Deferasirox by Dr. Reddy's Laboratories Inc / MSN LABORATORIES PRIVATE LIMITED DEFERASIROX tablet

Deferasirox by

Drug Labeling and Warnings

Deferasirox by is a Prescription medication manufactured, distributed, or labeled by Dr. Reddy's Laboratories Inc, MSN LABORATORIES PRIVATE LIMITED. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • BOXED WARNING (What is this?)

    WARNING: RENAL FAILURE, HEPATIC  FAILURE, AND  GASRTOINTESTINAL HEMORRHAGE

    Renal Failure

    • Deferasirox 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 function prior to starting or increasing deferasirox dosing in all patients. Deferasirox is contraindicated in adult and pediatric patients with eGFR less than 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 [see Dosage and Administration (2.1, 2.4, 2.5), Warnings and Precautions (5.1), Adverse Reactions (6.1, 6.2)].

    Hepatic Failure

    • Deferasirox 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 deferasirox in patients with severe (Child-Pugh C) hepatic impairment and reduce the dose in patients with moderate (Child-Pugh B) hepatic impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.2)].

    Gastrointestinal Hemorrhage

    • Deferasirox 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 deferasirox for suspected GI ulceration or hemorrhage [see Warnings and Precautions (5.3)].
  • 1 INDICATIONS AND USAGE

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

    Deferasirox tablets are indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older.
    Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s JADENU® (deferasirox) tablets. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

    1.3 Limitations of Use

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

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Transfusional Iron Overload

    Deferasirox tablets 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: 

    Initiating Therapy:
    The recommended initial dose of deferasirox tablets 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. 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 deferasirox tablets, 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 deferasirox tablets dose is greater than 17.5 mg/kg/day [see Adverse Reactions (6.1)].
      • If the serum ferritin falls below 500 mcg/L, interrupt deferasirox tablets 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[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 deferasirox tablets 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)].

    Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s JADENU® (deferasirox) tablets. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

    2.3 Administration

    Swallow deferasirox tablets once daily with water or other liquids, preferably at the same time each day. Take deferasirox 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 deferasirox tablets with aluminum-containing antacid products [see Drug Interactions (7.1)]. For patients who have difficulty swallowing whole tablets, deferasirox 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.
    For patients who are currently on chelation therapy with deferasirox tablets for oral suspension and converting to deferasirox tablets, the dose should be about 30% lower, rounded to the nearest whole tablet. The table below provides additional information on dosing conversion to deferasirox tablets.

     
    Deferasirox Tablets for oral  suspension (white round  tablet) 
    Deferasirox Tablets 
    (film coated yellow oval  tablet) 
    Transfusion-Dependent  Iron  Overload 
                     Starting  Dose
    20  mg/kg/day
    14  mg/kg/day
          Titration  Increments
    5 to10  mg/kg
    3.5 to 7  mg/kg
    Maximum Dose
    40  mg/kg/day
    28  mg/kg/day

    Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s JADENU® (deferasirox) tablets. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

    2.4 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 deferasirox tablets [ see Warnings and Precautions (5.2),Use in Specific Populations (8.7)].
    Patients with Baseline Renal Impairment
    Do not use deferasirox tablets 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 to 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)].

    2.5 Dose Modifications for Decrease in Renal Function While on Deferasirox Tablets

    Deferasirox tablets is contraindicated in patients with eGFR less than 40 mL/minute/1.73 m2[see Contraindications (4)]
    For decreases in renal function while receiving deferasirox tablets [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 to 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 deferasirox tablets 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 deferasirox tablets use. Use the minimum effective deferasirox tablets 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 deferasirox tablets to prevent severe and irreversible renal injury [see Warnings and Precautions (5.1)].

           All Patients (regardless of age):

    Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s JADENU® (deferasirox) tablets. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

    2.6 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 deferasirox tablets 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), 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 deferasirox tablets 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), Drug Interactions (7.6)].

  • 3 DOSAGE FORMS AND STRENGTHS

    • 90 mg deferasirox tablets

    Yellow colored, film coated oval, biconvex tablets with beveled edges debossed with 'D' on one side and '90' on another side.


    • 360 mg deferasirox tablets

    Yellow colored, film coated oval, biconvex tablets with beveled edges debossed with 'D' on one side and '360' on another side.

