Deferasirox
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From MedlinePlus, U.S. National Library of Medicine
Boxed warning
WARNING: RENAL FAILURE, HEPATIC FAILURE, and GASTROINTESTINAL HEMORRHAGE Renal Failure Exjade can cause acute renal failure and death, particularly in patients with comorbidities and those who are in the advanced stages of their hematologic disorders. Evaluate baseline renal function prior to starting or increasing Exjade dosing in all patients. Exjade is contraindicated in adult and pediatric patients with eGFR less than 40 mL/min/1.73 m 2 . Measure serum creatinine in duplicate prior to initiation of therapy. Monitor renal function at least monthly.
For patients with baseline renal impairment or increased risk of acute renal failure, monitor renal function weekly for the first month, then at least monthly. Reduce the starting dose in patients with preexisting renal disease. During therapy, increase the frequency of monitoring and modify the dose for patients with an increased risk of renal impairment, including use of concomitant nephrotoxic drugs, and pediatric patients with volume depletion or overchelation [see Dosage and Administration (2.1, 2.4, 2.5), Warnings and Precautions (5.1), Adverse Reactions (6.1, 6.2)] . Hepatic Failure Exjade can cause hepatic injury including hepatic failure and death.
Measure serum transaminases and bilirubin in all patients prior to initiating treatment, every 2 weeks during the first month, and at least monthly thereafter. Avoid use of Exjade in patients with severe (Child-Pugh C) hepatic impairment and reduce the dose in patients with moderate (Child-Pugh B) hepatic impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.2)] . Gastrointestinal Hemorrhage Exjade can cause gastrointestinal (GI) hemorrhages, which may be fatal, especially in elderly patients who have advanced hematologic malignancies and/or low platelet counts.
Monitor patients and discontinue Exjade for suspected GI ulceration or hemorrhage [see Warnings and Precautions (5.3)] . WARNING: RENAL FAILURE, HEPATIC FAILURE, and GASTROINTESTINAL HEMORRHAGE See full prescribing information for complete boxed warning. Exjade may cause: acute kidney injury, including acute renal failure requiring dialysis and renal tubular toxicity including Fanconi syndrome ( 5.1 ) hepatic toxicity, including failure ( 5.2 ) gastrointestinal hemorrhage ( 5.3 ) Exjade therapy requires close patient monitoring, including laboratory tests of renal and hepatic function. ( 5 )
Iron Chelator
Dosing in kidney impairment
Use in Patients With Baseline Hepatic or Renal Impairment Patients with Baseline Hepatic Impairment Mild (Child-Pugh A) Hepatic Impairment: No dose adjustment is necessary. Moderate (Child-Pugh B) Hepatic Impairment: Reduce the starting dose by 50%. Severe (Child-Pugh C) Hepatic Impairment: Avoid Exjade [see Warnings and Precautions, Use in Specific Populations] .
Patients with Baseline Renal Impairment Do not use Exjade in adult or pediatric patients with eGFR less than 40 mL/min/1.73 m 2 [see Dosage and Administration, Contraindications] . For patients with renal impairment (eGFR 40-60 mL/min/1.73 m 2 ), reduce the starting dose by 50% [see Use in Specific Populations] . Exercise caution in pediatric patients with eGFR between 40 and 60 mL/min/1.73 m 2 .
If treatment is needed, use the minimum effective dose and monitor renal function frequently. Individualize dose titration based on improvement in renal injury [see Use in Specific Populations] .
Dose Modifications for Decreases in Renal Function While on Exjade Exjade is contraindicated in patients with eGFR less than 40 mL/min/1.73 m 2 [see Contraindications]. For decreases in renal function while receiving Exjade [see Warnings and Precautions] , modify the dose as follows: Transfusional Iron Overload Adults: If the serum creatinine increases by 33% or more above the average baseline measurement, repeat the serum creatinine within 1 week, and if still elevated by 33% or more, reduce the dose by 10 mg per kg.
Pediatric Patients (ages 2 years–17 years): Reduce the dose by 10 mg/kg/day if eGFR decreases by greater than 33% below the average baseline measurement and repeat the eGFR within 1 week. Interrupt Exjade 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. Avoid use of other nephrotoxic drugs [see Warnings and Precautions] . In the setting of decreased renal function, evaluate the risk benefit profile of continued Exjade use. Use the minimum effective Exjade dose and monitor renal function more frequently, by evaluating tubular and glomerular function.
Titrate dosing based on renal injury. Consider dose reduction or interruption and less nephrotoxic therapies until improvement of renal function. If signs of renal tubular or glomerular injury occur in the presence of other risk factors such as volume depletion, reduce or interrupt Exjade to prevent severe and irreversible renal injury [see Warnings and Precautions] .
All Patients (regardless of age): Discontinue therapy for eGFR less than 40 mL/min/1.73 m 2 [see Contraindications] . Non-Transfusion-Dependent Thalassemia Syndromes Adults: If the serum creatinine increases by 33% or more above the average baseline measurement, repeat the serum creatinine within 1 week, and if still elevated by 33% or more, interrupt therapy if the dose is 5 mg per kg, or reduce by 50% if the dose is 10 or 20 mg per kg.
