Data from FDA (Food and Drug Administration, USA) - Curated by Marshall Pearce - Last updated 12 January 2018

Indication(s)

1 INDICATIONS AND USAGE Exjade is an iron chelator indicated for the treatment of chronic iron overload due to blood transfusions in patients 2 years of age and older. This indication is based on reduction in serum ferritin and liver iron concentration (LIC). An improvement in survival or disease-related symptoms has not been established. (1.1) Exjade is indicated for the treatment of chronic iron overload in patients 10 years of age and older with non-transfusion-dependent thalassemia (NTDT) syndromes and with a 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. This indication is based on achievement of an LIC less than 5 mg Fe/g dw. An improvement in survival or disease-related symptoms has not been established. (1.2) Limitation of Use Controlled clinical trials of Exjade in patients with myelodysplastic syndromes (MDS) and chronic iron overload due to blood transfusion have not been performed. (1.3) The safety and efficacy of Exjade when administered with other iron chelation therapy have not been established. (1.3) 1.1 Treatment of Chronic Iron Overload Due to Blood Transfusions (Transfusional Iron Overload) Exjade is indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older. This indication is based on a reduction of liver iron concentrations and serum ferritin levels [see Clinical Studies (14)]. An improvement in survival or disease-related symptoms has not been established [see Indications and Usage (1.3)]. 1.2 Treatment of Chronic Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes Exjade is indicated for the treatment of chronic iron overload in patients 10 years of age and older with non-transfusion-dependent thalassemia (NTDT) syndromes and with a liver iron concentration (LIC) of at least 5 milligrams of iron per gram of liver dry weight (mg Fe/g dw) and a serum ferritin greater than 300 mcg/L. This indication is based on achievement of an LIC less than 5 mg Fe/g dw [see Clinical Studies (14)]. An improvement in survival or disease-related symptoms has not been established. 1.3 Limitation of Use Controlled clinical trials of Exjade with myelodysplastic syndromes (MDS) and chronic iron overload due to blood transfusions have not been performed [see Clinical Studies (14)]. The safety and efficacy of Exjade when administered with other iron chelation therapy have not been established.

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Advisory information

contraindications
4 CONTRAINDICATIONS Exjade is contraindicated in patients with: Serum creatinine greater than 2 times the age-appropriate ULN or creatinine clearance less than 40 mL/min [see Warning and Precautions (5.1)]; Poor performance status; High-risk myelodysplastic syndromes; Advanced malignancies; Platelet counts less than 50 x 109/L; Known hypersensitivity to deferasirox or any component of Exjade [see Warnings and Precautions (5.6), Adverse Reactions (6.2)]. Serum creatinine greater than 2 times the age-appropriate upper limit of normal (ULN) or creatinine clearance less than 40 mL/min. (4) Patients with poor performance status. (4) Patients with high-risk myelodysplastic syndromes (MDS). (4) Patients with advanced malignancies. (4) Patients with platelet counts less than 50 x 109/L. (4) Known hypersensitivity to deferasirox or any component of Exjade. (4)
Adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are also discussed in other sections of the labeling: Renal Toxicity, Renal Failure, and Proteinuria [see Warnings and Precautions (5.1)] Hepatic Toxicity and Failure [see Warnings and Precautions (5.2)] Gastrointestinal (GI) Hemorrhage [see Warnings and Precautions (5.3)] Bone Marrow Suppression [see Warnings and Precautions (5.4)] Hypersensitivity [see Warnings and Precautions (5.6)] Severe Skin Reactions [see Warnings and Precautions (5.7)] Skin Rash [see Warnings and Precautions (5.8)] Auditory and Ocular Abnormalities [see Warnings and Precautions (5.9)] In patients with transfusional iron overload, the most frequently occurring (greater than 5%) adverse reactions are diarrhea, vomiting, nausea, abdominal pain, skin rashes, and increases in serum creatinine. In Exjade-treated patients with NTDT syndromes, the most frequently occurring (greater than 5%) adverse reactions are diarrhea, rash and nausea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Transfusional Iron Overload