  • 4 CONTRAINDICATIONS

    Deferasirox is contraindicated in patients with:

    • Estimated GFR less than 40 mL/min/1.73 m2[see Dosage and Administration (2.5), Warnings and Precautions (5.1)];
    • Poor performance status [see Warnings and Precautions (5.1,5.3)];
    • High-risk myelodysplastic syndromes (this patient population was not studied and is not expected to benefit from chelation therapy);
    • Advanced malignancies [see Warnings and Precautions (5.1,5.3)];
    • Platelet counts less than 50 x 109/L [see Warnings and Precautions (5.3, 5.4)];
    • Known hypersensitivity to deferasirox or any component of deferasirox [see Warnings and Precautions (5.7), Adverse Reactions (6.2)].
  • 5 WARNINGS AND PRECAUTIONS

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

    Deferasirox is contraindicated in patients with eGFR less than 40 mL/min/1.73 m2. 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)]. 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, 2.5), Use in Specific Populations (8.6)].
    Deferasirox 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 preexisting renal disease experienced dose-dependent mild, non-progressive 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 less than age 7 years. This can lead to a cycle of worsening renal function and further increases in deferasirox tablets for oral suspension  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 [see Warnings and Precautions (5.6), Adverse Reactions (6.1, 6.2), Use in Special Populations (8.4), Clinical Pharmacology (12.3)].
    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 [see Dosage and Administration (2.1)].
    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 deferasirox 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 [see Dosage and Administration (2.5), Warnings and Precautions (5.6), Adverse Reactions (6.1, 6.2), Use in Specific Populations (8.4)].

    5.2Hepatic Toxicity and Failure

    Deferasirox can cause hepatic injury, fatal in some patients. In Study 1, 4 patients (1.3%) 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 greater than 55 years of age. Hepatic failure was more common in patients with significant comorbidities, including liver cirrhosis and multiorgan failure [ see Adverse Reactions (6.1)].

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

    Measure transaminases (AST and 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 deferasirox in patients with severe (Child-Pugh C) hepatic impairment. Reduce the starting dose in patients with moderate (Child-Pugh B) hepatic impairment see Dosage and Administration (2.4), Use in Specific Populations (8.7)]. Patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment may be at higher risk for hepatic toxicity.


    5.3Gastrointestinal (GI) Ulceration, Hemorrhage, and Perforation

    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 [ see Adverse Reactions (6.1)].Monitor for signs and symptoms of GI ulceration and hemorrhage during deferasirox therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. The risk of gastrointestinal hemorrhage may be increased when administering deferasirox 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 gastrointestinal perforation (including fatal outcome) [ see Adverse Reactions (6.2)].

    5.4Bone 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 deferasirox in patients who develop cytopenias until the cause of the cytopenia has been determined. Deferasirox is contraindicated in patients with platelet counts below 50 x 109/L.

    5.5 Age Related Risk of Toxicity

    Elderly Patients
    Deferasirox has been associated with serious and fatal adverse reactions in the postmarketing setting among adults, predominantly in elderly patients. Monitor elderly patients treated with deferasirox more frequently for toxicity [see Use in Specific Populations (8.5)].
    Pediatric Patients
    Deferasirox 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 deferasirox tablets for oral suspension doses in the 20 to 40 mg/kg/day range equivalent to 14 to 28 mg/kg/day deferasirox when body iron burden was approaching or in the normal range. Interrupt deferasirox in patients with volume depletion, and resume deferasirox when renal function and fluid volume have normalized. Monitor liver and renal function more frequently during volume depletion and in patients receiving deferasirox 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 [see Dosage and Administration (2.4), Warnings and Precautions (5.6), Use in Specific Populations (8.4)].

    5.6 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 deferasirox tablets for oral suspension 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 deferasirox, 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 [see Adverse Reactions (6.1), Use in Specific Populations (8.4)].
    If the serum ferritin falls below 1,000 mcg/L at 2 consecutive visits, consider dose reduction, especially if the deferasirox 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 deferasirox 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 deferasirox 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 [see Dosage and Administration (2.1)].

    Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s JADENU® (deferasirox) tablets. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

    5.7 Hypersensitivity

    Deferasirox may cause serious hypersensitivity reactions (such as anaphylaxis and angioedema), with the onset of the reaction usually occurring within the first month of treatment

    [see Adverse Reactions (6.2)].If reactions are severe, discontinue deferasirox and institute appropriate medical intervention. Deferasirox 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.

    5.8 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 [see Adverse Reactions (6.1, 6.2)]. 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 deferasirox immediately and do not reintroduce deferasirox therapy.

    5.9 Skin Rash

    Rashes may occur during deferasirox treatment [see Adverse Reactions (6.1)]. For rashes of mild to moderate severity, deferasirox may be continued without dose adjustment, since the rash often resolves spontaneously. In severe cases, interrupt treatment with deferasirox. Reintroduction at a lower dose with escalation may be considered after resolution of the rash.

