Data from FDA - Curated by EPG Health - Last updated 01 June 2018

Indication(s)

1 INDICATIONS AND USAGE JADENU is an iron chelator indicated for the treatment of chronic iron overload due to blood transfusions in patients 2 years of age and older. (1.1) JADENU 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 (Fe/g dw) and a serum ferritin greater than 300 mcg/L. This indication is approved under accelerated approval based on a reduction of liver iron concentrations (to less than 5 mg Fe/g dw) and serum ferritin levels. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. (1.2) Limitations of Use: Controlled clinical trials of JADENU 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 JADENU 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) JADENU is indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older. 1.2 Treatment of Chronic Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes JADENU 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 approved under accelerated approval based on a reduction of liver iron concentrations (to less than 5 mg Fe/g dw) and serum ferritin levels [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. 1.3 Limitations of Use Controlled clinical trials of JADENU 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 JADENU when administered with other iron chelation therapy have not been established.

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Advisory information

contraindications
4 CONTRAINDICATIONS JADENU is contraindicated in patients with: Estimated GFR less than 40 mL/min/1.73 m2 [see Dosage and Administration (2.5), Warnings 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 JADENU [see Warnings and Precautions (5.7), Adverse Reactions (6.2)]. Estimated GFR less than 40 mL/min/1.73 m2 (4) Patients with poor performance status. (4) Patients with high-risk 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 JADENU. (4)
Adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are also discussed in other sections of the labeling: Acute Kidney Injury, Including Acute Renal Failure Requiring Dialysis, and Renal Tubular Toxicity Including Fanconi Syndrome [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 (5.7)] Severe Skin Reactions [see Warnings and Precautions (5.8)] Skin Rash [see Warnings and Precautions (5.9)] Auditory and Ocular Abnormalities [see Warnings and Precautions (5.10)] 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 deferasirox-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. JADENU was evaluated in healthy volunteer trials. Currently, there are no clinical data in patients with JADENU tablets and JADENU Sprinkle granules. JADENU contains the same active ingredient as Exjade (deferasirox) tablets for oral suspension. The following adverse reactions have been reported with Exjade tablets for oral suspension. Transfusional Iron Overload A total of 700 adult and pediatric patients were treated with 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 to 205 weeks. Six hundred twenty-seven 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 deferasirox at the completion of the study. Table 1 displays adverse reactions occurring in greater than 5% of deferasirox-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 deferasirox. Gastrointestinal symptoms, increases in serum creatinine, and skin rash were dose related. Table 1. Adverse Reactions *Occurring in > 5% of Deferasirox-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. See also Table 2. Study 1 (Beta-thalassemia) Study 3 (Sickle Cell Disease) MDS Pool Adverse Reaction Deferasirox N = 296 n (%) Deferoxamine N = 290 n (%) Deferasirox N = 132 n (%) Deferoxamine N = 63 n (%) Deferasirox 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 deferasirox 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 deferasirox 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 deferasirox 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 deferasirox 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 deferasirox 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 deferasirox-treated patients required dose reductions. In this study, 5 patients in the deferasirox group developed elevations in SGPT/ALT levels greater than 5 times the ULN at 2 consecutive visits and 1 patient subsequently had deferasirox permanently discontinued. Four additional patients discontinued 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 deferasirox 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 Deferasirox N = 296 n (%) Deferoxamine N = 290 n (%) Deferasirox N = 132 n (%) Deferoxamine N = 63 n (%) Deferasirox N = 627 n (%) Serum Creatinine Creatinine increase > 33% at 2 consecutive post-baseline visits 113 (38) 41 (14) 48 (36) 14 (22) 229 (37) Creatinine increase > 33% and > ULN at 2 consecutive post-baseline visits 7 (2) 1 (0) 3 (2) 2 (3) 126 (20) SGPT/ALT SGPT/ALT > 5 x ULN at 2 post-baseline visits 25 (8) 7 (2) 2 (2) 0 9 (1) SGPT/ALT > 5 x ULN at 2 consecutive post-baseline 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 deferasirox 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 deferasirox 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 > 5% in NTDT Patients Study 4 Study 5 Deferasirox Placebo Deferasirox 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 deferasirox-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 Deferasirox Placebo Deferasirox N = 110 N = 56 N = 130 Laboratory Parameter n (%) n (%) n (%) Serum creatinine (> 33% increase from baseline and > ULN at ≥ 2 consecutive post-baseline 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 deferasirox-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 deferasirox 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 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, erythema multiforme, and drug reaction with eosinophilia and systemic symptoms (DRESS). 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. Pooled Analysis of Pediatric Clinical Trial Data A nested case control analysis was conducted within a deferasirox pediatric pooled clinical trial dataset to evaluate the effects of dose and serum ferritin level, separately and combined, on kidney function. Among 1213 children (aged 2 to 15 years) with transfusion-dependent thalassemia, 162 cases of acute kidney injury (eGFR < 90 mL/min/1.73 m2) and 621 matched-controls with normal kidney function (eGFR > 120 mL/min/1.73 m2) were identified. The primary findings were: - A 26% increased risk of acute kidney injury was observed with each 5 mg/kg increase in daily Exjade dosage starting at 20 mg/kg/day (95% CI: 1.08-1.48). - A 25% increased risk for acute kidney injury was observed with each 250 mcg/L decrease in serum ferritin starting at 1250 mcg/L (95% CI: 1.01-1.56). - Among pediatric patients with a serum ferritin < 1000 mcg/L, those who received Exjade dosage > 30 mg/kg/day, compared to those who received lower dosages, had a higher risk for acute kidney injury (OR = 4.47, 95% CI: 1.25-15.95), consistent with overchelation. In addition, a cohort based analysis of adverse events was conducted in the deferasirox pediatric pooled clinical trial data. Pediatric patients who received Exjade dose > 25 mg/kg/day when their serum ferritin was < 1000 mcg/L (n = 158) had a 6-fold greater rate of renal adverse events (IRR = 6.00, 95% CI: 1.75-21.36) and a 2-fold greater rate of dose interruptions (IRR = 2.06, 95% CI: 1.33-3.17) compared to the time-period prior to meeting these simultaneous criteria. Adverse events of special interest (cytopenia, renal, hearing, and gastrointestinal disorders) occurred 1.9-fold more frequently when these simultaneous criteria were met, compared to preceding time-periods (IRR = 1.91, 95% CI: 1.05-3.48) [see Warnings and Precautions (5.6)]. 6.2 Postmarketing Experience The following adverse reactions have been spontaneously reported during post-approval use of deferasirox 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), leukocytoclastic 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), vomiting (n = 2), renal tubular disorder (n = 1), proteinuria (n = 1), hematuria (n = 1), upper gastrointestinal hemorrhage (n = 1), abdominal pain (n = 1), and hypokalemia (n = 1).

