Drug Safety-related Labeling Changes (SrLC)

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JADENU (NDA-206910)

(DEFERASIROX)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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07/23/2020 (SUPPL-15)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Acute Kidney Injury, Including Acute Renal Failure Requiring Dialysis and Renal Tubular Toxicity Including Fanconi Syndrome

(Newly added information)

Dose reduction or interruption may be considered if abnormalities occur in levels of markers of renal tubular function and/or as clinically indicated.

5.6 Overchelation

(Additions and/or revisions underlined)

For patients with transfusional iron overload, measure serum ferritin monthly to assess the patient’s response to therapy and minimize the risk of overchelation

8 Use in Specific Populations

8.4 Pediatric Use

(Newly added information)

Monitoring Recommendations for 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)].

Patient Counseling Information

(Newly added information)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

(Newly added information)

Symptoms that can happen if you take too much Exjade include: stomach-area (abdominal) pain,

diarrhea, nausea, and vomiting.

Patient Counseling Information

(Newly added information)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

07/26/2019 (SUPPL-12)

Approved Drug Label (PDF)

8 Use in Specific Populations

Newly added subsection:

8.3 Females and Males of Reproductive Potential

Contraception

Counsel patients to use non-hormonal method(s) of contraception since JADENU can render hormonal contraceptives ineffective.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Newly added; please refer to label for complete information.

PATIENT COUNSELING INFOMRATION

Newly added information:

Acute Kidney Injury, Including Acute Renal Failure

Caution patients about the potential for kidney toxicity when taking JADENU tablets or JADENU Sprinkle granules. Inform patients of the signs and symptoms of kidney injury. Advise patients to contact their healthcare provider immediately if they experience any of these symptoms.

Hepatic Toxicity and Failure

Caution patients about the potential for hepatic toxicity when taking JADENU tablets or JADENU Sprinkle granules. Inform patients of the signs and symptoms of hepatic toxicity. Advise patients to contact their healthcare provider immediately if they experience any of these symptoms.

Severe Skin Reactions

Severe skin reactions have been reported in patients taking JADENU tablets or JADENU Sprinkle granules. Inform patients of the signs and symptoms of severe skin reactions. If reactions are severe, advise patients to stop taking JADENU tablets or JADENU Sprinkle granules immediately and seek immediate medical attention.

Additions and/or revisions underlined:

Gastrointestinal Ulceration and Hemorrhage

… such as NSAIDs, corticosteroids, oral bisphosphonates, or anticoagulants. Inform patients of the signs and symptoms of GI ulcers or bleeding. Advise patients to contact their healthcare provider for symptoms of heartburn but to seek immediate medical attention for symptoms of gastrointestinal hemorrhage.

05/24/2019 (SUPPL-14)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

(additions underlined)

…

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).

…

12/12/2018 (SUPPL-11)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

• High-risk myelodysplastic syndromes (this patient population was not studied and is not expected to benefit from chelation therapy);

6 Adverse Reactions

‘Clinically significant’ added between following and adverse reactions.

7 Drug Interactions

Newly added subsection:

7.7 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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Gastrointestinal Ulceration and Hemorrhage

… oral bisphosphonates, or anticoagulants. Advise patients to contact their healthcare provider for signs and symptoms of gastrointestinal ulceration and hemorrhage.

Skin Rash

Skin rashes may occur during JADENU treatment. If the skin rash is severe, advise patients to stop taking JADENU and seek medical attention

Auditory and Ocular Testing

… conduct auditory testing and ophthalmic testing before starting JADENU treatment and thereafter at regular intervals. Advise patients to contact their healthcare provider if they develop visual or auditory changes during treatment

12/12/2018 (SUPPL-9)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

• High-risk myelodysplastic syndromes (this patient population was not studied and is not expected to benefit from chelation therapy);

6 Adverse Reactions

‘Clinically significant’ added between following and adverse reactions.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

… 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.

Addition of the following:

A trial conducted in treatment naïve pediatric patients, ages 2 years to < 18 years with transfusional iron overload did not include a sufficient number of patients to provide additional meaningful information about the safety or compliance of the deferasirox oral tablets for suspension dosage form (Exjade) compared to the deferasirox granules dosage form (Jadenu Sprinkle).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Gastrointestinal Ulceration and Hemorrhage

… oral bisphosphonates, or anticoagulants. Advise patients to contact their healthcare provider for signs and symptoms of gastrointestinal ulceration and hemorrhage.