    5.10 Auditory and Ocular Abmormalities

    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 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 deferasirox tablets for oral suspension doses greater than 25 mg/kg/day equivalent to 17.5 mg/kg/day deferasirox when serum ferritin was less than 1,000 mcg/L[see Warnings and Precautions (5.6)].
    Perform auditory and ophthalmic testing (including slit lamp examinations and dilated fundoscopy) before starting deferasirox treatment and thereafter at regular intervals (every 12 months). If disturbances are noted, monitor more frequently. Consider dose reduction or interruption.

  • 6 ADVERSE REACTIONS

    The following clinically significant adverse reactions are also discussed in other sections of the labeling:

    6.1Clinical Trials Experience

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Deferasirox was evaluated in healthy volunteer trials. Currently, there are no clinical data in patients with deferasirox tablets. Deferasirox contains the same active ingredient as deferasirox tablets for oral suspension. The following adverse reactions have been reported with deferasirox tablets for oral suspension.
    Transfusional Iron Overload
    A total of 700 adult and pediatric patients were treated with deferasirox for 48 weeks in premarketing studies. These included 469 patients with beta-thalassemia, 99 with rare anemias, and 132 with sickle cell disease. Of these patients, 45% were male, 70% were Caucasian and 292 patients were less than 16 years of age. In the sickle cell disease population, 89% of patients were black. Median treatment duration among the sickle cell patients was 51 weeks. Of the 700 patients treated, 469 (403 beta-thalassemia and 66 rare anemias) were entered into extensions of the original clinical protocols. In ongoing extension studies, median durations of treatment were 88 to 205 weeks.
    Six hundred twenty-seven patients with MDS were enrolled across 5 uncontrolled trials. These studies varied in duration from 1 to 5 years. The discontinuation rate across studies in the first year was 46% (AEs 20%, withdrawal of consent 10%, death 8%, other 4%, lab abnormalities 3%, and lack of efficacy 1%). Among 47 patients enrolled in the study of 5-year duration, 10 remained on deferasirox at the completion of the study.
    Table 1 displays adverse reactions occurring in greater than 5% of deferasirox -treated beta-thalassemia patients (Study 1), sickle cell disease patients (Study 3), and patients with MDS (MDS pool). Abdominal pain, nausea, vomiting, diarrhea, skin rashes, and increases in serum creatinine were the most frequent adverse reactions reported with a suspected relationship to deferasirox. Gastrointestinal symptoms, increases in serum creatinine, and skin rash were dose related.

    Table 1. Adverse Reactions* Occurring in >5% of Deferasirox -treated Patients in Study 1, Study 3,  and MDS  Pool

          Study 1       (Beta-thalassemia)        Study 3         (Sickle Cell Disease) MDS Pool
    Adverse  Reactions Deferasirox
     N=296
    n(%)
    Deferoxamine
    N=290    
    n(%) 
    Deferasirox
    N=132
    n(%) 
    Deferoxamine
    N=63
    n(%) 
    Deferasirox
    N=627
    n(%) 
    Abdominal Pain**63 (21)41 (14)37 (28)9 (14)145 (23)
    Diarrhea35 (12)21 (7)26 (20)3 (5)297 (47)
    Creatinine Increased***33 (11)0 (0)9 (7)089 (14)
    Nausea31 (11)14 (5)30 (23)7 (11)161 (26)
    Vomiting30 (10)28(10)28 (21)10 (16)83 (13)
    Rash25 (8)9 (3)14 (11)3 (5)83 (13)
    *Adverse reaction frequencies are based on adverse events reported regardless of relationship to study drug.
    **Includes ‘abdominal pain’, ‘abdominal pain lower’, ‘abdominal pain upper’, which were reported as adverse events.***Includes ‘ blood creatinine increased ‘and ‘blood creatinine abnormal’ which were reported as adverse events.  See also Table  2.

