Proteinuria

In clinical studies, urine protein was measured monthly. Intermittent proteinuria (urine protein/creatinine ratio >0.6mg/mg) occurred in 18.6% of Exjade-treated patients compared to 7.2% of deferoxamine-treated patients in Study1. Although no patients were discontinued from Exjade in clinical studies up to 1year due to proteinuria, monthly monitoring is recommended. The mechanism and clinical significance of the proteinuria are uncertain.

Other Adverse Reactions

In the population of more than 5,000patients who have been treated with Exjade during clinical trials, adverse reactions occurring in 0.1% to 1% of patients included gastritis, edema, sleep disorder, pigmentation disorder, dizziness, anxiety, maculopathy, cholelithiasis, pyrexia, fatigue, pharyngolaryngeal pain, early cataract, hearing loss, gastrointestinal hemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, and renal tubulopathy (Fanconi’s syndrome). Adverse reactions occurring in 0.01% to 0.1% of patients included optic neuritis, esophagitis, and erythema multiforme. Adverse reactions which most frequently led to dose interruption or dose adjustment during clinical trials were rash, gastrointestinal disorders, infections, increased serum creatinine, and increased serum transaminases.

6.2 Postmarketing ExperienceThe following adverse reactions have been spontaneously reported during postapproval 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.

Skin and subcutaneous tissue disorders:leukocytoclastic vasculitis, urticaria, alopecia

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

7 DRUG INTERACTIONS
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, do not administer Exjade with aluminum-containing antacid preparations.

7.1 Effect of Deferasirox on Drug Metabolizing Enzymes
Deferasirox inhibits human CYP3A4, CYP2C8, CYP1A2, CYP2A6, CYP2D6, and CYP2C19 in vitro. The clinical significance of deferasirox inhibition of CYP1A2, CYP2A6, CYP2D6, and CYP2C19 is unknown.

7.2 Interaction with Midazolam and Other Agents Metabolized by CYP3A4
In healthy volunteers, the concomitant administration of Exjade and midazolam (a CYP3A4 probe substrate) resulted in a decrease of midazolam peak concentration by 23 % and exposure by 17%. In the clinical setting, this effect may be more pronounced. Therefore, due to a possible decrease in CYP3A4 substrate concentration and potential loss of effectiveness, use caution when deferasirox is administered with drugs metabolized by CYP3A4 (e.g., cyclosporine, simvastatin, hormonal contraceptive agents).

7.3 Interaction with Repaglinide and Other Agents Metabolized by CYP2C8
In a healthy volunteer study, the concomitant administration of Exjade (30mg/kg/day for 4 days) and the CYP2C8 probe substrate repaglinide (single dose of 0.5 mg) resulted in an increase in repaglinide systemic exposure (