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Renal Failure Deferasirox tablets 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 tablets dosing in all patients. Deferasirox tablets are 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 , 2.4 , 2.5 ), Warnings and Precautions ( 5.1 ), Adverse Reactions ( 6.1 , 6.2 )] . Hepatic Failure Deferasirox tablets 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 tablets 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 tablets 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 tablets for suspected GI ulceration or hemorrhage [see Warnings and Precautions ( 5.3 )].

Deferasirox tablets 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 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 (Fe/g dw) and a serum ferritin greater than 300 mcg/L. (1.2) Limitations of Use: The safety and efficacy of deferasirox tablets when administered with other iron chelation therapy have not been established. ( 1.3 )

Transfusional Iron Overload: Initial dose for patients with estimated glomerular filtration rate (eGFR) greater than 60 mL/min/1.73 m 2 is 14 mg/kg (calculated to nearest whole tablet) once daily. (2.1) NTDT Syndromes: Initial dose for patients with eGFR greater than 60 mL/min/1.73 m 2 is 7 mg/kg (calculated to nearest whole tablet) once daily. (2.2) See full prescribing information for information regarding monitoring, administration, and dose-reductions for organ impairment. (2.1 , 2.2 , 2.3 , 2.4)

Deferasirox tablets 90 mg are light blue oval biconvex film-coated tablets with beveled edges, debossed with ‘S102’ on one side and plain on the other side. They are available in bottles of 30 tablets (NDC 57664-768-83). Deferasirox tablets 180 mg are medium blue oval biconvex film-coated tablets with beveled edges, debossed with ‘S103’ on one side and plain on the other side. They are available in bottles of 30 tablets (NDC 57664-769-83). Deferasirox tablets 360 mg are dark blue oval biconvex film-coated tablets with beveled edges, debossed with ‘S104’ on one side and plain on the other side. They are available in bottles of 30 tablets (NDC 57664-770-83). Store deferasirox tablets at 20°C-25°C (68°F-77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from moisture.

Deferasirox tablets are 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 tablets [see Warnings and Precautions (5.7) , Adverse Reactions (6.2) ] .

Deferasirox is an iron-chelating agent provided as a tablet for oral use. Deferasirox is designated chemically as 4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoic acid and has the following structural formula: Deferasirox is a white to slightly yellow powder. It has a molecular formula C 21 H 15 N 3 O 4 and molecular weight of 373.4 g/mol. It is insoluble in water with a pH of suspension of 4.1. Deferasirox tablets contain 90 mg, 180 mg, or 360 mg deferasirox. Inactive ingredients include colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, poloxamer and povidone. The film coating contains hypromellose, FD & C Blue No. 2, polyethylene glycol, talc and titanium dioxide.

Do not take deferasirox tablets with aluminum-containing antacid preparations. (7.1) Deferasirox increases the exposure of repaglinide. Consider repaglinide dose reduction and monitor blood glucose levels. (7.3) Avoid the use of deferasirox tablets with theophylline as theophylline levels could be increased. (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)

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Dosing Instructions Advise patients to take deferasirox tablets with water or other liquids. Advise patients to swallow deferasirox tablets once daily with water or other liquids, preferably at the same time each day. Advise patients to take deferasirox tablets 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). For patients who have difficulty swallowing whole tablets, deferasirox tablets may be crushed and mixed with soft foods (e.g., yogurt or applesauce) immediately prior to use and administered orally. Advise against the use of commercial crushers with serrated surfaces for crushing a single 90 mg tablet. Advise patients to immediately and completely consume the dose and not store it for future use [see Dosage and Administration (2.3) ]. Blood Testing Advise patients that blood tests will be performed frequently to check for damage to kidneys, liver, or blood cells [ see Warnings and Precautions (5.1 , 5.2 , 5.3 , 5.4 , 5.5) ]. Acute Kidney Injury, Including Acute Renal Failure Caution patients about the potential for kidney toxicity when taking deferasirox tablets. Inform patients of the signs and symptoms of kidney injury. Advise patients to contact their healthcare provider immediately if they experience any of these symptoms [see Warnings and Precautions (5.1) ] . Hepatic Toxicity and Failure Caution patients about the potential for hepatic toxicity when taking deferasirox tablets. Inform patients of the signs and symptoms of hepatic toxicity. Advise patients to contact their healthcare provider immediately if they experience any of these symptoms [see Warnings and Precautions (5.2) ] . GI Ulceration and Hemorrhage Caution patients about the potential for the development of GI ulcers or bleeding when taking deferasirox tablets in combination with drugs that have ulcerogenic or hemorrhagic potential, such as NSAIDs, corticosteroids, oral bisphosphonates, or anticoagulants. Inform patients of the signs and symptoms of GI ulcers or bleeding. Advise patients to contact their healthcare provider for symptoms of heartburn but to seek immediate medical attention for symptoms of GI hemorrhage [see Warnings and Precautions (5.3) ]. Allergic Reactions Serious allergic reactions (which include swelling of the throat) have been reported in patients taking deferasirox tablets, usually within the first month of treatment. If reactions are severe, advise patients to stop taking deferasirox tablets immediately and seek immediate medical attention [see Warnings and Precautions (5.7) ]. Severe Skin Reactions Severe skin reactions have been reported in patients taking deferasirox tablets. Inform patients of the signs and symptoms of severe skin reactions. If reactions are severe, advise patients to stop taking deferasirox tablets immediately and seek immediate medical attention [see Warnings and Precautions (5.8) ] . Skin Rash Skin rashes may occur during deferasirox tablets treatment. If the skin rash is severe, advise patients to stop taking deferasirox tablets and seek medical attention [ see Warnings and Precautions (5.9) ]. Pediatric Patients with Acute Illness Instruct pediatric patients and their caregivers to contact their healthcare provider during episodes of acute illness, especially if the patient has not been drinking fluids or the patient has volume depletion due to fever, vomiting, or diarrhea [see Warnings and Precautions (5.1) ] . Auditory and Ocular Testing Because auditory and ocular disturbances have been reported with deferasirox, conduct auditory testing and ophthalmic testing before starting deferasirox tablets treatment and thereafter at regular intervals. Advise patients to contact their healthcare provider if they develop visual or auditory changes during treatment [see Warnings and Precautions (5.10) ]. Drug Interactions Caution patients not to take aluminum containing antacids and deferasirox tablets simultaneously [see Drug Interactions (7.1) ]. Caution patients about potential loss of effectiveness of drugs metabolized by CYP3A4 (e.g., cyclosporine, simvastatin, hormonal contraceptive agents) when deferasirox tablets are administered with these drugs [see Drug Interactions (7.2) ]. Caution patients about potential loss of effectiveness of deferasirox tablets when administered with drugs that are potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir). Based on serum ferritin levels and clinical response, consider increases in the dose of deferasirox tablets when concomitantly used with potent UGT inducers [see Drug Interactions (7.5) ]. Caution patients about potential loss of effectiveness of deferasirox tablets when administered with drugs that are bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol). Based on serum ferritin levels and clinical response, consider increases in the dose of deferasirox tablets when concomitantly used with bile acid sequestrants [see Drug Interactions (7.6) ]. Caution patients with diabetes to monitor their glucose levels more frequently when repaglinide is used concomitantly with deferasirox tablets [see Drug Interactions (7.3) ] . Handling Instructions Advise patients to store deferasirox tablets in a dry, room-temperature environment [see How Supplied/Storage and Handling (16) ]. Driving and Using Machines Caution patients experiencing dizziness to avoid driving or operating machinery [see Adverse Reactions (6.1) ]. For more information, call Sun Pharmaceutical Industries, Inc. at 1-800-406-7984. Dispense with Medication Guide available at: www.sunpharma.com/usa/products All trademarks are the property of their respective owners. Manufactured by: ALKALOIDA Chemical Company Zrt. 4440 Tiszavasvári, Kabay János u. 29. Hungary Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 Rev. 09/2024

Transfusional Iron Overload The safety and effectiveness of deferasirox tablets have been established in pediatric patients 2 years of age and older for the treatment of transfusional iron overload [ see Dosage and Administration (2.1) ] . Safety and effectiveness have not been established in pediatric patients less than 2 years of age for the treatment of transfusional iron overload. Pediatric approval for treatment of transfusional iron overload was based on clinical studies of 292 pediatric patients 2 years to less than 16 years of age with various congenital and acquired anemias. Seventy percent of these patients had beta-thalassemia [see Indications and Usage (1) , Dosage and Administration (2.1) , Clinical Studies (14) ] . In those clinical studies, 173 children (ages 2 to < 12 years) and 119 adolescents (ages 12 to < 17 years) were exposed to deferasirox. A trial conducted in treatment naïve pediatric patients, 2 to < 18 years of age with transfusional iron overload (NCT02435212) did not provide additional relevant information about the safety or effectiveness of the deferasirox granules dosage form compared to the deferasirox oral tablets for suspension dosage form. Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes The safety and effectiveness of deferasirox tablets have been established in patients 10 years of age and older for the treatment of chronic iron overload with non-transfusion-dependent thalassemia (NTDT) syndromes [see Dosage and Administration (2.2) ] . Safety and effectiveness have not been established in patients less than 10 years of age with chronic iron overload in NTDT syndromes. Pediatric approval for treatment of NTDT syndromes with liver iron (Fe) concentration (LIC) of at least 5 mg Fe/g of dry weight and a serum ferritin greater than 300 mcg/L was based on 16 pediatric patients treated with deferasirox therapy (10 years to less than 16 years of age) with chronic iron overload and NTDT. Use of deferasirox tablets in these age groups is supported by evidence from adequate and well-controlled studies of deferasirox in adult and pediatric patients [see Indications and Usage (1.2) , Dosage and Administration (2.2) , Clinical Studies (14) ] . In general, risk factors for deferasirox-associated kidney injury include preexisting renal disease, volume depletion, overchelation, and concomitant use of other nephrotoxic drugs. Acute kidney injury, and acute liver injury and failure has occurred in pediatric patients. In a pooled safety analysis, pediatric patients with higher deferasirox exposures had a greater probability of renal toxicity and decreased renal function, resulting in increased deferasirox exposure and progressive renal toxicity/kidney injury. Higher rates of renal AEs have been identified among pediatric patients receiving deferasirox tablets for oral suspension doses greater than 25 mg/kg/day equivalent to 17.5 mg/kg/day deferasirox tablets when their serum ferritin values were less than 1,000 mcg/L [see Dosage and Administration (2.5) , Warnings and Precautions (5.1 , 5.6) , Adverse Reactions (6.1 , 6.2) ] . Monitoring recommendations for all pediatric patients with Transfusional Iron Overload and NTDT It is recommended that serum ferritin be monitored every month to assess the patient’s response to therapy and to minimize the risk of overchelation [see Warnings and Precautions (5.6) ] . Monitor renal function by estimating GFR using an eGFR prediction equation appropriate for pediatric patients and evaluate renal tubular function. Monitor renal function more frequently in pediatric patients in the presence of renal toxicity risk factors, including episodes of dehydration, fever and acute illness that may result in volume depletion or decreased renal perfusion. Use the minimum effective dose [see Warnings and Precautions (5.1) ] . Interrupt deferasirox tablets in pediatric patients with transfusional iron overload, and consider dose interruption in pediatric patients with non-transfusion-dependent iron overload, 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. Evaluate the risk benefit profile of continued deferasirox tablets use in the setting of decreased renal function. Avoid use of other nephrotoxic drugs [ see Dosage and Administration (2.5) , Warnings and Precautions (5.1) ]. Juvenile Animal Toxicity Data Renal toxicity was observed in adult mice, rats, and marmoset monkeys administered deferasirox at therapeutic doses. In a neonatal and juvenile toxicity study in rats, deferasirox was administered orally from postpartum Day 7 through 70, which equates to a human age range of term neonate through adolescence. Increased renal toxicity was identified in juvenile rats compared to adult rats at a dose based on mg/m 2 approximately 0.4 times the recommended dose of 20 mg/kg/day. A higher frequency of renal abnormalities was noted when deferasirox was administered to non-iron overloaded animals compared to iron overloaded animals.

