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...+
Safety profile is based on clinical trials conducted with EXJADE® (deferasirox) tablets for oral suspension
- JADENU® (deferasirox) tablets was evaluated in healthy subjects; currently, there are no clinical data of patients treated with JADENU1
- Deferasirox has been studied in more than 1200 patients with multiple transfusion–dependent chronic anemias1
- In patients with transfusional iron overload, the most frequent adverse reactions (>5%) were diarrhea, vomiting, nausea, abdominal pain, skin rashes, and increase in serum creatinine1
ADVERSE REACTIONSa OCCURRING IN >5% OF PATIENTS TREATED WITH DEFERASIROX TABLETS FOR ORAL SUSPENSION1
|β-THALASSEMIA (STUDY 1)||SCD (STUDY 3)||MDS POOL|
|Abdominal painb||63 (21)||41 (14)||37 (28)||9 (14)||145 (23)|
|Diarrhea||35 (12)||21 (7)||26 (20)||3 (5)||297 (47)|
|Creatinine increasedc||33 (11)||0 (0)||9 (7)||0 (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)|
DFO, deferoxamine; MDS, myelodysplastic syndromes; SCD, sickle cell disease.
a Adverse reaction frequencies are based on adverse events reported regardless of relationship to study drug.1
b Includes abdominal pain, abdominal pain lower, and abdominal pain upper, which were reported as adverse events.1
c Includes blood creatinine increased and blood creatinine abnormal, which were reported as adverse events.1
To evaluate the safety, pharmacokinetics, and patient-reported outcomes of JADENU tablets and EXJADE in patients aged ≥10 years with transfusion-dependent thalassemia (TDT) or very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS), requiring iron chelation therapy.2
ECLIPSE STUDY DESIGN2
Open-label, randomized, multicenter, two-arm, phase 2 study of chelation-naive and previously treated patients aged ≥10 years with TDT or revised International Prognostic Scoring System very low-, low-, or intermediate-risk MDS.
Patients were stratified by prior chelation therapy (yes/no) and type of anemia (MDS or TDT).
Long-term studies needed to confirm improved outcomes seen with JADENU tablets.
The study was not powered to assess statistical significance.
KEY INCLUSION CRITERIA
- Serum ferritin >1000 μg/mL
- Diagnosis of TDT and iron overload
- Diagnosis of very low-, low-, or intermediate-risk MDS and iron overload
KEY EXCLUSION CRITERIA
- CrCl <40 mL/min
- SCr >1.5x ULN
- ALT >5x ULN (unless liver iron concentration confirmed as >10 mg Fe/dry weight ≤6 months prior to screening)
- UPCR >0.5 mg/mg
- Impaired GI function
ALT, alanine transaminase; CrCl, creatinine clearance; GI, gastrointestinal; MDS, myelodysplastic syndromes; SCr, serum creatinine level; TDT, transfusion-dependent thalassemia; ULN, upper limit of normal; UPCR, urine protein/creatinine ratio.
PRIMARY END POINT
To evaluate the overall safety of JADENU tablets and EXJADE in patients with TDT or MDS at very low, low, or intermediate risk
SECONDARY END POINTS
- SELECTED GI ADVERSE EVENTS (AEs)
— (diarrhea, constipation, nausea, vomiting, and abdominal pain)
- PATIENT-REPORTED OUTCOMES
— GI symptoms
- Age range: 11 to 81 years
- 80.9% of patients had TDT
- 18.5% of patients had MDS
- 80.3% of patients had received prior deferasirox treatment
- Patients previously treated with EXJADE, deferoxamine, or deferiprone started on a JADENU or EXJADE dose equivalent to their prewashout dose
- Treatment-naive patients received a 14 mg/kg/day initial JADENU dose or a 20 mg/kg/day initial EXJADE dose
- Dose adjustments were recommended every 4 weeks after initial dose and every 3 months for pretreated patients in increments of:
— 3.5 to 7 mg/kg/day for JADENU or 5 to 10 mg/kg/day for EXJADE, based on serum ferritin levels and investigator’s judgment
— The maximum dose was 28 mg/kg/day for JADENU and 40 mg/kg/day for EXJADE
- Dose adjustments based on safety and dose reductions for patients unable to tolerate the protocol-specified dosing schedule were allowed at any time during the study
OVERALL AEs REPORTED IN THE ECLIPSE TRIAL
Overall AEs for EXJADE® (deferasirox) tablets for oral suspension and JADENU® (deferasirox) tablets (>10% in any group):
- Regardless of drug relationship
- Suspected to be drug related
- No new AEs were identified
- Overall AEs were similar between treatment groups (EXJADE: 90%; JADENU: 90%); however, patients treated with JADENU had a lower incidence of severe AEs (EXJADE: 26%; JADENU: 20%)
- Overall renal and urinary adverse events occurred in 13% of EXJADE-treated patients and 23% of JADENU-treated patients
— A post hoc evaluation showed that a higher rate of renal events was observed in patients who received doses higher than the protocol-defined starting dose
— The frequency of renal events in patients who started on the correct protocol-defined dose was similar between treatment arms
AE, adverse event.
