deferasirox 90 MG Oral Tablet [Jadenu]

INDICATIONS AND USAGE Deferasirox tablets for oral suspension are an iron chelator indicated for the treatment of chronic iron overload due to blood transfusions in patients 2 years of age and older. (1.1) Deferasirox tablets for oral suspension is indicated for the treatment of chronic iron overload in patients 10 years of age and older with non-transfusion-dependent thalassemia (NTDT) syndromes, and with a liver iron (Fe) concentration (LIC) of at least 5 mg Fe per gram of dry weight and a serum ferritin greater than 300 mcg/L. (1.2) Limitations of Use: The safety and efficacy of deferasirox tablets for oral suspension when administered with other iron chelation therapy have not been established. (1.3) 1.1 Treatment of Chronic Iron Overload Due to Blood Transfusions (Transfusional Iron Overload) Deferasirox tablets for oral suspension are indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older. 1.2 Treatment of Chronic Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes Deferasirox tablets for oral suspension are indicated for the treatment of chronic iron overload in patients 10 years of age and older with non-transfusion-dependent thalassemia (NTDT) syndromes and with a liver iron concentration (LIC) of at least 5 milligrams of iron per gram of liver dry weight (mg Fe/g dw) and a serum ferritin greater than 300 mcg/L. 1.3 Limitations of Use The safety and efficacy of deferasirox tablets for oral suspension when administered with other iron chelation therapy have not been established.

DOSAGE AND ADMINISTRATION Transfusional Iron Overload: Initial dose for patients with estimated glomerular filtration rate (eGFR) greater than 60 mL/min/1.73 m 2 is 14 mg per 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 per 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 ) 2.1Transfusional Iron Overload Deferasirox tablets therapy should only be considered when a patient has evidence of chronic transfusional iron overload. The evidence should include the transfusion of at least 100 mL/kg of packed red blood cells (e.g., at least 20 units of packed red blood cells for a 40 kg person or more in individuals weighing more than 40 kg), and a serum ferritin consistently greater than 1,000 mcg/L. Prior to starting therapy, or increasing dose, evaluate: Serum ferritin level Obtain renal function Obtain serum creatinine in duplicate (due to variations in measurements). Calculate the estimated glomerular filtration rate (eGFR). Use a prediction equation appropriate for adult patients (e.g., CKD-EPI, MDRD method) and in pediatric patients (e.g., Schwartz equations). Obtain urinalyses and serum electrolytes to evaluate renal tubular function [ see Dosage and Administration (2.4) , Warnings and Precautions (5.1)]. Serum transaminases and bilirubin [ see Dosage and Administration (2.4), Warnings and Precautions (5.2)] Baseline auditory and ophthalmic examinations [see Warnings and Precautions (5.10)] Initiating Therapy: The recommended initial dose of deferasirox tablets for patients 2 years of age and older with eGFR greater than 60 mL/min/1.73 m 2 is 14 mg per kg body weight orally, once daily. Calculate doses (mg per kg per day) to the nearest whole tablet. Changes in weight of pediatric patients over time must be taken into account when calculating the dose. During Therapy: Monitor serum ferritin monthly and adjust the dose of deferasirox tablets, if necessary, every 3 to 6 months based on serum ferritin trends. Use the minimum effective dose to achieve a trend of decreasing ferritin Make dose adjustments in steps of 3.5 or 7 mg per kg and tailor adjustments to the individual patient’s response and therapeutic goals. In patients not adequately controlled with doses of 21 mg per kg (e.g., serum ferritin levels persistently above 2,500 mcg/L and not showing a decreasing trend over time), doses of up to 28 mg per kg may be considered. Doses above 28 mg per kg are not recommended [ see Warnings and Precautions (5.6)]. Adjust dose based on serum ferritin levels If the serum ferritin falls below 1,000 mcg/L at 2 consecutive visits, consider dose reduction especially if the deferasirox tablets dose is greater than 17.5 mg/kg/day [see Adverse Reactions (6.1)]. If the serum ferritin falls below 500 mcg/L, interrupt deferasirox tablets therapy to minimize the risk of overchelation, and continue monthly monitoring [ see Warnings and Precautions (5.6)] . Evaluate the need for ongoing chelation therapy for patients whose conditions no longer require regular blood transfusions. Use the minimum effective dose to maintain iron burden in the target range [see Warnings and Precautions (5.6)]. Monitor blood counts, liver function, renal function and ferritin monthly [see Warnings and Precautions (5.1 , 5.2 , 5.4 )]. Interrupt deferasirox tablets for pediatric patients who have acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor more frequently. Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal [see Dosage and Administration ( 2.4 , 2.5 ), Warnings and Precautions ( 5.1) , Use in Specific Populations ( 8.4), Clinical Pharmacology ( 12.3)]. 2.2 Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes Deferasirox tablets therapy should only be considered when a patient with NTDT syndrome has an LIC of at least 5 mg Fe/g dw and a serum ferritin greater than 300 mcg/L. Prior to starting therapy, obtain: LIC by liver biopsy or by an FDA-cleared or approved method for identifying patients for treatment with deferasirox therapy Serum ferritin level on at least 2 measurements 1-month apart [ see Clinical Studies (14)] Baseline renal function: Obtain serum creatinine in duplicate (due to variations in measurements). Calculate the estimated glomerular filtration rate (eGFR). Use a prediction equation appropriate for adult patients (e.g., CKD-EPI, MDRD method) and in pediatric patients (e.g., Schwartz equations). Obtain urinalyses and serum electrolytes to evaluate renal tubular function [ see Dosage and Administration (2.4), Warnings and Precautions (5.1)]. Serum transaminases and bilirubin [ see Dosage and Administration (2.4), Warnings and Precautions (5.2)] Baseline auditory and ophthalmic examinations [ see Warnings and Precautions (5.10)] Initiating Therapy: The recommended initial dose of deferasirox tablets for patients with eGFR greater than 60 mL/min/1.73 m 2 is 7 mg per kg body weight orally once daily. Calculate doses (mg per kg per day) to the nearest whole tablet. If the baseline LIC is greater than 15 mg Fe/g dw, consider increasing the dose to 14 mg/kg/day after 4 weeks. During Therapy: Monitor serum ferritin monthly to assess the patient’s response to therapy and to minimize the risk of overchelation [ see Warnings and Precautions (5.6)]. Interrupt treatment when serum ferritin is less than 300 mcg/L and obtain an LIC to determine whether the LIC has fallen to less than 3 mg Fe/g dw. Use the minimum effective dose to achieve a trend of decreasing ferritin. Monitor LIC every 6 months. After 6 months of therapy, if the LIC remains greater than 7 mg Fe/g dw, increase the dose of deferasirox to a maximum of 14 mg/kg/day. Do not exceed a maximum of 14 mg/kg/day. If after 6 months of therapy, the LIC is 3 to 7 mg Fe/g dw, continue treatment with deferasirox at no more than 7 mg/kg/day. When the LIC is less than 3 mg Fe/g dw, interrupt treatment with deferasirox and continue to monitor the LIC. Monitor blood counts, liver function, renal function and ferritin monthly [ see Warnings and Precautions (5.1, 5.2, 5.4)]. Increase monitoring frequency for pediatric patients who have acute illness, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake. Consider dose interruption until oral intake and volume status are normal [ see Dosage and Administration (2.4, 2.5 ), Warnings and Precautions (5.1 ), Use in Specific Populations (8.4), Clinical Pharmacology (12.3)]. Restart treatment when the LIC rises again to more than 5 mg Fe/g dw. 2.3Administration Swallow deferasirox tablets once daily with water or other liquids, preferably at the same time each day. 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). Do not take deferasirox tablets with aluminum-containing antacid products [ see Drug Interactions (7.1) ] . 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. Commercial crushers with serrated surfaces should be avoided for crushing a single 90 mg tablet. The dose should be immediately and completely consumed and not stored for future use. For patients who are currently on chelation therapy with deferasirox tablets for oral suspension and converting to deferasirox tablets, the dose sh