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Transfusional Iron Overload: Initial dose for patients with estimated glomerular filtration rate (eGFR) greater than 60 mL/min/1.73 m2 is 14 mg/kg (calculated to nearest whole tablet or nearest whole sachet content for granules) once daily. (2.1) NTDT Syndromes: Initial dose for patients with eGFR greater than 60 mL/min/1.73 m2 is 7 mg/kg (calculated to nearest whole tablet or nearest whole sachet content for granules) once daily. (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) Take on an empty stomach or with a light meal. Sprinkle JADENU Sprinkle granules on soft foods (2.3) Reduce dose for moderate (Child-Pugh B) hepatic impairment by 50%. Avoid in patients with severe (Child-Pugh C) hepatic impairment. (2.4) Reduce dose by 50% in patients with renal impairment (eGFR 40–60 mL/min/1.73 m2). Exercise caution in pediatric patients with eGFR between 40 and 60 mL/minute/1.73 m2. (2.4) 2.1 Transfusional Iron Overload JADENU 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, or increasing dose, evaluate: Serum ferritin level Baseline renal function: Obtain serum creatinine in duplicate (due to variations in measurements) Calculate the estimated glomerular filtration rate (eGFR). Use a prediction equation appropriate for adult patients (e.g., CKD-EPI, MDRD method) and in pediatric patients (e.g., Schwartz equations). Obtain urinalyses and serum electrolytes to evaluate renal tubular function [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 (5.10)] Initiating Therapy: The recommended initial dose of JADENU for patients 2 years of age and older with eGFR greater than 60 mL/min/1.73 m2 is 14 mg per kg body weight orally, once daily. Calculate doses (mg per kg per day) to the nearest whole tablet or nearest whole sachet content for granules. Changes in weight of pediatric patients over time must be taken into account when calculating the dose. During Therapy: Monitor serum ferritin monthly and adjust the dose of JADENU, if necessary, every 3 to 6 months based on serum ferritin trends. Use the minimum effective dose to achieve a trend of decreasing ferritin Make dose adjustments in steps of 3.5 or 7 mg per kg and tailor adjustments to the individual patient’s response and therapeutic goals. In patients not adequately controlled with doses of 21 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 28 mg per kg may be considered. Doses above 28 mg per kg are not recommended [see Warnings and Precautions (5.6)]. Adjust dose based on serum ferritin levels If the serum ferritin falls below 1000 mcg/L at 2 consecutive visits, consider dose reduction, especially if the JADENU dose is greater than 17.5 mg/kg/day [see Adverse Reactions (6.1)]. If the serum ferritin falls below 500 mcg/L, interrupt JADENU therapy and continue monthly monitoring. Evaluate the need for ongoing chelation therapy for patients whose conditions no longer require regular blood transfusions. Use the minimum effective dose to maintain iron burden in the target range [see Warnings and Precautions (5.6)]. Monitor blood counts, liver function, renal function and ferritin monthly [see Warnings and Precautions (5.1, 5.2, 5.4)]. Interrupt JADENU for pediatric patients who have 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 [see Dosage and Administration (2.4, 2.5), Warnings and Precautions (5.1), Use in Specific Populations (8.4), Clinical Pharmacology (12.3)]. 2.2 Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes JADENU 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 renal function: Obtain serum creatinine in duplicate (due to variations in measurements) Calculate the estimated glomerular filtration rate (eGFR). Use a prediction equation appropriate for adult patients (e.g., CKD-EPI, MDRD method) and in pediatric patients (e.g., Schwartz equations). Obtain urinalyses and serum electrolytes to evaluate renal tubular function [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 (5.10)] Initiating Therapy: The recommended initial dose of JADENU for patients with eGFR greater than 60 mL/min/1.73 m2 is 7 mg per kg body weight orally once daily. Calculate doses (mg per kg per day) to the nearest whole tablet or nearest whole sachet content for granules. If the baseline LIC is greater than 15 mg Fe/g dw, consider increasing the dose to 14 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. Use the minimum effective dose to achieve a trend of decreasing ferritin. 