Jadenu

     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.        

     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.

1.3     Limitations of Use

The safety and efficacy of JADENU when administered with other iron chelation therapy have not been established.

     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 1,000 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 2,500 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 1,000 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 to minimize the risk of overchelation, and continue monthly monitoring [see Warnings and Precautions (5.6)].
  • 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)].         

     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 to assess the patient’s response to therapy and to minimize the risk of overchelation [see Warnings and Precautions (5.6)]. 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.        

     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 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.        

         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 applesauce) 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.        

     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)].

     Dose Modifications for Decreases in Renal Function While on JADENU

JADENU is contraindicated in patients with eGFR less than 40 mL/min/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)].         

     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)].

     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 a 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).

     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 child, 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 a breastfeeding child 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.

     Females and Males of Reproductive Potential

Contraception

Counsel patients to use non-hormonal method(s) of contraception since JADENU can render hormonal contraceptives ineffective [see Drug Interactions (7.2)].

     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)]. 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 [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 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 [see Dosage and Administration (2.5), Warnings and Precautions (5.1, 5.6), Adverse Reactions (6.1, 6.2)].

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 [see Warnings and Precautions (5.6)].

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 [see Warnings and Precautions (5.1)].

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.

     Geriatric Use

Four hundred thirty-one (431) 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 (225) 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.

In elderly patients, including those with MDS, individualize the decision to remove accumulated iron based on clinical circumstances and the anticipated clinical benefit and risks of deferasirox tablets for oral suspension therapy.

     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/min/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)].

     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)].