WARNINGS AND PRECAUTIONS Acute Kidney Injury: Measure serum creatinine in duplicate before starting therapy. Monitor renal function during deferasirox therapy and reduce dose or interrupt therapy for toxicity. ( 2.1 , 2.4 , 5.1 ) Hepatic Toxicity: Monitor hepatic function. Reduce dose or interrupt therapy for toxicity. ( 5.2 ) Fatal and Nonfatal Gastrointestinal (GI) Bleeding, Ulceration, and Irritation: Risk may be greater in patients who are taking deferasirox in combination with drugs that have known ulcerogenic or hemorrhagic potential. ( 5.3 ) Bone Marrow Suppression: Neutropenia, agranulocytosis, worsening anemia, and thrombocytopenia, including fatal events; monitor blood counts during deferasirox therapy. Interrupt therapy for toxicity. ( 5.4 ) Age-related Risk of Toxicity: Monitor elderly and pediatric patients closely for toxicity. ( 5.5 ) Hypersensitivity Reactions: Discontinue deferasirox for severe 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. ( 5.8 ) 5.1 Acute Kidney Injury, Including Acute Renal Failure Requiring Dialysis and Renal Tubular Toxicity Including Fanconi Syndrome Deferasirox is contraindicated in patients with eGFR less than 40 mL/min/1.73 m 2 . Exercise caution in pediatric patients with eGFR between 40 and 60 mL/min/1.73 m 2 . If treatment is needed, use the minimum effective dose and monitor renal function frequently. Individualize dose titration based on improvement in renal injury [see Use in Specific Populations (8.6)] . For patients with renal impairment (eGFR 40 to 60 mL/min/1.73 m 2 ) reduce the starting dose by 50% [see Dosage and Administration (2.4 , 2.5 ), Use in Specific Populations (8.6)] . Deferasirox can cause acute kidney injury including renal failure requiring dialysis that has resulted in fatal outcomes. Based on postmarketing experience, most fatalities have occurred in patients with multiple comorbidities and who were in advanced stages of their hematological disorders. In the clinical trials, adults and pediatric deferasirox-treated patients with no preexisting renal disease experienced dose-dependent mild, non-progressive increases in serum creatinine and proteinuria. Preexisting renal disease and concomitant use of other nephrotoxic drugs may increase the risk of acute kidney injury in adult and pediatric patients. Acute illnesses associated with volume depletion and overchelation may increase the risk of acute kidney injury in pediatric patients. In pediatric patients, small decreases in eGFR can result in increases in deferasirox exposure, particularly in younger patients with body surface area typical of patients less than age 7 years. This can lead to a cycle of worsening renal function and further increases in deferasirox tablets for oral suspension exposure, unless the dose is reduced or interrupted. Renal tubular toxicity, including acquired Fanconi syndrome, has been reported in patients treated with deferasirox, most commonly in pediatric patients with beta-thalassemia and serum ferritin levels less than 1,500 mcg/L [see Warnings and Precautions (5.6) , Adverse Reactions (6.1 , 6.2 ), Use in Specific Populations (8.4), Clinical Pharmacology (12.3) ] . Evaluate renal glomerular and tubular function before initiating therapy or increasing the dose. Use prediction equations validated for use in adult and pediatric patients to estimate GFR. Obtain serum electrolytes and urinalysis in all patients to evaluate renal tubular function [ s ee Dosage and Administration (2.1,2.2)]. Monitor all patients for changes in eGFR and for renal tubular toxicity weekly during the first month after initiation or modification of therapy and at least monthly thereafter.Dose reduction or interruption may be considered if abnormalities occur in levels of markers of renal tubular function and/or as clinically indicated. Monitor serum ferritin monthly to evaluate for overchelation. Use the minimum dose to establish and maintain a low iron burden. Monitor renal function more frequently in patients with preexisting renal disease or decreased renal function. In pediatric patients, interrupt deferasirox during acute illnesses, which can cause volume depletion such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor renal function more frequently. Promptly correct fluid deficits to prevent renal injury. Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal [see Dosage and Administration (2.5) , Warnings and Precautions (5.6) , Adverse Reactions (6.1 , 6.2) , Use in Specific Populations (8.4) ] . 5.2Hepatic Toxicity and Failure Deferasirox can cause hepatic injury, fatal in some patients. In Study 1, 4 patients (1.3%) discontinued deferasirox because of hepatic toxicity (drug-induced hepatitis in 2 patients and increased serum transaminases in 2 additional patients). Hepatic toxicity appears to be more common in patients greater than 55 years of age. Hepatic failure was more common in patients with significant comorbidities, including liver cirrhosis and multiorgan failure [ see Adverse Reactions (6.1)]. Acute liver injury and failure, including fatal outcomes, have occurred in pediatric deferasirox-treated patients. Liver failure occurred in association with acute kidney injury in pediatric patients at risk for overchelation during a volume-depleting event. Interrupt deferasirox therapy when acute liver injury or acute kidney injury is suspected and during volume depletion. Monitor liver and renal function more frequently in pediatric patients who are receiving deferasirox in the 14 to 28 mg/kg/day range and when iron burden is approaching normal. Use the minimum effective dose to achieve and maintain a low iron burden [see Dosage and Administration (2.5) , Warnings and Precautions (5.6), Adverse Reactions (6.1) ]. Measure transaminases [aspartate transaminase (AST) and alanine transaminase (ALT)] and bilirubin in all patients before the initiation of treatment and every 2 weeks during the first month and at least monthly thereafter. Consider dose modifications or interruption of treatment for severe or persistent elevations. Avoid the use of deferasirox in patients with severe (Child-Pugh C) hepatic impairment. Reduce the starting dose in patients with moderate (Child-Pugh B) hepatic impairment [ see Dosage and Administration (2.4), Use in Specific Populations (8.7)]. Patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment may be at higher risk for hepatic toxicity. 5.3Gastrointestinal (GI) Ulceration, Hemorrhage, and Perforation GI hemorrhage, including deaths, has been reported, especially in elderly patients who had advanced hematologic malignancies and/or low platelet counts. Nonfatal upper GI irritation, ulceration and hemorrhage have been reported in patients, including children and adolescents, receiving deferasirox [ see Adverse Reactions (6.1)]. Monitor for signs and symptoms of GI ulceration and hemorrhage during deferasirox therapy, and promptly initiate additional evaluation and treatment if a serious GI adverse reaction is suspected. The risk of GI hemorrhage may be increased when administering deferasirox in combination with drugs that have ulcerogenic or hemorrhagic potential, such as nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, oral bisphosphonates, or anticoagulants. There have been reports of ulcers complicated with GI perforation (including fatal outcome) [ see Adverse Reactions (6.2)]. 5.4Bone Marrow Suppression Neutropenia, agranulocytosis, worsening anemia, and thrombocytopenia, including fatal events, have been reported in patients treated with deferasirox. Preexisting hematologic disorders may increase this risk. Monitor blood counts in all patients. Interrupt treatment with def

CONTRAINDICATIONS Deferasirox tablets for oral suspension are contraindicated in patients with: • Estimated GFR less than 40 mL/min/1.73 m 2 [see Dosage and Administration ( Error! Hyperlink reference not valid. ), Warnings and Precautions ( Error! Hyperlink reference not valid. )]; • Poor performance status [see Warnings and Precautions ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )]; • 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 ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )]; • Platelet counts less than 50 x 10 9 /L [see Warnings and Precautions ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )]; Known hypersensitivity to deferasirox or any component of deferasirox tablets for oral suspension [see Warnings and Precautions ( Error! Hyperlink reference not valid. ), Adverse Reactions ( Error! Hyperlink reference not valid. )] . • Estimated GFR less than 40 mL/min/1.73 m 2 . ( 4 ) • Patients with poor performance status. ( 4 ) • Patients with high-risk myelodysplastic syndrome (MDS). ( 4 ) • Patients with advanced malignancies. ( 4 ) • Patients with platelet counts less than 50 x 10 9 /L. ( 4 ) • Known hypersensitivity to deferasirox or any component of deferasirox tablets for oral suspension. ( 4 )