     In Study 1, a total of 113 (38%) patients treated with deferasirox had increases in serum creatinine greater than 33% above baseline on 2 separate occasions (Table 2) and 25 (8%) patients required dose reductions. Increases in serum creatinine appeared to be dose related [see Warnings and Precautions (5.1)]. In this study, 17 (6%) patients treated with deferasirox developed elevations in SGPT/ALT levels greater than 5 times the ULN at 2 consecutive visits. Of these, 2 patients had liver biopsy proven drug-induced hepatitis and both discontinued deferasirox therapy [see Warnings and Precautions (5.2)]. An additional 2 patients, who did not have elevations in SGPT/ALT greater than 5 times the ULN, discontinued deferasirox because of increased SGPT/ALT. Increases in transaminases did not appear to be dose related. Adverse reactions that led to discontinuations included abnormal liver function tests (2 patients) and drug-induced hepatitis (2 patients), skin rash, glycosuria/proteinuria, Henoch Schönlein purpura, hyperactivity/insomnia, drug fever, and cataract (1 patient each).
    In Study 3, a total of 48 (36%) patients treated with deferasirox had increases in serum creatinine greater than 33% above baseline on 2 separate occasions (Table 2) [see Warnings and Precautions (5.1)]. Of the patients who experienced creatinine increases in Study 3, 8 deferasirox-treated patients required dose reductions. In this study, 5 patients in the deferasirox group developed elevations in SGPT/ALT levels greater than 5 times the ULN at 2 consecutive visits and 1 patient subsequently had deferasirox permanently discontinued.  Four additional patients discontinued due to adverse reactions with a suspected relationship to study drug, including diarrhea, pancreatitis associated with gallstones, atypical tuberculosis, and skin rash.
    In the MDS pool, in the first year, a total of 229 (37%) patients treated with deferasirox had increases in serum creatinine greater than 33% above baseline on 2 consecutive occasions (Table 2) and 8 (3.5%) patients permanently discontinued [see Warnings and Precautions (5.1)]. A total of 5 (0.8%) patients developed SGPT/ALT levels greater than 5 times the ULN at 2 consecutive visits. The most frequent adverse reactions that led to discontinuation included increases in serum creatinine, diarrhea, nausea, rash, and vomiting. Death was reported in the first year in 52 (8%) of patients [see Clinical Studies (14)].


    Table 2. Number (%) of Patients with Increases in Serum Creatinine or SGPT/ALT in Study 1, Study 3, and MDS Pool


     
    Study 1
    (Beta-thalassemia)
    Study 3
    (Sickle Cell Disease)
    MDS Pool 
    Laboratory Parameter
    Deferasirox
    N=296
    n(%) 
    Deferoxamine
    N=290
    n(%) 
    Deferasirox
    N=132
    n(%) 
    Deferoxamine
    N=63
    n(%) 
    Deferasirox
    N=627
    n(%) 
    Serum Creatinine 
    Creatinine increase >33% at 2 consecutive post-baseline visits
    113 (38)
    41 (14)
    48 (36)
    14 (22)
    229 (37)
    Creatinine increase >33% and >ULN at 2 consecutive post-baseline visits
    7 (2)
    1 (0)
    3 (2)
    2 (3)
    126 (20)
    SGPT/ALT 
    SGPT/ALT >5 x ULN at 2 post-baseline visits
    25 (8)
    7 (2)
    2 (2)
    0
    9 (1)
    SGPT/ALT >5 x ULN at 2 consecutive post-baseline visits
    17 (6)
    5 (2)
    5 (4)
    0
    5 (1)

    Proteinuria
    In clinical studies, urine protein was measured monthly. Intermittent proteinuria (urine protein/creatinine ratio greater than 0.6 mg/mg) occurred in 18.6% of deferasirox-treated patients compared to 7.2% of deferoxamine-treated patients in Study 1 [see Warnings and Precautions (5.1)].
    Other Adverse Reactions
    In the population of more than 5,000 patients with transfusional iron overload, who have been treated with deferasirox  during clinical trials, adverse reactions occurring in 0.1% to 1% of patients included gastritis, edema, sleep disorder, pigmentation disorder, dizziness, anxiety, maculopathy, cholelithiasis, pyrexia, fatigue, laryngeal pain, cataract, hearing loss, gastrointestinal hemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, renal tubular disorder (Fanconi syndrome), and acute pancreatitis (with and without underlying biliary conditions). Adverse reactions occurring in 0.01% to 0.1% of patients included optic neuritis, esophagitis, erythema multiforme and drug reaction with eosinophilia and systemic symptoms (DRESS). Adverse reactions, which most frequently led to dose interruption or dose adjustment during clinical trials were rash, gastrointestinal disorders, infections, increased serum creatinine, and increased serum transaminases.
    Pooled Analysis of Pediatric Clinical Trial Data
    A nested case control analysis was conducted within a deferasirox pediatric-pooled clinical trial dataset to evaluate the effects of dose and serum ferritin level, separately and combined, on kidney function. Among 1213 children (aged 2 to 15 years) with transfusion-dependent thalassemia, 162 cases of acute kidney injury (eGFR < 90 mL/min/1.73 m2) and 621 matched-controls with normal kidney function (eGFR 120 mL/min/1.73 m2) were identified. The primary findings were:

