substrate concentration when these drugs are coadministered. Closely monitor patients for signs of reduced effectiveness when deferasirox is administered with drugs metabolized by CYP3A4 (e.g., alfentanil, aprepitant, budesonide, buspirone, conivaptan, cyclosporine, darifenacin, darunavir, dasatinib, dihydroergotamine, dronedarone, eletriptan, eplerenone, ergotamine, everolimus, felodipine, fentanyl, hormonal contraceptive agents, indinavir, fluticasone, lopinavir, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, pimozide, quetiapine, quinidine, saquinavir, sildenafil, simvastatin, sirolimus, tacrolimus, tolvaptan, tipranavir, triazolam, ticagrelor, and vardenafil) [see Clinical Pharmacology (12.3) ]. 7.3 Agents Metabolized by CYP2C8 Deferasirox inhibits CYP2C8 resulting in an increase in CYP2C8 substrate (e.g., repaglinide and paclitaxel) concentration when these drugs are coadministered. If deferasirox and repaglinide are used concomitantly, consider decreasing the dose of repaglinide and perform careful monitoring of blood glucose levels. Closely monitor patients for signs of exposure related toxicity when deferasirox is coadministered with other CYP2C8 substrates [see Clinical Pharmacology (12.3) ]. 7.4 Agents Metabolized by CYP1A2 Deferasirox inhibits CYP1A2 resulting in an increase in CYP1A2 substrate (e.g., alosetron, caffeine, duloxetine, melatonin, ramelteon, tacrine, theophylline, tizanidine) concentration when these drugs are coadministered. An increase in theophylline plasma concentrations could lead to clinically significant theophylline-induced CNS or other adverse reactions. Avoid the concomitant use of theophylline or other CYP1A2 substrates with a narrow therapeutic index (e.g., tizanidine) with deferasirox. Monitor theophylline concentrations and consider theophylline dose modification if you must coadminister theophylline with deferasirox. Closely monitor patients for signs of exposure related toxicity when deferasirox is coadministered with other drugs metabolized by CYP1A2 [see Clinical Pharmacology (12.3) ]. 7.5 Agents Inducing UDP-glucuronosyltransferase (UGT) Metabolism Deferasirox is a substrate of UGT1A1 and to a lesser extent UGT1A3. The concomitant use of deferasirox with potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) may result in a decrease in deferasirox efficacy due to a possible decrease in deferasirox concentration. Avoid the concomitant use of potent UGT inducers with deferasirox. Consider increasing the initial dose of deferasirox if you must coadminister these agents together [see Dosage and Administration (2.5) , Clinical Pharmacology (12.3) ]. 7.6 Bile Acid Sequestrants Avoid the concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol) with deferasirox due to a possible decrease in deferasirox concentration. If you must coadminister these agents together, consider increasing the initial dose of deferasirox [see Dosage and Administration (2.5), Clinical Pharmacology (12.3) ]. 7.7 Busulfan Increased exposure of busulfan was observed with concomitant use with deferasirox. Monitor plasma concentrations of busulfan when coadministered with deferasirox to allow dose adjustment of busulfan as needed [ see Clinical Pharmacology (12.3)].
Uses
1 INDICATIONS AND USAGE 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. ( 1.1 ) Deferasirox tablets for oral suspension are 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. ( 1.2 ) Limitations of Use: The safety and efficacy of deferasirox when administered with other iron chelation therapy have not been established. ( 1.3 ) 1.1 Treatment of Chronic Iron Overload Due to Blood Transfusions (Transfusional Iron Overload) Deferasirox tablets for oral suspension are indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older. 1.2 Treatment of Chronic Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes Deferasirox tablets for oral suspension are 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. 1.3 Limitations of Use The safety and efficacy of deferasirox tablets for oral suspension when administered with other iron chelation therapy have not been established.
