Jadenu Drug Information

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 myelodysplastic syndrome (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% (Adverse Events (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 a Occurring in > 5% of Deferasirox-treated Patients in Study 1, Study 3, and MDS Pool Abbreviation: MDS, myelodysplastic syndrome. a Adverse reaction frequencies are based on AEs reported regardless of relationship to study drug. b Includes ‘abdominal pain’, ‘abdominal pain lower’, and ‘abdominal pain upper’. c Includes ‘blood creatinine increased’ and ‘blood creatinine abnormal’. See also Table 2. Study 1 (Beta-thalassemia) Study 3 (Sickle Cell Disease) MDS Pool Adverse Reactions Deferasirox N = 296 n (%) Deferoxamine N = 290 n (%) Deferasirox N = 132 n (%) Deferoxamine N = 63 n (%) Deferasirox N = 627 n (%) Abdominal Pain b 63 41 37 9 145 Diarrhea 35 21 26 3 297 Creatinine Increased c 33 0 9 0 89 Nausea 31 14 30 7 161 Vomiting 30 28 28 10 83 Rash 25 9 14 3 83 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 . In this study, 17 (6%) patients treated with deferasirox developed elevations in serum glutamic-pyruvic transaminase (SGPT)/ALT levels greater than 5 times the upper limit of normal (ULN) at 2 consecutive visits. Of these, 2 patients had liver biopsy proven drug-induced hepatitis and both discontinued deferasirox therapy. 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) . 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 . 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 . Table 2. Number (%) of Patients with Increases in Serum Creatinine or SGPT/ALT in Study 1, Study 3, and MDS Pool Abbreviations: ALT, alanine transaminase; MDS, myelodysplastic syndrome; SGPT, serum glutamic-pyruvic transaminase; ULN, upper limit of normal.

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 41 48 14 229 Creatinine increase > 33% and > ULN at 2 consecutive post-baseline visits 7 1 3 2 126 SGPT/ALT SGPT/ALT > 5 x ULN at 2 post-baseline visits 25 7 2 0 9 SGPT/ALT > 5 x ULN at 2 consecutive post-baseline visits 17 5 5 0 5 Non-Transfusion-Dependent Thalassemia Syndromes In Study 5, 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 6, 130 of the patients who completed Study 5 were treated with open-label deferasirox at 5, 10, or 20 mg/kg/day (depending on the baseline LIC) for 1 year . In Study 7, 134 patients with NTDT of 10 years of age or older with iron overload, received deferasirox tablets for oral suspension for up to 5 years, at a starting dose of 10 mg/kg/day followed by dose adjustment at Week4, and then approximately every 6 months thereafter based on LIC levels. Table 3 and 4 display the frequency of adverse reactions in patients with NTDT. Adverse reactions with a suspected relationship to study drug were included in Table 3 if they occurred at ≥ 5% of patients in Study 5. Table 3. Adverse Reactions Occurring in Greater Than 5% Patients with NTDT Abbreviation: NTDT, non-transfusion-dependent thalassemia. a The occurrence of nausea, and rash are included for Study 6 and rash for Study 7 for consistency.

There were no additional adverse reactions with a suspected relationship to study drug occurring in > 5% of patients in Study 6 and Study 7. Study 5 Study 6 Study 7 Deferasirox Placebo Deferasirox Deferasirox N = 110 N = 56 N = 130 N = 134 n (%) n (%) n (%) n (%) Any adverse reaction 31 9 27 50 Nausea 7 4 2 a 7 Rash 7 1 2 a 3 a Diarrhea 5 1 7 8 In Study 5, 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 5. The number (%) of patients with NTDT with increase in serum creatinine or SGPT/ALT in Study 5, Study 6, and Study 7 are presented in Table 4 below. Table 4. Number (%) of Patients with NTDT with Increases in Serum Creatinine or SGPT/ALT Abbreviations: ALT, alanine transaminase; NTDT, non-transfusion-dependent thalassemia; SGPT, serum glutamic-pyruvic transaminase; ULN, upper limit of normal. Study 5 Study 6 Study 7 Deferasirox Placebo Deferasirox Deferasirox N = 110 N = 56 N = 130 N = 134 Laboratory Parameter n (%) n (%) n (%) n (%) Serum creatinine (> 33% increase from baseline and > ULN at ≥ 2 consecutive post-baseline values) 3 0 2 2 SGPT/ALT (> 5 x ULN and > 2 x baseline) 1 1 2 1 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 . 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, GI 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, GI 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 tablets for oral suspension 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 m 2 ) and 621 matched-controls with normal kidney function (eGFR > 120 mL/min/1.73 m 2 ) 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 equivalent to 3.5 mg/kg JADENU, starting at 20 mg/kg/day equivalent to 14 mg/kg/day JADENU (95% confidence interval (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 < 1,000 mcg/L, those who received Exjade dosage > 30 mg/kg/day, equivalent to 21 mg/kg/day JADENU compared to those who received lower dosages, had a higher risk for acute kidney injury (Odds ratio (OR) = 4.47, 95% CI: 1.25-15.95), consistent with overchelation. In addition, a cohort-based analysis of ARs was conducted in the deferasirox tablets for oral suspension pediatric pooled clinical trial data. Pediatric patients who received Exjade dose > 25 mg/kg/day equivalent to 17.5 mg/kg/day JADENU when their serum ferritin was < 1,000 mcg/L (n = 158), had a 6-fold greater rate of renal adverse reactions (Incidence Rate Ratio (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 reactions of special interest (cytopenia, renal, hearing, and GI 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) .

