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Deferasirox for the Treatment of Chronic Iron Overload in Transfusional Hemosiderosis

Deferasirox for the Treatment of Chronic Iron Overload in Transfusional Hemosiderosis

Purpose: This report describes the Food and Drug Administration's review of data and analyses leading to the approval of the oral iron chelator, deferasirox for the treatment of chronic iron overload due to transfusional hemosiderosis.

Experimental Design: The FDA reviewed findings of a controlled, open-label, randomized multicenter phase III study of deferasirox vs deferoxamine in 586 patients with beta-thalessemia and transfusional hemosiderosis. The study results as well as the results of the FDA review of chemistry, preclinical pharmacology, and supportive studies are described.

Results: Following 48 weeks of treatment in the phase III study, patients' liver iron concentrations (a key endpoint variable) had decreased an average of 2.4 mg of iron (Fe)/g dry weight (dw) and 2.9 mg Fe/g dw in the deferasirox and deferoxamine groups, respectively, despite continued blood transfusions in both cohorts. Deferasirox was associated with serum creatinine increases in approximately a third of patients. Common adverse events included gastrointestinal symptoms and skin rash. Other data provided supportive evidence of deferasirox safety and efficacy.

Conclusions: The FDA granted deferasirox accelerated approval on November 2, 2005, for use in treating chronic iron overload due to transfusional hemosiderosis in patients ≥ 2 years of age. The sponsor must obtain clinical data demonstrating the drug's long-term safety and effectiveness.

Red blood cell transfusion therapy administered on a long-term, recurrent basis is a mainstay in the treatment of several chronic congenital and acquired anemias.[1-3] However, patients receiving such transfusions may consequently develop transfusional hemosiderosis, a major complication of iron overload that sometimes results in heart failure, cirrhosis, diabetes mellitus, or other endocrinopathies.[4-6]

Lessening the body's iron burden through chelation therapy with the parenteral agent deferoxamine has been shown to prevent or delay the complications of transfusional hemosiderosis.[1,2] However, the pharmacologic features of deferoxamine require its prolonged infusion, usually for 8 to 12 hours at least 5 days a week. This inconvenience and infectious complications associated with the route of administration limit compliance with the deferoxamine regimen, and patients may consequently develop progressive manifestations of transfusional hemosiderosis.[7,8]

Deferasirox (Exjade) was developed for use as an orally administered therapeutic iron chelation agent.[9,10] Its safety and efficacy were demonstrated in 48-week controlled clinical trials (with some patients entering extension studies of up to 3 years duration). This review summarizes the major clinical and supportive data and the regulatory process leading to the US Food and Drug Administration's (FDA's) approval of deferasirox for use in the treatment of chronic iron overload resulting from transfusional hemosiderosis in patients ≥ 2 years of age.[11]

Regulatory Background

Prior to the approval of deferasirox, the only drug approved by the FDA for the treatment of transfusional hemosiderosis was deferoxamine.[12,13] Because deferoxamine must be administered parenterally over 8 to 12 hours, the FDA regarded an oral alternative to deferoxamine as an important, unmet medical need. The original deferasirox investigational drug application was submitted on June 30, 1999, and deferasirox received FDA Fast Track status on February 21, 2003. The Fast Track program facilitates development and expedites review of new drugs for serious or life-threatening conditions not otherwise being addressed. Additionally, because of the relative rarity of transfusional hemosiderosis, the FDA designated deferasirox an Orphan Drug (a product that treats a disease affecting fewer than 200,000 Americans). On November 2, 2005, deferasirox received accelerated approval; this approval category requires the sponsor to demonstrate the drug's long-term safety and efficacy.[11]

Iron Metabolism and Chelation Therapy

The process of iron metabolism in the human body (including the limitations on iron excretion) has been well described.[4,5] In a state of metabolic balance, the human body absorbs 1 to 2 mg of iron daily from the diet and loses a similar amount through cellular sloughing. Iron administration in excess of this amount results in sequestration within the body, where it accumulates in end organs and can result in toxicity and organ damage. Since transfusional therapy may require administration of 2 to 3 units of red blood cells per month (each unit containing 200-250 mg of iron [Fe]), patients may present evidence of transfusional hemosiderosis within a few years of monthly transfusions.[14]

Methods to monitor iron stores in patients undergoing long-term transfusion therapy are limited in utility and meaningfulness. Serum ferritin measurement is convenient but correlates incompletely with the body's iron stores.[4] Measurement of iron concentration in a liver tissue biopsy sample is thought to more accurately reflect total body iron stores. Normally, iron concentration in the liver is < 1.5 mg Fe/g dry weight (dw). In patients with hemosiderosis, liver iron concentration (LIC) usually exceeds 2 mg Fe/g dw and may reach ≥ 55 mg Fe/g dw. A patient's cumulative blood transfusion history has been shown to correlate with LIC.[1,4]

A correlation between LIC and the risk of cirrhosis and cardiac damage has not been established.[6,15] However, exploration of the clinical utility of LIC has been especially limited by the invasive nature of liver biopsy. This limitation has prompted the development of noninvasive methods to measure LIC. Assessment techniques such as magnetic resonance imaging and magnetic field detection procedures using a superconducting quantum interference device (SQUID) were partially explored in the deferasirox clinical development program.


Deferasirox is the active component of Exjade tablets for oral suspension. Designated chemically as 4-[3,5-Bis (2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]-benzoic acid, this agent is a white to slightly yellow powder with a molecular formula of C21H15N3O4 and a molecular weight of 373.4. The structural formula of deferasirox is shown in Figure 1.

The drug product is a tablet in three strengths: 125, 250, and 500 mg. Doses should be calculated so that whole tablets will be used (rounded to the nearest whole tablet). Tablets are not swallowed directly but are dispersed in 3.5 oz of liquid for doses < 1 g or in 7.0 oz of liquid for doses > 1 g. Patients should drink the resulting suspension. The suspension should be used immediately after preparation.

Pharmacology and Toxicology

Deferasirox is a member of the tridentate iron chelator class of drugs. Two molecules of deferasirox bind one ferric atom.

Absorption, Distribution, Metabolism, and Excretion

Deferasirox was rapidly absorbed following single oral doses in mice, rats, dogs, marmosets, monkeys, and humans. The drug and its iron complex were extensively bound (> 98%) to plasma proteins in all species tested, including man. Whole-body autoradiography tissue distribution studies in rats showed the highest levels of radioactivity in the gastrointestinal tract and excretory organs (liver, kidneys, and intestine). Regardless of the route of administration, deferasirox was excreted predominantly via bile/feces in all tested species. Renal excretion of deferasirox and its metabolites was approximately 8% of the administered dose.


The major target organ of deferasirox toxicity in all tested animal species was the kidney; toxicity in other target organs (eye, heart, gastrointestinal tract) varied according to species. Deferasirox was not tumorigenic in rats and transgenic mice.

Human Experience

In humans, peak deferasirox plasma levels were achieved 1 to 4 hours after oral administration. The mean maximum blood concentration (Cmax) and area under the concentration—time curve (AUC) values of deferasirox and its iron complex increased in a dose-related manner within a dose range of 2.5 to 80 mg/kg. Deferasirox steady-state was achieved after 3 days of daily dosing. The drug's terminal half-life ranged from 8 to 16 hours following oral administration. In vitro metabolism studies in human liver microsomes and human hepatocytes have shown deferasirox to be primarily metabolized by glucuronidation, with an acyl-glucuronide being the major metabolite.


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