Pediatric Patients (ages 10 years–17 years): Reduce the dose by 5 mg/kg/day if eGFR decreases by greater than 33% below the average baseline measurement and repeat the eGFR within 1 week. Increase monitoring frequency for pediatric patients who have acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake.
Consider dose interruption until oral intake and volume status are normal. Avoid use of other nephrotoxic drugs [see Warnings and Precautions] . In the setting of decreased renal function, evaluate the risk benefit profile of continued Exjade use. Use the minimum effective Exjade dose and monitor renal function more frequently, by evaluating tubular and glomerular function.
Titrate dosing based on renal injury. Consider dose reduction or interruption and less nephrotoxic therapies until improvement of renal function. If signs of renal tubular or glomerular injury occur in the presence of other risk factors such as volume depletion, reduce or interrupt Exjade to prevent severe and irreversible renal injury [see Warnings and Precautions] .
All Patients (regardless of age): Discontinue therapy for eGFR less than 40 mL/min/1.73 m 2 [see Contraindications] .
Dosing in liver impairment
Hepatic Impairment Avoid the use of Exjade 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, Warnings and Precautions] .
Preparation and administration
Administration Do not chew tablets or swallow them whole. Take Exjade once daily on an empty stomach at least 30 minutes before food, preferably at the same time each day. Completely disperse tablets by stirring in water, orange juice, or apple juice until a fine suspension is obtained. Disperse doses of less than 1 g in 3.5 ounces of liquid and doses of 1 g or greater in 7 ounces of liquid.
After swallowing the suspension, resuspend any residue in a small volume of liquid and swallow. Do not take Exjade with aluminum-containing antacid products [see Drug Interactions].
Drug interactions
Check deferasirox against a medication listLabel text (9 paragraphs)
Do not take Exjade with aluminum-containing antacid preparations. ( 7.1 ) Exjade increases the exposure of the CYP2C8 substrate repaglinide. Consider repaglinide dose reduction and monitor blood glucose levels. ( 7.3 ) Avoid the use of Exjade with CYP1A2 substrate theophylline. ( 7.4 ) Deferasirox increases exposure of busulfan. Monitor plasma concentrations of busulfan when coadministered with deferasirox to allow dose adjustment of busulfan as needed. ( 7.7 )
7.1 Aluminum-Containing Antacid Preparations 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 take Exjade with aluminum-containing antacid preparations due to the mechanism of action of Exjade.
7.2 Agents Metabolized by CYP3A4 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)] .
7.3 Agents Metabolized by CYP2C8 Deferasirox inhibits CYP2C8 resulting in an increase in CYP2C8 substrate (e.g., repaglinide and paclitaxel) concentration when these drugs are coadministered. If Exjade 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 Exjade is coadministered with other CYP2C8 substrates [see Clinical Pharmacology (12.3)].
7.4 Agents Metabolized by CYP1A2 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 Exjade. Monitor theophylline concentrations and consider theophylline dose modification if you must coadminister theophylline with Exjade.
Closely monitor patients for signs of exposure related toxicity when Exjade is coadministered with other drugs metabolized by CYP1A2 [see Clinical Pharmacology (12.3)].
7.5 Agents Inducing UDP-glucuronosyltransferase (UGT) Metabolism Deferasirox is a substrate of UGT1A1 and to a lesser extent UGT1A3. The concomitant use of Exjade with potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) may result in a decrease in Exjade efficacy due to a possible decrease in deferasirox concentration. Avoid the concomitant use of potent UGT inducers with Exjade. Consider increasing the initial dose of Exjade if you must coadminister these agents together [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)] .
7.6 Bile Acid Sequestrants Avoid the concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol) with Exjade due to a possible decrease in deferasirox concentration. If you must coadminister these agents together, consider increasing the initial dose of Exjade [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)] .
7.7 Busulfan 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)].
Contraindications
Exjade is contraindicated in patients with: Estimated GFR less than 40 mL/min/1.73 m 2 [see Dosage and Administration (2.5), Warnings and Precautions (5.1)] ; Poor performance status; [see Warnings and Precautions (5.1, 5.3)] High-risk myelodysplastic syndromes; (this patient population was not studied and is not expected to benefit from chelation therapy) Advanced malignancies. [see Warnings and Precautions (5.1, 5.3)] Platelet counts less than 50 x 10 9 /L [see Warnings and Precautions (5.3, 5.4) Known hypersensitivity to deferasirox or any component of Exjade [see Warnings and Precautions (5.7), Adverse Reactions (6.2)] . Estimated GFR less than 40 mL/min/1.73 m 2 .
( 4 ) Patients with poor performance status. ( 4 ) Patients with high-risk myelodysplastic syndrome (MDS). ( 4 ) Patients with advanced malignancies. ( 4 ) Patients with platelet counts less than 50 x 10 9 /L. ( 4 ) Known hypersensitivity to deferasirox or any component of Exjade. ( 4 )
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Risk Summary There are no studies with the use of Exjade 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/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. Exjade 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. 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 an 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).
For breastfeeding, also see LactMed (National Library of Medicine), which summarizes milk levels and infant effects.
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