Skin Rash

Skin rashes may occur during JADENU treatment. If the skin rash is severe, advise patients to stop taking JADENU and seek medical attention

Auditory and Ocular Testing

… conduct auditory testing and ophthalmic testing before starting JADENU treatment and thereafter at regular intervals. Advise patients to contact their healthcare provider if they develop visual or auditory changes during treatment

08/03/2018 (SUPPL-10)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.5 Age-Related Risk of Toxicity

Pediatric Patients

… These events were frequently associated with volume depletion or with continued Exjade doses in the 20-40 mg/kg/day range equivalent to 14-28 mg/kg/day JADENU when body iron burden was approaching or in the normal range. Interrupt JADENU …

5.6 Overchelation

… 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 greater than 25 mg/kg/day equivalent to 17.5 mg/kg/day JADENU, while their serum ferritin values …

5.10 Auditory and Ocular Abnormalities

… The frequency of auditory adverse events irrespective of causality was increased among pediatric patients, who received Exjade doses greater than 25 mg/kg/day equivalent to 17.5 mg/kg/day JADENU when serum ferritin was less …

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Pooled Analysis of Pediatric Clinical Trial Data

• 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% CI: 1.08-1.48).

• Among pediatric patients with a serum ferritin < 1000 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 …

In addition, a cohort-based analysis of adverse events was conducted in the deferasirox pediatric pooled clinical trial data. Pediatric patients who received Exjade dose > 25 mg/kg/day equivalent to 17.5 mg/kg/day JADENU when their serum ferritin …

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes

… Higher rates of renal adverse events 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 …

05/11/2018 (SUPPL-6)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

WARNING: RENAL FAILURE, HEPATIC FAILURE, AND GASTROINTESTINAL HEMORRHAGE

Renal Failure

• JADENU can cause acute renal failure and death …

• Evaluate baseline renal function prior to starting or increasing Jadenu dosing in all patients. JADENU is contraindicated in adult and pediatric patients with eGFR less than 40 mL/minute/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 pre-existing 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.

4 Contraindications

Additions and/or revisions underlined:

JADENU is contraindicated in patients with:

• Estimated GFR less than 40 mL/min/1.73 m2

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Acute Kidney Injury, Including Acute Renal Failure Requiring Dialysis and Renal Tubular Toxicity Including Fanconi Syndrome

Addition of the following:

JADENU is contraindicated in patients with eGFR less than 40 mL/min/1.73m2. 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. For patients with renal impairment (eGFR 40–60 mL/min/1.73m2) reduce the starting dose by 50%.

Additions and/or revisions underlined:

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 hematological disorders. In the clinical trials, adults and pediatric deferasirox-treated patients with no pre-existing renal disease experienced dose-dependent mild, non- progressive increases in serum creatinine and proteinuria. Pre-existing 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 Jadenu exposure, particularly in younger patients with body surface area typical of patients less than age 7 years. This can lead to a cycle of worsening renal function and further increases in Jadenu 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 beta-thalassemia and serum ferritin levels less than 1,500 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 pre-existing 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

5.2 Hepatic Toxicity and Failure

Addition of the following:

… Acute liver injury and failure, including fatal outcomes, have occurred in pediatric deferasirox-treated patients. 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 14-28 mg/kg/day range and when iron burden is approaching normal. Use the minimum effective dose to achieve and maintain a low iron burden …

5.5 Age-Related Risk of Toxicity

Additions and/or revisions underlined:

Elderly Patients

JADENU has been associated with serious and fatal adverse reactions in the postmarketing setting among adults, predominantly …

Addition of the following:

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 Jadenu doses in the 20-40 mg/kg/day range when body iron burden was approaching or 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 14-28 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.