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 14 mg/kg/day. Do not exceed a maximum of 14 mg/kg/day. If after 6 months of therapy, the LIC is 3 to 7 mg Fe/g dw, continue treatment with deferasirox at no more than 7 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, liver function, renal function and ferritin monthly [see Warnings and Precautions (5.1, 5.2, 5.4)]. Increase monitoring frequency for pediatric patients who have acute illness 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 [see Dosage and Administration (2.4, 2.5), Warnings and Precautions (5.1), Use in Specific Populations (8.4), Clinical Pharmacology (12.3)]. Restart treatment when the LIC rises again to more than 5 mg Fe/g dw. 2.3 Administration Swallow JADENU tablets once daily with water or other liquids, preferably at the same time each day. Take JADENU tablets on an empty stomach or with a light meal (contains less than 7% fat content and approximately 250 calories). Examples of light meals include 1 whole wheat English muffin, 1 packet jelly (0.5 ounces), and skim milk (8 fluid ounces) or a turkey sandwich (2 oz. turkey on whole wheat bread w/ lettuce, tomato, and 1 packet mustard). Do not take JADENU tablets with aluminum-containing antacid products [see Drug Interactions (7.1)]. For patients who have difficulty swallowing whole tablets, JADENU tablets may be crushed and mixed with soft foods (e.g., yogurt or apple sauce) immediately prior to use and administered orally. Commercial crushers with serrated surfaces should be avoided for crushing a single 90 mg tablet. The dose should be immediately and completely consumed and not stored for future use. Take JADENU Sprinkle granules on an empty stomach or with a light meal [see Clinical Pharmacology (12.3)]. Administer JADENU Sprinkle granules by sprinkling the full dose on soft food (e.g., yogurt or apple sauce) immediately prior to use and administered orally. JADENU Sprinkle granules should be taken once a day, preferably at the same time each day. Do not take JADENU Sprinkle granules with aluminum-containing antacid products [see Drug Interactions (7.1)]. For patients who are currently on chelation therapy with Exjade tablets for oral suspension and converting to JADENU, the dose should be about 30% lower, rounded to the nearest whole tablet or nearest whole sachet content for granules. The table below provides additional information on dosing conversion to JADENU. EXJADE Tablets for oral suspension (white round tablet) JADENU Tablets (film coated blue oval tablet) JADENU Sprinkle Granules (white to almost white granules) Transfusion-Dependent Iron Overload Starting Dose 20 mg/kg/day 14 mg/kg/day Titration Increments 5–10 mg/kg 3.5–7 mg/kg Maximum Dose 40 mg/kg/day 28 mg/kg/day Non-Transfusion-Dependent Thalassemia Syndromes Starting Dose 10 mg/kg/day 7 mg/kg/day Titration Increments 5–10 mg/kg 3.5–7 mg/kg Maximum Dose 20 mg/kg/day 14 mg/kg/day 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 JADENU tablets or JADENU Sprinkle granules [see Warnings and Precautions (5.2), Use in Specific Populations (8.7)]. Patients with Baseline Renal Impairment Do not use JADENU in adult or pediatric patients with eGFR less than 40 mL/min/1.73 m2 [see Dosage and Administration (2.5), Contraindications (4)]. For patients with renal impairment (eGFR 40-60 mL/min/1.73 m2), reduce the starting dose by 50% [see Use in Specific Populations (8.6)]. Exercise caution in pediatric patients with eGFR between 40 and 60 mL/minute/1.73 m2. 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 (8.6)]. 