A total of 700 adult and pediatric patients were treated with Exjade (deferasirox) for 48 weeks in premarketing studies. These included 469 patients with beta-thalassemia, 99 with rare anemias, and 132 with sickle cell disease. Of these patients, 45% were male, 70% were Caucasian and 292 patients were less than 16 years of age. In the sickle cell disease population, 89% of patients were black. Median treatment duration among the sickle cell patients was 51 weeks. Of the 700 patients treated, 469 (403 beta-thalassemia and 66 rare anemias) were entered into extensions of the original clinical protocols. In ongoing extension studies, median durations of treatment were 88-205 weeks. Six hundred twenty-seven (627) patients with MDS were enrolled across 5 uncontrolled trials. These studies varied in duration from 1 to 5 years. The discontinuation rate across studies in the first year was 46% (AEs 20%, withdrawal of consent 10%, death 8%, other 4%, lab abnormalities 3%, and lack of efficacy 1%). Among 47 patients enrolled in the study of 5-year duration, 10 remained on Exjade at the completion of the study. Table 1 displays adverse reactions occurring in greater than 5% of Exjade-treated beta-thalassemia patients (Study 1), sickle cell disease patients (Study 3), and patients with MDS (MDS pool). Abdominal pain, nausea, vomiting, diarrhea, skin rashes, and increases in serum creatinine were the most frequent adverse reactions reported with a suspected relationship to Exjade. Gastrointestinal symptoms, increases in serum creatinine, and skin rash were dose related. Table 1. Adverse Reactions* Occurring in Greater Than 5% of Exjade-treated Patients in Study 1, Study 3, and MDS Pool *Adverse reaction frequencies are based on adverse events reported regardless of relationship to study drug. **Includes ‘abdominal pain’, ‘abdominal pain lower’, and ‘abdominal pain upper’ which were reported as adverse events. ***Includes ‘blood creatinine increased’ and ‘blood creatinine abnormal’ which were reported as adverse events. Also see Table 2. Study 1 (Beta-thalassemia) Study 3 (Sickle Cell Disease) MDS Pool Preferred Term Exjade N=296 n (%) Deferoxamine N=290 n (%) Exjade N=132 n (%) Deferoxamine N=63 n (%) Exjade N=627 n (%) Abdominal Pain** 63 (21) 41 (14) 37 (28) 9 (14) 145 (23) Diarrhea 35 (12) 21 (7) 26 (20) 3 (5) 297 (47) Creatinine Increased*** 33 (11) 0 (0) 9 (7) 0 89 (14) Nausea 31 (11) 14 (5) 30 (23) 7 (11) 161 (26) Vomiting 30 (10) 28 (10) 28 (21) 10 (16) 83 (13) Rash 25 (8) 9 (3) 14 (11) 3 (5) 83 (13) In Study 1, a total of 113 (38%) patients treated with Exjade had increases in serum creatinine greater than 33% above baseline on 2 separate occasions (Table 2) and 25 (8%) patients required dose reductions. Increases in serum creatinine appeared to be dose related [see Warnings and Precautions (5.1)]. In this study, 17 (6%) patients treated with Exjade developed elevations in SGPT/ALT levels greater than 5 times the ULN at 2 consecutive visits. Of these, 2 patients had liver biopsy proven drug-induced hepatitis and both discontinued Exjade therapy [see Warnings and Precautions (5.2)]. An additional 2 patients, who did not have elevations in SGPT/ALT greater than 5 times the ULN, discontinued Exjade because of increased SGPT/ALT. Increases in transaminases did not appear to be dose related. Adverse reactions that led to discontinuations included abnormal liver function tests (2 patients) and drug-induced hepatitis (2 patients), skin rash, glycosuria/proteinuria, Henoch Schönlein purpura, hyperactivity/insomnia, drug fever, and cataract (1 patient each). In Study 3, a total of 48 (36%) patients treated with Exjade had increases in serum creatinine greater than 33% above baseline on 2 separate occasions (Table 2) [see Warnings and Precautions (5.1)]. Of the patients who experienced creatinine increases in Study 3, 8 Exjade-treated patients required dose reductions. In this study, 5 patients in the Exjade group developed elevations in SGPT/ALT levels greater than 5 times the ULN at 2 consecutive visits and 1 patient subsequently had Exjade permanently discontinued. Four additional patients discontinued Exjade due to adverse reactions with a suspected relationship to study drug, including diarrhea, pancreatitis associated with gallstones, atypical tuberculosis, and skin rash. In the MDS pool, in the first year, a total of 229 (37%) patients treated with Exjade had increases in serum creatinine greater than 33% above