The following adverse reactions have been spontaneously reported during postapproval use of deferasirox tablets for oral suspension in the transfusional-iron overload setting. 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: Stevens-Johnson syndrome (SJS), hypersensitivity vasculitis, urticaria, alopecia, toxic epidermal necrolysis (TEN)
Immune System Disorders: hypersensitivity reactions (including anaphylactic reaction and angioedema)
Renal and Urinary Disorders: acute renal failure, tubulointerstitial nephritis
Hepatobiliary Disorders: hepatic failure
Gastrointestinal Disorders: gastrointestinal perforation
Blood and Lymphatic System Disorders: worsening anemia
5-Year Pediatric Registry
In a 5-year observational study, 267 pediatric patients 2 to <6 years of age (at enrollment) with transfusional hemosiderosis received deferasirox. Of the 242 patients who had pre-and post-baseline eGFR measurements, 116 (48%) patients had a decrease in eGFR of ≥33% observed at least once. Twenty-one (18%) of these 116 patients with decreased eGFR had a dose interruption, and 15 (13%) of these 116 patients had a dose decrease within 30 days. Adverse events leading to permanent discontinuation from the study included liver injury (n=11), renal tubular disorder (n=1), proteinuria (n=1), hematuria (n=1), upper gastrointestinal hemorrhage (n=1), vomiting (n=2), abdominal pain (n=1), and hypokalemia (n=1).
The concomitant administration of deferasirox tablets for oral suspension and aluminum-containing antacid preparations has not been formally studied. Although deferasirox has a lower affinity for aluminum than for iron, do not take deferasirox tablets for oral suspension with aluminum-containing antacid preparations due to the mechanism of action of deferasirox tablets for oral suspension.
Deferasirox may induce CYP3A4 resulting in a decrease in CYP3A4 substrate concentration when these drugs are coadministered. Closely monitor patients for signs of reduced effectiveness when deferasirox is administered with drugs metabolized by CYP3A4 (e.g., alfentanil, aprepitant, budesonide, buspirone, conivaptan, cyclosporine, darifenacin, darunavir, dasatinib, dihydroergotamine, dronedarone, eletriptan, eplerenone, ergotamine, everolimus, felodipine, fentanyl, hormonal contraceptive agents, indinavir, fluticasone, lopinavir, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, pimozide, quetiapine, quinidine, saquinavir, sildenafil, simvastatin, sirolimus, tacrolimus, tolvaptan, tipranavir, triazolam, ticagrelor, and vardenafil) [see Clinical Pharmacology (12.3)].
Deferasirox inhibits CYP2C8 resulting in an increase in CYP2C8 substrate (e.g., repaglinide and paclitaxel) concentration when these drugs are coadministered. If deferasirox tablets for oral suspension and repaglinide are used concomitantly, consider decreasing the dose of repaglinide and perform careful monitoring of blood glucose levels. Closely monitor patients for signs of exposure related toxicity when deferasirox tablets for oral suspension are coadministered with other CYP2C8 substrates [see Clinical Pharmacology (12.3)].
Deferasirox inhibits CYP1A2 resulting in an increase in CYP1A2 substrate (e.g., alosetron, caffeine, duloxetine, melatonin, ramelteon, tacrine, theophylline, tizanidine) concentration when these drugs are coadministered. An increase in theophylline plasma concentrations could lead to clinically significant theophylline-induced CNS or other adverse reactions. Avoid the concomitant use of theophylline or other CYP1A2 substrates with a narrow therapeutic index (e.g., tizanidine) with deferasirox tablets for oral suspension. Monitor theophylline concentrations and consider theophylline dose modification if you must coadminister theophylline with deferasirox tablets for oral suspension. Closely monitor patients for signs of exposure related toxicity when deferasirox tablets for oral suspension are coadministered with other drugs metabolized by CYP1A2 [see Clinical Pharmacology (12.3)].
Deferasirox is a substrate of UGT1A1 and to a lesser extent UGT1A3. The concomitant use of deferasirox tablets for oral suspension with potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) may result in a decrease in deferasirox tablets for oral suspension efficacy due to a possible decrease in deferasirox concentration. Avoid the concomitant use of potent UGT inducers with deferasirox tablets for oral suspension. Consider increasing the initial dose of deferasirox tablets for oral suspension if you must coadminister these agents together [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].
Avoid the concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol) with deferasirox tablets for oral suspension due to a possible decrease in deferasirox concentration. If you must coadminister these agents together, consider increasing the initial dose of deferasirox tablets for oral suspension [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].
Increased exposure of busulfan was observed with concomitant use with deferasirox. Monitor plasma concentrations of busulfan when coadministered with deferasirox to allow dose adjustment of busulfan as needed [see Clinical Pharmacology (12.3)].
There are no studies with deferasirox tablets for oral suspension 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 an mg/m2 basis. No fetal effects were noted in pregnant rabbits at doses equivalent to the human recommended dose on an mg/m2 basis. Deferasirox tablets for oral suspension 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 have 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.
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/m2 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 times the MRHD on an mg/m2 basis). Maternal toxicity, loss of litters, and decreased offspring viability occurred at 90 mg/kg/day (1 times the MRHD on a mg/m2 basis) and increases in renal anomalies in male offspring occurred at 30 mg/kg/day (0.3 times the MRHD on a mg/m2 basis).
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.
Counsel patients to use non-hormonal method(s) of contraception since deferasirox tablets for oral suspension can render hormonal contraceptives ineffective [see Drug Interactions (7.2)].
Transfusional Iron Overload
The safety and effectiveness of deferasirox tablets for oral suspension 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 tablets for oral suspension 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 tablets for oral suspension 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 tablets for oral suspension 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 tablets for oral suspension 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/m2 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.
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