Four hundred thirty-one (431) patients greater than or equal to 65 years of age were studied in clinical trials of deferasirox in the transfusional iron overload setting. Two hundred twenty-five (225) of these patients were between 65 and 75 years of age while 206 were greater than or equal to 75 years of age. The majority of these patients had myelodysplastic syndrome (MDS) (n = 393). In these trials, elderly patients experienced a higher frequency of adverse reactions than younger patients. Monitor elderly patients for early signs or symptoms of adverse reactions that may require a dose adjustment. Elderly patients are at increased risk for toxicity due to the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range. In elderly patients, including those with MDS, individualize the decision to remove accumulated iron based on clinical circumstances and the anticipated clinical benefit and risks of deferasirox tablets for oral suspension therapy.

A 104-week oral carcinogenicity study in Wistar rats showed no evidence of carcinogenicity from deferasirox at doses up to 60 mg/kg/day (0.7 times the MRHD on a mg/m 2 basis). A 26-week oral carcinogenicity study in p53 (+/-) transgenic mice has shown no evidence of carcinogenicity from deferasirox at doses up to 200 mg/kg/day (1.2 times the MRHD on a mg/m 2 basis) in males and 300 mg/kg/day (1.7 times the MRHD on a mg/m 2 basis) in females. Deferasirox was negative in the Ames test and chromosome aberration test with human peripheral blood lymphocytes. It was positive in 1 of 3 in vivo oral rat micronucleus tests. Deferasirox at oral doses up to 75 mg/kg/day (0.9 times the MRHD on a mg/m 2 basis) was found to have no adverse effect on fertility and reproductive performance of male and female rats.

The following clinically significant adverse reactions are also discussed in other sections of the labeling: Acute Kidney Injury, Including Acute Renal Failure Requiring Dialysis, and Renal Tubular Toxicity Including Fanconi Syndrome [ see Warnings and Precautions ( 5.1 , 5.6 ) ] Hepatic Toxicity and Failure [see Warnings and Precautions ( 5.2 , 5.6 )] GI Hemorrhage [see Warnings and Precautions (5.3) ] Bone Marrow Suppression [see Warnings and Precautions (5.4) ] Hypersensitivity [see Warnings and Precautions (5.7) ] Severe Skin Reactions [see Warnings and Precautions (5.8) ] Skin Rash [see Warnings and Precautions (5.9) ] Auditory and Ocular Abnormalities [see Warnings and Precautions (5.10) ]

Cases of overdose (2 to 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 of deferasirox up to 80 mg/kg/day with the tablet for oral suspension formulation in iron-overloaded beta-thalassemic patients have been tolerated with nausea and diarrhea noted. In healthy subjects, single doses of up to 40 mg/kg/day with the tablet for oral suspension formulation were tolerated. 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 tablets. In case of overdose, it may be treated with induction of vomiting or gastric lavage, and by symptomatic treatment.

Deferasirox tablets were evaluated in healthy subjects. There are no clinical data in patients with deferasirox tablets. Deferasirox tablets contain the same active ingredient as deferasirox tablets for oral suspension. The following information is based on clinical trials conducted with deferasirox tablets for oral suspension. Transfusional Iron Overload The primary efficacy study, Study 1 (NCT00061750), was a multicenter, open-label, randomized, active-comparator control study to compare deferasirox tablets for oral suspension and deferoxamine in patients with beta-thalassemia and transfusional hemosiderosis. Patients greater than or equal to 2 years of age were randomized in a 1:1 ratio to receive either oral deferasirox tablets for oral suspension at starting doses of 5, 10, 20, or 30 mg/kg once daily or subcutaneous deferoxamine at starting doses of 20 to 60 mg/kg for at least 5 days per week based on LIC at baseline (2 to 3, greater than 3 to 7, greater than 7 to 14, and greater than 14 mg Fe/g dry weight). Patients randomized to deferoxamine who had LIC values less than 7 mg Fe/g dry weight were permitted to continue on their prior deferoxamine dose, even though the dose may have been higher than specified in the protocol. Patients were to have a liver biopsy at baseline and end of study (after 12 months) for LIC. The primary efficacy endpoint was defined as a reduction in LIC of greater than or equal to 3 mg Fe/g dry weight for baseline values greater than or equal to 10 mg Fe/g dry weight, reduction of baseline values between 7 and less than 10 to less than 7 mg Fe/g dry weight, or maintenance or reduction for baseline values less than 7 mg Fe/g dry weight. A total of 586 patients were randomized and treated, 296 with deferasirox tablets for oral suspension and 290 with deferoxamine. The mean age was 17.1 years (range, 2 to 53 years); 52% were females and 88% were Caucasian. The primary efficacy population consisted of 553 patients (deferasirox tablets for oral suspension n = 276; deferoxamine n = 277) who had LIC evaluated at baseline and 12 months or discontinued due to an adverse reaction. The percentage of patients achieving the primary endpoint was 52.9% for deferasirox tablets for oral suspension and 66.4% for deferoxamine. The relative efficacy of deferasirox to deferoxamine cannot be determined from this study. In patients who had an LIC at baseline and at end of study, the mean change in LIC was -2.4 mg Fe/g dry weight in patients treated with deferasirox tablets for oral suspension and -2.9 mg Fe/g dry weight in patients treated with deferoxamine. Reduction of LIC and serum ferritin was observed with deferasirox tablet for oral suspension doses of 20 to 30 mg/kg/day. Deferasirox tablets for oral suspension doses below 20 mg/kg/day failed to provide consistent lowering of LIC and serum ferritin levels (Figure 1). Therefore, a starting dose of 20 mg/kg/day is recommended [see Dosage and Administration (2.1 )] . Figure 1. Changes in Liver Iron Concentration and Serum Ferritin Following Deferasirox Tablets for Oral Suspension (5 to 30 mg/kg/day) in Study 1 Study 2 (NCT00061763) was an open-label, noncomparative trial of efficacy and safety of deferasirox tablets for oral suspension given for 1 year to patients with chronic anemias and transfusional hemosiderosis. Similar to Study 1, patients received 5, 10, 20, or 30 mg/kg/day of deferasirox tablets for oral suspension based on baseline LIC. A total of 184 patients were treated in this study: 85 patients with beta-thalassemia and 99 patients with other congenital or acquired anemias (myelodysplastic syndromes, n = 47; Diamond-Blackfan syndrome, n = 30; other, n = 22). Nineteen percent (19%) of patients were less than 16 years of age and 16% were greater than or equal to 65 years of age. There was a reduction in the absolute LIC from baseline to end of study (-4.2 mg Fe/g dry weight). Study 3 (NCT00067080) was a multicenter, open-label, randomized trial of the safety and efficacy of deferasirox tablets for oral suspension relative to deferoxamine given for 1 year in patients with sickle cell disease and transfusional hemosiderosis. Patients were randomized to deferasirox tablets for oral suspension at doses of 5, 10, 20, or 30 mg/kg/day or subcutaneous deferoxamine at doses of 20-60 mg/kg/day for 5 days per week according to baseline LIC. A total of 195 patients were treated in this study: 132 with deferasirox tablets for oral suspension and 63 with deferoxamine. Forty-four percent (44%) of patients were less than 16 years of age and 91% were black. At end of study, the mean change in LIC (as measured by magnetic susceptometry by a superconducting quantum interference device) in the per protocol-1 (PP-1) population, which consisted of patients who had at least 1 post-baseline LIC assessment, was -1.3 mg Fe/g dry weight for patients receiving deferasirox tablets for oral suspension (n = 113) and -0.7 mg Fe/g dry weight for patients receiving deferoxamine (n = 54). One-hundred five (105) patients with thalassemia major and cardiac iron overload were enrolled in a study assessing the change in cardiac magnetic resonance imaging (MRI) T2* value (measured in milliseconds, [ms]) before and after treatment with deferasirox. Cardiac T2* values at baseline ranged from 5 to less than 20 ms. The geometric mean of cardiac T2* in the 68 patients who completed 3 years of deferasirox tablets for oral suspension therapy increased from 11.98 ms at baseline to 17.12 ms at 3 years. Cardiac T2* values improved in patients with severe cardiac iron overload (less than 10 ms) and in those with mild to moderate cardiac iron overload (greater than or equal to 10 to less than 20 ms). The clinical significance of these observations is unknown. Six hundred twenty-seven (627) patients with MDS were enrolled across 5 uncontrolled trials. Two hundred thirty-nine of the 627 patients were enrolled in trials that limited enrollment to patients with IPSS Low or Intermediate 1 risk MDS, and the remaining 388 patients were enrolled in trials that did not specify MDS risk stratification but required a life expectancy of greater than 1 year. Planned duration of treatment in these trials ranged from 1 year (365 patients) to 5 years (47 patients). These trials evaluated the effects of deferasirox tablets for oral suspension therapy on parameters of iron overload, including LIC (125 patients) and serum ferritin (627 patients). The percent of patients completing planned duration of treatment was 51% in the largest 1-year study, 52% in the 3-year study and 22% in the 5-year study. The major causes for treatment discontinuation were withdrawal of consent, adverse reaction, and death. Over 1 year of follow-up across these pooled studies, mean change in serum ferritin was -332.8 (± 2615.59) mcg/L (n = 593) and mean change in LIC was -5.9 (± 8.32) mg Fe/g dw (n = 68). Results of these pooled studies in 627 patients with MDS suggest a progressive decrease in serum ferritin and LIC beyond 1 year in those patients who are able to continue deferasirox tablets for oral suspension. Study 4 (TELESTO; NCT 00940602) was a randomized, double-blind, placebo-controlled trial performed in 225 patients with MDS (Low/Int-1 risk) and transfusional iron overload of which 149 were treated with deferasirox and 76 received placebo. The observed hazard ratio of 0.64 (95% CI: 0.42, 0.96) suggests a positive impact of deferasirox on event-free survival (EFS, a composite endpoint defined as death, worsening cardiac function, hospitalization for congestive heart failure, liver function impairment, liver cirrhosis, or progression to acute myeloid leukemia; whichever occurred first). Non-Transfusion-Dependent Thalassemia Study 5 (NCT00873041) was a randomized, double-blind, placebo-controlled trial of treatment with deferasirox tablets for oral suspension for patients 10 years of age or older with NTDT syndromes and iron overload. Eligible patients had an LIC of at least 5 mg Fe/g dw measured by R2 MRI and a serum ferritin exceeding 300 mcg/L at screening (2 consecutive values at least 14 days apart from each other). A total of 166 patients were randomized, 55 to the deferasirox tablets for oral suspension 5 mg/kg/day dose group, 55 to the deferasirox tablets for oral suspension 10 mg/kg/day dose group, and 56 to placebo (28 to each matching placebo group). Doses could be increased after 6 months if the LIC exceeded 7 mg Fe/g dw and the LIC reduction from baseline was less than 15%. The patients enrolled included 89 males and 77 females. The underlying disease was beta-thalassemia intermedia in 95 (57%) patients, HbE beta-thalassemia in 49 (30%) patients, and alpha-thalassemia in 22 (13%) patients. There were 17 pediatric patients in the study. Caucasians comprised 57% of the study population and Asians comprised 42%. The median baseline LIC (range) for all patients was 12.1 (2.6 to 49.1) mg Fe/g dw. Follow-up was for 1 year. The primary efficacy endpoint of change in LIC from baseline to Week 52 was statistically significant in favor of both deferasirox dose groups compared with placebo (p less than or equal to 0.001) (Table 5). Furthermore, a statistically significant dose effect of deferasirox was observed in favor of the 10 mg/kg/day dose group (10 versus 5 mg/kg/day, p = 0.009). In a descriptive analysis, the target LIC (less than 5 mg Fe/g dw) was reached by 15 (27%) of 55 patients in the 10 mg/kg/day arm, 8 (15%) of 55 patients in the 5 mg/kg/day arm and 2 (4%) of 56 patients in the combined placebo groups. Study 6 (NCT00873041) was an open-label trial of deferasirox tablets for oral suspension for the treatment of patients previously enrolled on Study 5, including cross-over to active treatment for those previously treated with placebo. The starting dose of deferasirox tablets for oral suspension in Study 6 was assigned based on the patient’s LIC at completion of Study 5, being 20 mg/kg/day for an LIC exceeding 15 mg Fe/g dw, 10 mg/kg/day for LIC 3 to 15 mg Fe/g dw, and observation if the LIC was less than 3 mg Fe/g dw. Patients could continue on 5 mg/kg/day if they had previously exhibited at least a 30% reduction in LIC. Doses could be increased to a maximum of 20 mg/kg/day after 6 months if the LIC was more than 7 mg Fe/g dw and the LIC reduction from baseline was less than 15%. The primary efficacy endpoint in Study 6 was the proportion of patients achieving an LIC less than 5 mg Fe/g dw. A total of 133 patients were enrolled. Twenty patients began Study 6 with an LIC less than 5 mg Fe/g dw. Of the 113 patients with a baseline LIC of at least 5 mg Fe/g dw in Study 6, the target LIC (less than 5 mg Fe/g dw) was reached by 39 patients (35%). The responders included 4 (10%) of 39 patients treated at 20 mg/kg/day for a baseline LIC exceeding 15 mg Fe/g dw, and 31 (51%) of 61 patients treated at 10 mg/kg/day for a baseline LIC between 5 and 15 mg Fe/g dw. The absolute change in LIC at Week 52 by starting dose is shown in Table 5 below. Study 7 (NCT01709838) was an open-label, single-arm, multi-center, 5-year study to evaluate the efficacy and safety of deferasirox tablets for oral suspension in iron overloaded patients with NTDT of 10 years of age or older. All patients started treatment on 10 mg/kg/day deferasirox tablets for oral suspension for four weeks. At Week 4, dose escalation was based on baseline LIC. At Week 24 and every 6 months thereafter, further dose adjustments were made according to the LIC at that visit. Treatment was interrupted when LIC < 3 mg Fe/g dw or serum ferritin < 300 ng/mL and was re-started at 10 mg/kg/day when LIC ≥ 5 mg Fe/g dw and serum ferritin ≥ 300 ng/mL. Throughout the study, the maximum dose of deferasirox tablets for oral suspension given was 30 mg/kg/day. A total of 134 patients were enrolled in the study. Eligible patients were required to have an LIC of at least 5 mg Fe/g dw measured by R2 MRI and a serum ferritin at least of 300 ng/mL at screening. The mean absolute change of LIC from Baseline to Week 52 was -6.7 mg Fe/g dw. The reduction in LIC was sustained until Week 260 (5 years) with the mean absolute change in LIC from Baseline to Week 260 of -10.6 mg Fe/g dw. In the subset of patients with Baseline LIC > 15 mg Fe/g dw (49 patients), 51.0% achieved a first LIC < 5 mg Fe/g dw (95% CI: 37.5, 64.4) with a median time of 28.6 months. In the subset of patients with target LIC of < 3 mg Fe/g dw (61 patients), 39.3% developed first LIC ≥ 5 mg Fe/g dw in the follow-up period, with a median time of 13.9 months. Table 5. Absolute Change in LIC at Week 52 in Patients with NTDT Deferasirox Tablets for Oral Suspension Starting Dose 1 Placebo 5 mg/kg/day 10 mg/kg/day 20 mg/kg/day Study 5 2 Number of Patients n = 54 n = 51 n = 54 - Mean LIC at Baseline (mg Fe/g dw) 16.1 13.4 14.4 - Mean Change (mg Fe/g dw) +0.4 -2.0 -3.8 - (95% Confidence Interval) (-0.6, +1.3) (-2.9, -1.0) (-4.8, -2.9) - Study 6 Number of Patients - n = 8 n = 77 n = 43 Mean LIC at Baseline (mg Fe/g dw) - 5.6 8.8 23.5 Mean Change (mg Fe/g dw) - -1.5 -2.8 -9.1 (95% Confidence Interval) - (-3.7, +0.7) (-3.4, -2.2) (-11.0, -7.3) Study 7 Number of Patients - - n = 127 - Mean LIC at Baseline (mg Fe/g dw) - - 15.1 - Mean Change (mg Fe/g dw) - - -6.7 - (95% Confidence Interval) - - (-7.9, -5.5) - Abbreviation: LIC, liver iron concentration; NTDT, non-transfusion-dependent thalassemia. 1 Randomized dose in Study 5 or assigned starting dose in Study 6 and Study 7. 2 Least square mean change for Study 5