SEVERE AEs REPORTED IN THE ECLIPSE TRIAL
Severe AEs (of most common AEs)†:
- Regardless of drug relationship
- Suspected to be drug related
*Suspected to be drug related.
†Severe=grades 3 and 4.
- Patients should receive the appropriate starting dose and recommended dose adjustments
DIFFERENCES ACROSS PATIENT-REPORTED OUTCOMES SEEN IN PATIENTS WHO RECEIVED JADENU TABLETS VS THOSE WHO RECEIVED EXJADE TABLETS FOR ORAL SUSPENSION2
|PRO domain||Assessment method||Scoring|
|Satisfaction/Preference||SICT||2-10; higher scores indicating worse satisfaction/preference|
|Adherence||SICT||6-30; higher scores indicating worse adherence|
|Converns||SICT||3-15; higher scores indicating fewer concerns|
|Palatability||Questionnaire||0-11; higher scores indicating better palatability|
|GI Symptoms||Daily diary||0-50; higher scores indicating worse symptoms|
|Compliance||Daily diary||Weekly dose violation rate|
- All 4 patient-reported outcomes instruments (modified Satisfaction with Iron Chelation Therapy questionnaire, palatability questionnaire, GI symptom diary and compliance diary) were fully validated after undergoing thorough qualitative, linguistic, and psychometric evaluation
- Completion rates for patient-reported outcomes instruments were: ~80% for the patient-reported outcome questionnaire at the beginning of the study (reduced to ~70% by Week 24), ~60% for the compliance diary (reduced to ~30% by Week 24), and ~70% for the GI symptom diary (reduced to ~35% by Week 24)
GI, gastrointestinal; PRO, patient-reported outcomes; SICT, Satisfaction with Iron Chelation Therapy.
Patient-reported outcomes scores were better for JADENU vs EXJADE in every category
A REPORTED DIFFERENCE IN PALATABILITY2
100% of respondents taking JADENU reported the taste as very good, good, or neutral
Patient-reported palatability (amount of taste) at the end of treatment
- The palatability questionnaire consisted of 4 items: taste and aftertaste of the medication (5-point response scale: 1 = very good; 5 = very bad), whether the medication was taken (ie, whether the patient vomited after swallowing medication or not), and how the patient perceived the amount of liquid required to take the medication (not enough, just enough, or too much)
- Palatability at baseline was similar to that seen at end of study (JADENU: 54% very good/good; 46% neutral; 0% very bad/bad. EXJADE: 28% very good/good; 44% neutral; 29% very bad/bad)
- Patient-reported aftertaste ratings at baseline and end of treatment closely mirrored those for amount of taste
- At baseline, 90% (63/70) of patients who received JADENU found the amount of liquid “just enough”; 87% (52/60) felt the same at end of treatment
Mean adherence was reported as “better” with JADENU tablets
Mean adherence (95% CI)
- The adherence domain had a minimum score of 6 and a maximum score of 30, with higher scores indicating worse adherence. The results of the modified Satisfaction with Iron Chelation Therapy for Adherence domain suggested that patients on JADENU treatment found it easier to remember to take medication, thought less often about stopping medication, followed instructions from the doctor more closely, found medication easier to take, and were less bothered by the time taken to prepare medication and the waiting time before eating2,3
CI, confidence interval.