    • A 26% increased risk of acute kidney injury was observed with each 5 mg/kg increase in daily deferasirox tablets for oral suspension dosage equivalent to 3.5 mg/kg deferasirox, starting at 20 mg/kg/day equivalent to 14 mg/kg/day deferasirox (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 1,250 mcg/L (95% CI: 1.01-1.56).
    • Among pediatric patients with a serum ferritin < 1,000 mcg/L, those who received deferasirox tablets for oral suspension dosage > 30 mg/kg/day, equivalent to 21 mg/kg/day deferasirox compared to those who received lower dosages, had a higher risk for acute kidney injury (OR = 4.47, 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 deferasirox tablets for oral suspension  dose > 25 mg/kg/day equivalent to 17.5 mg/kg/day deferasirox when their serum ferritin was < 1,000 mcg/L (n = 158), had a 6-fold greater rate of renal adverse events (IRR = 6.00, 95% CI: 1.75-21.36), and a 2-fold greater rate of dose interruptions (IRR = 2.06, 95% CI: 1.33-3.17) compared to the time-period prior to meeting these simultaneous criteria. Adverse 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 (IRR = 1.91, 95% CI: 1.05-3.48) [see Warnings and Precautions (5.6)].

    Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s JADENU® (deferasirox) tablets. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

    6.2 Postmarketing Experience

    The following adverse reactions have been spontaneously reported during post-approval use of deferasirox in the transfusional iron overload setting. Because these reactions are reported voluntarily from a population of uncertain size, in which patients may have received concomitant medication, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure.
    Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome (SJS), leukocytoclastic vasculitis, urticaria, alopecia, toxic epidermal necrolysis (TEN)
    Immune System Disorders: hypersensitivity reactions (including anaphylactic reaction and angioedema)
    Renal and Urinary Disorders: acute renal failure, tubulointerstitial nephritis
    Hepatobiliary Disorders: hepatic failure
    Gastrointestinal Disorders: gastrointestinal perforation
    Blood and Lymphatic System Disorders: worsening anemia
    5-Year Pediatric Registry
    In a 5-year observational study, 267 pediatric patients 2 to < 6 years of age (at enrollment) with transfusional hemosiderosis received deferasirox. Of the 242 patients who had pre- and post-baseline eGFR measurements, 116 (48%) patients had a decrease in eGFR of ≥ 33% observed at least once. Twenty-one (18%) of these 116 patients with decreased eGFR had a dose interruption, and 15 (13%) of these 116 patients had a dose decrease within 30 days. Adverse events leading to permanent discontinuation from the study included liver injury (n = 11), vomiting (n = 2), renal tubular disorder (n = 1), proteinuria (n = 1), hematuria (n = 1), upper gastrointestinal hemorrhage (n = 1), abdominal pain (n = 1), and hypokalemia (n = 1).

  • 7 DRUG INTERACTIONS

    7.1Aluminum-Containing Antacid Preparations

    The concomitant administration of deferasirox and aluminum-containing antacid preparations has not been formally studied. Although deferasirox has a lower affinity for aluminum than for iron, do not take deferasirox with aluminum-containing antacid preparations.

    7.2Agents Metabolized by CYP3A4

    Deferasirox may induce CYP3A4 resulting in a decrease in CYP3A4 substrate concentration when these drugs are coadministered. Closely monitor patients for signs of reduced effectiveness when deferasirox is administered with drugs metabolized by CYP3A4 (e.g., alfentanil, aprepitant, budesonide, buspirone, conivaptan, cyclosporine, darifenacin, darunavir, dasatinib, dihydroergotamine, dronedarone, eletriptan, eplerenone, ergotamine, everolimus, felodipine, fentanyl, hormonal contraceptive agents, indinavir, fluticasone, lopinavir, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, pimozide, quetiapine, quinidine, saquinavir, sildenafil, simvastatin, sirolimus, tacrolimus, tolvaptan, tipranavir, triazolam, ticagrelor, and vardenafil) [ see Clinical Pharmacology (12.3)].

    7.3Agents Metabolized by CYP2C8

    Deferasirox inhibits CYP2C8 resulting in an increase in CYP2C8 substrate (e.g., repaglinide and paclitaxel) concentration when these drugs are coadministered. If deferasirox and repaglinide are used concomitantly, consider decreasing the dose of repaglinide and perform careful monitoring of blood glucose levels. Closely monitor patients for signs of exposure related toxicity when deferasirox is coadministered with other CYP2C8 substrates [ see Clinical Pharmacology (12.3)].

    7.4Agents Metabolized by CYP1A2

    Deferasirox inhibits CYP1A2 resulting in an increase in CYP1A2 substrate (e.g., alosetron, caffeine, duloxetine, melatonin, ramelteon, tacrine, theophylline, tizanidine) concentration when these drugs are coadministered. An increase in theophylline plasma concentrations could lead to clinically significant theophylline induced CNS or other adverse reactions. Avoid the concomitant use of theophylline or other CYP1A2 substrates with a narrow therapeutic index (e.g., tizanidine) with deferasirox. Monitor theophylline concentrations and consider theophylline dose modification if you must coadminister theophylline with deferasirox. Closely monitor patients for signs of exposure related toxicity when Deferasirox is coadministered with other drugs metabolized by CYP1A2 [ see Clinical Pharmacology (12.3)].