Risk Summary There are no studies with the use of deferasirox tablets in pregnant women to inform drug-associated risks. Administration of deferasirox to rats during pregnancy resulted in decreased offspring viability and an increase in renal anomalies in male offspring at doses that were about or less than the recommended human dose on a mg/m 2 basis. No fetal effects were noted in pregnant rabbits at doses equivalent to the human recommended dose on an mg/m 2 basis. Deferasirox tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies had a background risk of birth defect, loss, or other adverse outcomes. However, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data In embryo-fetal developmental studies, pregnant rats and rabbits received oral deferasirox during the period of organogenesis at doses up to 100 mg/kg/day in rats and 50 mg/kg/day in rabbits (1.2 times the maximum recommended human dose (MRHD) on an mg/m 2 basis). These doses resulted in maternal toxicity but no fetal harm was observed. In a prenatal and postnatal developmental study, pregnant rats received oral deferasirox daily from organogenesis through lactation day 20 at doses of 10, 30, and 90 mg/kg/day (0.1, 0.3, and 1.0 times the MRHD on a mg/m 2 basis). Maternal toxicity, loss of litters, and decreased offspring viability occurred at 90 mg/kg/day (1.0 times the MRHD on a mg/m 2 basis), and increases in renal anomalies in male offspring occurred at 30 mg/kg/day (0.3 times the MRHD on a mg/m 2 basis).

Deferasirox tablets are indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older.

Deferasirox Tablets (dee fer′ a sir ox) What is the most important information I should know about deferasirox tablets? Deferasirox tablets can cause serious side effects, including: Kidney problems: Deferasirox tablets can cause sudden (acute) kidney problems, including kidney failure that may require treatment with dialysis, and may cause death. Deaths have happened mostly in people who also have other health problems and had a blood disorder that was in an advanced stage. Adults and children who already have kidney problems and are taking certain medicines with deferasirox tablets may also have an increased risk of sudden kidney problems. Be sure to tell your healthcare provider about all the medicines you take during treatment with deferasirox tablets. Your healthcare provider should do blood and urine tests to check your or your child’s kidney function before and during treatment with deferasirox tablets. Call your healthcare provider right away if: your child becomes sick with fever, vomiting, or diarrhea and cannot drink fluids normally during treatment with deferasirox tablets. Your child may be dehydrated. Your healthcare provider may need to temporarily stop treatment with deferasirox tablets and treat your child for dehydration to help prevent kidney problems. Your healthcare provider may monitor your child’s kidney function more closely. you notice that you or your child are passing less urine than usual during treatment with deferasirox tablets. Liver problems. Deferasirox tablets can cause liver problems, including liver failure that can sometimes cause death. Liver problems with deferasirox tablets may be more common in people who are over 55 years of age but can also happen in children. Liver failure has happened more often in people with cirrhosis of the liver and failure of other organs. Liver failure has also happened along with kidney problems in certain children who become dehydrated. See “Kidney problems” above. Your healthcare provider should do blood tests to check your liver function before you start and regularly during treatment with deferasirox tablets. Call your healthcare provider right away, if you develop any of the following signs and symptoms: drowsiness yellowing or increased yellowing of your skin or eyes upper right stomach-area (abdomen) pain dark urine Bleeding, ulcers, and tears of the stomach or intestine. Severe stomach and intestine bleeding (hemorrhage) that have caused death have happened in some people treated with deferasirox tablets, especially in elderly people who have advanced blood cancers or low platelet counts. Some people have also had ulcers of the stomach or intestine, sometimes with tears (perforation) that have caused death. In some people who have taken deferasirox tablets, including children and adolescents, irritation of the upper gastrointestinal tract, ulcers, and bleeding have happened, but did not cause death. Your risk of severe bleeding (hemorrhage) may be increased if you take deferasirox tablets along with other medicines that can cause ulcers or bleeding, such as: nonsteroidal anti-inflammatory drugs (NSAIDs) certain osteoporosis medicines called oral bisphosphonates corticosteroids blood thinner medicines Before you start taking deferasirox tablets, tell your healthcare provider if you are taking one of these medicines. Ask your healthcare provider if you are not sure. If you develop an ulcer of the stomach or intestine, or severe bleeding, your healthcare provider may stop deferasirox tablets. Elderly people may be at a higher risk of developing serious side effects and death due to serious side effects with deferasirox tablets. Your healthcare provider may need to monitor you more closely during treatment with deferasirox tablets. Tell your healthcare provider if you get heartburn during treatment with deferasirox tablets. Get emergency medical help right away if you vomit blood or pass black or bloody stools, or if you have severe stomach-area (abdomen) pain during treatment with deferasirox tablets. See “What are the possible side effects of deferasirox tablets?” for more information about side effects. What are deferasirox tablets? Deferasirox tablets are prescription medicines that are used to treat: people 2 years of age and older who have an increased amount of iron in their blood for a long period of time (chronic), caused by repeated blood transfusions certain people 10 years of age or older with thalassemia who have an increased amount of iron in their blood but who are not receiving regular blood transfusions It is not known if deferasirox tablets are safe and effective when used with other medicines to treat an increased amount of iron in the blood. It is not known if deferasirox tablets are safe and effective for treating children under 2 years of age who have an increased amount of iron in their blood for a long period of time (chronic) caused by repeated blood transfusions. It is not known if deferasirox tablets are safe and effective for treating children under 10 years of age with thalassemia who have an increased amount of iron in their blood, but who are not receiving regular blood transfusions. Do not take deferasirox tablets if you: have certain kidney problems have high-risk myelodysplastic syndrome (MDS) have advanced cancer have a low platelet count are allergic to deferasirox or any of the ingredients in deferasirox tablets. See the end of this medication guide for a list of the ingredients in deferasirox tablets. Ask your healthcare provider if you are not sure if you have any of the medical conditions listed above. Before taking deferasirox tablets tell your healthcare provider about all of your medical conditions, including if you: have kidney problems have liver problems have advanced cancer. See “Do not take deferasirox tablets if you?” have a blood disorder that may increase your risk for bleeding are pregnant or plan to become pregnant. It is not known if deferasirox tablets can harm your unborn baby. Hormonal forms of birth control may not be as effective if used during treatment with deferasirox tablets. You could become pregnant. Talk to your healthcare provider about other birth control options that you can use during this time. Tell your healthcare provider right away if you become pregnant during treatment with deferasirox tablets. are breastfeeding or plan to breastfeed. It is not known if deferasirox tablets pass into your breast milk and can harm your baby. You and your healthcare provider should decide if you will take deferasirox tablets or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take , including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements. Some medicines may affect how deferasirox tablets works, and deferasirox tablets may affect how other medicines work. Also, your risk of sudden kidney problems or severe bleeding may be increased if you take deferasirox tablets with certain medicines. See ‘What is the most important information I should know about deferasirox tablets?” Avoid taking the following medicines during treatment with deferasirox tablets: antacid products (medicines used to treat heartburn) that contain aluminum theophylline certain medicines to lower your cholesterol, called bile acid sequestrants. Ask your healthcare provider if you are not sure if you take one of these medicines. Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine. How should I take deferasirox tablets? Take deferasirox tablets exactly as your healthcare provider tells you. Do not change your dose of deferasirox tablets or stop taking unless your healthcare provider tells you to. Deferasirox tablets comes as tablets. You may take deferasirox tablets on an empty stomach or with a light meal. Examples of a light meal include: 1 whole wheat English muffin, 1 packet of jelly (0.5 ounce), and skim milk (8 fluid ounces), or A turkey sandwich (2 ounces of turkey on whole wheat bread with lettuce, tomato, and 1 packet of mustard) Taking deferasirox tablets: Take deferasirox tablets by mouth with water or other liquids 1 time every day, preferably at the same time every day. If you have trouble swallowing the tablets whole, you may crush deferasirox tablets and mix them with soft foods such as yogurt or applesauce right before taking your dose. Take the dose right away. Do not save any of the deferasirox tablets and soft food mixture for later use. Do not use store-bought pill crushers with serrated surfaces for crushing deferasirox tablets 90 mg tablets. Do not take deferasirox tablets with aluminum-containing antacid products. See “Before taking deferasirox tablets” Tell your healthcare provider if you or your child gain or lose any weight. Your or your child’s dose of deferasirox tablets may need to be adjusted. If you take the diabetes medicine repaglinide during treatment with deferasirox tablets you may need to test your blood sugar (glucose) levels more often. Follow your healthcare provider’s instructions about how often to test your blood sugar during this time. Your healthcare provider should do blood and urine tests before, and during treatment to check how you respond to deferasirox tablets, and to monitor you for side effects. Your healthcare provider may change your dose, or temporarily or permanently stop deferasirox tablets if you have certain side effects. In people who have thalassemia, your healthcare provider will check the amount of iron in your liver before and during treatment with deferasirox tablets. If you or your child take too much deferasirox tablets, call your healthcare provider right away or go to the nearest hospital emergency room. Symptoms that can happen if you take too much deferasirox tablets include: stomach-area (abdominal) pain, diarrhea, nausea and vomiting. What should I avoid while taking deferasirox tablets? Deferasirox tablets may cause dizziness. Avoid driving or operating machinery until you know how deferasirox tablets affect you. Do not drive or operate machinery if deferasirox tablets make you dizzy. What are the possible side effects of deferasirox tablets? Deferasirox tablets can cause serious side effects, including: See “What is the most important information I should know about deferasirox tablets?” Effects on your bone marrow. Deferasirox tablets can affect your bone marrow and cause you to have low white blood cell count which can be serious, decreased platelets, or worsening of your anemia, and may lead to death. Your risk for effects on your bone marrow may be increased if you already have other blood disorders. Your healthcare provider will do blood tests to monitor your blood cell counts for these problems. Serious allergic reactions. Deferasirox tablets may cause serious allergic reactions, which usually start within the first month of treatment. Get medical help right away if you develop any of the following symptoms of a serious allergic reaction including: difficulty in breathing or swallowing swelling of the face, lips, mouth, tongue, or throat chest pain severe itching of the skin with a red rash or raised bumps rapid heartbeat feeling faint hives Skin rash and severe skin reactions. Skin rashes are common with deferasirox tablets. If you get a more severe rash, your healthcare provider may temporarily stop deferasirox tablets. Severe skin reactions can also happen with deferasirox tablets and can be life-threatening or lead to death. Get medical help right away if you develop any one or more of the following signs and symptoms of a severe skin reaction, including: rash or red skin skin peeling blisters on your lips, or around your mouth or eyes high fever or flu-like symptoms mouth sores enlarged lymph nodes Hearing and vision problems. Deferasirox tablets can cause decreased hearing and changes in your vision including cataracts, increased pressure in your eye, and problems with your retinas. Your healthcare provider should do hearing and vision tests before you start and then regularly during treatment. Your healthcare provider may decrease your dose or stop deferasirox tablets if you develop hearing or vision problems. The most common side effects in anyone who takes deferasirox tablets include: diarrhea and nausea. Other common side effects in people with too much iron in their blood due to repeated blood transfusions include: vomiting, stomach-area (abdomen) pain, and an abnormal kidney function blood test. These are not all the possible side effects of deferasirox tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store deferasirox tablets? Store deferasirox tablets at room temperature between 68°F to 77°F (20°C to 25°C). Keep the bottle closed tightly and away from moisture . Keep deferasirox tablets and all medicines out of the reach of children. General information about the safe and effective use of deferasirox tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use deferasirox tablets for a condition for which it was not prescribed. Do not give it to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for more information about deferasirox tablets. What are the ingredients in deferasirox tablets? Deferasirox tablets: Active ingredient: deferasirox Inactive ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, poloxamer and povidone. The film coating contains hypromellose, FD & C Blue No. 2, polyethylene glycol, talc and titanium dioxide. Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 For more information, call 1-800-818-4555. This Medication Guide has been approved by the U.S. Food and Drug Administration. Rev. 09/2024