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 GI Disorders: GI 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 reactions 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 GI hemorrhage (n = 1), abdominal pain (n = 1), and hypokalemia (n = 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, do not take JADENU with aluminum-containing antacid preparations.

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) .

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.

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 .

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 .

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 .

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 .

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/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.

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/m 2 basis). These doses resulted in maternal toxicity but no fetal harm was observed. In a prenatal and postnatal developmental study, pregnant rats received oral deferasirox daily from organogenesis through lactation day 20 at doses of 10, 30, and 90 mg/kg/day (0.1, 0.3, and 1.0 times the MRHD on a mg/m 2 basis). Maternal toxicity, loss of litters, and decreased offspring viability occurred at 90 mg/kg/day (1.0 times the MRHD on a mg/m 2 basis), and increases in renal anomalies in male offspring occurred at 30 mg/kg/day (0.3 times the MRHD on a mg/m 2 basis).

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 . 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 . In those clinical studies, 173 children (ages 2 to < 12 years) and 119 adolescents (ages 12 to < 17 years) were exposed to deferasirox.

A trial conducted in treatment naïve pediatric patients, 2 to < 18 years of age with transfusional iron overload (NCT02435212) did not provide additional relevant information about the safety or effectiveness of the deferasirox granules dosage form (JADENU Sprinkle) compared to the deferasirox oral tablets for suspension dosage form (Exjade). 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 . 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 . In general, risk factors for deferasirox-associated kidney injury include preexisting renal disease, volume depletion, overchelation, and concomitant use of other nephrotoxic drugs. Acute kidney injury, and acute liver injury and failure has occurred in pediatric patients.

In a pooled safety analysis, pediatric patients with higher deferasirox exposures had a greater probability of renal toxicity and decreased renal function, resulting in increased deferasirox exposure and progressive renal toxicity/kidney injury. Higher rates of renal AEs have been identified among pediatric patients receiving Exjade doses greater than 25 mg/kg/day equivalent to 17.5 mg/kg/day JADENU when their serum ferritin values were less than 1,000 mcg/L . Monitoring recommendations for all pediatric patients with Transfusional Iron Overload and NTDT It is recommended that serum ferritin be monitored every month to assess the patient’s response to therapy and to minimize the risk of overchelation . 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 . Juvenile Animal Toxicity Data Renal toxicity was observed in adult mice, rats, and marmoset monkeys administered deferasirox at therapeutic doses. In a neonatal and juvenile toxicity study in rats, deferasirox was administered orally from postpartum Day 7 through 70, which equates to a human age range of term neonate through adolescence. Increased renal toxicity was identified in juvenile rats compared to adult rats at a dose based on mg/m 2 approximately 0.4 times the recommended dose of 20 mg/kg/day.

A higher frequency of renal abnormalities was noted when deferasirox was administered to non-iron overloaded animals compared to iron overloaded animals.

is contraindicated in patients with: Estimated GFR less than 40 mL/min/1.73 m 2 ; Poor performance status ; High-risk myelodysplastic syndromes (this patient population was not studied and is not expected to benefit from chelation therapy) ; Advanced malignancies ; Platelet counts less than 50 x 10 9 /L ; Known hypersensitivity to deferasirox or any component of JADENU . Estimated GFR less than 40 mL/min/1.73 m 2. Patients with poor performance status. Patients with high-risk myelodysplastic syndrome (MDS). Patients with advanced malignancies. Patients with platelet counts less than 50 x 10 9 /L. Known hypersensitivity to deferasirox or any component of JADENU.

Cases of overdose (2 to 3 times the prescribed dose for several weeks) have been reported. In one case, this resulted in hepatitis which resolved without long-term consequences after a dose interruption. In one pediatric case, a dose of 2-3 times the prescribed dose for 6 days resulted in acute renal failure requiring hemofiltration and acute liver injury/failure, which were reversible with intensive care support.

Single doses of deferasirox up to 80 mg per kg per day with the tablet for oral suspension formulation in iron-overloaded beta-thalassemic patients have been tolerated with nausea and diarrhea noted. In healthy subjects, single doses of up to 40 mg per kg per day with the tablet for oral suspension formulation were tolerated. Early signs of acute overdose are digestive effects such as abdominal pain, diarrhea, nausea, and vomiting.

Hepatic and renal disorders have been reported, including cases of liver enzyme and creatinine increased with recovery after treatment discontinuation. An erroneously administered single dose of 90 mg/kg led to Fanconi syndrome which resolved after treatment. There is no specific antidote for JADENU. In case of overdose, it may be treated with induction of vomiting or gastric lavage, and by symptomatic treatment.