    7.5Agents Inducing UDP-glucuronosyltransferase (UGT) Metabolism

    Deferasirox is a substrate of UGT1A1 and to a lesser extent UGT1A3. The concomitant use of deferasirox with strong UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) may result in a decrease in deferasirox efficacy due to a possible decrease in deferasirox concentration. Avoid the concomitant use of strong UGT inducers with deferasirox. Consider increasing the initial dose of deferasirox if you must coadminister these agents together [ see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

    7.6Bile Acid Sequestrants

    Avoid the concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol) with deferasirox due to a possible decrease in deferasirox concentration. If you must coadminister these agents together, consider increasing the initial dose of deferasirox [ see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

    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 [see Clinical Pharmacology (12.3)].

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary
    There are no studies with the use of deferasirox 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. Deferasirox 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).

    8.2 Lactation

    Risk Summary
    No data are available regarding the presence of deferasirox 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.

    8.3 Females and Males of Reproductive Potential

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


    8.4 Pediatric Use

    Transfusional Iron Overload
    The safety and effectiveness of deferasirox 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.
    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 adverse events have been identified among pediatric patients receiving deferasirox tablets for oral suspension doses greater than 25 mg/kg/day equivalent to 17.5 mg/kg/day deferasirox 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)].
    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 deferasirox in pediatric patients with transfusional 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 deferasirox 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)].
    JuveRenile 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.

    Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s JADENU® (deferasirox) tablets. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

    8.5 Geriatric Use

    Four hundred thirty-one 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 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.

    8.6Renal Impairment

    Deferasirox 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/minute/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)].
    Deferasirox 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 deferasirox treatment. If either develops, consider dose reduction, interruption or discontinuation of deferasirox until glomerular or renal tubular function returns to baseline [see Dosage and Administration (2.4, 2.5),Warnings and Precautions (5.1)].

    8.7 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 titrationsee Dosage and Administration (2.4),Warnings and Precautions (5.2), Clinical Pharmacology (12.3)].

  • 10 OVERDOSAGE

    Cases of overdose (2 to 3 times the prescribed dose for several weeks) have been reported. In one case, this resulted in hepatitis which resolved without long-term consequences after a dose interruption. In one pediatric case, a dose of 2-3 times the prescribed dose for 6 days resulted in acute renal failure requiring hemofiltration and acute liver injury/failure, which were reversible with intensive care support. Single doses of deferasirox up to 80 mg per kg per day with the tablet for oral suspension formulation in iron-overloaded beta-thalassemic patients have been tolerated with nausea and diarrhea noted. In healthy subjects, single doses of up to 40 mg per kg per day with the tablet for oral suspension formulation were tolerated. There is no specific antidote for deferasirox. In case of overdose, induce vomiting and employ gastric lavage.

  • 11 DESCRIPTION

    Deferasirox is an iron-chelating agent provided as a tablet for oral use. Deferasirox is designated chemically as 4-[3,5-bis(2-hydroxy-phenyl)-1H-1,2,4-triazol-1-yl] benzoic acid and has the following structural formula:


    structure

    Deferasirox is a white to slightly yellow colour powder. It has a molecular formula C21H15N3O4 and molecular weight of 373.36.
    Deferasirox tablets contain 90 mg, or 360 mg deferasirox. Inactive ingredients include colloidal silicon dioxide, croscarmellose sodium, hydrogenated castor oil, lactose monohydrate, low substituted hydroxy propyl cellulose, microcrystalline cellulose, poloxamer (188), povidone (K30) and sodium stearyl fumarate. The film coating contains .hypromellose, titanium dioxide, propylene glycol, talc and iron oxide yellow.

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Deferasirox is an orally active chelator that is selective for iron (as Fe3+). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Although deferasirox has very low affinity for zinc and copper, there are variable decreases in the serum concentration of these trace metals after the administration of deferasirox.
    The clinical significance of these decreases is uncertain.

    12.2 Pharmacodynamics

    Pharmacodynamic effects tested in an iron balance metabolic study with the tablet for oral suspension formulation showed that deferasirox (10, 20, and 40 mg per kg per day) was able to induce a mean net iron excretion (0.119, 0.329, and 0.445 mg Fe/kg body weight per day, respectively) within the clinically relevant range (0.1 to 0.5 mg per kg per day). Iron excretion was predominantly fecal.
    An analysis of pooled pediatric clinical trial data found a statistically significant relationship between exposure and the probability of renal toxicity (increase in serum creatinine and urinary protein), resulting in a decrease in renal function. Decreases in renal function resulted in an increase in deferasirox exposure which may increase the probability of renal toxicity.
    Cardiac Electrophysiology
    At the maximum approved recommended dose, deferasirox does not prolong the QT interval to any clinically relevant extent.