Deferasirox tablets 90 mg tablets are light blue oval biconvex film-coated tablet with beveled edges, debossed with ‘S102’ on one side and plain on the other side. Deferasirox tablets 180 mg tablets are medium blue oval biconvex film-coated tablet with beveled edges, debossed with ‘S103’ on one side and plain on the other side. Deferasirox tablets 360 mg tablets are dark blue oval biconvex film-coated tablet with beveled edges, debossed with ‘S104’ on one side and plain on the other side.

Deferasirox is an orally active chelator that is selective for iron (as Fe 3+ ). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Although deferasirox has very low affinity for zinc and copper, there are variable decreases in the serum concentration of these trace metals after the administration of deferasirox. The clinical significance of these decreases is uncertain.

Pharmacodynamic effects tested in an iron balance metabolic study with the tablet for oral suspension formulation showed that deferasirox (10, 20, and 40 mg/kg/day) was able to induce a mean net iron excretion (0.119, 0.329, and 0.445 mg Fe/kg body weight/day, respectively) within the clinically relevant range (0.1 to 0.5 mg/kg/day). Iron excretion was predominantly fecal. An analysis of pooled pediatric clinical trial data found a statistically significant relationship between exposure and the probability of renal toxicity (increase in serum creatinine and urinary protein), resulting in a decrease in renal function. Decreases in renal function resulted in an increase in deferasirox exposure which may increase the probability of renal toxicity. Cardiac Electrophysiology At the maximum approved recommended dose, deferasirox does not prolong the QT interval to any clinically relevant extent.

Absorption Based on studies in patients with the tablet for oral suspension, deferasirox is absorbed following oral administration with median times to maximum plasma concentration (T max ) of about 1.5 to 4 hours. In healthy subjects, deferasirox tablets showed comparable T max . The maximal concentrations (C max ) and area under the curve (AUC 0-24h , AUC τ ) of deferasirox increase approximately linearly with dose after both single administration and under steady-state conditions. Exposure to deferasirox increased by an accumulation factor of 1.3 to 2.3 after multiple doses with the tablet for oral suspension formulation. Tablets The absolute bioavailability [as measured by area under the curve over time to infinity (AUC inf )] of deferasirox tablets for oral suspension is 70% compared to an intravenous dose. The bioavailability (as measured by AUC inf ) of deferasirox tablets was 36% greater than with deferasirox tablets for oral suspension. After strength-adjustment, the mean AUC inf of deferasirox tablets (i.e., 360 mg strength) was similar to that of deferasirox tablets for oral suspension (i.e., 500 mg strength) under fasting conditions; however the mean C max was increased by 30%. The 30% increase in C max observed with deferasirox tablets is not clinically meaningful. The administration of deferasirox tablets with a light meal (approximately 250 calories with fat content less than 7% of total calories) indicated that the AUC inf and C max were similar to that under fasting conditions. The administration of deferasirox tablets with a high-fat meal (approximately 1,000 calories with fat content greater than 50% of total calories), increased AUC inf by 18% and C max by 29% compared to that under fasting conditions [see Dosage and Administration (2.3) ]. Distribution Deferasirox is highly (~99%) protein bound almost exclusively to serum albumin. The percentage of deferasirox confined to the blood cells was 5% in humans. The volume of distribution at steady state (V ss ) of deferasirox is 14.37 ± 2.69 L in adults. Metabolism Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion. Deconjugation of glucuronidates in the intestine and subsequent reabsorption (enterohepatic recycling) is likely to occur. Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450-catalyzed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). Deconjugation of glucuronide metabolites in the intestine and subsequent reabsorption (enterohepatic recycling) was confirmed in a healthy subjects study in which the administration of cholestyramine 12 g twice daily (strongly binds to deferasirox and its conjugates) 4 and 10 hours after a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC inf ) by interfering with the enterohepatic recycling of deferasirox. Excretion Deferasirox and metabolites are primarily (84% of the dose) excreted in the feces. Renal excretion of deferasirox and metabolites is minimal (8% of the dose). The mean elimination half-life (t 1/2 ) ranged from 8 to 16 hours following oral administration. Drug Interactions Midazolam: The concomitant administration of deferasirox tablets for oral suspension and CYP3A4 probe substrate midazolam resulted in a decrease of midazolam C max by 23% and AUC inf by 17%. In the clinical setting, this effect may be more pronounced, as the study was not adequately designed to conclusively assess the potential induction of CYP3A4 by deferasirox [see Drug Interactions (7.2) ] . Repaglinide: The concomitant administration of deferasirox tablets for oral suspension (30 mg/kg/day for 4 days) and the CYP2C8 probe substrate repaglinide (single dose of 0.5 mg) increased repaglinide AUC inf to 2.3-fold and C max of 1.6-fold [see Drug Interactions (7.3) ] . Theophylline: The concomitant administration of deferasirox tablets for oral suspension (repeated dose of 30 mg/kg/day) and the CYP1A2 substrate theophylline (single dose of 120 mg) resulted in an approximate doubling of the theophylline AUC inf and elimination half-life. The single dose C max was not affected, but an increase in theophylline C max is expected to occur with chronic dosing [see Drug Interactions (7.4) ] . Rifampicin: The concomitant administration of deferasirox tablets for oral suspension (single dose of 30 mg/kg) and the strong uridine diphosphate glucuronosyltransferase (UGT) inducer rifampicin (600 mg/day for 9 days) decreased deferasirox AUC inf by 44% [see Drug Interactions (7.5) ] . Cholestyramine: The concomitant administration of cholestyramine after a single dose of deferasirox tablets for oral suspension decreased deferasirox AUC inf by 45% [see Drug Interactions (7.6) ] . Busulfan : Concomitant administration of deferasirox and busulfan resulted in an increase of busulfan exposure (AUC). In vitro Studies: Deferasirox inhibited human CYP2A6, CYP2D6, and CYP2C19 in vitro . Deferasirox is not a substrate of P-glycoprotein, MRP1 or MRP2. Pharmacokinetics in Specific Populations Pediatric: Following oral administration of single or multiple doses, systemic exposure of adolescents and children to deferasirox was less than in adult patients. In children less than 6 years of age, systemic exposure was about 50% lower than in adults. Sex: The apparent clearance is 17.5% lower in females compared to males. Renal Impairment : Compared to patients with MDS and eGFR greater than 60 mL/min/1.73 m 2 , patients with MDS and eGFR 40 to 60 mL/min/1.73 m 2 (n = 34) had approximately 50% higher mean deferasirox trough plasma concentrations. Hepatic Impairment: In a single dose (20 mg/kg) study in patients with varying degrees of hepatic impairment, deferasirox exposure was increased compared to patients with normal hepatic function. The average total (free and bound) AUC inf of deferasirox increased 16% in 6 patients with mild (Child-Pugh A) hepatic impairment, and 76% in 6 patients with moderate (Child-Pugh B) hepatic impairment compared to 6 patients with normal hepatic function. The impact of severe (Child-Pugh C) hepatic impairment was assessed in only 1 patient.

Lactation: Advise women not to breastfeed. (8.2)

Acute Kidney Injury: Measure serum creatinine in duplicate before starting therapy. Monitor renal function during deferasirox tablets 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 (GI) Bleeding, Ulceration, and Irritation: Risk may be greater in patients who are taking deferasirox tablets 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 tablets 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 tablets for severe reactions 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 tablets. (5.8)

Package Label – 90mg

Risk Summary No data are available regarding the presence of deferasirox tablets 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.

Contraception Counsel patients to use non-hormonal method(s) of contraception since deferasirox tablets can render hormonal contraceptives ineffective [see Drug Interactions (7.2) ] .

