A total of 700 patients were treated with Exjade® (deferasirox) in premarketing studies lasting for 48 weeks in adult and pediatric patients. These 700 patients included 469 with β-thalassemia, 99 with rare anemias, and 132 with sickle cell disease. Of these patients, 45% were male, 70% were Caucasian and 292 patients were < 16 years of age. In the sickle cell disease population, 89% of patients were Black. Four hundred sixty-nine patients (403 β-thalassemia and 66 rare anemias) were entered into extensions of the original clinical protocols. In ongoing extension studies, median durations of treatment were 88 to 205 weeks.

The most frequently occurring adverse events in the therapeutic studies of Exjade were diarrhea, vomiting, nausea, headache, abdominal pain, pyrexia, cough, and increases in serum creatinine. Maintenance of adequate hydration for patients experiencing diarrhea or vomiting is recommended. Gastrointestinal symptoms, increases in serum creatinine, and skin rash were dose related.

Table 1 displays adverse events occurring in > 5% of patients in either treatment group in Study 1. Abdominal pain, nausea, vomiting, diarrhea, and skin rashes were the most frequent adverse events reported with a suspected relationship to Exjade.

Table 1: Adverse Events Occurring in > 5% of β-Thalassemia Patients in Study 1

In Study 1, 113 patients treated with Exjade had increases in serum creatinine > 33% above baseline on 2 separate occasions (Table 2). Twenty-five patients required dose reductions. Increases in serum creatinine appeared to be dose related. (See WARNINGS, Renal.) Seventeen patients developed elevations in SGPT/ALT levels > 5 times the upper limit of normal at 2 consecutive visits. Two patients had liver biopsy proven drug-induced hepatitis and both discontinued Exjade therapy. (See WARNINGS, Hepatic.) Two additional patients, who did not have elevations in SGPT/ALT > 5 times the upper limit of normal, discontinued Exjade because of increased SGPT/ALT. Increases in transaminases did not appear to be dose related.

Table 2: Number (%) of Patients with Increases in Serum Creatinine or SGPT/ALT in Study 1

Adverse events that led to discontinuations included abnormal liver function tests (2 patients) and drug-induced hepatitis (2 patients ), skin rash, glycosuria/proteinuria, Henoch Schönlein purpura, hyperactivity/insomnia, drug fever, and cataract (1 patient each).

In the overall population of 700 patients, uncommon adverse reactions (0.1% to 1%) included gastritis, edema, sleep disorder, pigmentation disorder, dizziness, anxiety, maculopathy, cholelithiasis, pyrexia, fatigue, pharyngolaryngeal pain, early cataract and hearing loss (see PRECAUTIONS). Adverse events which most frequently led to dose interruption or dose adjustment were rash, gastrointestinal disorders, infections, increased serum creatinine, and increased serum transaminases.

Postmarketing Experience

The following adverse reactions have been spontaneously reported during post-approval use of Exjade. Because these reactions are reported voluntarily from a population of uncertain size, in which patients may have received concomitant medication, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure.

There have been reports of cytopenias, including agranulocytosis, neutropenia and thrombocytopenia, in patients treated with Exjade. Although most of these patients had preexisting hematologic disorders that are frequently associated with bone marrow failure, a contributory role for Exjade cannot be excluded. Cases of acute renal failure have been reported in the context of severe complications relating to the underlying disease. There have been postmarketing reports of hepatic failure, some with a fatal outcome, in patients treated with Exjade. Most of these events occurred in patients greater than 55 years of age. Most reports of hepatic failure involved patients with significant comorbidities, including liver cirrhosis and multi-organ failure. (See WARNINGS.)

Skin and subcutaneous tissue disorders: leukocytoclastic vasculitis, urticaria.

Immune system disorders: hypersensitivity reactions (including anaphylaxis and angioedema).

The concomitant administration of Exjade and aluminum-containing antacid preparations has not been formally studied. Although deferasirox has a lower affinity for aluminum than for iron, Exjade should not be taken with aluminum-containing antacid preparations.

In healthy volunteers, Exjade had no effect on the pharmacokinetics of digoxin. The effect of digoxin on Exjade pharmacokinetics has not been studied.

The concomitant administration of Exjade and vitamin C has not been formally studied. Doses of vitamin C up to 200 mg were allowed in clinical studies without negative consequences.

The interaction of Exjade with hydroxyurea has not been formally studied. No inhibition of deferasirox metabolism by hydroxyurea is expected based on the results of an in vitro study.

Exjade should not be combined with other iron chelator therapies, as safety of such combinations has not been established.

Drug/Food Interactions

The bioavailability (AUC) of deferasirox was variably increased when taken with a meal. Deferasirox should be taken on an empty stomach 30 minutes before eating.

Exjade tablets for oral suspension can be dispersed in water, orange juice, or apple juice.

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