Patients treated with JADENU also reported3:
- Finding it easier to remember to take their medication
- Closer adherence to doctor’s instructions
- Ease of administration
- Less cumbersome preparation and administration processes
A REPORTED DIFFERENCE IN PATIENT SATISFACTION2
Nearly all respondents who received JADENU were satisfied with treatment
Satisfaction/preference at end of treatment
- More patients were very satisfied with JADENU vs EXJADE tablets for oral suspension (69% vs 24%)
- Ratings were based on3:
— The medication overall (eg, which product was preferable and rated higher for general satisfaction)
ADMINISTRATION OF JADENU TABLETS1,4
- A light meal contains: <7% fat content and <250 calories; eg, 1 whole wheat English mufﬁn, 1 packet of jelly (0.5 ounce), and skim milk (8 ﬂ ounces) or a turkey sandwich (2 ounces turkey on whole wheat bread with lettuce, tomato, and 1 packet mustard)
- For patients who have difﬁculty swallowing whole tablets, JADENU tablets may be crushed and mixed with soft foods (eg, yogurt or applesauce) 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
- JADENU and EXJADE must not be taken with aluminum-containing antacid products
ADMINISTRATION OF EXJADE1,4
aJADENU and EXJADE should be taken once daily, preferably at the same time each day.
JADENU requires regular monitoring
- Adverse reactions occurred mostly in elderly patients as a result of decreased hepatic, renal, or cardiac function; concomitant disease; or other drug therapy1
The most common adverse reactions led to dose adjustment, interruption, or discontinuation
- In clinical trials, dose adjustment, interruption, or discontinuation was used to resolve adverse reactions5-7
NUMBER (%) OF PATIENTS WITH INCREASE IN SERUM CREATININE OR SGPT/ALT WITH DEFERASIROX TABLETS FOR ORAL SUSPENSION1
|β-THALASSEMIA (STUDY 1)||SCD (STUDY 3)||MDS POOL|
|Deferasirox (n=296) |
|DFO (n=290) |
|Deferasirox (n=132) |
|DFO (n=63) |
|Deferasirox (n=627) |
|Serum creatinine increase
> 33% at 2 consecutive
|113 (38)||41 (14)||48 (36)||14 (22)||229 (37)|
|Serum creatinine increase
> 33% and >ULN at 2 consecutive
|7 (2)||1 (0)||3 (2)||2 (3)||126 (20)|
|SGPT/ALT > 5× ULN at
2 postbaseline visits
|25 (8)||7 (2)||2 (2)||0||9 (1.4)|
|SGPT/ALT >5× ULN at
2 consecutive postbaseline visits
|17 (6)||5 (2)||5 (4)||0||5 (0.8)|
DFO, deferoxamine; MDS, myelodysplastic syndromes; SCD, sickle cell disease; SGPT/ALT, serum glutamic-pyruvic transaminase/alanine aminotransferase.
1. Jadenu [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2019. 2. Data on file. Novartis Pharmaceuticals Corp; November 2016. 3. Taher AT, Origa R, Perrotta S, et al. New film-coated tablet formulation of deferasirox is well tolerated in patients with thalassemia or lower-risk MDS: results of the randomized, phase II ECLIPSE study. Am J Hematol. January 31, 2017. doi:10.1002/ajh.24668. 4. Exjade [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2019. 5. Data on file. Study CICL670A0107. Novartis Pharmaceuticals Corp; 2005. 6. Data on file. Study. CICL670A0109. Novartis Pharmaceuticals Corp; 2005. 7. Data on file. Study CICL 670A0108. Novartis Pharmaceuticals Corp; 2005.
Treatment of Chronic Iron Overload Due to Blood Transfusions (Transfusional Iron Overload)
JADENU® (deferasirox) tablets for oral use and JADENU® Sprinkle (deferasirox) granules are indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older.
Limitation of Use
The safety and efficacy of JADENU, when administered with other iron chelation therapy, have not been established.
IMPORTANT SAFETY INFORMATION for JADENU® (deferasirox) tablets for oral use and JADENU® Sprinkle (deferasirox) granules
JADENU is contraindicated in patients with:
- Estimated GFR ˂40 mL/min/1.73 m2;
- Poor performance status;
- High-risk myelodysplastic syndromes (MDS);
- Advanced malignancies;
- Platelet counts <50 x 109/L;
- Known hypersensitivity to deferasirox or any component of JADENU
WARNINGS AND PRECAUTIONS
Acute Kidney Injury, Including Acute Renal Failure Requiring Dialysis and Renal Tubular Toxicity Including Fanconi Syndrome
JADENU is contraindicated in patients with eGFR ˂40 mL/min/1.73m2. Exercise caution in pediatric patients with eGFR between 40 and 60 mL/min/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. For patients with renal impairment (eGFR 40 to 60 mL/min/1.73m2), reduce the starting dose by 50%.
