Deferasirox is an oral iron chelating agent used to treat chronic iron overload. Deferasirox has been linked to a low rate of transient serum aminotransferase elevations during therapy and to rare instances of clinically apparent liver injury, which can be severe and even fatal.
Deferasirox (dee fer’ a sir ox) is an orally available iron chelating agent that is selective for ferric iron and binds iron with a high affinity. Deferasirox binds two iron molecules and is eliminated in the feces after hepatic metabolism by glucuronidation. Deferasirox also binds zinc and copper, but to a far lower extent than iron. In clinical trials in patients with transfusion related iron overload, deferasirox lowered both circulating and tissue (cardiac, liver) iron. Deferasirox was approved for use in the United States in 2005 and current indications are for chronic iron overload due to blood transfusion and in nontransfusion dependent thalassemia syndromes. Deferasirox is available in tablets of 125, 250 and 500 mg under the brand name Exjade. The recommended initial dose is 10 to 20 mg/kg daily. Side effects can include diarrhea, nausea, abdominal pain, headache, dizziness, rash and increases in serum creatinine. Uncommon, but potentially severe adverse events are renal failure, gastrointestinal bleeding, bone marrow suppression and hypersensitivity reactions including Stevens Johnson syndrome.
In large clinical trials of deferasirox, elevations in serum aminotransferase levels above 5 times the upper limit of normal (ULN) occurred in 6% of patients and led to drug discontinuation in 1% to 2%. In addition, there have been several single case reports of clinically apparent liver injury arising during deferasirox therapy which was often severe and occasionally fatal. The onset of acute liver injury ranged from a few days to severak years after starting deferasirox but most cases occurred within 1 to 3 months. The pattern of liver injury was typically hepatocellular or mixed with prominent elevations in serum aminotransferase levels. Immunoallergic and autoimmune features were absent. Recovery was usually rapid once deferasirox was stopped, but some cases were associated with progressive liver injury and hepatic failure. Because patients with iron overload often have underlying liver disease, a superimposed acute hepatocellular injury may result in an increased risk of acute liver failure. Deferasirox has a boxed warning regarding hepatotoxicity and regular monitoring of serum bilirubin and aminotransferase levels is recommended.
Likelihood score: C (probable cause of clinically apparent liver injury).
Mechanism of Injury
The mechanism of injury accounting for serum enzyme elevations during deferasirox therapy is not known. The injury may be due to direct, intrinsic toxicity and to have a more severe outcome in patients with pre-existing liver disease as a result of iron overload or concurrent hepatitis B or C. Deferasirox is metabolized in the liver largely by glucuronidation and biliary excretion. At least one case of severe liver injury attributed to deferasirox was associated with polymorphisms of the hepatic genes known to be involved in deferasirox excretion.
Outcome and Management
Deferasirox is well known to cause transient serum aminotransferase elevations that are usually self-limited and benign. However, it has also been implicated in cases of clinically apparent liver injury and acute liver failure.. The product label recommends monitoring of serum aminotransferase levels and bilirubin before and every 2 weeks for the first month of treatment, followed by at least monthly thereafter. Persistent serum aminotransferase elevations and values above 5 times ULN should lead to dose reduction or temporary cessation. There does not appear to be cross reactivity in risk for hepatic injury between deferasirox and other chelators including deferoxamine or deferiprone.
Drug Class: Hematological Agents; Chelating Agents, Iron Chelators
Other Drugs in the Subclass, Iron Chelators: Deferiprone, Deferoxamine
REPRESENTATIVE TRADE NAMES
Deferasirox – Exjade®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NO.
References updated: 26 December 2017
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