Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)
WARNINGS AND PRECAUTIONS
Gastrointestinal (GI) Ulceration, Hemorrhage, and Perforation
- … There have been reports of ulcers complicated with gastrointestinal perforation (including fatal outcome)
Severe Skin Reactions
- If SJS or erythema multiforme is suspected… do not reintroduce Exjade therapy
- Skin Rash Reintroduction… after resolution of the rash.
- Renal and urinary disorders: renal tubular necrosis…
- Gastrointestinal disorders: … gastrointestinal perforation
WARNING: RENAL, HEPATIC FAILURE AND/OR GASTROINTESTINAL HEMORRHAGE
- Exjade may cause : renal impairment, including failure; hepatic impairment, including failure; gastrointestinal hemorrhage
- In some reported cases, these reactions were fatal. These reactions were more frequently observed in patients with advanced age, high risk myelodysplastic syndromes (MDS), underlying renal or hepatic impairment or low platelet counts (<50 x 109/L). Exjade therapy requires close patient monitoring, including laboratory tests of renal and hepatic function.
- serum creatinine and/or creatinine clearance prior to initiation of therapy and monthly thereafter; in patients with underlying renal impairment or risk factors for renal impairment, monitor creatinine and/or creatinine clearance weekly for the first month, then monthly thereafter;
- serum transaminases and bilirubin prior to initiation of therapy, every two weeks during the first month and monthly thereafter.
Exjade is contraindicated in patients with:
- creatinine clearance <40 mL/min or serum creatinine >2 times the age-appropriate upper limit of normal;
- poor performance status and high-risk myelodysplastic syndromes or advanced malignancies
WARNINGS AND PRECAUTIONS
- Acute renal failure, fatal in some patients and requiring dialysis in others, has been reported following the postmarketing use of Exjade (deferasirox). Most fatalities occurred in patients with multiple comorbidities and who were in advanced stages of their hematological disorders. Monitor serum creatinine and/or creatinine clearance in patients who: are at increased risk of complications, have preexisting renal conditions, are elderly, have comorbid conditions, or are receiving medicinal products that depress renal function. Closely monitor the renal function of patients with creatinine clearances between 40 and less than 60 mL/min, particularly in situations where patients have additional risk factors that may further impair renal function such as concomitant medications, dehydration, or severe infections.
- In the clinical studies, Exjade-treated patients experienced dose-dependent increases in serum creatinine. These increases occurred at a greater frequency compared to deferoxamine-treated patients (38% vs. 14%, respectively, in Study 1 and 36% vs 22%, respectively, in Study 3). Most of the creatinine elevations remained within the normal range. There have also been reports of renal tubulopathy in patients treated with Exjade. The majority of these patients were children and adolescents with ß thalassemia and serum ferritin levels <1500 mcg/L.
- Fatal GI hemorrhages, especially in elderly patients who had advanced hematologic malignancies and/or low platelet counts, have been reported. Non-fatal upper GI irritation, ulceration and hemorrhage have been reported in patients, including children and adolescents, receiving Exjade [see Adverse Reactions (6.1)]. Physicians and patients should remain alert 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. Use caution when administering Exjade in combination with drugs that have ulcerogenic or hemorrhagic potential, such as non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, oral bisphosphonates, or anticoagulants.
- Rashes may occur during Exjade (deferasirox) treatment. For rashes of mild to moderate severity, Exjade may be continued without dose adjustment, since the rash often resolves spontaneously. In severe cases, Exjade may be interrupted. Reintroduction at a lower dose with escalation may be considered in combination with a short period of oral steroid administration. Erythema multiforme has been reported during Exjade treatment.
- Clinical trials to demonstrate increased survival or to confirm clinical benefit have not been completed. Exjade has been shown to decrease serum ferritin and liver iron concentration in clinical trials. Consider the importance of these factors as well as individual patient factors and the prognosis associated with any underlying conditions before initiation of Exjade therapy.
- In postmarketing experience, there have been reports of serious adverse reactions, some with a fatal outcome, in patients taking Exjade therapy, predominantly when the drug was administered to patients with advanced age, complications from underlying conditions or very advanced disease. Most of these deaths occurred within six months of Exjade initiation and generally involved worsening of the underlying condition. The reports do not rule out the possibility that Exjade may have contributed to the deaths.