2.5 Dose Modifications for Decreases in Renal Function while on JADENU JADENU is contraindicated in patients with eGFR less than 40 mL/minute/1.73 m2 [see Contraindications (4)] For decreases in renal function while receiving JADENU [see Warnings and Precautions (5.1)], 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 7 mg per kg. Pediatric Patients (ages 2 years–17 years): Reduce the dose by 7 mg per kg if eGFR decreases by greater than 33% below the average baseline measurement and repeat eGFR within 1 week Interrupt JADENU 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 (5.1)]. In the setting of decreased renal function, evaluate the risk benefit profile of continued JADENU use. Use the minimum effective JADENU 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 JADENU to prevent severe and irreversible renal injury [see Warnings and Precautions (5.1)]. All Patients (regardless of age): Discontinue therapy for eGFR less than 40 mL/min/1.73 m2 [see Contraindications (4)]. 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 3.5 mg per kg, or reduce by 50% if the dose is 7 or 14 mg per kg. Pediatric Patients (ages 10 years – 17 years): Reduce the dose by 3.5 mg per kg 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 (5.1)]. In the setting of decreased renal function, evaluate the risk benefit profile of continued JADENU use. Use the minimum effective JADENU 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 JADENU to prevent severe and irreversible renal injury [see Warnings and Precautions (5.1)]. All Patients (regardless of age): Discontinue therapy for eGFR less than 40 mL/min/1.73 m2 [see Contraindications (4)]. 2.6 Dose Modifications Based on Concomitant Medications UDP-glucuronosyltransferases (UGT) Inducers Concomitant use of UGT inducers decreases systemic exposure. Avoid the concomitant use of strong UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir). If you must administer JADENU tablets or JADENU Sprinkle granules with a strong UGT inducer, consider increasing the initial dose 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 systemic exposure. Avoid the concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol). If you must administer JADENU tablets or JADENU Sprinkle granules with a bile acid sequestrant, consider increasing the initial dose 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) Lactation: Discontinue drug or breastfeeding, taking into consideration importance of drug to mother. (8.2) 8.1 Pregnancy Risk Summary There are no studies with the use of JADENU 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/m2 basis. No fetal effects were noted in pregnant rabbits at doses equivalent to the human recommended dose on an mg/m2 basis. JADENU 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/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 1.0 times the MRHD on a mg/m2 basis). Maternal toxicity, loss of litters, and decreased offspring viability occurred at 90 mg/kg/day (1.0 times the MRHD on an 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). 8.2 Lactation Risk Summary No data are available regarding the presence of JADENU or its metabolites in human milk, the effects of the drug on the breastfed infant, 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 nursing infants 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. 8.4 Pediatric Use Transfusional Iron Overload The safety and effectiveness of JADENU 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)]. Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes The safety and effectiveness of JADENU 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 JADENU 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 Exjade 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 Exjade 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 Interrupt JADENU 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 JADENU 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. 8.5 Geriatric Use Four hundred thirty-one 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 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. 8.6 Renal Impairment JADENU is contraindicated in patients with eGFR less than 40 mL/min/1.73 m2 [see Contraindications (4)]. For patients with renal impairment (eGFR 40 to 60 mL/min/1.73 m2), 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 m2 [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)]. JADENU 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 JADENU treatment. If either develops, consider dose reduction, interruption or discontinuation of JADENU 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)].