5.6 Overchelation

Additions and/or revisions underlined:

For patients with transfusional iron overload, measure serum ferritin monthly to assess for possible overchelation of iron. An analysis of pediatric patients treated with Jadenu in pooled clinical trials (nequals158) found a higher rate of renal adverse events among patients receiving doses greater than 25 mg/kg/day while their serum ferritin values were less than 1,000 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 falls below 1000 mcg/L at 2 consecutive visits, consider dose reduction, especially if the JADENU dose is greater than 17.5 mg/kg/day [see Adverse reactions (6.1)]. If the serum ferritin falls below 500 mcg/L, interrupt 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 within the normal range can result in life threatening adverse events.

For patients with NTDT, measure LIC by liver biopsy or by using an FDA-cleared …

5.10 Auditory and Ocular Abnormalities

Additions and/or revisions underlined:

were reported at a frequency of less than 1% with deferasirox therapy in the clinical studies. The frequency of auditory adverse events irrespective of causality was increased among pediatric patients who received JADENU doses greater than 25 mg/kg/day when serum ferritin was less than 1,000 mcg/L.

6 Adverse Reactions

Additions and/or revisions underlined:

• Acute Kidney Injury, Including Acute Renal Failure Requiring Dialysis, and Renal Tubular Toxicity Including Fanconi Syndrome

6.1 Clinical Trials Experience

Following Table 4, underneath Other Adverse Reactions, the following is newly added:

Pooled Analysis of Pediatric Clinical Trial Data

A nested case control analysis was conducted within a deferasirox pediatric pooled clinical trial dataset to evaluate the effects of dose and serum ferritin level, separately and combined, on kidney function. Among 1213 children (aged 2 to 15 years) with transfusion-dependent thalassemia, 162 cases of acute kidney injury (eGFR less than 90 ml/min/1.73m2) and 621 matched-controls with normal kidney function (eGFR greater than 120 ml/min/1.73m2) were identified. The primary findings were:

• A 26% increased risk of acute kidney injury was observed with each 5 mg/kg increase in daily Jadenu dosage starting at 20 mg/kg/day (95%CI: 1.08-1.48).

• A 25% increased risk for acute kidney injury was observed with each 250 mcg/L decrease in serum ferritin starting at 1250 µg/L (95%CI: 1.01-1.56).

• Among pediatric patients with a serum ferritin less than 1000 mcg/L, those who received Jadenu dosage greater than 30 mg/kg/day, compared to those who received lower dosages, had a higher risk for acute kidney injury (ORequals4.47, 95%CI: 1.25-15. 95), consistent with overchelation.

In addition, a cohort based analysis of adverse events was conducted in the deferasirox pediatric pooled clinical trial data. Pediatric patients who received Jadenu dose greater than 25 mg/kg/day when their serum ferritin was less than 1000 mcg/L (nequals158) had a 6-fold greater rate of renal adverse events (IRR equals 6.00, 95% CI: 1.75-21.36) and a 2-fold greater rate of dose interruptions (IRR equals 2.06, 95% CI: 1.33-3.17) compared to the time-period prior to meeting these simultaneous criteria. Adverse events of special interest (cytopenia, renal, hearing, and gastrointestinal disorders) occurred 1.9-fold more frequently when these simultaneous criteria were met, compared to preceding time-periods (IRRequals1.91, 95% CI: 1.05-3.48).

6.2 Postmarketing Experience

Addition of the following:

5-Year Pediatric Registry

In a 5-year observational study, 267 pediatric patients 2 to less than 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 greater than or equal to33% observed at least once. Twenty-one (18%) of these 116 patients with decreased eGFR had a dose interruption, and 15 (13%) of these 116 patients had a dose decrease within 30 days. Adverse events leading to permanent discontinuation from the study included liver injury (equals 11), vomiting (equals 2), renal tubular disorder (equals 1), proteinuria (equals 1), hematuria (equals 1), upper gastrointestinal hemorrhage (equals 1), abdominal pain (equals 1), and hypokalemia (equals 1).

8 Use in Specific Populations

Additions and/or revisions underlined:

8.1 Pregnancy

… 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 …

8.4 Pediatric Use

Additions and/or revisions underlined:

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.

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.

Addition of the following:

In general, risk factors for deferasirox-associated kidney injury include pre-existing 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 Jadenu exposures had a greater probability of renal toxicity and decreased renal function, resulting in increased deferasirox exposure and progressive renal toxicity/kidney injury. Higher rates of renal adverse events have been identified among pediatric patients receiving Jadenu doses greater than 25 mg/kg/day when their serum ferritin values were less than 1,000 mcg/L.

