Deferasirox (Page 6 of 9)

8.4 Pediatric Use

Transfusional Iron Overload

The safety and effectiveness of deferasirox have been established in pediatric patients 2 years of age and older for the treatment of transfusional iron overload [ see Dosage and Administration ( 2.1)].

Safety and effectiveness have not been established in pediatric patients less than 2 years of age for the treatment of transfusional iron overload.

Pediatric approval for treatment of transfusional iron overload was based on clinical studies of 292 pediatric patients 2 years to less than 16 years of age with various congenital and acquired anemias. Seventy percent of these patients had beta-thalassemia [see Indications and Usage ( 1), Dosage and Administration ( 2.1), Clinical Studies ( 14)] . In those clinical studies, 173 children (ages 2 to < 12 years) and 119 adolescents (ages 12 to < 17 years) were exposed to deferasirox.

In general, risk factors for deferasirox-associated kidney injury include preexisting renal disease, volume depletion, overchelation, and concomitant use of other nephrotoxic drugs. Acute kidney injury, and acute liver injury and failure has occurred in pediatric patients. In a pooled safety analysis, pediatric patients with higher deferasirox exposures had a greater probability of renal toxicity and decreased renal function, resulting in increased deferasirox exposure and progressive renal toxicity/kidney injury. Higher rates of renal adverse events have been identified among pediatric patients receiving deferasirox doses greater than 25 mg/kg/day when their serum ferritin values were less than 1,000 mcg/L [see Dosage and Administration ( 2.5), Warnings and Precautions ( 5.1, 5.6), Adverse Reactions ( 6.1, 6.2)] .

Monitor renal function by estimating GFR using an eGFR prediction equation appropriate for pediatric patients and evaluate renal tubular function. Monitor renal function more frequently in pediatric patients in the presence of renal toxicity risk factors, including episodes of dehydration, fever and acute illness that may result in volume depletion or decreased renal perfusion. Use the minimum effective dose [see Warnings and Precautions ( 5.1)] .

Interrupt deferasirox in pediatric patients with transfusional iron overload for acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor more frequently. Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal. Evaluate the risk benefit profile of continued deferasirox use in the setting of decreased renal function. Avoid use of other nephrotoxic drugs [see Dosage and Administration ( 2.5), Warnings and Precautions ( 5.1)] .

Juvenile Animal Toxicity Data

Renal toxicity was observed in adult mice, rats, and marmoset monkeys administered deferasirox at therapeutic doses. In a neonatal and juvenile toxicity study in rats, deferasirox was administered orally from postpartum Day 7 through 70, which equates to a human age range of term neonate through adolescence. Increased renal toxicity was identified in juvenile rats compared to adult rats at a dose based on mg/m 2 approximately 0.4 times the recommended dose of 20 mg/kg/day. A higher frequency of renal abnormalities was noted when deferasirox was administered to non-iron overloaded animals compared to iron overloaded animals.

Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s EXJADE ® (deferasirox) tablets for oral suspension. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

8.5 Geriatric Use

Four hundred thirty-one (431) patients greater than or equal to 65 years of age were studied in clinical trials of deferasirox in the transfusional iron overload setting. The majority of these patients had myelodysplastic syndrome (MDS) (n = 393). In these trials, elderly patients experienced a higher frequency of adverse reactions than younger patients. Monitor elderly patients for early signs or symptoms of adverse reactions that may require a dose adjustment. Elderly patients are at increased risk for toxicity due to the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range.

In elderly patients, including those with MDS, individualize the decision to remove accumulated iron based on clinical circumstances and the anticipated clinical benefit and risks of deferasirox therapy.

8.6 Renal Impairment

Deferasirox is contraindicated in patients with eGFR less than 40 mL/min/1.73 m 2 [see Contraindications ( 4)] . For patients with renal impairment (eGFR 40–60 mL/min/1.73 m 2), reduce the starting dose by 50% [see Dosage and Administration ( 2.4)]. Exercise caution in pediatric patients with eGFR between 40 and 60 mL/minute/1.73 m 2 [see Dosage and Administration ( 2.4)] . If treatment is needed, use the minimum effective dose with enhanced monitoring of glomerular and renal tubular function. Individualize dose titration based on improvement in renal injury [see Dosage and Administration ( 2.4, 2.5)] .

Deferasirox can cause glomerular dysfunction, renal tubular toxicity, or both, and can result in acute renal failure. Monitor all patients closely for changes in eGFR and renal tubular dysfunction during deferasirox treatment. If either develops, consider dose reduction, interruption or discontinuation of deferasirox until glomerular or renal tubular function returns to baseline [see Dosage and Administration ( 2.4, 2.5), Warnings and Precautions ( 5.1)] .

8.7 Hepatic Impairment

Avoid the use of deferasirox in patients with severe (Child-Pugh C) hepatic impairment. For patients with moderate (Child-Pugh B) hepatic impairment, the starting dose should be reduced by 50%. Closely monitor patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment for efficacy and adverse reactions that may require dose titration [see Dosage and Administration ( 2.4), Warnings and Precautions ( 5.2)] .

10 OVERDOSAGE

Cases of overdose (2 to 3 times 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. In one pediatric case, a dose of 2 to 3 times the prescribed dose for 6 days, resulted in acute renal failure requiring hemofiltration and acute liver injury/failure, which were reversible with intensive care support. Single doses up to 80 mg per kg per day in iron overloaded beta-thalassemic patients have been tolerated with nausea and diarrhea noted. In healthy volunteers, single doses of up to 40 mg per kg per day were tolerated. There is no specific antidote for deferasirox. In case of overdose, induce vomiting and employ gastric lavage.

11 DESCRIPTION

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

Molecular Structure
(click image for full-size original)

Deferasirox is an off-white to pale yellow color powder. Its molecular formula is C 21 H 15 N 3 O 4 and its molecular weight is 373.36 g/mol.

Inactive Ingredients: anhydrous colloidal silica, crospovidone, low substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, polyvinylpyrrolidone, and sodium lauryl sulphate.

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