baseline on 2 consecutive occasions (Table 2) and 8 (3.5%) patients permanently discontinued [see Warnings and Precautions (5.1)]. A total of 5 (0.8%) patients developed SGPT/ALT levels greater than 5 times the ULN at 2 consecutive visits. The most frequent adverse reactions that led to discontinuation included increases in serum creatinine, diarrhea, nausea, rash, and vomiting. Death was reported in the first year in 52 (8%) of patients [see Clinical Studies (14)]. Table 2. Number (%) of Patients with Increases in Serum Creatinine or SGPT/ALT in Study 1, Study 3, and MDS Pool Study 1 (Beta-thalassemia) Study 3 (Sickle Cell Disease) MDS Pool Laboratory Parameter Exjade N=296 n (%) Deferoxamine N=290 n (%) Exjade N=132 n (%) Deferoxamine N=63 n (%) Exjade N=627 n (%) Serum Creatinine Creatinine increase >33% at 2 consecutive postbaseline visits 113 (38) 41 (14) 48 (36) 14 (22) 229 (37) Creatinine increase >33% and >ULN at 2 consecutive postbaseline visits 7 (2) 1 (0) 3 (2) 2 (3) 126 (20) SGPT/ALT SGPT/ALT >5 x ULN at 2 postbaseline visits 25 (8) 7 (2) 2 (2) 0 9 (1) SGPT/ALT >5 x ULN at 2 consecutive postbaseline visits 17 (6) 5 (2) 5 (4) 0 5 (1) Non-Transfusion-Dependent Thalassemia Syndromes In Study 4, 110 patients with NTDT received 1 year of treatment with Exjade 5 or 10 mg/kg/day and 56 patients received placebo in a double-blind, randomized trial. In Study 5, 130 of the patients who completed Study 4 were treated with open-label Exjade at 5, 10, or 20 mg/kg/day (depending on the baseline LIC) for 1 year [see Clinical Studies (14)]. Table 3 displays adverse reactions occurring in greater than 5% in any group. The most frequent adverse reactions with a suspected relationship to study drug were nausea, rash, and diarrhea. Table 3. Adverse Reactions Occurring in Greater Than 5% in NTDT Patients Study 4 Study 5 Exjade Placebo Exjade N=110 N=56 N=130 n (%) n (%) n (%) Any adverse reaction 31 (28) 9 (16) 27 (21) Nausea 7 (6) 4 (7) 2 (2) Rash 7 (6) 1 (2) 2 (2) Diarrhea 5 (5) 1 (2) 7 (5) In Study 4, 1 patient in the placebo 10 mg/kg/day group experienced an ALT increase to greater than 5 times ULN and greater than 2 times baseline (Table 4). Three Exjade-treated patients (all in the 10 mg/kg/day group) had 2 consecutive serum creatinine level increases greater than 33% from baseline and greater than ULN. Serum creatinine returned to normal in all 3 patients (in 1 spontaneously and in the other 2 after drug interruption). Two additional cases of ALT increase and 2 additional cases of serum creatinine increase were observed in the 1-year extension of Study 4. Table 4. Number (%) of NTDT Patients with Increases in Serum Creatinine or SGPT/ALT Study 4 Study 5 Exjade Placebo Exjade N=110 N=56 N=130 Laboratory Parameter n (%) n (%) n (%) Serum creatinine (>33% increase from baseline and >ULN at ≥2 consecutive postbaseline values) 3 (3) 0 2 (2) SGPT/ALT (>5 x ULN and >2 x baseline) 1 (1) 1 (2) 2 (2) Proteinuria In clinical studies, urine protein was measured monthly. Intermittent proteinuria (urine protein/creatinine ratio greater than 0.6 mg/mg) occurred in 18.6% of Exjade-treated patients compared to 7.2% of deferoxamine-treated patients in Study 1 [see Warnings and Precautions (5.1)]. Other Adverse Reactions In the population of more than 5,000 patients with transfusional iron overload who have been treated with Exjade during clinical trials, adverse reactions occurring in 0.1% to 1% of patients included gastritis, edema, sleep disorder, pigmentation disorder, dizziness, anxiety, maculopathy, cholelithiasis, pyrexia, fatigue, laryngeal pain, cataract, hearing loss, gastrointestinal hemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, renal tubular disorder (Fanconi’s Syndrome), and acute pancreatitis (with and without underlying biliary conditions). Adverse reactions occurring in 0.01% to 0.1% of patients included optic neuritis, esophagitis, and erythema multiforme. Adverse reactions which most frequently led to dose interruption or dose adjustment during clinical trials were rash, gastrointestinal disorders, infections, increased serum creatinine, and increased serum transaminases. 6.2 Postmarketing Experience The following adverse reactions have been spontaneously reported during postapproval use of Exjade 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