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/m2 approximately 0.4 times the recommended dose of 20 mg/kg/day. A higher frequency of renal abnormalities was noted when deferasirox was administered to non-iron overloaded animals compared to iron overloaded animals.

8.6 Renal Impairment

Additions and/or revisions underlined:

JADENU is contraindicated in patients with eGFR less than 40 mL/min/1.73 m2. For patients with renal impairment (eGFR 40 to 60 mL/min/1.73 m2), reduce the starting dose by 50%. Exercise caution in pediatric patients with an eGFR between 40 and 60 mL/minute/1.73 m2. 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. 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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Significant changes to this section; please refer to label for complete information.

02/16/2018 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Severe Skin Reactions

(additions underlined)

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 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.

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

…

Other Adverse Reactions

In the population of more than 5,000 patients with transfusional iron overload who have been treated with deferasirox during clinical trials, adverse reactions occurring in 0.1% to 1% of patients included gastritis, edema, sleep disorder, pigmentation disorder, dizziness, anxiety, maculopathy, cholelithiasis, pyrexia, fatigue, laryngeal pain, cataract, hearing loss, gastrointestinal hemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, renal tubular disorder (Fanconi’s syndrome), and acute pancreatitis (with and without underlying biliary conditions). Adverse reactions occurring in 0.01% to 0.1% of patients included optic neuritis, esophagitis, erythema multiforme, and drug reaction with eosinophilia and systemic symptoms (DRESS).

Adverse reactions which most frequently led to dose interruption or dose adjustment during clinical trials were rash, gastrointestinal disorders, infections, increased serum creatinine, and increased serum transaminases.

01/26/2018 (SUPPL-5)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

… Currently, there are no clinical data in patients with JADENU tablets and JADENU Sprinkle granules…

7 Drug Interactions

7.5 Agents Inducing UDP-glucuronosyltransferase (UGT) Metabolism

(Additions and/or revisions are underlined)

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…

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

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 a mg/m2 basis…

8.2 Lactation

(Additions and/or revisions are underlined)

Risk Summary

No data are available regarding the presence of JADENU or its metabolites in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Blood Testing

Advise patients that blood tests will be performed frequently to check for damage to kidneys, liver, or blood cells.

Gastrointestinal Ulceration and Hemorrhage

Caution patients about the potential for the development of GI ulcers or bleeding…

Skin and Allergic Reactions

Skin rashes may occur during JADENU treatment and if severe, interrupt treatment…

Auditory and Ocular Testing

Because auditory and ocular disturbances have been reported…

Drug Interactions

Caution patients not to take aluminum containing antacids and JADENU tablets or granules simultaneously.

…

Dosing Instructions

Advise patients to take JADENU tablets with water or other liquids. Advise patients to swallow JADENU tablets once daily with water or other liquids, preferably at the same time each day…

Advise patients to take JADENU Sprinkle granules by sprinkling the full dose on soft food (e.g., yogurt or apple sauce) immediately prior to use and administered orally. Advise patients to take JADENU Sprinkle granules once a day, preferably at the same time each day. JADENU Sprinkle granules may be taken on an empty stomach or with a light meal.

Handling Instructions

Advise patients to store JADENU in a dry, room-temperature environment.

Driving and Using Machines

Caution patients experiencing dizziness to avoid driving or operating machinery.

08/12/2016 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

Hypersensitivity (revised bolded)

• 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 (revised bolded)

• Severe skin reactions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and erythema multiforme, have been reported during deferasirox therapy. The risk of other skin reactions including DRESS (drug reaction with eosinophilia and systemic symptoms) cannot be excluded. If severe skin reactions are suspected, discontinue JADENU immediately and do not reintroduce JADENU therapy.

6 Adverse Reactions

Clinical Trials Experience

Other Adverse Reactions (revisions below; additions bolded)

• cataract…and acute pancreatitis (with and without underlying biliary conditions).

Postmarketing Experience

• Skin and subcutaneous tissue disorders: ...hypersensitivity vasculitis, … toxic epidermal necrolysis (TEN).