Renal Failure Deferasirox tablets 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 tablets dosing in all patients. Deferasirox tablets are 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 , 2.4 , 2.5 ), Warnings and Precautions ( 5.1 ), Adverse Reactions ( 6.1 , 6.2 )] . Hepatic Failure Deferasirox tablets 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 tablets 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 tablets 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 tablets for suspected GI ulceration or hemorrhage [see Warnings and Precautions ( 5.3 )].

Deferasirox tablets 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 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 (Fe/g dw) and a serum ferritin greater than 300 mcg/L. (1.2) Limitations of Use: The safety and efficacy of deferasirox tablets when administered with other iron chelation therapy have not been established. ( 1.3 )

Transfusional Iron Overload: Initial dose for patients with estimated glomerular filtration rate (eGFR) greater than 60 mL/min/1.73 m 2 is 14 mg/kg (calculated to nearest whole tablet) once daily. (2.1) NTDT Syndromes: Initial dose for patients with eGFR greater than 60 mL/min/1.73 m 2 is 7 mg/kg (calculated to nearest whole tablet) once daily. (2.2) See full prescribing information for information regarding monitoring, administration, and dose-reductions for organ impairment. (2.1 , 2.2 , 2.3 , 2.4)

Deferasirox tablets 90 mg are light blue oval biconvex film-coated tablets with beveled edges, debossed with ‘S102’ on one side and plain on the other side. They are available in bottles of 30 tablets (NDC 57664-768-83). Deferasirox tablets 180 mg are medium blue oval biconvex film-coated tablets with beveled edges, debossed with ‘S103’ on one side and plain on the other side. They are available in bottles of 30 tablets (NDC 57664-769-83). Deferasirox tablets 360 mg are dark blue oval biconvex film-coated tablets with beveled edges, debossed with ‘S104’ on one side and plain on the other side. They are available in bottles of 30 tablets (NDC 57664-770-83). Store deferasirox tablets at 20°C-25°C (68°F-77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from moisture.

Deferasirox tablets are 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 tablets [see Warnings and Precautions (5.7) , Adverse Reactions (6.2) ] .

Do not take deferasirox tablets with aluminum-containing antacid preparations. (7.1) Deferasirox increases the exposure of repaglinide. Consider repaglinide dose reduction and monitor blood glucose levels. (7.3) Avoid the use of deferasirox tablets with theophylline as theophylline levels could be increased. (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)

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Dosing Instructions Advise patients to take deferasirox tablets with water or other liquids. Advise patients to swallow deferasirox tablets once daily with water or other liquids, preferably at the same time each day. Advise patients to take deferasirox tablets 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). For patients who have difficulty swallowing whole tablets, deferasirox tablets may be crushed and mixed with soft foods (e.g., yogurt or applesauce) immediately prior to use and administered orally. Advise against the use of commercial crushers with serrated surfaces for crushing a single 90 mg tablet. Advise patients to immediately and completely consume the dose and not store it for future use [see Dosage and Administration (2.3) ]. Blood Testing Advise patients that blood tests will be performed frequently to check for damage to kidneys, liver, or blood cells [ see Warnings and Precautions (5.1 , 5.2 , 5.3 , 5.4 , 5.5) ]. Acute Kidney Injury, Including Acute Renal Failure Caution patients about the potential for kidney toxicity when taking deferasirox tablets. Inform patients of the signs and symptoms of kidney injury. Advise patients to contact their healthcare provider immediately if they experience any of these symptoms [see Warnings and Precautions (5.1) ] . Hepatic Toxicity and Failure Caution patients about the potential for hepatic toxicity when taking deferasirox tablets. Inform patients of the signs and symptoms of hepatic toxicity. Advise patients to contact their healthcare provider immediately if they experience any of these symptoms [see Warnings and Precautions (5.2) ] . GI Ulceration and Hemorrhage Caution patients about the potential for the development of GI ulcers or bleeding when taking deferasirox tablets in combination with drugs that have ulcerogenic or hemorrhagic potential, such as NSAIDs, corticosteroids, oral bisphosphonates, or anticoagulants. Inform patients of the signs and symptoms of GI ulcers or bleeding. Advise patients to contact their healthcare provider for symptoms of heartburn but to seek immediate medical attention for symptoms of GI hemorrhage [see Warnings and Precautions (5.3) ]. Allergic Reactions Serious allergic reactions (which include swelling of the throat) have been reported in patients taking deferasirox tablets, usually within the first month of treatment. If reactions are severe, advise patients to stop taking deferasirox tablets immediately and seek immediate medical attention [see Warnings and Precautions (5.7) ]. Severe Skin Reactions Severe skin reactions have been reported in patients taking deferasirox tablets. Inform patients of the signs and symptoms of severe skin reactions. If reactions are severe, advise patients to stop taking deferasirox tablets immediately and seek immediate medical attention [see Warnings and Precautions (5.8) ] . Skin Rash Skin rashes may occur during deferasirox tablets treatment. If the skin rash is severe, advise patients to stop taking deferasirox tablets and seek medical attention [ see Warnings and Precautions (5.9) ]. Pediatric Patients with Acute Illness Instruct pediatric patients and their caregivers to contact their healthcare provider during episodes of acute illness, especially if the patient has not been drinking fluids or the patient has volume depletion due to fever, vomiting, or diarrhea [see Warnings and Precautions (5.1) ] . Auditory and Ocular Testing Because auditory and ocular disturbances have been reported with deferasirox, conduct auditory testing and ophthalmic testing before starting deferasirox tablets treatment and thereafter at regular intervals. Advise patients to contact their healthcare provider if they develop visual or auditory changes during treatment [see Warnings and Precautions (5.10) ]. Drug Interactions Caution patients not to take aluminum containing antacids and deferasirox tablets simultaneously [see Drug Interactions (7.1) ]. Caution patients about potential loss of effectiveness of drugs metabolized by CYP3A4 (e.g., cyclosporine, simvastatin, hormonal contraceptive agents) when deferasirox tablets are administered with these drugs [see Drug Interactions (7.2) ]. Caution patients about potential loss of effectiveness of deferasirox tablets when administered with drugs that are potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir). Based on serum ferritin levels and clinical response, consider increases in the dose of deferasirox tablets when concomitantly used with potent UGT inducers [see Drug Interactions (7.5) ]. Caution patients about potential loss of effectiveness of deferasirox tablets when administered with drugs that are bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol). Based on serum ferritin levels and clinical response, consider increases in the dose of deferasirox tablets when concomitantly used with bile acid sequestrants [see Drug Interactions (7.6) ]. Caution patients with diabetes to monitor their glucose levels more frequently when repaglinide is used concomitantly with deferasirox tablets [see Drug Interactions (7.3) ] . Handling Instructions Advise patients to store deferasirox tablets in a dry, room-temperature environment [see How Supplied/Storage and Handling (16) ]. Driving and Using Machines Caution patients experiencing dizziness to avoid driving or operating machinery [see Adverse Reactions (6.1) ]. For more information, call Sun Pharmaceutical Industries, Inc. at 1-800-406-7984. Dispense with Medication Guide available at: www.sunpharma.com/usa/products All trademarks are the property of their respective owners. Manufactured by: ALKALOIDA Chemical Company Zrt. 4440 Tiszavasvári, Kabay János u. 29. Hungary Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 Rev. 09/2024

Transfusional Iron Overload The safety and effectiveness of deferasirox tablets have been established in pediatric patients 2 years of age and older for the treatment of transfusional iron overload [ see Dosage and Administration (2.1) ] . Safety and effectiveness have not been established in pediatric patients less than 2 years of age for the treatment of transfusional iron overload. Pediatric approval for treatment of transfusional iron overload was based on clinical studies of 292 pediatric patients 2 years to less than 16 years of age with various congenital and acquired anemias. Seventy percent of these patients had beta-thalassemia [see Indications and Usage (1) , Dosage and Administration (2.1) , Clinical Studies (14) ] . In those clinical studies, 173 children (ages 2 to < 12 years) and 119 adolescents (ages 12 to < 17 years) were exposed to deferasirox. A trial conducted in treatment naïve pediatric patients, 2 to < 18 years of age with transfusional iron overload (NCT02435212) did not provide additional relevant information about the safety or effectiveness of the deferasirox granules dosage form compared to the deferasirox oral tablets for suspension dosage form. Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes The safety and effectiveness of deferasirox tablets have been established in patients 10 years of age and older for the treatment of chronic iron overload with non-transfusion-dependent thalassemia (NTDT) syndromes [see Dosage and Administration (2.2) ] . Safety and effectiveness have not been established in patients less than 10 years of age with chronic iron overload in NTDT syndromes. Pediatric approval for treatment of NTDT syndromes with liver iron (Fe) concentration (LIC) of at least 5 mg Fe/g of dry weight and a serum ferritin greater than 300 mcg/L was based on 16 pediatric patients treated with deferasirox therapy (10 years to less than 16 years of age) with chronic iron overload and NTDT. Use of deferasirox tablets in these age groups is supported by evidence from adequate and well-controlled studies of deferasirox in adult and pediatric patients [see Indications and Usage (1.2) , Dosage and Administration (2.2) , Clinical Studies (14) ] . In general, risk factors for deferasirox-associated kidney injury include preexisting renal disease, volume depletion, overchelation, and concomitant use of other nephrotoxic drugs. Acute kidney injury, and acute liver injury and failure has occurred in pediatric patients. In a pooled safety analysis, pediatric patients with higher deferasirox exposures had a greater probability of renal toxicity and decreased renal function, resulting in increased deferasirox exposure and progressive renal toxicity/kidney injury. Higher rates of renal AEs have been identified among pediatric patients receiving deferasirox tablets for oral suspension doses greater than 25 mg/kg/day equivalent to 17.5 mg/kg/day deferasirox tablets when their serum ferritin values were less than 1,000 mcg/L [see Dosage and Administration (2.5) , Warnings and Precautions (5.1 , 5.6) , Adverse Reactions (6.1 , 6.2) ] . Monitoring recommendations for all pediatric patients with Transfusional Iron Overload and NTDT It is recommended that serum ferritin be monitored every month to assess the patient’s response to therapy and to minimize the risk of overchelation [see Warnings and Precautions (5.6) ] . Monitor renal function by estimating GFR using an eGFR prediction equation appropriate for pediatric patients and evaluate renal tubular function. Monitor renal function more frequently in pediatric patients in the presence of renal toxicity risk factors, including episodes of dehydration, fever and acute illness that may result in volume depletion or decreased renal perfusion. Use the minimum effective dose [see Warnings and Precautions (5.1) ] . Interrupt deferasirox tablets in pediatric patients with transfusional iron overload, and consider dose interruption in pediatric patients with non-transfusion-dependent iron overload, 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. Evaluate the risk benefit profile of continued deferasirox tablets use in the setting of decreased renal function. Avoid use of other nephrotoxic drugs [ see Dosage and Administration (2.5) , Warnings and Precautions (5.1) ]. Juvenile Animal Toxicity Data Renal toxicity was observed in adult mice, rats, and marmoset monkeys administered deferasirox at therapeutic doses. In a neonatal and juvenile toxicity study in rats, deferasirox was administered orally from postpartum Day 7 through 70, which equates to a human age range of term neonate through adolescence. Increased renal toxicity was identified in juvenile rats compared to adult rats at a dose based on mg/m 2 approximately 0.4 times the recommended dose of 20 mg/kg/day. A higher frequency of renal abnormalities was noted when deferasirox was administered to non-iron overloaded animals compared to iron overloaded animals.

Four hundred thirty-one (431) patients greater than or equal to 65 years of age were studied in clinical trials of deferasirox in the transfusional iron overload setting. Two hundred twenty-five (225) of these patients were between 65 and 75 years of age while 206 were greater than or equal to 75 years of age. The majority of these patients had myelodysplastic syndrome (MDS) (n = 393). In these trials, elderly patients experienced a higher frequency of adverse reactions than younger patients. Monitor elderly patients for early signs or symptoms of adverse reactions that may require a dose adjustment. Elderly patients are at increased risk for toxicity due to the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range. In elderly patients, including those with MDS, individualize the decision to remove accumulated iron based on clinical circumstances and the anticipated clinical benefit and risks of deferasirox tablets for oral suspension therapy.

