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Drug Safety and Availability

New Molecular Entity (NME) - Early Safety Findings - Volume 1, Number 1, Fall 2007

Deferasirox (marketed as Exjade)

Deferasirox is an orally active chelating agent that is selective for iron (Fe3+) and was approved for marketing in the United States in November 2005 in accordance with the regulations governing accelerated approval of new drugs for serious or life-threatening illnesses. Deferasirox is indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients two years of age and older. Deferasirox is a tridentate ligand that binds iron with high affinity in a 2:1 ratio.1

Deferasirox is distributed by a limited number of specialty pharmacies in the U.S., and many of the suspected adverse drug reaction reports described below are based on these pharmacies' telephone inquiries of patients and healthcare professionals.

Between November 2, 2005, and June 20, 2006, FDA received 115 reports of suspected adverse drug reactions in association with the use of deferasirox (the number of reports represents crude counts that may reflect duplicates). Of these 115 reports, 108 reported a serious outcome including death (19; 17 unduplicated), hospitalization (74), life-threatening (6), disabled (4), and/or required intervention (1). For cases with an outcome of death, the cause of death reported in many cases was due to progression or complication of the underlying disease. The number of males was slightly greater than females (54% versus 46%), and the source of the reports was mainly domestic (86%). The ages ranged from 6 to 91 years, and 37% (43 of 115 cases) of the patients were 65 years of age or older. Thus far, the adverse events reported in the pediatric population (17 unduplicated cases) have been of no greater severity than those described in the adult population. No fatal events were reported in pediatric patients.

Of the 115 reports, commonly reported adverse event terms involved the gastrointestinal (including hepatic), renal, and hematological systems (see Table). Selected hepatic, renal, and hematological events are discussed below.


Deferasirox - Commonly Reported Reaction Terms
n=115 reports
MedDRA* Preferred Terms

Total Case/Event Count

    Gastrointestinal:
     Alanine aminotransferase  
     increased

17

     Blood bilirubin increased

16

     Diarrhea

17

     Nausea

16

    Renal:
     Blood urea increased

14

     Blood creatinine increased

17

     Renal failure acute

7

    Hematological:
     Hemoglobin decreased

18

     Platelet count decreased

11

     Hematocrit decreased

9

     Sickle cell anemia with crisis

7

    Other:
     Pyrexia

27

     Dyspnea

10

     Fatigue

10

     Rash

9

     Dehydration

9

     Malaise

8

     Asthenia

7

* MedDRA (Medical Dictionary of Regulatory Activities)
Preferred Terms are not mutually exclusive; one report may contain an unlimited number of preferred terms

Hepatic events: 24 unduplicated reports involved hepatic adverse events, which augmented preapproval hepatotoxicity signals, described in product labeling, of increased serum transaminase and drug-induced hepatitis. The reported events include increased aminotransferases, increased bilirubin, jaundice, ascites, subclinical and clinical hepatitis, liver failure, hepatic encephalopathy, and cholecystitis. Three cases of hepatic failure were reported in patients with significant hepatic history and/or use of concomitant medication with known hepatic adverse events. The contribution of deferasirox therapy to hepatic failure is unclear in these cases.

Renal events: 16 unduplicated reports described renal adverse events, including renal failure, acute renal failure, glomerulonephritis, interstitial nephritis, and renal tubulopathy. Four patients had a history of renal disease. Seven patients improved after discontinuation of deferasirox. In the seven cases of acute renal failure, time to onset was 15 days (range 5 to 58) after initiation of deferasirox therapy; and 2 cases were fatal, two required treatment with hemodialysis, and four improved or recovered.

Hematologic events: There have been postmarketing reports (both spontaneous (15 unduplicated reports) and from clinical trials) of cytopenias, including agranulocytosis, neutropenia, and thrombocytopenia, in patients treated with deferasirox. Some of these patients died. Although most of these patients had preexisting hematologic disorders that are frequently associated with bone marrow failure, a contributory role for deferasirox cannot be excluded.

Healthcare professionals are requested to report any suspect serious adverse reactions in association with deferasirox therapy, particularly:

  • Hepatic adverse events
  • Renal failure, including fatal renal failure
  • Cytopenias, including agranulocytosis, neutropenia, and thrombocytopenia

Recently, the product labeling has been updated to reflect the current information regarding the cases of acute renal failure and cytopenias in the Warnings and the Adverse Reactions sections, and to provide recommendations to healthcare professionals for monitoring patients. Additionally, a Dear Healthcare Professional Letter has been issued to alert the public to these serious adverse events.2 FDA continues to receive reports of suspected adverse drug reactions in association with use of deferasirox and is evaluating and closely monitoring these reports. As a condition of approval, in accordance with the regulations governing accelerated approval of new drugs for serious or life-threatening illnesses, further studies are being performed to determine the long-term benefits and risks of deferasirox.

References:

  1. Deferasirox (Exjade) product label.
  2. Dear Healthcare Professional Letter.