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION In patients with transfusional iron overload, the recommended initial daily dose is 20 mg per kg body weight once daily, as oral suspension. Calculate dose to the nearest whole tablet. (2.1) In patients with NTDT syndromes, the recommended initial daily dose is 10 mg per kg body weight once daily, as oral suspension. Calculate dose to the nearest whole tablet. (2.2) Monitor serum ferritin monthly and adjust dose accordingly. (2.1, 2.2) Monitor LIC every 6 months and adjust dose accordingly. (2.2) Do not chew or swallow tablets whole. (2.3) Take on an empty stomach at least 30 minutes before food. Disperse tablets by stirring in an appropriate amount of water, orange juice, or apple juice. (2.3) Reduce the starting dose in patients with moderate (Child-Pugh B) hepatic impairment by 50%. Avoid the use of Exjade in patients with severe (Child-Pugh C) hepatic impairment. (2.4) Reduce the starting dose by 50% in patients with renal impairment (ClCr 40-60 mL/min). (2.4) 2.1 Transfusional Iron Overload Exjade therapy should only be considered when a patient has evidence of chronic transfusional iron overload. The evidence should include the transfusion of at least 100 mL/kg of packed red blood cells (e.g., at least 20 units of packed red blood cells for a 40 kg person or more in individuals weighing more than 40 kg), and a serum ferritin consistently greater than 1000 mcg/L. Prior to starting therapy, obtain: serum ferritin level baseline serum creatinine in duplicate (due to variations in measurements) and determine the creatinine clearance (Cockcroft-Gault method) [see Dosage and Administration (2.4), Warnings and Precautions (5.1)] serum transaminases and bilirubin [see Dosage and Administration (2.4), Warnings and Precautions (5.2)] baseline auditory and ophthalmic examinations [see Warnings and Precautions (5.9)] The recommended initial dose of Exjade for patients 2 years of age and older is 20 mg per kg body weight orally, once daily. Calculate doses (mg per kg per day) to the nearest whole tablet. After commencing therapy, monitor serum ferritin monthly and adjust the dose of Exjade, if necessary, every 3-6 months based on serum ferritin trends. Make dose adjustments in steps of 5 or 10 mg per kg and tailor adjustments to the individual patient’s response and therapeutic goals. In patients not adequately controlled with doses of 30 mg per kg (e.g., serum ferritin levels persistently above 2500 mcg/L and not showing a decreasing trend over time), doses of up to 40 mg per kg may be considered. Doses above 40 mg per kg are not recommended. If the serum ferritin falls consistently below 500 mcg/L, consider temporarily interrupting therapy with Exjade [see Warnings and Precautions (5.10)]. 2.2 Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes Exjade therapy should only be considered when a patient with NTDT syndrome has an LIC of at least 5 mg Fe/g dw and a serum ferritin greater than 300 mcg/L. Prior to starting therapy, obtain: LIC by liver biopsy or by an FDA-cleared or approved method for identifying patients for treatment with deferasirox therapy Serum ferritin level on at least 2 measurements 1 month apart [see Clinical Studies (14)] Baseline serum creatinine in duplicate (due to variations in measurements) and determine the creatinine clearance (Cockcroft-Gault method) [see Dosage and Administration (2.4), Warnings and Precautions (5.1)] Serum transaminases and bilirubin [see Dosage and Administration (2.4), Warnings and Precautions (5.2)] Baseline auditory and ophthalmic examinations [see Warnings and Precautions (5.9)] Initiating therapy: The recommended initial dose of Exjade is 10 mg per kg body weight orally once daily. Calculate doses (mg per kg per day) to the nearest whole tablet. If the baseline LIC is greater than 15 mg Fe/g dw, consider increasing the dose to 20 mg/kg/day after 4 weeks. During therapy: Monitor serum ferritin monthly. Interrupt treatment when serum ferritin is less than 300 mcg/L and obtain an LIC to determine whether the LIC has fallen to less than 3 mg Fe/g dw. Monitor LIC every 6 months. After 6 months of therapy, if the LIC remains greater than 7 mg Fe/g dw, increase the dose of deferasirox to a maximum of 20 mg/kg/day. Do not exceed a maximum of 20 mg/kg/day. If after 6 months of therapy, the LIC is 3-7 mg Fe/g dw, continue treatment with deferasirox at no more than 10 mg/kg/day. When the LIC is less than 3 mg Fe/g dw, interrupt treatment with deferasirox and continue to monitor the LIC. Monitor blood counts, hepatic function, and renal function [see Warnings and Precautions (5.1, 5.2, 5.4)]. Restart treatment when the LIC rises again to more than 5 mg Fe/g dw. 2.3 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 (7.1)]. 