Deferasirox (Page 2 of 9)

2.4 Use in Patients with Baseline Hepatic or Renal Impairment

Patients with Baseline Hepatic Impairment

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

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

Severe (Child-Pugh C) Hepatic Impairment: Avoid deferasirox tablets for oral suspension [see Warnings and Precautions ( 5.2), Use in Specific Populations ( 8.7)].

Patients with Baseline Renal Impairment

Do not use deferasirox tablets for oral suspension in adult or pediatric patients with eGFR less than 40 mL/min/1.73 m 2 [see Dosage and Administration ( 2.5), Contraindications ( 4)].

For patients with renal impairment (eGFR 40–60 mL/min/1.73 m 2), reduce the starting dose by 50% [see Use in Specific Populations ( 8.6)].

Exercise caution in pediatric patients with eGFR between 40 and 60 mL/min/1.73 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)] .

2.5 Dose Modifications for Decreases in Renal Function while on Deferasirox Tablets for Oral Suspension

Deferasirox tablets for oral suspension is contraindicated in patients with eGFR less than 40 mL/min/1.73 m 2 [see Contraindications ( 4)].

For decreases in renal function while receiving deferasirox tablets for oral suspension [see Warnings and Precautions ( 5.1)], modify the dose as follows:

Transfusional Iron Overload

Adults:

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

Pediatric Patients (ages 2 years to 17 years):

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

All Patients (regardless of age):

  • Discontinue therapy for eGFR less than 40 mL/min/1.73 m 2 [see Contraindications ( 4)].

Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s EXJADE ® (deferasirox) tablets for oral suspension. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2.6 Dose Modifications Based on Concomitant Medications

UDP-glucuronosyltransferases (UGT) Inducers

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

Bile Acid Sequestrants

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

3 DOSAGE FORMS AND STRENGTHS

  • 125 mg tablets
    White to off-white, round, flat, beveled-edged tablet debossed with “D1” on one side.
  • 250 mg tablets
    White to off-white, round, flat, beveled-edged tablet debossed with “D2” on one side.
  • 500 mg tablets White to off-white, round, flat, beveled-edged tablet debossed with “D3” on one side.

4 CONTRAINDICATIONS

Deferasirox is contraindicated in patients with:

  • Estimated GFR less than 40 mL/min/1.73 m 2 [see Dosage and Administration ( 2.5) , Warnings and Precautions ( 5.1)] ;
  • Poor performance status; [see Warnings and Precautions ( 5.1, 5.3)]
  • High-risk myelodysplastic syndromes; (this patient population was not studied and is not expected to benefit from chelation therapy)
  • Advanced malignancies. [see Warnings and Precautions ( 5.1, 5.3)]
  • Platelet counts less than 50 x 10 9 /L [see Warnings and Precautions ( 5.3, 5.4)]
  • Known hypersensitivity to deferasirox or any component of deferasirox tablets for oral suspension [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 is contraindicated in patients with eGFR less than 40 mL/min/1.73 m 2. Exercise caution in pediatric patients with eGFR between 40 and 60 mL/minute/1.73 m 2. If treatment is needed, use the minimum effective dose and monitor renal function frequently. Individualize dose titration based on improvement in renal injury [see Use in Specific Populations ( 8.6)] . For patients with renal impairment (eGFR 40–60 mL/min/1.73 m 2), reduce the starting dose by 50% [see Dosage and Administration ( 2.4, 2.5), Use in Specific Populations ( 8.6)].

Deferasirox can cause acute kidney injury including renal failure requiring dialysis that has resulted in fatal outcomes. Based on postmarketing experience, most fatalities have occurred in patients with multiple comorbidities and who were in advanced stages of their hematological disorders. In the clinical trials, adult and pediatric deferasirox-treated patients with no preexisting renal disease experienced dose-dependent mild, non-progressive increases in serum creatinine and proteinuria. Preexisting renal disease and concomitant use of other nephrotoxic drugs may increase the risk of acute kidney injury in adult and pediatric patients. Acute illnesses associated with volume depletion and overchelation may increase the risk of acute kidney injury in pediatric patients. In pediatric patients, small decreases in eGFR can result in increases in deferasirox exposure, particularly in younger patients with body surface area typical of patients less than age 7 years. This can lead to a cycle of worsening renal function and further increases in deferasirox exposure, unless the dose is reduced or interrupted. Renal tubular toxicity, including acquired Fanconi syndrome, has been reported in patients treated with deferasirox, most commonly in pediatric patients with beta‑thalassemia and serum ferritin levels less than 1,500 mcg/L [see Warnings and Precautions ( 5.6), Adverse Reactions ( 6.1, 6.2), Use in Special Populations ( 8.4), Clinical Pharmacology ( 12.3)].

Evaluate renal glomerular and tubular function before initiating therapy or increasing the dose. Use prediction equations validated for use in adult and pediatric patients to estimate GFR. Obtain serum electrolytes and urinalysis in all patients to evaluate renal tubular function [see Dosage and Administration ( 2.1)].

Monitor all patients for changes in eGFR and for renal tubular toxicity weekly during the first month after initiation or modification of therapy and at least monthly thereafter. Monitor serum ferritin monthly to evaluate for overchelation. Use the minimum dose to establish and maintain a low iron burden. Monitor renal function more frequently in patients with preexisting renal disease or decreased renal function. In pediatric patients, interrupt deferasirox during acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor renal function more frequently. Promptly correct fluid deficits to prevent renal injury. Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal [see Dosage and Administration ( 2.5), Warnings and Precautions ( 5.6), Adverse Reactions ( 6.1, 6.2), Use in Specific Populations ( 8.4)].

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