    12.3 Pharmacokinetics

    Absorption
    Based on studies in patients with the tablet for oral suspension, deferasirox is absorbed following oral administration with median times to maximum plasma concentration (Tmax) of about 1.5 to 4 hours. In healthy subjects, deferasirox showed comparable Tmax. The maximal concentrations (Cmax) and area under the curve (AUC0-24h, AUCτ) of deferasirox increase approximately linearly with dose after both single administration and under steady-state conditions. Exposure to deferasirox increased by an accumulation factor of 1.3 to 2.3 after multiple doses with the tablet for oral suspension formulation.
    Tablets
    The absolute bioavailability [as measured by area under the curve over time to infinity (AUCinf)] of deferasirox tablets for oral suspension is 70% compared to an intravenous dose. The bioavailability (as measured by AUC inf) of deferasirox tablets was 36% greater than with deferasirox tablets for oral suspension. After strength- adjustment, the mean AUCinf of deferasirox tablets (i.e., 360 mg strength) was similar to that of deferasirox tablets for oral suspension (i.e., 500 mg strength) under fasting conditions; however the mean Cmax was increased by 30%. The 30% increase in Cmax observed with deferasirox tablets is not clinically meaningful.
    The administration of deferasirox tablets with a light meal (approximately 250 calories with fat content less than 7% of total calories) indicated that the AUCinf and Cmax were similar to that under fasting conditions. The administration of deferasirox tablets with a high-fat meal (approximately 1000 calories with fat content greater than 50% of total calories), increased AUCinf by 18% and Cmax by 29% compared to that under fasting conditions [see Dosage and Administration (2.3)].
    Distribution
    Deferasirox is highly (~99%) protein bound almost exclusively to serum albumin. The percentage of deferasirox confined to the blood cells was 5% in humans. The volume of distribution at steady state (Vss) of deferasirox is 14.37 ± 2.69 L in adults.
    Metabolism
    Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion. Deconjugation of glucuronidates in the intestine and subsequent reabsorption (enterohepatic recycling) is likely to occur. Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450-catalyzed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). Deconjugation of glucuronide metabolites in the intestine and subsequent reabsorption (enterohepatic recycling) was confirmed in a healthy subjects study in which the administration of cholestyramine 12 g twice daily (strongly binds to deferasirox and its conjugates) 4 and 10 hours after a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure (AUCinf) by interfering with the enterohepatic recycling of deferasirox.
    Excretion
    Deferasirox and metabolites are primarily (84% of the dose) excreted in the feces. Renal excretion of deferasirox and metabolites is minimal (8% of the dose). The mean elimination half-life (t1/2) ranged from 8 to 16 hours following oral administration.
    Drug Interactions
    Midazolam: The concomitant administration of deferasirox tablets for oral suspension and CYP3A4 probe substrate midazolam resulted in a decrease of midazolam Cmax by 23% and AUCinf by 17%. In the clinical setting, this effect may be more pronounced, as the study was not adequately designed to conclusively assess the potential induction of CYP3A4 by deferasirox [ see Drug Interactions (7.2)].
    Repaglinide: The concomitant administration of deferasirox tablets for oral suspension (30 mg per kg/day for 4 days) and the CYP2C8 probe substrate repaglinide (single dose of 0.5 mg) increased repaglinide AUCinf to 2.3­ fold and Cmax of 1.6-fold [see Drug Interactions (7.3)].
    Theophylline: The concomitant administration of deferasirox tablets for oral suspension (repeated dose of 30 mg per kg/day) and the CYP1A2 substrate theophylline (single dose of 120 mg) resulted in an approximate doubling of the theophylline AUCinf  and elimination half-life. The single dose Cmax was not affected, but an increase in theophylline Cmax is expected to occur with chronic dosing [ see Drug Interactions (7.4)].
    Rifampicin: The concomitant administration of deferasirox tablets for oral suspension (single dose of 30 mg per kg) and the strong uridine diphosphate glucuronosyltransferase (UGT) inducer rifampicin (600 mg per day for 9 days)  decreased deferasirox AUCinf by 44% [ see Drug Interactions (7.5)].
    Cholestyramine: The concomitant administration of cholestyramine after a single dose of deferasirox tablets for oral suspension decreased deferasirox AUCinf by 45% [ see Drug Interactions (7.6)].
    Busulfan: Concomitant administration of deferasirox and busulfan resulted in an increase of busulfan exposure (AUC).
    In vitro studies:Deferasirox inhibited human CYP2A6, CYP2D6, and CYP2C19 in vitro.
    Deferasirox is not a substrate of P-glycoprotein, MRP1 or MRP2.
    Pharmacokinetics in Specific Populations
    Pediatric: Following oral administration of single or multiple doses, systemic exposure of adolescents and children to deferasirox was less than in adult patients. In children less than 6 years of age, systemic exposure was about 50% lower than in adults.
    Sex: The apparent clearance is 17.5% lower in females compared to males.
    Renal Impairment: Compared to patients with MDS and eGFR greater than 60 mL/min/1.73m2, patients with MDS and eGFR 40 to 60 mL/min/1.73m2 (n=34) had approximately 50% higher mean deferasirox trough plasma concentrations.
    Hepatic Impairment: In a single dose (20 mg/kg) study in patients with varying degrees of hepatic impairment, deferasirox exposure was increased compared to patients with normal hepatic function. The average total (free and bound) AUCinf of deferasirox increased 16% in 6 patients with mild (Child-Pugh A) hepatic impairment, and 76% in 6 patients with moderate (Child-Pugh B) hepatic impairment compared to 6 patients with normal hepatic function. The impact of severe (Child-Pugh C) hepatic impairment was assessed in only 1 patient.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

