Important Safety Information 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...+

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Indication

Treatment of Chronic Iron Overload Due to Blood Transfusions (Transfusional Iron Overload)

JADENU® (deferasirox) tablets 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.

Dosing & Administration

Administration Options for Deferasirox

  • JADENU should be taken once daily, preferably at the same time each day1
  • JADENU tablets and JADENU Sprinkle are availabile in 90 mg and 180 mg and 360 mg strengths1
  • JADENU and EXJADE must not be taken with aluminum-containing antacid products1,2

*Water, orange juice, or apple juice.2

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).1

Transition From EXJADE

SIMPLIFIED ADMINISTRATION AND SEAMLESS TRANSITION FOR YOUR PATIENTS

NEW PATIENTS

Consider JADENU for patients with serum ferritin consistently >1000 μg/L and ≥20 packed red blood cell units/40-kg person.

EVALUATE at baseline: weight; serum ferritin level; serum creatinine (measure twice due to variations in measurements); eGFR (use prediction equation appropriate for adult patients, eg, CKD-EPI, MDRD method, and for pediatric patients, eg, Schwartz equations); renal tubular function: obtain urinalyses and serum electrolytes; ALT, AST, and bilirubin; auditory and ophthalmic function.1

CALCULATE the dose to the nearest whole tablet based on patient weight

ASSESS AS REQUIRED and titrate every 3 to 6 months based on serum ferritin trends and individual patient's needs

 

TRANSITIONING PATIENTS

Seamless transition from EXJADE, with no washout period needed1

 

  • For patients already taking EXJADE, start JADENU at the nearest equivalent dose (eg, EXJADE 30 mg/kg/day = JADENU 21 mg/kg/day)
  • In patients not adequately controlled with JADENU 21 mg/kg/day, up to 28 mg/kg/day may be considered. Doses >28 mg/kg/day are not recommended1 
  • Dose may be increased or decreased every 3 to 6 months based on serum ferritin trends and individual patient’s therapeutic goals and tolerability1 
  • If serum ferritin falls below 1000 mcg/L at 2 consecutive visits, consider dose reduction, especially if JADENU dose is greater than 17.5 mg/kg/day
  • If 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 and to achieve a trend of decreasing ferritin

 

DIFFICULTY SWALLOWING

JADENU Sprinkle granules - An additional administration alternative for patients taking EXJADE or JADENU tablets

  • May be appropriate for patients 2 years of age and older with chronic iron overload who have difficulty swallowing whole JADENU tablets or are transitioning from EXJADE
  • Sprinkled on soft food (eg, yogurt or applesauce) immediately prior to use and administered orally1
  • Contains the same active ingredient as EXJADE1

JADENU tablets can be crushed for those who have difficulty swallowing1

  • Mix JADENU with soft foods (eg, yogurt or applesauce) immediately prior to use and administer orally
  • Avoid commercial crushers with serrated surfaces when crushing a single 90-mg tablet
  • The patient should consume the dose immediately and completely, and the dose should not be stored for future use

 

TITRATION

TITRATE TO THE APPROPRIATE DOSE

 

Titrate JADENU based on iron burden and tolerability

  • Demonstrated serum ferritin reductions with deferasirox were dose dependent1
  • JADENU® (deferasirox) tablets and JADENU® Sprinkle (deferasirox) granules were approved by the FDA based on equivalence to EXJADE® (deferasirox) tablets for oral suspension as demonstrated in pharmacokinetic studies of healthy subjects1
  • JADENU was evaluated in healthy subjects. There are no clinical data in patients with JADENU1

*Patients with eGFR >60 mL/min/1.73 m2.

 

Mean serum ferritin reductions1,3

 

Every milligram counts when bringing down serum ferritin

  • Titrate in increments of 3.5 or 7 mg/kg/day every 3 to 6 months based on serum ferritin levels and individual patient’s therapeutic goals and tolerability1
  • In patients not adequately controlled with 21 mg/kg/day, up to 28 mg/kg/day may be considered. Doses >28 mg/kg/day are not recommended1
  • If serum ferritin falls below 1000 mcg/L at 2 consecutive visits, consider dose reduction, especially if JADENU dose is greater than 17.5 mg/kg/day
  • If 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

 

JADENU requires regular monitoring1

Monitoring required throughout treatment

  • Increase monitoring frequency for pediatric patients who have acute illness that can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake. Consider dose interruption until oral intake and volume status are normal
  • Prior to starting therapy, or increasing dose, evaluate serum ferritin level, serum creatinine in duplicate, eGFR, and renal tubular function

Important Dose Limitations

  • JADENU may require dose adjustment, interruption, or cessation of therapy due to toxicity, serum ferritin, or serum creatinine levels
  • Decreased renal function
    • — Adults (ages 18 and older): If the serum creatinine increases by 33% or more above the average baseline measurement, repeat the serum creatinine within 1 week, and if still elevated by 33% or more, reduce the dose by 7 mg/kg
    • — Pediatric patients (ages 2-17 years): Reduce the dose by 7 mg/kg if eGFR decreases by greater than 33% above the average baseline measurement and repeat eGFR within 1 week. In the setting of decreased renal function, evaluate the risk-benefit profile of continued JADENU use
    • — All patients (regardless of age): Discontinue therapy for eGFR <40 mL/min/1.73 m2
  • Avoid the concomitant use of bile acid sequestrants (eg, cholestyramine, colesevelam, colestipol) with JADENU. If you must coadminister JADENU and any of these agents, consider increasing the initial dose of JADENU by 50% and monitor serum ferritin levels and clinical responses for further dose modification
  • Avoid the concomitant use of potent UGT inducers (eg, rifampicin, phenytoin, phenobarbital, ritonavir) with JADENU.  If you must coadminister JADENU and any of these agents, consider increasing the initial dose of JADENU by 50% and monitor serum ferritin levels and clinical responses for further dose modification
  • Reduce the starting dose of JADENU by 50% in patients with eGFR 40–60 mL/min/1.73 m2. Do not use JADENU in patients with eGFR <40 mL/min
  • Avoid the use of JADENU in patients with severe (Child-Pugh C) hepatic impairment. Reduce the starting dose by 50% in patients with moderate (Child-Pugh B) hepatic impairment. 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
  • Gastrointestinal symptoms, increases in serum creatinine, and skin rash were dose related in clinical trials

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease Study; UGT, UDP-glucuronosyltransferase.

References:

1. Jadenu [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018.
2. Exjade [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018.
3. Data on file. Study CICL670A0107. Novartis Pharmaceuticals Corp; 2005.

INDICATION

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.

Limitations of Use

  • Controlled clinical trials of JADENU in patients with myelodysplastic syndromes (MDS) and chronic iron overload due to blood transfusions have not been performed 
  • 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  

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 functions prior to starting or increasing JADENU dosing in all patients. JADENU is contraindicated in adult and pediatric patients with estimated glomerular filtration rate (eGFR) ˂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  

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

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

 

CONTRAINDICATIONS

JADENU is contraindicated in patients with:

  • Estimated GFR ˂40 mL/min/1.73 m2;
  • Poor performance status;
  • High-risk 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 which 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. 

Overchelation 

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. 

Hypersensitivity

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.

Skin Rash

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. 

ADVERSE REACTIONS

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.