A 104-week oral carcinogenicity study in Wistar rats showed no evidence of carcinogenicity from deferasirox at doses up to 60 mg/kg/day (0.7 times the MRHD on a mg/m 2 basis). A 26-week oral carcinogenicity study in p53 (+/-) transgenic mice has shown no evidence of carcinogenicity from deferasirox at doses up to 200 mg/kg/day (1.2 times the MRHD on a mg/m 2 basis) in males and 300 mg/kg/day (1.7 times the MRHD on a mg/m 2 basis) in females. Deferasirox was negative in the Ames test and chromosome aberration test with human peripheral blood lymphocytes. It was positive in 1 of 3 in vivo oral rat micronucleus tests. Deferasirox at oral doses up to 75 mg/kg/day (0.9 times the MRHD on a mg/m 2 basis) was found to have no adverse effect on fertility and reproductive performance of male and female rats.

The following clinically significant adverse reactions are also discussed in other sections of the labeling: Acute Kidney Injury, Including Acute Renal Failure Requiring Dialysis, and Renal Tubular Toxicity Including Fanconi Syndrome [ see Warnings and Precautions ( 5.1 , 5.6 ) ] Hepatic Toxicity and Failure [see Warnings and Precautions ( 5.2 , 5.6 )] GI Hemorrhage [see Warnings and Precautions (5.3) ] Bone Marrow Suppression [see Warnings and Precautions (5.4) ] Hypersensitivity [see Warnings and Precautions (5.7) ] Severe Skin Reactions [see Warnings and Precautions (5.8) ] Skin Rash [see Warnings and Precautions (5.9) ] Auditory and Ocular Abnormalities [see Warnings and Precautions (5.10) ]

Cases of overdose (2 to 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 of deferasirox up to 80 mg/kg/day with the tablet for oral suspension formulation in iron-overloaded beta-thalassemic patients have been tolerated with nausea and diarrhea noted. In healthy subjects, single doses of up to 40 mg/kg/day with the tablet for oral suspension formulation were tolerated. 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 tablets. In case of overdose, it may be treated with induction of vomiting or gastric lavage, and by symptomatic treatment.

Deferasirox is an iron-chelating agent provided as a tablet for oral use. Deferasirox is designated chemically as 4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoic acid and has the following structural formula: Deferasirox is a white to slightly yellow powder. It has a molecular formula C 21 H 15 N 3 O 4 and molecular weight of 373.4 g/mol. It is insoluble in water with a pH of suspension of 4.1. Deferasirox tablets contain 90 mg, 180 mg, or 360 mg deferasirox. Inactive ingredients include colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, poloxamer and povidone. The film coating contains hypromellose, FD & C Blue No. 2, polyethylene glycol, talc and titanium dioxide.

Deferasirox tablets were evaluated in healthy subjects. There are no clinical data in patients with deferasirox tablets. Deferasirox tablets contain the same active ingredient as deferasirox tablets for oral suspension. The following information is based on clinical trials conducted with deferasirox tablets for oral suspension. Transfusional Iron Overload The primary efficacy study, Study 1 (NCT00061750), was a multicenter, open-label, randomized, active-comparator control study to compare deferasirox tablets for oral suspension and deferoxamine in patients with beta-thalassemia and transfusional hemosiderosis. Patients greater than or equal to 2 years of age were randomized in a 1:1 ratio to receive either oral deferasirox tablets for oral suspension at starting doses of 5, 10, 20, or 30 mg/kg once daily or subcutaneous deferoxamine at starting doses of 20 to 60 mg/kg for at least 5 days per week based on LIC at baseline (2 to 3, greater than 3 to 7, greater than 7 to 14, and greater than 14 mg Fe/g dry weight). Patients randomized to deferoxamine who had LIC values less than 7 mg Fe/g dry weight were permitted to continue on their prior deferoxamine dose, even though the dose may have been higher than specified in the protocol. Patients were to have a liver biopsy at baseline and end of study (after 12 months) for LIC. The primary efficacy endpoint was defined as a reduction in LIC of greater than or equal to 3 mg Fe/g dry weight for baseline values greater than or equal to 10 mg Fe/g dry weight, reduction of baseline values between 7 and less than 10 to less than 7 mg Fe/g dry weight, or maintenance or reduction for baseline values less than 7 mg Fe/g dry weight. A total of 586 patients were randomized and treated, 296 with deferasirox tablets for oral suspension and 290 with deferoxamine. The mean age was 17.1 years (range, 2 to 53 years); 52% were females and 88% were Caucasian. The primary efficacy population consisted of 553 patients (deferasirox tablets for oral suspension n = 276; deferoxamine n = 277) who had LIC evaluated at baseline and 12 months or discontinued due to an adverse reaction. The percentage of patients achieving the primary endpoint was 52.9% for deferasirox tablets for oral suspension and 66.4% for deferoxamine. The relative efficacy of deferasirox to deferoxamine cannot be determined from this study. In patients who had an LIC at baseline and at end of study, the mean change in LIC was -2.4 mg Fe/g dry weight in patients treated with deferasirox tablets for oral suspension and -2.9 mg Fe/g dry weight in patients treated with deferoxamine. Reduction of LIC and serum ferritin was observed with deferasirox tablet for oral suspension doses of 20 to 30 mg/kg/day. Deferasirox tablets for oral suspension doses below 20 mg/kg/day failed to provide consistent lowering of LIC and serum ferritin levels (Figure 1). Therefore, a starting dose of 20 mg/kg/day is recommended [see Dosage and Administration (2.1 )] . Figure 1. Changes in Liver Iron Concentration and Serum Ferritin Following Deferasirox Tablets for Oral Suspension (5 to 30 mg/kg/day) in Study 1 Study 2 (NCT00061763) was an open-label, noncomparative trial of efficacy and safety of deferasirox tablets for oral suspension given for 1 year to patients with chronic anemias and transfusional hemosiderosis. Similar to Study 1, patients received 5, 10, 20, or 30 mg/kg/day of deferasirox tablets for oral suspension based on baseline LIC. A total of 184 patients were treated in this study: 85 patients with beta-thalassemia and 99 patients with other congenital or acquired anemias (myelodysplastic syndromes, n = 47; Diamond-Blackfan syndrome, n = 30; other, n = 22). Nineteen percent (19%) of patients were less than 16 years of age and 16% were greater than or equal to 65 years of age. There was a reduction in the absolute LIC from baseline to end of study (-4.2 mg Fe/g dry weight). Study 3 (NCT00067080) was a multicenter, open-label, randomized trial of the safety and efficacy of deferasirox tablets for oral suspension relative to deferoxamine given for 1 year in patients with sickle cell disease and transfusional hemosiderosis. Patients were randomized to deferasirox tablets for oral suspension at doses of 5, 10, 20, or 30 mg/kg/day or subcutaneous deferoxamine at doses of 20-60 mg/kg/day for 5 days per week according to baseline LIC. A total of 195 patients were treated in this study: 132 with deferasirox tablets for oral suspension and 63 with deferoxamine. Forty-four percent (44%) of patients were less than 16 years of age and 91% were black. At end of study, the mean change in LIC (as measured by magnetic susceptometry by a superconducting quantum interference device) in the per protocol-1 (PP-1) population, which consisted of patients who had at least 1 post-baseline LIC assessment, was -1.3 mg Fe/g dry weight for patients receiving deferasirox tablets for oral suspension (n = 113) and -0.7 mg Fe/g dry weight for patients receiving deferoxamine (n = 54). One-hundred five (105) patients with thalassemia major and cardiac iron overload were enrolled in a study assessing the change in cardiac magnetic resonance imaging (MRI) T2* value (measured in milliseconds, [ms]) before and after treatment with deferasirox. Cardiac T2* values at baseline ranged from 5 to less than 20 ms. The geometric mean of cardiac T2* in the 68 patients who completed 3 years of deferasirox tablets for oral suspension therapy increased from 11.98 ms at baseline to 17.12 ms at 3 years. Cardiac T2* values improved in patients with severe cardiac iron overload (less than 10 ms) and in those with mild to moderate cardiac iron overload (greater than or equal to 10 to less than 20 ms). The clinical significance of these observations is unknown. Six hundred twenty-seven (627) patients with MDS were enrolled across 5 uncontrolled trials. Two hundred thirty-nine of the 627 patients were enrolled in trials that limited enrollment to patients with IPSS Low or Intermediate 1 risk MDS, and the remaining 388 patients were enrolled in trials that did not specify MDS risk stratification but required a life expectancy of greater than 1 year. Planned duration of treatment in these trials ranged from 1 year (365 patients) to 5 years (47 patients). These trials evaluated the effects of deferasirox tablets for oral suspension therapy on parameters of iron overload, including LIC (125 patients) and serum ferritin (627 patients). The percent of patients completing planned duration of treatment was 51% in the largest 1-year study, 52% in the 3-year study and 22% in the 5-year study. The major causes for treatment discontinuation were withdrawal of consent, adverse reaction, and death. Over 1 year of follow-up across these pooled studies, mean change in serum ferritin was -332.8 (± 2615.59) mcg/L (n = 593) and mean change in LIC was -5.9 (± 8.32) mg Fe/g dw (n = 68). Results of these pooled studies in 627 patients with MDS suggest a progressive decrease in serum ferritin and LIC beyond 1 year in those patients who are able to continue deferasirox tablets for oral suspension. Study 4 (TELESTO; NCT 00940602) was a randomized, double-blind, placebo-controlled trial performed in 225 patients with MDS (Low/Int-1 risk) and transfusional iron overload of which 149 were treated with deferasirox and 76 received placebo. The observed hazard ratio of 0.64 (95% CI: 0.42, 0.96) suggests a positive impact of deferasirox on event-free survival (EFS, a composite endpoint defined as death, worsening cardiac function, hospitalization for congestive heart failure, liver function impairment, liver cirrhosis, or progression to acute myeloid leukemia; whichever occurred first). Non-Transfusion-Dependent Thalassemia Study 5 (NCT00873041) was a randomized, double-blind, placebo-controlled trial of treatment with deferasirox tablets for oral suspension for patients 10 years of age or older with NTDT syndromes and iron overload. Eligible patients had an LIC of at least 5 mg Fe/g dw measured by R2 MRI and a serum ferritin exceeding 300 mcg/L at screening (2 consecutive values at least 14 days apart from each other). A total of 166 patients were randomized, 55 to the deferasirox tablets for oral suspension 5 mg/kg/day dose group, 55 to the deferasirox tablets for oral suspension 10 mg/kg/day dose group, and 56 to placebo (28 to each matching placebo group). Doses could be increased after 6 months if the LIC exceeded 7 mg Fe/g dw and the LIC reduction from baseline was less than 15%. The patients enrolled included 89 males and 77 females. The underlying disease was beta-thalassemia intermedia in 95 (57%) patients, HbE beta-thalassemia in 49 (30%) patients, and alpha-thalassemia in 22 (13%) patients. There were 17 pediatric patients in the study. Caucasians comprised 57% of the study population and Asians comprised 42%. The median baseline LIC (range) for all patients was 12.1 (2.6 to 49.1) mg Fe/g dw. Follow-up was for 1 year. The primary efficacy endpoint of change in LIC from baseline to Week 52 was statistically significant in favor of both deferasirox dose groups compared with placebo (p less than or equal to 0.001) (Table 5). Furthermore, a statistically significant dose effect of deferasirox was observed in favor of the 10 mg/kg/day dose group (10 versus 5 mg/kg/day, p = 0.009). In a descriptive analysis, the target LIC (less than 5 mg Fe/g dw) was reached by 15 (27%) of 55 patients in the 10 mg/kg/day arm, 8 (15%) of 55 patients in the 5 mg/kg/day arm and 2 (4%) of 56 patients in the combined placebo groups. Study 6 (NCT00873041) was an open-label trial of deferasirox tablets for oral suspension for the treatment of patients previously enrolled on Study 5, including cross-over to active treatment for those previously treated with placebo. The starting dose of deferasirox tablets for oral suspension in Study 6 was assigned based on the patient’s LIC at completion of Study 5, being 20 mg/kg/day for an LIC exceeding 15 mg Fe/g dw, 10 mg/kg/day for LIC 3 to 15 mg Fe/g dw, and observation if the LIC was less than 3 mg Fe/g dw. Patients could continue on 5 mg/kg/day if they had previously exhibited at least a 30% reduction in LIC. Doses could be increased to a maximum of 20 mg/kg/day after 6 months if the LIC was more than 7 mg Fe/g dw and the LIC reduction from baseline was less than 15%. The primary efficacy endpoint in Study 6 was the proportion of patients achieving an LIC less than 5 mg Fe/g dw. A total of 133 patients were enrolled. Twenty patients began Study 6 with an LIC less than 5 mg Fe/g dw. Of the 113 patients with a baseline LIC of at least 5 mg Fe/g dw in Study 6, the target LIC (less than 5 mg Fe/g dw) was reached by 39 patients (35%). The responders included 4 (10%) of 39 patients treated at 20 mg/kg/day for a baseline LIC exceeding 15 mg Fe/g dw, and 31 (51%) of 61 patients treated at 10 mg/kg/day for a baseline LIC between 5 and 15 mg Fe/g dw. The absolute change in LIC at Week 52 by starting dose is shown in Table 5 below. Study 7 (NCT01709838) was an open-label, single-arm, multi-center, 5-year study to evaluate the efficacy and safety of deferasirox tablets for oral suspension in iron overloaded patients with NTDT of 10 years of age or older. All patients started treatment on 10 mg/kg/day deferasirox tablets for oral suspension for four weeks. At Week 4, dose escalation was based on baseline LIC. At Week 24 and every 6 months thereafter, further dose adjustments were made according to the LIC at that visit. Treatment was interrupted when LIC < 3 mg Fe/g dw or serum ferritin < 300 ng/mL and was re-started at 10 mg/kg/day when LIC ≥ 5 mg Fe/g dw and serum ferritin ≥ 300 ng/mL. Throughout the study, the maximum dose of deferasirox tablets for oral suspension given was 30 mg/kg/day. A total of 134 patients were enrolled in the study. Eligible patients were required to have an LIC of at least 5 mg Fe/g dw measured by R2 MRI and a serum ferritin at least of 300 ng/mL at screening. The mean absolute change of LIC from Baseline to Week 52 was -6.7 mg Fe/g dw. The reduction in LIC was sustained until Week 260 (5 years) with the mean absolute change in LIC from Baseline to Week 260 of -10.6 mg Fe/g dw. In the subset of patients with Baseline LIC > 15 mg Fe/g dw (49 patients), 51.0% achieved a first LIC < 5 mg Fe/g dw (95% CI: 37.5, 64.4) with a median time of 28.6 months. In the subset of patients with target LIC of < 3 mg Fe/g dw (61 patients), 39.3% developed first LIC ≥ 5 mg Fe/g dw in the follow-up period, with a median time of 13.9 months. Table 5. Absolute Change in LIC at Week 52 in Patients with NTDT Deferasirox Tablets for Oral Suspension Starting Dose 1 Placebo 5 mg/kg/day 10 mg/kg/day 20 mg/kg/day Study 5 2 Number of Patients n = 54 n = 51 n = 54 - Mean LIC at Baseline (mg Fe/g dw) 16.1 13.4 14.4 - Mean Change (mg Fe/g dw) +0.4 -2.0 -3.8 - (95% Confidence Interval) (-0.6, +1.3) (-2.9, -1.0) (-4.8, -2.9) - Study 6 Number of Patients - n = 8 n = 77 n = 43 Mean LIC at Baseline (mg Fe/g dw) - 5.6 8.8 23.5 Mean Change (mg Fe/g dw) - -1.5 -2.8 -9.1 (95% Confidence Interval) - (-3.7, +0.7) (-3.4, -2.2) (-11.0, -7.3) Study 7 Number of Patients - - n = 127 - Mean LIC at Baseline (mg Fe/g dw) - - 15.1 - Mean Change (mg Fe/g dw) - - -6.7 - (95% Confidence Interval) - - (-7.9, -5.5) - Abbreviation: LIC, liver iron concentration; NTDT, non-transfusion-dependent thalassemia. 1 Randomized dose in Study 5 or assigned starting dose in Study 6 and Study 7. 2 Least square mean change for Study 5