2.4 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 (5.2), Use in Specific Populations (8.7)]. Patients with Baseline Renal Impairment For patients with renal impairment (ClCr 40–60 mL/min), reduce the starting dose by 50% [see Use in Specific Populations (8.6)]. Do not use Exjade in patients with serum creatinine greater than 2 times the upper limit of normal (ULN) or creatinine clearance less than 40 mL/min [see Contraindications (4)]. 2.5 Dose Modifications for Increases in Serum Creatinine on Exjade For serum creatinine increases while receiving Exjade [see Warnings and Precautions (5.1)] modify the dose as follows: Transfusional Iron Overload Adults and Adolescents (ages 16 years and older): 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 2-15 years): Reduce the dose by 10 mg per kg if serum creatinine increases to greater than 33% above the average baseline measurement and greater than the age appropriate ULN. All Patients (regardless of age): Discontinue therapy for serum creatinine greater than 2 times the age-appropriate ULN or for creatinine clearance less than 40 mL/min [see Contraindications (4)]. Non-Transfusion-Dependent Thalassemia Syndromes Adults and Adolescents (ages 16 years and older): 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 10-15 years): Reduce the dose by 5 mg per kg if serum creatinine increases to greater than 33% above the average baseline measurement and greater than the age appropriate ULN. All Patients (regardless of age): Discontinue therapy for serum creatinine greater than 2 times the age-appropriate ULN or for creatinine clearance less than 40 mL/min [see Contraindications (4)]. 2.6 Dose Modifications Based on Concomitant Medications UDP-glucuronosyltransferases (UGT) Inducers Concomitant use of UGT inducers decreases Exjade systemic exposure. Avoid the concomitant use of potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) with Exjade. If you must administer Exjade with 1 of these agents, consider increasing the initial dose of Exjade by 50%, and monitor serum ferritin levels and clinical responses for further dose modification [see Dosage and Administration (2.1, 2.2), Drug Interactions (7.5)]. Bile Acid Sequestrants Concomitant use of bile acid sequestrants decreases Exjade systemic exposure. Avoid the concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol) with Exjade. If you must administer Exjade with 1 of these agents, consider increasing the initial dose of Exjade by 50%, and monitor serum ferritin levels and clinical responses for further dose modification [see Dosage and Administration (2.1, 2.2), Drug Interactions (7.6)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal studies, may cause fetal harm. (8.1) Nursing Mothers: Discontinue drug or nursing, taking into consideration importance of drug to mother. (8.3) 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies with Exjade in pregnant women. Administration of deferasirox to animals during pregnancy and lactation resulted in decreased offspring viability and an increase in renal anomalies in male offspring at exposures that were less than the recommended human exposure. Exjade should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In embryofetal developmental studies, pregnant rats and rabbits received oral deferasirox during the period of organogenesis at doses up to (100 mg per kg/day in rats and 50 mg per kg/day in rabbits) 0.8 times the maximum recommended human dose (MRHD) on a 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 (10, 30, and 90 mg per kg/day) 0.08, 0.2, and 0.7 times the MRHD on a mg/m2 basis. Maternal toxicity, loss of litters, and decreased offspring viability occurred at 0.7 times the MRHD on a mg/m2 basis, and increases in renal anomalies in male offspring occurred at 0.2 times the MRHD on a mg/m2 basis. 8.3 Nursing Mothers It is not known whether Exjade is excreted in human milk. 