Important Safety Information:

EXJADE can cause acute renal failure and death, particularly in patients with comorbidities and those who are in the advanced stages of their hematologic disorders.

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INDICATIONS

Treatment of Chronic Iron Overload Due to Blood Transfusions (Transfusional Iron Overload)

EXJADE® (deferasirox) is indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older.

Limitations of Use

  • Controlled clinical trials of EXJADE with myelodysplastic syndromes (MDS) and chronic iron overload due to blood transfusions have not been performed
  • The safety and efficacy of EXJADE, when administered with other iron chelation therapy, have not been established

IMPORTANT SAFETY INFORMATION for EXJADE® (deferasirox)

WARNING: RENAL FAILURE, HEPATIC FAILURE, AND GASTROINTESTINAL HEMORRHAGE

Renal Failure

  • EXJADE can cause acute renal failure and death, particularly in patients with comorbidities and those who are in the advanced stages of their hematologic disorders
  • Evaluate baseline renal function prior to starting or increasing EXJADE dosing in all patients. EXJADE is contraindicated in adult and pediatric patients with estimated glomerular filtration rates (eGFR) ˂40 mL/min/1.73 m2. Measure serum creatinine in duplicate prior to initiation of therapy. Monitor renal function at least monthly. For patients with baseline renal impairment or increased risk of acute renal failure, monitor renal function weekly for the first month, then at least monthly. Reduce the starting dose in patients with preexisting renal disease. During therapy, increase the frequency of monitoring and modify the dose for patients with an increased risk of renal impairment, including use of concomitant nephrotoxic drugs, and pediatric patients with volume depletion or overchelation

Hepatic Failure

  • EXJADE can cause hepatic injury, including hepatic failure and death
  • Measure serum transaminases and bilirubin in all patients prior to initiating treatment, every 2 weeks during the first month, and at least monthly thereafter
  • Avoid use of EXJADE in patients with severe (Child-Pugh C) hepatic impairment, and reduce the dose in patients with moderate (Child-Pugh B) hepatic impairment

Gastrointestinal Hemorrhage

  • EXJADE can cause gastrointestinal (GI) hemorrhages, which may be fatal, especially in elderly patients who have advanced hematologic malignancies and/or low platelet counts
  • Monitor patients, and discontinue EXJADE for suspected GI ulceration or hemorrhage

CONTRAINDICATIONS

EXJADE is contraindicated in patients with:

  • eGFR ˂40 mL/min/1.73 m2;
  • Poor performance status;
  • High-risk MDS;
  • Advanced malignancies;
  • Platelet counts ˂50 x 109/L;
  • Known hypersensitivity to deferasirox or any component of EXJADE

WARNINGS AND PRECAUTIONS

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

EXJADE is contraindicated in patients with eGFR ˂40 mL/min/1.73 m2. 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. For patients with renal impairment (eGFR 40 to 60 mL/min/1.73 m2) reduce the starting dose by 50%.

EXJADE 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 hematologic disorders. In the clinical trials, adult and pediatric patients treated with EXJADE with no preexisting renal disease experienced dose-dependent mild, nonprogressive 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 EXJADE exposure, particularly in younger patients with body surface area typical of patients ˂7 years of age. This can lead to a cycle of worsening renal function and further increases in EXJADE exposure, unless the dose is reduced or interrupted. Renal tubular toxicity, including acquired Fanconi Syndrome, has been reported in patients treated with EXJADE, most commonly in pediatric patients with β-thalassemia and serum ferritin levels ˂1500 mcg/L.

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.

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 EXJADE 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.

Hepatic Toxicity and Failure

EXJADE can cause hepatic injury, fatal in some patients. In Study 1, 4 (1.3%) patients discontinued EXJADE 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 >55 years of age. Hepatic failure was more common in patients with significant comorbidities, including liver cirrhosis and multiorgan failure. Acute liver injury and failure, including fatal outcomes, have occurred in pediatric patients treated with EXJADE. Liver failure occurred in association with acute kidney injury in pediatric patients at risk for overchelation during a volume depleting event. Interrupt EXJADE 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 EXJADE 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.

Measure aspartate aminotransferase (AST) and alanine aminotransferase (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 EXJADE in patients with severe (Child-Pugh C) hepatic impairment. Reduce the starting dose in patients with moderate (Child-Pugh B) hepatic impairment. Patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment may be at higher risk for hepatic toxicity.

Gastrointestinal Ulceration, Hemorrhage, and Perforation

Gastrointestinal (GI) hemorrhages, including deaths, have 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 EXJADE. Monitor for signs and symptoms of GI ulceration and hemorrhage during EXJADE therapy, and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. The risk of GI hemorrhage may be increased when administering EXJADE 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).