Interactions

7 DRUG INTERACTIONS Avoid the use of JADENU with aluminum-containing antacid preparations. (7.1) Deferasirox increases the exposure of repaglinide. Consider repaglinide dose reduction and monitor blood glucose levels. (7.3) Avoid the use of JADENU with theophylline as theophylline levels could be increased. (7.4) 7.1 Aluminum-Containing Antacid Preparations The concomitant administration of JADENU and aluminum-containing antacid preparations has not been formally studied. Although deferasirox has a lower affinity for aluminum than for iron, avoid use of JADENU with aluminum-containing antacid preparations. 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 JADENU 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 JADENU 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 JADENU. Monitor theophylline concentrations and consider theophylline dose modification if you must coadminister theophylline with JADENU. Closely monitor patients for signs of exposure related toxicity when JADENU 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 JADENU with strong UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) may result in a decrease in JADENU efficacy due to a possible decrease in deferasirox concentration. Avoid the concomitant use of strong UGT inducers with JADENU. Consider increasing the initial dose of JADENU 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 JADENU due to a possible decrease in deferasirox concentration. If you must coadminister these agents together, consider increasing the initial dose of JADENU [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

More information

Category Value
Authorisation number NDA206910
Agency product number V8G4MOF2V9
Orphan designation No
Product NDC 0078-0727,0078-0720,0078-0656,0078-0654,0078-0655,0078-0713
Date Last Revised 11-05-2018
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Novartis Pharmaceuticals Corporation
Warnings WARNING: RENAL FAILURE, HEPATIC FAILURE, AND GASTROINTESTINAL HEMORRHAGE Renal Failure JADENU 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 Jadenu dosing in all patients. JADENU is contraindicated in adult and pediatric patients with eGFR less than 40 mL/min/1.73 m2. 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 JADENU 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 JADENU 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 JADENU 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 JADENU 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. JADENU may cause serious and fatal: 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) JADENU therapy requires close patient monitoring, including laboratory tests of renal and hepatic function. (5)