Risk Summary There are no studies with the use of deferasirox tablets in pregnant women to inform drug-associated risks. Administration of deferasirox to rats during pregnancy resulted in decreased offspring viability and an increase in renal anomalies in male offspring at doses that were about or less than the recommended human dose on a mg/m 2 basis. No fetal effects were noted in pregnant rabbits at doses equivalent to the human recommended dose on an mg/m 2 basis. Deferasirox tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies had a background risk of birth defect, loss, or other adverse outcomes. However, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data In embryo-fetal developmental studies, pregnant rats and rabbits received oral deferasirox during the period of organogenesis at doses up to 100 mg/kg/day in rats and 50 mg/kg/day in rabbits (1.2 times the maximum recommended human dose (MRHD) on an mg/m 2 basis). These doses resulted in maternal toxicity but no fetal harm was observed. In a prenatal and postnatal developmental study, pregnant rats received oral deferasirox daily from organogenesis through lactation day 20 at doses of 10, 30, and 90 mg/kg/day (0.1, 0.3, and 1.0 times the MRHD on a mg/m 2 basis). Maternal toxicity, loss of litters, and decreased offspring viability occurred at 90 mg/kg/day (1.0 times the MRHD on a mg/m 2 basis), and increases in renal anomalies in male offspring occurred at 30 mg/kg/day (0.3 times the MRHD on a mg/m 2 basis).

Deferasirox tablets are indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older.

Deferasirox Tablets (dee fer′ a sir ox) What is the most important information I should know about deferasirox tablets? Deferasirox tablets can cause serious side effects, including: Kidney problems: Deferasirox tablets can cause sudden (acute) kidney problems, including kidney failure that may require treatment with dialysis, and may cause death. Deaths have happened mostly in people who also have other health problems and had a blood disorder that was in an advanced stage. Adults and children who already have kidney problems and are taking certain medicines with deferasirox tablets may also have an increased risk of sudden kidney problems. Be sure to tell your healthcare provider about all the medicines you take during treatment with deferasirox tablets. Your healthcare provider should do blood and urine tests to check your or your child’s kidney function before and during treatment with deferasirox tablets. Call your healthcare provider right away if: your child becomes sick with fever, vomiting, or diarrhea and cannot drink fluids normally during treatment with deferasirox tablets. Your child may be dehydrated. Your healthcare provider may need to temporarily stop treatment with deferasirox tablets and treat your child for dehydration to help prevent kidney problems. Your healthcare provider may monitor your child’s kidney function more closely. you notice that you or your child are passing less urine than usual during treatment with deferasirox tablets. Liver problems. Deferasirox tablets can cause liver problems, including liver failure that can sometimes cause death. Liver problems with deferasirox tablets may be more common in people who are over 55 years of age but can also happen in children. Liver failure has happened more often in people with cirrhosis of the liver and failure of other organs. Liver failure has also happened along with kidney problems in certain children who become dehydrated. See “Kidney problems” above. Your healthcare provider should do blood tests to check your liver function before you start and regularly during treatment with deferasirox tablets. Call your healthcare provider right away, if you develop any of the following signs and symptoms: drowsiness yellowing or increased yellowing of your skin or eyes upper right stomach-area (abdomen) pain dark urine Bleeding, ulcers, and tears of the stomach or intestine. Severe stomach and intestine bleeding (hemorrhage) that have caused death have happened in some people treated with deferasirox tablets, especially in elderly people who have advanced blood cancers or low platelet counts. Some people have also had ulcers of the stomach or intestine, sometimes with tears (perforation) that have caused death. In some people who have taken deferasirox tablets, including children and adolescents, irritation of the upper gastrointestinal tract, ulcers, and bleeding have happened, but did not cause death. Your risk of severe bleeding (hemorrhage) may be increased if you take deferasirox tablets along with other medicines that can cause ulcers or bleeding, such as: nonsteroidal anti-inflammatory drugs (NSAIDs) certain osteoporosis medicines called oral bisphosphonates corticosteroids blood thinner medicines Before you start taking deferasirox tablets, tell your healthcare provider if you are taking one of these medicines. Ask your healthcare provider if you are not sure. If you develop an ulcer of the stomach or intestine, or severe bleeding, your healthcare provider may stop deferasirox tablets. Elderly people may be at a higher risk of developing serious side effects and death due to serious side effects with deferasirox tablets. Your healthcare provider may need to monitor you more closely during treatment with deferasirox tablets. Tell your healthcare provider if you get heartburn during treatment with deferasirox tablets. Get emergency medical help right away if you vomit blood or pass black or bloody stools, or if you have severe stomach-area (abdomen) pain during treatment with deferasirox tablets. See “What are the possible side effects of deferasirox tablets?” for more information about side effects. What are deferasirox tablets? Deferasirox tablets are prescription medicines that are used to treat: people 2 years of age and older who have an increased amount of iron in their blood for a long period of time (chronic), caused by repeated blood transfusions certain people 10 years of age or older with thalassemia who have an increased amount of iron in their blood but who are not receiving regular blood transfusions It is not known if deferasirox tablets are safe and effective when used with other medicines to treat an increased amount of iron in the blood. It is not known if deferasirox tablets are safe and effective for treating children under 2 years of age who have an increased amount of iron in their blood for a long period of time (chronic) caused by repeated blood transfusions. It is not known if deferasirox tablets are safe and effective for treating children under 10 years of age with thalassemia who have an increased amount of iron in their blood, but who are not receiving regular blood transfusions. Do not take deferasirox tablets if you: have certain kidney problems have high-risk myelodysplastic syndrome (MDS) have advanced cancer have a low platelet count are allergic to deferasirox or any of the ingredients in deferasirox tablets. See the end of this medication guide for a list of the ingredients in deferasirox tablets. Ask your healthcare provider if you are not sure if you have any of the medical conditions listed above. Before taking deferasirox tablets tell your healthcare provider about all of your medical conditions, including if you: have kidney problems have liver problems have advanced cancer. See “Do not take deferasirox tablets if you?” have a blood disorder that may increase your risk for bleeding are pregnant or plan to become pregnant. It is not known if deferasirox tablets can harm your unborn baby. Hormonal forms of birth control may not be as effective if used during treatment with deferasirox tablets. You could become pregnant. Talk to your healthcare provider about other birth control options that you can use during this time. Tell your healthcare provider right away if you become pregnant during treatment with deferasirox tablets. are breastfeeding or plan to breastfeed. It is not known if deferasirox tablets pass into your breast milk and can harm your baby. You and your healthcare provider should decide if you will take deferasirox tablets or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take , including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements. Some medicines may affect how deferasirox tablets works, and deferasirox tablets may affect how other medicines work. Also, your risk of sudden kidney problems or severe bleeding may be increased if you take deferasirox tablets with certain medicines. See ‘What is the most important information I should know about deferasirox tablets?” Avoid taking the following medicines during treatment with deferasirox tablets: antacid products (medicines used to treat heartburn) that contain aluminum theophylline certain medicines to lower your cholesterol, called bile acid sequestrants. Ask your healthcare provider if you are not sure if you take one of these medicines. Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine. How should I take deferasirox tablets? Take deferasirox tablets exactly as your healthcare provider tells you. Do not change your dose of deferasirox tablets or stop taking unless your healthcare provider tells you to. Deferasirox tablets comes as tablets. You may take deferasirox tablets on an empty stomach or with a light meal. Examples of a light meal include: 1 whole wheat English muffin, 1 packet of jelly (0.5 ounce), and skim milk (8 fluid ounces), or A turkey sandwich (2 ounces of turkey on whole wheat bread with lettuce, tomato, and 1 packet of mustard) Taking deferasirox tablets: Take deferasirox tablets by mouth with water or other liquids 1 time every day, preferably at the same time every day. If you have trouble swallowing the tablets whole, you may crush deferasirox tablets and mix them with soft foods such as yogurt or applesauce right before taking your dose. Take the dose right away. Do not save any of the deferasirox tablets and soft food mixture for later use. Do not use store-bought pill crushers with serrated surfaces for crushing deferasirox tablets 90 mg tablets. Do not take deferasirox tablets with aluminum-containing antacid products. See “Before taking deferasirox tablets” Tell your healthcare provider if you or your child gain or lose any weight. Your or your child’s dose of deferasirox tablets may need to be adjusted. If you take the diabetes medicine repaglinide during treatment with deferasirox tablets you may need to test your blood sugar (glucose) levels more often. Follow your healthcare provider’s instructions about how often to test your blood sugar during this time. Your healthcare provider should do blood and urine tests before, and during treatment to check how you respond to deferasirox tablets, and to monitor you for side effects. Your healthcare provider may change your dose, or temporarily or permanently stop deferasirox tablets if you have certain side effects. In people who have thalassemia, your healthcare provider will check the amount of iron in your liver before and during treatment with deferasirox tablets. If you or your child take too much deferasirox tablets, call your healthcare provider right away or go to the nearest hospital emergency room. Symptoms that can happen if you take too much deferasirox tablets include: stomach-area (abdominal) pain, diarrhea, nausea and vomiting. What should I avoid while taking deferasirox tablets? Deferasirox tablets may cause dizziness. Avoid driving or operating machinery until you know how deferasirox tablets affect you. Do not drive or operate machinery if deferasirox tablets make you dizzy. What are the possible side effects of deferasirox tablets? Deferasirox tablets can cause serious side effects, including: See “What is the most important information I should know about deferasirox tablets?” Effects on your bone marrow. Deferasirox tablets can affect your bone marrow and cause you to have low white blood cell count which can be serious, decreased platelets, or worsening of your anemia, and may lead to death. Your risk for effects on your bone marrow may be increased if you already have other blood disorders. Your healthcare provider will do blood tests to monitor your blood cell counts for these problems. Serious allergic reactions. Deferasirox tablets may cause serious allergic reactions, which usually start within the first month of treatment. Get medical help right away if you develop any of the following symptoms of a serious allergic reaction including: difficulty in breathing or swallowing swelling of the face, lips, mouth, tongue, or throat chest pain severe itching of the skin with a red rash or raised bumps rapid heartbeat feeling faint hives Skin rash and severe skin reactions. Skin rashes are common with deferasirox tablets. If you get a more severe rash, your healthcare provider may temporarily stop deferasirox tablets. Severe skin reactions can also happen with deferasirox tablets and can be life-threatening or lead to death. Get medical help right away if you develop any one or more of the following signs and symptoms of a severe skin reaction, including: rash or red skin skin peeling blisters on your lips, or around your mouth or eyes high fever or flu-like symptoms mouth sores enlarged lymph nodes Hearing and vision problems. Deferasirox tablets can cause decreased hearing and changes in your vision including cataracts, increased pressure in your eye, and problems with your retinas. Your healthcare provider should do hearing and vision tests before you start and then regularly during treatment. Your healthcare provider may decrease your dose or stop deferasirox tablets if you develop hearing or vision problems. The most common side effects in anyone who takes deferasirox tablets include: diarrhea and nausea. Other common side effects in people with too much iron in their blood due to repeated blood transfusions include: vomiting, stomach-area (abdomen) pain, and an abnormal kidney function blood test. These are not all the possible side effects of deferasirox tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store deferasirox tablets? Store deferasirox tablets at room temperature between 68°F to 77°F (20°C to 25°C). Keep the bottle closed tightly and away from moisture . Keep deferasirox tablets and all medicines out of the reach of children. General information about the safe and effective use of deferasirox tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use deferasirox tablets for a condition for which it was not prescribed. Do not give it to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for more information about deferasirox tablets. What are the ingredients in deferasirox tablets? Deferasirox tablets: Active ingredient: deferasirox Inactive ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, poloxamer and povidone. The film coating contains hypromellose, FD & C Blue No. 2, polyethylene glycol, talc and titanium dioxide. Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 For more information, call 1-800-818-4555. This Medication Guide has been approved by the U.S. Food and Drug Administration. Rev. 09/2024