JADENU can cause acute kidney injury including renal failure requiring dialysis that has resulted in fatal outcomes. Based on postmarketing experience, most fatalities have occurred in patients with multiple comorbidities and who were in advanced stages of their hematologic disorders. In the clinical trials, adults and pediatric patients treated with deferasirox with no preexisting renal disease experienced dose-dependent mild, nonprogressive increases in serum creatinine and proteinuria. Preexisting renal disease and concomitant use of other nephrotoxic drugs may increase the risk of acute kidney injury in adult and pediatric patients. Acute illnesses associated with volume depletion and overchelation may increase the risk of acute kidney injury in pediatric patients. In pediatric patients, small decreases in eGFR can result in increases in deferasirox exposure, particularly in younger patients with body surface area typical of patients ˂7 years of age. This can lead to a cycle of worsening renal function and further increases in deferasirox exposure, unless the dose is reduced or interrupted. Renal tubular toxicity, including acquired Fanconi Syndrome, has been reported in patients treated with deferasirox, most commonly in pediatric patients with β-thalassemia and serum ferritin levels ˂1500 mcg/L. Evaluate renal glomerular and tubular function before initiating therapy or increasing the dose. Use prediction equations validated for use in adult and pediatric patients to estimate GFR. Obtain serum electrolytes and urinalysis in all patients to evaluate renal tubular function.
Monitor all patients for changes in eGFR and for renal tubular toxicity weekly during the first month after initiation or modification of therapy, and at least monthly thereafter. Monitor serum ferritin monthly to evaluate for overchelation. Use the minimum dose to establish and maintain a low iron burden. Monitor renal function more frequently in patients with preexisting renal disease or decreased renal function. In pediatric patients, interrupt JADENU during acute illnesses that can cause volume depletion such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor renal function more frequently. Promptly correct fluid deficits to prevent renal injury. Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal.
Hepatic Toxicity and Failure
JADENU can cause hepatic injury, fatal in some patients. In Study 1, 4 (1.3%) patients discontinued deferasirox because of hepatic toxicity (drug-induced hepatitis in 2 patients and increased serum transaminases in 2 additional patients). Hepatic toxicity appears to be more common in patients >55 years of age. Hepatic failure was more common in patients with significant comorbidities, including liver cirrhosis and multiorgan failure.
Acute liver injury and failure, including fatal outcomes, have occurred in pediatric patients treated with deferasirox. Liver failure occurred in association with acute kidney injury in pediatric patients at risk for overchelation during a volume-depleting event. Interrupt JADENU therapy when acute liver injury, or acute kidney injury, is suspected and during volume depletion. Monitor liver and renal function more frequently in pediatric patients who are receiving JADENU in the 14 to 28 mg/kg/day range, and when iron burden is approaching normal. Use the minimum effective dose to achieve and maintain a low iron burden.
Measure aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and bilirubin in all patients before the initiation of treatment and every 2 weeks during the first month, and at least monthly thereafter. Consider dose modifications or interruption of treatment for severe or persistent elevations.
Avoid the use of JADENU in patients with severe (Child-Pugh C) hepatic impairment. Reduce the starting dose in patients with moderate (Child-Pugh B) hepatic impairment. Patients with mild (Child-Pugh A), or moderate (Child-Pugh B) hepatic impairment, may be at higher risk for hepatic toxicity.
Gastrointestinal Ulceration, Hemorrhage, and Perforation
Gastrointestinal (GI) hemorrhage, including deaths, has been reported, especially in elderly patients who had advanced hematologic malignancies and/or low platelet counts. Nonfatal upper GI irritation, ulceration, and hemorrhage have been reported in patients, including children and adolescents, receiving deferasirox. Monitor for signs and symptoms of GI ulceration and hemorrhage during JADENU therapy, and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. The risk of GI hemorrhage may be increased when administering JADENU in combination with drugs that have ulcerogenic or hemorrhagic potential such as nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, oral bisphosphonates, or anticoagulants. There have been reports of ulcers complicated with GI perforation (including fatal outcome).
Bone Marrow Suppression
Neutropenia, agranulocytosis, worsening anemia, and thrombocytopenia, including fatal events, have been reported in patients treated with deferasirox. Preexisting hematologic disorders may increase this risk. Monitor blood counts in all patients. Interrupt treatment with JADENU in patients who develop cytopenias until the cause of the cytopenia has been determined. JADENU is contraindicated in patients with platelet counts ˂50 x 109/L.
Age-Related Risk of Toxicity
Elderly Patients: JADENU has been associated with serious and fatal adverse reactions in the postmarketing setting among adults, predominantly in elderly patients. Monitor elderly patients treated with JADENU more frequently for toxicity.