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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. 12.2 Pharmacodynamics Pharmacodynamic effects tested in an iron balance metabolic study showed that deferasirox (10, 20, and 40 mg per kg per day) was able to induce a mean net iron excretion (0.119, 0.329, and 0.445 mg Fe/kg body weight per day, respectively) within the clinically relevant range (0.1 to 0.5 mg per kg per 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. 12.3 Pharmacokinetics Absorption Deferasirox is absorbed following oral administration with median times to maximum plasma concentration (T max ) of about 1.5 to 4 hours. The C max and area under the curve (AUC) 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. The absolute bioavailability (AUC) of deferasirox tablets for oral suspension is 70% compared to an intravenous dose. The bioavailability (AUC) of deferasirox was variably increased when taken with a meal. 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 volunteer 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) 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 administered dose). The mean elimination half-life (t 1/2 ) ranged from 8 to 16 hours following oral administration. Drug Interactions Midazolam : In healthy volunteers, the concomitant administration of deferasirox and midazolam (a CYP3A4 probe substrate) resulted in a decrease of midazolam peak concentration by 23% and exposure by 17%. In the clinical setting, this effect may be more pronounced. The study was not adequately designed to conclusively assess the potential induction of CYP3A4 by deferasirox [see Drug Interactions (7.2) ]. Repaglinide : In a healthy volunteer study, the concomitant administration of deferasirox (30 mg per kg/day for 4 days) and the CYP2C8 probe substrate repaglinide (single dose of 0.5 mg) resulted in an increase in repaglinide systemic exposure (AUC) to 2.3-fold of control and an increase in C max of 62% [see Drug Interactions (7.3) ]. Theophylline : In a healthy volunteer study, the concomitant administration of deferasirox (repeated dose of 30 mg per kg/day) and the CYP1A2 substrate theophylline (single dose of 120 mg) resulted in an approximate doubling of the theophylline AUC 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 : In a healthy volunteer study, the concomitant administration of deferasirox (single dose of 30 mg per kg) and the potent UDP-glucuronosyltransferase (UGT) inducer rifampicin (600 mg/day for 9 days) resulted in a decrease of deferasirox systemic exposure (AUC) by 44% [see Drug Interactions (7.5) ]. Cholestyramine : The concomitant use of deferasirox with bile acid sequestrants may result in a decrease in deferasirox efficacy. In healthy volunteers, the administration of cholestyramine after a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC) [see Drug Interactions (7.6) ]. Busulfan : Concomitant administration of deferasirox and busulfan resulted in an increase of busulfan exposure (AUC). In vitro S tudies : Cytochrome P450 Enzymes: Deferasirox inhibits human CYP3A4, CYP2C8, CYP1A2, CYP2A6, CYP2D6, and CYP2C19 in vitro . Transporter Systems: The addition of cyclosporin A (PgP/MRP1/MRP2 inhibitor) or verapamil (PgP/MRP1 inhibitor) did not influence ICL670 permeability in vitro . 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. Geriatric : The pharmacokinetics of deferasirox have not been studied in elderly patients (65 years of age or older). Gender : Females have a moderately lower apparent clearance (by 17.5%) for deferasirox 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 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.