Bone Marrow Suppression

Neutropenia, agranulocytosis, worsening anemia, and thrombocytopenia, including fatal events, have been reported in patients treated with EXJADE. Preexisting hematologic disorders may increase this risk.  Monitor blood counts in all patients. Interrupt treatment with EXJADE in patients who develop cytopenias until the cause of the cytopenia has been determined. EXJADE is contraindicated in patients with platelet counts ˂50 x 109/L.

Age-Related Risk of Toxicity

Elderly Patients: EXJADE has been associated with serious and fatal adverse reactions in the postmarketing setting among adults, predominantly in elderly patients. Monitor elderly patients treated with EXJADE more frequently for toxicity.

Pediatric Patients: EXJADE has been associated with serious and fatal adverse reactions in pediatric patients in the postmarketing setting. These events were frequently associated with volume depletion or with continued EXJADE doses in the 20 to 40 mg/kg/day range when body iron burden was approaching or was in the normal range. Interrupt EXJADE in patients with volume depletion, and resume EXJADE when renal function and fluid volume have normalized. Monitor liver and renal function more frequently during volume depletion and in patients receiving EXJADE in the 20 to 40 mg/kg/day range when iron burden is approaching the normal range. Use the minimum effective dose to achieve and maintain a low iron burden.

Overchelation

For patients with transfusional iron overload, measure serum ferritin monthly to assess for possible overchelation of iron. An analysis of pediatric patients treated with EXJADE in pooled clinical trials (n=158) found a higher rate of renal adverse events among patients receiving doses >25 mg/kg/day while their serum ferritin values were ˂1000 mcg/L. Consider dose reduction or closer monitoring of renal and hepatic function, and serum ferritin levels during these periods. Use the minimum effective dose to maintain a low iron burden. 

If the serum ferritin is ˂1000 mcg/L at 2 consecutive visits, consider dose reduction, especially if the dose is >25 mg/kg/day. If the serum ferritin is ˂500 mcg/L, interrupt therapy with EXJADE and continue monthly monitoring. Evaluate the need for ongoing chelation for patients whose conditions do not require regular blood transfusions. Use the minimum effective dose to maintain iron burden in the target range. Continued administration of EXJADE in the 20 to 40 mg/kg/day range, when the body iron burden is approaching or within the normal range, has resulted in life-threatening adverse events.

For patients with NTDT, measure LIC by liver biopsy or by using the US Food and Drug Administration (FDA)-cleared or approved method for monitoring patients receiving deferasirox therapy every 6 months on treatment. Interrupt EXJADE administration when the LIC is ˂3 mg Fe/g dw. Measure serum ferritin monthly, and if the serum ferritin is ˂300 mcg/L, interrupt EXJADE and obtain a confirmatory LIC.

Hypersensitivity

EXJADE may cause serious hypersensitivity reactions (such as anaphylaxis and angioedema), with the onset of the reaction usually occurring within the first month of treatment. If reactions are severe, discontinue EXJADE and institute appropriate medical intervention. EXJADE is contraindicated in patients with known hypersensitivity to deferasirox products and should not be reintroduced in patients who have experienced previous hypersensitivity reactions on deferasirox products due to the risk of anaphylactic shock.

Severe Skin Reactions

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) which could be life-threatening or fatal, have been reported during EXJADE therapy. Cases of erythema multiforme have been observed. Advise patients of the signs and symptoms of severe skin reactions, and closely monitor. If any severe skin reactions are suspected, discontinue EXJADE immediately and do not reintroduce EXJADE therapy. 

Skin Rash

Rashes may occur during EXJADE treatment. For rashes of mild to moderate severity, EXJADE may be continued without dose adjustment, since the rash often resolves spontaneously. In severe cases, interrupt treatment.

Auditory and Ocular Abnormalities

Auditory disturbances (high frequency hearing loss, decreased hearing), and ocular disturbances (lens opacities, cataracts, elevations in intraocular pressure, and retinal disorders) were reported at a frequency of ˂1% with EXJADE therapy in the clinical studies. The frequency of auditory adverse events, irrespective of causality, was increased among pediatric patients who received EXJADE doses >25 mg/kg/day when serum ferritin was ˂1000 mcg/L.

Perform auditory and ophthalmic testing (including slit lamp examinations and dilated fundoscopy) before starting EXJADE treatment and thereafter at regular intervals (every 12 months). If disturbances are noted, monitor more frequently. Consider dose reduction or interruption.

ADVERSE REACTIONS

For patients with transfusional iron overload, the most common adverse reactions occurring in >5% of patients treated with EXJADE who had β‑thalassemia, sickle cell disease, and MDS were abdominal pain, nausea, vomiting, diarrhea, skin rashes, and increases in serum creatinine. Gastrointestinal symptoms, increases in serum creatinine, and skin rash were dose related.

For patients with NTDT, the most common adverse reactions occurring in >5% of patients treated with EXJADE were nausea, rash, and diarrhea.

Please see full Prescribing Information, including Boxed WARNING, for EXJADE® (deferasirox).