Deferasirox tablets 90 mg tablets are light blue oval biconvex film-coated tablet with beveled edges, debossed with ‘S102’ on one side and plain on the other side. Deferasirox tablets 180 mg tablets are medium blue oval biconvex film-coated tablet with beveled edges, debossed with ‘S103’ on one side and plain on the other side. Deferasirox tablets 360 mg tablets are dark blue oval biconvex film-coated tablet with beveled edges, debossed with ‘S104’ on one side and plain on the other side.

Deferasirox is an orally active chelator that is selective for iron (as Fe 3+ ). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Although deferasirox has very low affinity for zinc and copper, there are variable decreases in the serum concentration of these trace metals after the administration of deferasirox. The clinical significance of these decreases is uncertain.

Pharmacodynamic effects tested in an iron balance metabolic study with the tablet for oral suspension formulation showed that deferasirox (10, 20, and 40 mg/kg/day) was able to induce a mean net iron excretion (0.119, 0.329, and 0.445 mg Fe/kg body weight/day, respectively) within the clinically relevant range (0.1 to 0.5 mg/kg/day). Iron excretion was predominantly fecal. An analysis of pooled pediatric clinical trial data found a statistically significant relationship between exposure and the probability of renal toxicity (increase in serum creatinine and urinary protein), resulting in a decrease in renal function. Decreases in renal function resulted in an increase in deferasirox exposure which may increase the probability of renal toxicity. Cardiac Electrophysiology At the maximum approved recommended dose, deferasirox does not prolong the QT interval to any clinically relevant extent.

Absorption Based on studies in patients with the tablet for oral suspension, deferasirox is absorbed following oral administration with median times to maximum plasma concentration (T max ) of about 1.5 to 4 hours. In healthy subjects, deferasirox tablets showed comparable T max . The maximal concentrations (C max ) and area under the curve (AUC 0-24h , AUC τ ) of deferasirox increase approximately linearly with dose after both single administration and under steady-state conditions. Exposure to deferasirox increased by an accumulation factor of 1.3 to 2.3 after multiple doses with the tablet for oral suspension formulation. Tablets The absolute bioavailability [as measured by area under the curve over time to infinity (AUC inf )] of deferasirox tablets for oral suspension is 70% compared to an intravenous dose. The bioavailability (as measured by AUC inf ) of deferasirox tablets was 36% greater than with deferasirox tablets for oral suspension. After strength-adjustment, the mean AUC inf of deferasirox tablets (i.e., 360 mg strength) was similar to that of deferasirox tablets for oral suspension (i.e., 500 mg strength) under fasting conditions; however the mean C max was increased by 30%. The 30% increase in C max observed with deferasirox tablets is not clinically meaningful. The administration of deferasirox tablets with a light meal (approximately 250 calories with fat content less than 7% of total calories) indicated that the AUC inf and C max were similar to that under fasting conditions. The administration of deferasirox tablets with a high-fat meal (approximately 1,000 calories with fat content greater than 50% of total calories), increased AUC inf by 18% and C max by 29% compared to that under fasting conditions [see Dosage and Administration (2.3) ]. Distribution Deferasirox is highly (~99%) protein bound almost exclusively to serum albumin. The percentage of deferasirox confined to the blood cells was 5% in humans. The volume of distribution at steady state (V ss ) of deferasirox is 14.37 ± 2.69 L in adults. Metabolism Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion. Deconjugation of glucuronidates in the intestine and subsequent reabsorption (enterohepatic recycling) is likely to occur. Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450-catalyzed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). Deconjugation of glucuronide metabolites in the intestine and subsequent reabsorption (enterohepatic recycling) was confirmed in a healthy subjects study in which the administration of cholestyramine 12 g twice daily (strongly binds to deferasirox and its conjugates) 4 and 10 hours after a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC inf ) by interfering with the enterohepatic recycling of deferasirox. Excretion Deferasirox and metabolites are primarily (84% of the dose) excreted in the feces. Renal excretion of deferasirox and metabolites is minimal (8% of the dose). The mean elimination half-life (t 1/2 ) ranged from 8 to 16 hours following oral administration. Drug Interactions Midazolam: The concomitant administration of deferasirox tablets for oral suspension and CYP3A4 probe substrate midazolam resulted in a decrease of midazolam C max by 23% and AUC inf by 17%. In the clinical setting, this effect may be more pronounced, as the study was not adequately designed to conclusively assess the potential induction of CYP3A4 by deferasirox [see Drug Interactions (7.2) ] . Repaglinide: The concomitant administration of deferasirox tablets for oral suspension (30 mg/kg/day for 4 days) and the CYP2C8 probe substrate repaglinide (single dose of 0.5 mg) increased repaglinide AUC inf to 2.3-fold and C max of 1.6-fold [see Drug Interactions (7.3) ] . Theophylline: The concomitant administration of deferasirox tablets for oral suspension (repeated dose of 30 mg/kg/day) and the CYP1A2 substrate theophylline (single dose of 120 mg) resulted in an approximate doubling of the theophylline AUC inf and elimination half-life. The single dose C max was not affected, but an increase in theophylline C max is expected to occur with chronic dosing [see Drug Interactions (7.4) ] . Rifampicin: The concomitant administration of deferasirox tablets for oral suspension (single dose of 30 mg/kg) and the strong uridine diphosphate glucuronosyltransferase (UGT) inducer rifampicin (600 mg/day for 9 days) decreased deferasirox AUC inf by 44% [see Drug Interactions (7.5) ] . Cholestyramine: The concomitant administration of cholestyramine after a single dose of deferasirox tablets for oral suspension decreased deferasirox AUC inf by 45% [see Drug Interactions (7.6) ] . Busulfan : Concomitant administration of deferasirox and busulfan resulted in an increase of busulfan exposure (AUC). In vitro Studies: Deferasirox inhibited human CYP2A6, CYP2D6, and CYP2C19 in vitro . Deferasirox is not a substrate of P-glycoprotein, MRP1 or MRP2. Pharmacokinetics in Specific Populations Pediatric: Following oral administration of single or multiple doses, systemic exposure of adolescents and children to deferasirox was less than in adult patients. In children less than 6 years of age, systemic exposure was about 50% lower than in adults. Sex: The apparent clearance is 17.5% lower in females compared to males. Renal Impairment : Compared to patients with MDS and eGFR greater than 60 mL/min/1.73 m 2 , patients with MDS and eGFR 40 to 60 mL/min/1.73 m 2 (n = 34) had approximately 50% higher mean deferasirox trough plasma concentrations. Hepatic Impairment: In a single dose (20 mg/kg) study in patients with varying degrees of hepatic impairment, deferasirox exposure was increased compared to patients with normal hepatic function. The average total (free and bound) AUC inf of deferasirox increased 16% in 6 patients with mild (Child-Pugh A) hepatic impairment, and 76% in 6 patients with moderate (Child-Pugh B) hepatic impairment compared to 6 patients with normal hepatic function. The impact of severe (Child-Pugh C) hepatic impairment was assessed in only 1 patient.

Lactation: Advise women not to breastfeed. (8.2)

Acute Kidney Injury: Measure serum creatinine in duplicate before starting therapy. Monitor renal function during deferasirox tablets 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 (GI) Bleeding, Ulceration, and Irritation: Risk may be greater in patients who are taking deferasirox tablets 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 tablets 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 tablets for severe reactions 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 tablets. (5.8)

Package Label – 90mg

Risk Summary No data are available regarding the presence of deferasirox tablets 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.

Contraception Counsel patients to use non-hormonal method(s) of contraception since deferasirox tablets can render hormonal contraceptives ineffective [see Drug Interactions (7.2) ] .