Deferasiroxdosage

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 sachet content for granules) once daily.

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 sachet content for granules) once daily. See full prescribing information for information regarding monitoring, administration, and dose-reductions for organ impairment.

2.1 Transfusional

Iron Overload Deferasirox oral granules therapy should only be considered when a patient has evidence of chronic transfusional iron overload. The evidence should include the transfusion of at least 100 mL/kg of packed red blood cells (e.g., at least 20 units of packed red blood cells for a 40 kg person or more in individuals weighing more than 40 kg), and a serum ferritin consistently greater than 1,000 mcg/L. Prior to starting therapy, or increasing dose, evaluate: Serum ferritin level Baseline renal function: Obtain serum creatinine in duplicate (due to variations in measurements). Calculate the estimated glomerular filtration rate (eGFR). Use a prediction equation appropriate for adult patients (e.g., CKD-EPI, MDRD method) and in pediatric patients (e.g., Schwartz equations). Obtain urinalyses and serum electrolytes to evaluate renal tubular function. Serum transaminases and bilirubin Baseline auditory and ophthalmic examinations Initiating Therapy: The recommended initial dose of deferasirox oral granules for patients 2 years of age and older with eGFR greater than 60 mL/min/1.73 m 2 is 14 mg per kg body weight orally, once daily. Calculate doses (mg per kg per day) to the nearest whole sachet content for granules. Changes in weight of pediatric patients over time must be taken into account when calculating the dose.

During Therapy: Monitor serum ferritin monthly and adjust the dose of deferasirox oral granules, if necessary, every 3 to 6 months based on serum ferritin trends. Use the minimum effective dose to achieve a trend of decreasing ferritin Make dose adjustments in steps of 3.5 or 7 mg per kg and tailor adjustments to the individual patient’s response and therapeutic goals. In patients not adequately controlled with doses of 21 mg per kg (e.g., serum ferritin levels persistently above 2,500 mcg/L and not showing a decreasing trend over time), doses of up to 28 mg per kg may be considered. Doses above 28 mg per kg are not recommended. Adjust dose based on serum ferritin levels If the serum ferritin falls below 1,000 mcg/L at 2 consecutive visits, consider dose reduction especially if the deferasirox oral granules dose is greater than 17.5 mg/kg/day. If the serum ferritin falls below 500 mcg/L, interrupt deferasirox oral granules therapy to minimize the risk of overchelation, and continue monthly monitoring. 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. Monitor blood counts, liver function, renal function and ferritin monthly. Interrupt deferasirox oral granules for pediatric patients who have acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor more frequently. Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal.

2.2 Iron Overload in

Non-Transfusion-Dependent Thalassemia Syndromes Deferasirox oral granules therapy should only be considered when a patient with NTDT syndrome has an LIC of at least 5 mg Fe/g dw and a serum ferritin greater than 300 mcg/L. Prior to starting therapy, obtain: LIC by liver biopsy or by an FDA-cleared or approved method for identifying patients for treatment with deferasirox therapy Serum ferritin level on at least 2 measurements 1-month apart 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. Serum transaminases and bilirubin Baseline auditory and ophthalmic examinations Initiating Therapy: The recommended initial dose of deferasirox oral granules 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 sachet content for granules. If the baseline LIC is greater than 15 mg Fe/g dw, consider increasing the dose to 14 mg/kg/day after 4 weeks.

During Therapy: Monitor serum ferritin monthly to assess the patient’s response to therapy and to minimize the risk of overchelation. 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. 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. Restart treatment when the LIC rises again to more than 5 mg Fe/g dw.

2.3 Administration

Take deferasirox oral granules on an empty stomach or with a light meal (contains less than 7% fat content and approximately 250 calories). Examples of light meals include 1 whole wheat English muffin, 1 packet jelly (0.5 ounces), and skim milk (8 fluid ounces) or a turkey sandwich (2 oz. turkey on whole wheat bread w/ lettuce, tomato, and 1 packet mustard). Administer deferasirox oral granules by sprinkling the full dose on soft food (e.g., yogurt or applesauce) immediately prior to use and administered orally. Deferasirox oral granules should be taken once a day, preferably at the same time each day. Do not take deferasirox oral granules with aluminum-containing antacid products. For patients who are currently on chelation therapy with deferasirox tablets for oral suspension and converting to deferasirox oral granules, the dose should be about 30% lower, rounded to the nearest whole sachet content for granules. The table below provides additional information on dosing conversion to deferasirox granules. Deferasirox Tablets for Oral S uspension Deferasirox Oral Granules Transfusion-Dependent Iron Overload Starting Dose 20 mg/kg/day 14 mg/kg/day Titration Increments 5 to10 mg/kg 3.5 to 7 mg/kg Maximum Dose 40 mg/kg/day 28 mg/kg/day Non-Transfusion-Dependent Thalassemia Syndromes Starting Dose 10 mg/kg/day 7 mg/kg/day Titration Increments 5 to10 mg/kg 3.5 to 7 mg/kg Maximum Dose 20 mg/kg/day 14 mg/kg/day

