Deferasirox (Page 2 of 9)

2.3 Administration

Do not chew tablets or swallow them whole.

Take deferasirox tablets once daily on an empty stomach at least 30 minutes before food, preferably at the same time each day. Completely disperse tablets by stirring in water, orange juice, or apple juice until a fine suspension is obtained. Disperse doses of less than 1 g in 3.5 ounces of liquid and doses of 1 g or greater in 7 ounces of liquid. After swallowing the suspension, resuspend any residue in a small volume of liquid and swallow. Do not take deferasirox tablets with aluminum-containing antacid products [see Drug Interactions (7.1)].

2.4 Use in Patients With Baseline Hepatic or Renal Impairment


Patients with Baseline Hepatic Impairment

Mild (Child-Pugh A) Hepatic Impairment: No dose adjustment is necessary.

Moderate (Child-Pugh B) Hepatic Impairment: Reduce the starting dose by 50%.

Severe (Child-Pugh C) Hepatic Impairment: Avoid deferasirox tablets [see Warnings and Precautions (5.2), Use in Specific Populations (8.7)].
Patients with Baseline Renal Impairment
Do not use deferasirox tablets in adult or pediatric patients with eGFR less than 40 mL/min/1.73 m2 [see Dosage and Administration (2.5), Contraindications (4)].
For patients with renal impairment (eGFR 40 to 60 mL/min/1.73 m2), reduce the starting dose by 50% [see Use in Specific Populations (8.6)].
Exercise caution in pediatric patients with eGFR between 40 and 60 mL/min/1.73 m2. If treatment is needed, use the minimum effective dose and monitor renal function frequently. Individualize dose titration based on improvement in renal injury [see Use in Specific Populations (8.6)].

2.5 Dose Modifications for Decreases in Renal Function While on Deferasirox Tablets

Deferasirox tablets are contraindicated in patients with eGFR less than 40 mL/min/1.73 m2 [see Contraindications (4)].
For decreases in renal function while receiving deferasirox tablets [see Warnings and Precautions (5.1)], modify the dose as follows:
Transfusional Iron Overload
Adults:

  • If the serum creatinine increases by 33% or more above the average baseline measurement, repeat the serum creatinine within 1 week, and if still elevated by 33% or more, reduce the dose by 10 mg per kg.

Pediatric Patients (ages 2 years to 17 years):

  • Reduce the dose by 10 mg/kg/day if eGFR decreases by greater than 33% below the average baseline measurement and repeat the eGFR within 1 week.
  • Interrupt deferasirox tablets for acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor more frequently. Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal. Avoid use of other nephrotoxic drugs [see Warnings and Precautions (5.1)].
  • In the setting of decreased renal function, evaluate the risk benefit profile of continued deferasirox tablets use. Use the minimum effective deferasirox tablets dose and monitor renal function more frequently, by evaluating tubular and glomerular function. Titrate dosing based on renal injury. Consider dose reduction or interruption and less nephrotoxic therapies until improvement of renal function. If signs of renal tubular or glomerular injury occur in the presence of other risk factors such as volume depletion, reduce or interrupt deferasirox tablets to prevent severe and irreversible renal injury [see Warnings and Precautions (5.1)].

All Patients (regardless of age):

  • Discontinue therapy for eGFR less than 40 mL/min/1.73 m2 [see Contraindications (4)].


Non-Transfusion-Dependent Thalassemia Syndromes

Adults:

  • If the serum creatinine increases by 33% or more above the average baseline measurement, repeat the serum creatinine within 1 week, and if still elevated by 33% or more, interrupt therapy if the dose is 5 mg per kg, or reduce by 50% if the dose is 10 or 20 mg per kg.

Pediatric Patients (ages 10 years to 17 years):

  • Reduce the dose by 5 mg/kg/day if eGFR decreases by greater than 33% below the average baseline measurement and repeat the eGFR within 1 week.
  • Increase monitoring frequency for pediatric patients who have acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake. Consider dose interruption until oral intake and volume status are normal. Avoid use of other nephrotoxic drugs [see Warnings and Precautions (5.1)].
  • In the setting of decreased renal function, evaluate the risk benefit profile of continued deferasirox tablet use. Use the minimum effective deferasirox tablet 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 tablet to prevent severe and irreversible renal injury [see Warnings and Precautions (5.1)].

All Patients (regardless of age):

Discontinue therapy for eGFR less than 40 mL/min/1.73 m2 [see Contraindications (4)].

2.6 Dose Modifications Based on Concomitant Medications

UDP-glucuronosyltransferases (UGT) Inducers

Concomitant use of UGT inducers decreases deferasirox tablets systemic exposure. Avoid the concomitant use of potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) with deferasirox tablets. If you must administer deferasirox tablets with 1 of these agents, consider increasing the initial dose of deferasirox tablets by 50%, and monitor serum ferritin levels and clinical responses for further dose modification [see Dosage and Administration (2.1, 2.2), Drug Interactions (7.5)].


Bile Acid Sequestrants

Concomitant use of bile acid sequestrants decreases deferasirox systemic exposure. Avoid the concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol) with deferasirox tablets. If you must administer deferasirox tablets with 1 of these agents, consider increasing the initial dose of deferasirox tablets by 50%, and monitor serum ferritin levels and clinical responses for further dose modification [see Dosage and Administration (2.1, 2.2), Drug Interactions (7.6)].

3 DOSAGE FORMS AND STRENGTHS

  • 125 mg tablets

Off-white, round uncoated tablets, flat with beveled edge, debossed with “568” on one side and plain on other side.

  • 250 mg tablets

Off-white, round uncoated tablets, flat with beveled edge, debossed with “569” on one side and plain on other side.

  • 500 mg tablets

Off-white, round uncoated tablets, flat with beveled edge, debossed with “570” on one side and plain on other side.

4 CONTRAINDICATIONS

Deferasirox is contraindicated in patients with:

  • Estimated GFR less than 40 mL/min/1.73 m2 [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 109 /L [see Warnings and Precautions (5.3, 5.4)]
  • Known hypersensitivity to deferasirox or any component of deferasirox [see Warnings and Precautions (5.7), Adverse Reactions (6.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Acute Kidney Injury, Including Acute Renal Failure Requiring Dialysis, and Renal Tubular Toxicity Including Fanconi Syndrome

Deferasirox tablets are contraindicated in patients with eGFR less than 40 mL/min/1.73 m2. Exercise caution in pediatric patients with eGFR between 40 and 60 mL/minute/1.73 m2. 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 m2), reduce the starting dose by 50% [see Dosage and Administration (2.4, 2.5), Use in Specific Populations (8.6)].
Deferasirox tablets can cause acute kidney injury including renal failure requiring dialysis that has resulted in fatal outcomes. Based on postmarketing experience, most fatalities have occurred in patients with multiple comorbidities and who were in advanced stages of their hematological disorders. In the clinical trials, adult and pediatric Deferasirox tablets-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 tablets 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 exposure, unless the dose is reduced or interrupted. Renal tubular toxicity, including acquired Fanconi syndrome, has been reported in patients treated with deferasirox tablets, 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 [see Dosage and Administration (2.1, 2.2)].

Monitor all patients for changes in eGFR and for renal tubular toxicity weekly during the first month after initiation or modification of therapy and at least monthly thereafter. 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 tablets 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)].

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