Pediatric Patients: JADENU has been associated with serious and fatal adverse reactions in pediatric patients in the postmarketing setting. These events were frequently associated with volume depletion or with continued EXJADE® (deferasirox) tablets for oral suspension doses in the 20 to 40 mg/kg/day range, equivalent to 14-28 mg/kg/day JADENU, when body iron burden was approaching or was in the normal range. Interrupt JADENU in patients with volume depletion, and resume JADENU when renal function and fluid volume have normalized. Monitor liver and renal function more frequently during volume depletion, and in patients receiving JADENU in the 14 to 28 mg/kg/day range, when iron burden is approaching the normal range. Use the minimum effective dose to achieve and maintain a low iron burden.
For patients with transfusional iron overload, measure serum ferritin monthly to assess for possible overchelation of iron. An analysis of pediatric patients treated with EXJADE in pooled clinical trials (n=158) found a higher rate of renal adverse events among patients receiving doses >25 mg/kg/day, equivalent to 17.5 mg/kg/day JADENU, while their serum ferritin values were ˂1000 mcg/L. Consider dose reduction or closer monitoring of renal and hepatic function, and serum ferritin levels during these periods. Use the minimum effective dose to maintain a low iron burden.
If the serum ferritin is ˂1000 mcg/L at 2 consecutive visits, consider dose reduction, especially if the JADENU dose is >17.5 mg/kg/day [see Adverse Reactions (6.1)]. If the serum ferritin is ˂500 mcg/L, interrupt therapy with JADENU and continue monthly monitoring. Evaluate the need for ongoing chelation for patients whose conditions do not require regular blood transfusions. Use the minimum effective dose to maintain iron burden in the target range. Continued administration of JADENU in the 14 to 28 mg/kg/day range, when the body iron burden is approaching or is within the normal range, can result in life-threatening adverse events.
JADENU may cause serious hypersensitivity reactions (such as anaphylaxis and angioedema), with the onset of the reaction usually occurring within the first month of treatment. If reactions are severe, discontinue JADENU and institute appropriate medical intervention. JADENU is contraindicated in patients with known hypersensitivity to deferasirox products and should not be reintroduced in patients who have experienced previous hypersensitivity reactions on deferasirox products due to the risk of anaphylactic shock.
Severe Skin Reactions
Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) which could be life-threatening or fatal, have been reported during deferasirox therapy. Cases of erythema multiforme have been observed. Advise patients of the signs and symptoms of severe skin reactions, and closely monitor. If any severe skin reactions are suspected, discontinue JADENU immediately and do not reintroduce JADENU therapy.
Rashes may occur during JADENU treatment. For rashes of mild to moderate severity, JADENU may be continued without dose adjustment since the rash often resolves spontaneously. In severe cases, interrupt treatment with JADENU. Reintroduction at a lower dose, with escalation, may be considered after resolution of the rash.
Auditory and Ocular Abnormalities
Auditory disturbances (high-frequency hearing loss, decreased hearing), and ocular disturbances (lens opacities, cataracts, elevations in intraocular pressure, and retinal disorders) were reported at a frequency of <1% with deferasirox therapy in the clinical studies. The frequency of auditory adverse events, irrespective of causality, was increased among pediatric patients who received EXJADE doses >25 mg/kg/day, equivalent to 17.5 mg/kg/day JADENU, when serum ferritin was ˂1000 mcg/L.
Perform auditory and ophthalmic testing (including slit-lamp examinations and dilated fundoscopy) before starting JADENU treatment and thereafter at regular intervals (every 12 months). If disturbances are noted, monitor more frequently. Consider dose reduction or interruption.
JADENU was evaluated in healthy subjects, and there are no clinical data in patients treated with JADENU tablets or JADENU Sprinkle granules. JADENU contains the same active ingredient, deferasirox, as EXJADE® (deferasirox) tablets for oral suspension. For patients with transfusional iron overload, the most common adverse reactions occurring in >5% of patients treated with deferasirox who have β-thalassemia, sickle cell disease, and MDS were abdominal pain, nausea, vomiting, diarrhea, skin rashes, and increases in serum creatinine. Gastrointestinal symptoms, increases in serum creatinine, and skin rash were dose related.
Please see full Prescribing Information, including Boxed WARNING, for JADENU® (deferasirox) tablets for oral use and JADENU® Sprinkle (deferasirox) granules.