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 nursing infants from deferasirox and its metabolites, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Of the 700 patients with transfusional iron overload who received Exjade during clinical studies, 292 were pediatric patients 2 to less than 16 years of age with various congenital and acquired anemias, including 52 patients age 2 to less than 6 years, 121 patients age 6 to less than 12 years and 119 patients age 12 to less than 16 years. Seventy percent of these patients had beta-thalassemia. Children between the ages of 2 to less than 6 years have a systemic exposure to Exjade approximately 50% of that of adults [see Clinical Pharmacology (12.3)]. However, the safety and efficacy of Exjade in pediatric patients was similar to that of adult patients, and younger pediatric patients responded similarly to older pediatric patients. The recommended starting dose and dosing modification are the same for children and adults [see Clinical Studies (14), Indications and Usage (1), Dosage and Administration (2.1)]. Growth and development in patients with chronic iron overload due to blood transfusions were within normal limits in children followed for up to 5 years in clinical trials. Sixteen (16) pediatric patients (10 to less than 16 years of age) with chronic iron overload and NTDT were treated with Exjade in clinical studies. The safety and efficacy of Exjade in these children was similar to that seen in the adults. The recommended starting dose and dosing modification are the same for children and adults with chronic iron overload in NTDT [see Clinical Studies (14), Indications and Usage (1.2), Dosage and Administration (2.2)]. Safety and effectiveness have not been established in pediatric patients with chronic iron overload due to blood transfusions who are less than 2 years of age or pediatric patients with chronic iron overload and NTDT who are less than 10 years of age. 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 Exjade 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. 8.6 Renal Impairment For patients with renal impairment (ClCr 40-60 mL/min), reduce the starting dose by 50% [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. Exjade is contraindicated in patients with a creatinine clearance less than 40 mL/min or serum creatinine greater than 2 times the age-appropriate ULN [see Contraindications (4)]. Exjade can cause renal failure. Monitor serum creatinine and calculate creatinine clearance (using Cockcroft-Gault method) during treatment in all patients. Reduce, interrupt or discontinue Exjade dosing based on increases in serum creatinine [see Dosage and Administration (2.4, 2.5), Warnings and Precautions (5.1)]. 8.7 Hepatic Impairment In a single dose (20 mg/kg) study in patients with varying degrees of hepatic impairment, deferasirox exposure was increased compared to patients with normal hepatic function. The average total (free and bound) AUC of deferasirox increased 16% in 6 patients with mild (Child-Pugh A) hepatic impairment, and 76% in 6 patients with moderate (Child-Pugh B) hepatic impairment compared to 6 patients with normal hepatic function. The impact of severe (Child-Pugh C) hepatic impairment was assessed in only 1 patient. 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 (2.4), Warnings and Precautions (5.2)].
Pregnancy and lactation
8.3 Nursing Mothers It is not known whether Exjade is excreted in human milk. 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 nursing infants from deferasirox and its metabolites, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Interactions

7 DRUG INTERACTIONS Avoid the use of 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) 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, avoid use of 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)].

More information

Category Value
Authorisation number NDA021882
Agency product number V8G4MOF2V9
Orphan designation No
Product NDC 0078-0469,0078-0468,0078-0470
Date Last Revised 12-08-2016
Type HUMAN PRESCRIPTION DRUG
RXCUI 597768
Marketing authorisation holder Novartis Pharmaceuticals Corporation
Warnings 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. Measure serum creatinine and determine creatinine clearance in duplicate prior to initiation of therapy and monitor renal function at least monthly thereafter. For patients with baseline renal impairment or increased risk of acute renal failure, monitor creatinine weekly for the first month, then at least monthly. Consider dose reduction, interruption, or discontinuation based on increases in serum creatinine [see Dosage and Administration (2.4, 2.5), Warnings and Precautions (5.1)]. 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: renal toxicity, including failure (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)