2.4 Use in Patients

With Baseline Hepatic or Renal Impairment Patients with Baseline Hepatic Impairment Mild (Child-Pugh A) Hepatic Impairment: No dose adjustment is necessary. Moderate (Child-Pugh B) Hepatic Impairment: Reduce the starting dose by 50%. Severe (Child-Pugh C) Hepatic Impairment: Avoid deferasirox oral granules. Patients with Baseline Renal Impairment Do not use deferasirox oral granules in adult or pediatric patients with eGFR less than 40 mL/min/1.73 m 2. For patients with renal impairment (eGFR 40 to 60 mL/min/1.73 m 2 ), reduce the starting dose by 50%. Exercise caution in pediatric patients with eGFR between 40 and 60 mL/minute/1.73 m 2. If treatment is needed, use the minimum effective dose and monitor renal function frequently. Individualize dose titration based on improvement in renal injury.

2.5 Dose Modifications for

Decreases in Renal Function While on Deferasirox Oral Granules Deferasirox oral granules are contraindicated in patients with eGFR less than 40 mL/min/1.73 m 2. For decreases in renal function while receiving deferasirox oral granules, modify the dose as follows: Transfusional Iron Overload Adults: If the serum creatinine increases by 33% or more above the average baseline measurement, repeat the serum creatinine within 1 week, and if still elevated by 33% or more, reduce the dose by 7 mg per kg. Pediatric Patients (ages 2 years to 17 years): Reduce the dose by 7 mg per kg if eGFR decreases by greater than 33% below the average baseline measurement and repeat eGFR within 1 week. Interrupt deferasirox oral granules for acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor more frequently. Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal. Avoid use of other nephrotoxic drugs. In the setting of decreased renal function, evaluate the risk benefit profile of continued deferasirox oral granules use. Use the minimum effective deferasirox oral granules dose and monitor renal function more frequently, by evaluating tubular and glomerular function. Titrate dosing based on renal injury. Consider dose reduction or interruption and less nephrotoxic-therapies until improvement of renal function. If signs of renal tubular or glomerular injury occur in the presence of other risk factors such as volume depletion, reduce or interrupt deferasirox oral granules to prevent severe and irreversible renal injury. All Patients (regardless of age): Discontinue therapy for eGFR less than 40 mL/min/1.73 m 2. Non-Transfusion-Dependent Thalassemia Syndromes Adults If the serum creatinine increases by 33% or more above the average baseline measurement, repeat the serum creatinine within 1 week, and if still elevated by 33% or more, interrupt therapy if the dose is 3.5 mg per kg, or reduce by 50% if the dose is 7 or 14 mg per kg. Pediatric Patients (ages 10 years to17 years): Reduce the dose by 3.5 mg per kg if eGFR decreases by greater than 33% below the average baseline measurement and repeat the eGFR within 1 week. Increase monitoring frequency for pediatric patients who have acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake. Consider dose interruption until oral intake and volume status are normal. Avoid use of other nephrotoxic drugs. In the setting of decreased renal function, evaluate the risk benefit profile of continued deferasirox oral granules use. Use the minimum effective deferasirox oral granules dose and monitor renal function more frequently, by evaluating tubular and glomerular function. Titrate dosing based on renal injury. Consider dose reduction or interruption and less nephrotoxic therapies until improvement of renal function. If signs of renal tubular or glomerular injury occur in the presence of other risk factors such as volume depletion, reduce or interrupt deferasirox oral granules to prevent severe and irreversible renal injury. All Patients (regardless of age): Discontinue therapy for eGFR less than 40 mL/min/1.73 m 2.

2.6 Dose Modifications

Based on Concomitant Medications UDP-glucuronosyltransferases (UGT) Inducers Concomitant use of UGT inducers decreases systemic exposure. Avoid the concomitant use of strong UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir). If you must administer deferasirox oral granules with a strong UGT inducer, consider increasing the initial dose by 50%, and monitor serum ferritin levels and clinical responses for further dose modification. Bile Acid Sequestrants Concomitant use of bile acid sequestrants decreases systemic exposure. Avoid the concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol). If you must administer deferasirox oral granules with a bile acid sequestrant, consider increasing the initial dose by 50%, and monitor serum ferritin levels and clinical responses for further dose modification.