Dosage forms & strengths
2 DOSAGE AND ADMINISTRATION Transfusional Iron Overload: Initial dose for patients with estimated glomerular filtration rate (eGFR) greater than 60 mL/min/1.73 m 2 is 20 mg per kg body weight once daily, as oral suspension. Calculate dose to the nearest whole tablet. ( 2.1 ) 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) 2.1 Transfusional Iron Overload Deferasirox tablets for oral suspension 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: o Obtain serum creatinine in duplicate (due to variations in measurements) to establish accurate baseline o 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). o 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 tablets for oral suspension for patients 2 years of age and older with eGFR greater than 60 mL/min/1.73 m 2 is 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 tablets for oral suspension, if necessary, every 3-6 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 ( 5.6 )]. • Adjust dose based on serum ferritin levels o 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 ( 6.1 )]. o If the serum ferritin falls below 500 mcg/L, interrupt deferasirox tablets for oral suspension and continue monthly monitoring. o Evaluate the need for ongoing chelation therapy for patients whose conditions no longer require regular blood transfusions. o 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 tablets for oral suspension 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 tablets for oral suspension 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: o Obtain serum creatinine in duplicate (due to variations in measurements) to establish accurate baseline o Calculate eGFR. Use a prediction equation appropriate for adult patients (e.g., CKD-EPI, MDRD method) and in pediatric patients (e.g., Schwartz equations). o 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 tablets for oral suspension for patients with eGFR greater than 60 mL/min/1.73 m 2 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 ( 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 20 mg/kg/day. Do not exceed a maximum of 20 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 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 ( 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 Do not chew tablets or swallow them whole. Take deferasirox once daily on an empty stomach at least 30 minutes before food, preferably at the same time each day. Completely disperse tablets by stirring in water, orange juice, or apple juice until a fine suspension is obtained. Disperse doses of less than 1 g in 3.5 ounces of liquid and doses of 1 g or greater in 7 ounces of liquid. After swallowing the suspension, resuspend any residue in a small volume of liquid and swallow. Do not take deferasirox tablets for oral suspension with aluminum-containing antacid products [see Drug Interactions (7.1) ]. 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 tablets for oral suspension [see Warnings and Precautions (5.2) , Use in Specific Populations (8.7)] . Patients with Baseline Renal Impairment Do not use deferasirox tablets for oral suspension in adult or pediatric patients with eGFR less than 40 mL/min/1.73m 2 [ see Dosage and Administration (2.5), Contraindications (4) ]. For patients with renal impairment (eGFR 40 to 60 mL/min/1.73m 2 ), 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/min/1.73m 2 . 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)]. 2.5 Dose Modifications for Decreases in Renal Function while on Deferasirox Tablets for Oral Suspension Deferasirox tablets for oral suspension are contraindicated in patients with eGFR less than 40 mL/min/1.73 m 2 [see Contraindications ( 4 )]. For decreases in renal function while receiving deferasirox tablets for oral suspension [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 10 mg per kg. Pediatric Patients (ages 2 years to 17 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 tablets for oral suspension 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 tablets for oral suspension use. Use the minimum effective deferasirox tablets for oral suspension 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 tablets for oral suspension to prevent severe and irreversible renal injury [see Warnings and Precautions ( 5.1 )]. All Patients (regardless of age): • Discontinue therapy for eGFR less than less than 40 mL/min/1.73m 2 [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 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 ( 5.1 )]. In the setting of decreased renal function, evaluate the risk benefit profile of continued deferasirox tablets for oral suspension use. Use the minimum effective deferasirox tablets for oral suspension 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 tablets for oral suspension 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 m 2 [see Contraindications ( 4 )]. 2.6 Dose Modifications Based on Concomitant Medications UDP-glucuronosyltransferases (UGT) Inducers Concomitant use of UGT inducers decreases deferasirox tablets for oral suspension systemic exposure. Avoid the concomitant use of potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) with deferasirox tablets for oral suspension. If you must administer deferasirox tablets for oral suspension with 1 of these agents, consider increasing the initial dose of deferasirox tablets for oral suspension by 50%, and monitor serum ferritin levels and clinical responses for further dose modification [see Dosage and Administration (2.1), Drug Interactions (7.5) ]. Bile Acid Sequestrants Concomitant use of bile acid sequestrants decreases deferasirox tablets for oral suspension systemic exposure. Avoid the concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol) with deferasirox tablets for oral suspension. If you must administer deferasirox tablets for oral suspension with 1 of these agents, consider increasing the initial dose of deferasirox tablets for oral suspension by 50%, and monitor serum ferritin levels and clinical responses for further dose modification [see Dosage and Administration (2.1) , Drug Interactions (7.6) ].