Deferasirox

Pregnancy

8.1 Pregnancy Risk Summary There are no studies with the use of deferasirox in pregnant women to inform drug-associated risks. Administration of deferasirox to rats during pregnancy resulted in decreased offspring viability and an increase in renal anomalies in male offspring at doses that were about or less than the recommended human dose on a mg/m 2 basis. No fetal effects were noted in pregnant rabbits at doses equivalent to the human recommended dose on an mg/m 2 basis. Deferasirox should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown.All pregnancies had a background risk of birth defect, loss, or other adverse outcomes. However, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data In embryo-fetal developmental studies, pregnant rats and rabbits received oral deferasirox during the period of organogenesis at doses up to 100 mg/kg/day in rats and 50 mg/kg/day in rabbits (1.2 times the maximum recommended human dose (MRHD) on an mg/m 2 basis). These doses resulted in maternal toxicity but no fetal harm was observed. In a prenatal and postnatal developmental study, pregnant rats received oral deferasirox daily from organogenesis through lactation day 20 at doses of 10, 30, and 90 mg/kg/day (0.1, 0.3, and 1.0 times the MRHD on a mg/m 2 basis). Maternal toxicity, loss of litters, and decreased offspring viability occurred at 90 mg/kg/day (1.0 times the MRHD on a mg/m 2 basis), and increases in renal anomalies in male offspring occurred at 30 mg/kg/day (0.3 times the MRHD on a mg/m 2 basis).

Lactation

Lactation: Advise women not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary There are no studies with the use of deferasirox in pregnant women to inform drug-associated risks. Administration of deferasirox to rats during pregnancy resulted in decreased offspring viability and an increase in renal anomalies in male offspring at doses that were about or less than the recommended human dose on a mg/m 2 basis. No fetal effects were noted in pregnant rabbits at doses equivalent to the human recommended dose on an mg/m 2 basis. Deferasirox should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown.All pregnancies had a background risk of birth defect, loss, or other adverse outcomes. However, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data In embryo-fetal developmental studies, pregnant rats and rabbits received oral deferasirox during the period of organogenesis at doses up to 100 mg/kg/day in rats and 50 mg/kg/day in rabbits (1.2 times the maximum recommended human dose (MRHD) on an mg/m 2 basis). These doses resulted in maternal toxicity but no fetal harm was observed. In a prenatal and postnatal developmental study, pregnant rats received oral deferasirox daily from organogenesis through lactation day 20 at doses of 10, 30, and 90 mg/kg/day (0.1, 0.3, and 1.0 times the MRHD on a mg/m 2 basis). Maternal toxicity, loss of litters, and decreased offspring viability occurred at 90 mg/kg/day (1.0 times the MRHD on a mg/m 2 basis), and increases in renal anomalies in male offspring occurred at 30 mg/kg/day (0.3 times the MRHD on a mg/m 2 basis). 8.2 Lactation Risk Summary No data are available regarding the presence of deferasirox or its metabolites in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production. Deferasirox and its metabolites were excreted in rat milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in a breastfeeding child from deferasirox and its metabolites, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of the drug to the mother. 8.3 Females and Males of Reproductive Potential Contraception Counsel patients to use non-hormonal method(s) of contraception since deferasirox can render hormonal contraceptives ineffective [see Drug Interactions (7.2) ]. 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. Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes The safety and effectiveness of Deferasirox have been established in patients 10 years of age and older for the treatment of chronic iron overload with non-transfusion-dependent thalassemia (NTDT) syndromes [ see Dosage and Administration (2.2)]. Safety and effectiveness have not been established in patients less than 10 years of age with chronic iron overload in NTDT syndromes. Pediatric approval for treatment of NTDT syndromes with liver iron (Fe) concentration (LIC) of at least 5 mg Fe per gram of dry weight and a serum ferritin greater than 300 mcg/L was based on 16 pediatric patients treated with deferasirox therapy (10 years to less than 16 years of age) with chronic iron overload and NTDT. Use of deferasirox in these age groups is supported by evidence from adequate and well-controlled studies of deferasirox in adult and pediatric patients [ see Indications and Usage (1.2), Dosage and Administration (2.2), Clinical Studies (14)]. 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 AEs have been identified among pediatric patients receiving deferasirox tablets for oral suspension doses greater than 25 mg/kg/day equivalent to 17.5 mg/kg/day deferasirox 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 )] . Monitoring recommendations for all pediatric patients with Transfusional Iron Overload and NTDT It is recommended that serum ferritin be monitored every month to assess the patient’s response to therapy and to minimize the risk of overchelation [ see Warnings and Precautions (5.6)]. 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, and consider dose interruption in pediatric patients with non-transfusion-dependent 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 JADENU ® (deferasirox) tablets. 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. Two hundred twenty-five (225) of these patients were between 65 and 75 years of age while 206 were greater than or equal to 75 years of age. 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 tablets for oral suspension therapy. 8.6Renal 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 to 60 mL/min/1.73 m 2 ), reduce the starting dose by 50% [ see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) ] . Exercise caution in pediatric patients with an 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 use in patients with severe (Child-Pugh C) hepatic impairment. For patients with moderate (Child-Pugh B) hepatic impairment, reduce the starting dose 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), Clinical Pharmacology (12.3)].