Deferasirox (Page 2 of 8)

2.6 Dose Modifications Based on Concomitant Medications

UDP-glucuronosyltransferases (UGT) Inducers

Concomitant use of UGT inducers decreases deferasirox tablets for oral suspension 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 tablets for oral suspension 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 tablets debossed with “L461” on one side and plain on the other side.

  • 250 mg tablets

White to off-white, round, flat tablets debossed with “L462” on one side and plain on the other side.

  • 500 mg tablets

White to off-white, round, flat tablets debossed with “L463” on one side and plain on the other side.

4 CONTRAINDICATIONS

Deferasirox tablets for oral suspension are 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 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 tablets for oral suspension 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 for oral suspension 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 for oral suspension-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 for oral suspension 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 tablets for oral suspension, 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 tablets for oral suspension 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)].

5.2 Hepatic Toxicity and Failure

Deferasirox tablets for oral suspension can cause hepatic injury, fatal in some patients. In Study 1, 4 patients (1.3%) discontinued deferasirox tablets for oral suspension 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 tablets for oral suspension-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 tablets for oral suspension 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 tablets for oral suspension in the 20 to 40 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 (AST and 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 tablets for oral suspension 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.

5.3 Gastrointestinal (GI) Ulceration, Hemorrhage, and Perforation

GI hemorrhage, including deaths, has been reported in deferasirox tablets for oral suspension-treated patients, 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 tablets for oral suspension [see Adverse Reactions (6.1)]. Monitor for signs and symptoms of GI ulceration and hemorrhage during deferasirox tablets for oral suspension therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. The risk of gastrointestinal hemorrhage may be increased when administering deferasirox tablets for oral suspension 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 gastrointestinal perforation (including fatal outcome) [see Adverse Reactions (6.2)].

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