10 OVERDOSAGE
Cases of overdose (2-3times the prescribed dose for several weeks) have been reported. In one case, this resulted in hepatitis which resolved without long-term consequences after a dose interruption. Single doses up to 80mg/kg/day in iron overloaded β-thalassemic patients have been tolerated with nausea and diarrhea noted. In healthy volunteers, single doses of up to 40mg/kg/day were tolerated. There is no specific antidote for Exjade. In case of overdose, induce vomiting and employ gastric lavage.

11 DESCRIPTION
Exjade(deferasirox) is an iron chelating agent. Exjade tablets for oral suspension contain 125mg, 250mg, or 500mg deferasirox. Deferasirox is designated chemically as 4-[3,5-Bis (2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]-benzoic acid and its structural formula is

Deferasirox is a white to slightly yellow powder. Its molecular formula is C21H15N3O4 and its molecular weight is 373.4.

Inactive Ingredients: Lactose monohydrate(NF), crospovidone(NF), povidone(K30)(NF), sodium lauryl sulphate(NF), microcrystalline cellulose(NF), silicon dioxide(NF), and magnesium stearate(NF).

12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Exjade(deferasirox) is an orally active chelator that is selective for iron (as Fe3+). It is a tridentate ligand that binds iron with high affinity in a 2:1ratio. Although deferasirox has very low affinity for zinc and copper there are variable decreases in the serum concentration of these trace metals after the administration of deferasirox. The clinical significance of these decreases is uncertain.

12.2 Pharmacodynamics
Pharmacodynamic effects tested in an iron balance metabolic study showed that deferasirox (10, 20 and 40mg/kg per day) was able to induce a mean net iron excretion (0.119, 0.329 and 0.445mg Fe/kg body weight per day, respectively) within the clinically relevant range (0.1-0.5mg/kg per day). Iron excretion was predominantly fecal.

12.3 Pharmacokinetics
Absorption

Exjade is absorbed following oral administration with median times to maximum plasma concentration (tmax) of about 1.5-4hours.The Cmax and AUC of deferasirox increase approximately linearly with dose after both single administration and under steady-state conditions. Exposure to deferasirox increased by an accumulation factor of 1.3-2.3 after multiple doses. The absolute bioavailability (AUC) of deferasirox tablets for oral suspension is 70% compared to an intravenous dose. The bioavailability (AUC) of deferasirox was variably increased when taken with a meal.

Distribution

Deferasirox is highly (~99%) protein bound almost exclusively to serum albumin. The percentage of deferasirox confined to the blood cells was 5% in humans. The volume of distribution at steady state (Vss) of deferasirox is 14.37±2.69L in adults.

Metabolism

Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion. Deconjugation of glucuronidates in the intestine and subsequent reabsorption (enterohepatic recycling) is likely to occur. Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450-catalyzed (oxidative) metabolism of deferasirox appears to be minor in humans (abou