    A 104-week oral carcinogenicity study in Wistar rats showed no evidence of carcinogenicity from deferasirox at doses up to 60 mg/kg/day (0.7 times the MRHD on a mg/m2 basis). A 26-week oral carcinogenicity study in p53 (+/-) transgenic mice has shown no evidence of carcinogenicity from deferasirox at doses up to 200 mg/kg/day (1.2 times the MRHD on an mg/m2 basis) in males and 300 mg/kg/day (1.7 times the MRHD on an mg/m2 basis) in females.
    Deferasirox was negative in the Ames test and chromosome aberration test with human peripheral blood lymphocytes. It was positive in 1 of 3 in vivo oral rat micronucleus tests.
    Deferasirox at oral doses up to 75 mg/kg/day (0.9 times the MRHD on an mg/m2 basis) was found to have no adverse effect on fertility and reproductive performance of male and female rats.

  • 14 CLINICAL STUDIES

    Deferasirox was evaluated in healthy subjects. There are no clinical data in patients with deferasirox. Deferasirox contains the same active ingredient as deferasirox tablets for oral suspension. The following information is based on clinical trials conducted with deferasirox tablets for oral suspension.
    Transfusional Iron Overload
    The primary efficacy study, Study 1(NCT00061750), was a multicenter, open-label, randomized, active-comparator control study to compare deferasirox tablets for oral suspension and deferoxamine in patients with beta-thalassemia and transfusional hemosiderosis. Patients greater than or equal to 2 years of age were randomized in a 1:1 ratio to receive either oral deferasirox tablets for oral suspension at starting doses of 5, 10, 20, or 30 mg per kg once daily or subcutaneous deferoxamine at starting doses of 20 to 60 mg per kg for at least 5 days per week based on LIC at baseline (2 to 3, greater than 3 to 7, greater than 7 to 14, and greater than14 mg Fe/g dry weight). Patients randomized to deferoxamine who had LIC values less than 7 mg Fe/g dry weight were permitted to continue on their prior deferoxamine dose, even though the dose may have been higher than specified in the protocol.
    Patients were to have a liver biopsy at baseline and end of study (after 12 months) for LIC. The primary efficacy endpoint was defined as a reduction in LIC of greater than or equal to 3 mg Fe/g dry weight for baseline values greater than or equal to10 mg Fe/g dry weight, reduction of baseline values between 7 and less than10 to less than 7 mg Fe/g dry weight, or maintenance or reduction for baseline values less than 7 mg Fe/g dry weight.
    A total of 586 patients were randomized and treated, 296 with deferasirox tablets for oral suspension and 290 with deferoxamine. The mean age was 17.1 years (range, 2 to 53 years); 52% were females and 88% were Caucasian. The primary efficacy population consisted of 553 patients (deferasirox tablets for oral suspension n=276; deferoxamine n=277) who had LIC evaluated at baseline and 12 months or discontinued due to an adverse event. The percentage of patients achieving the primary endpoint was 52.9% for deferasirox tablets for oral suspension and 66.4% for deferoxamine. The relative efficacy of deferasirox to deferoxamine cannot be determined from this study.
    In patients who had an LIC at baseline and at end of study, the mean change in LIC was -2.4 mg Fe/g dry weight in patients treated with deferasirox tablets for oral suspension and -2.9 mg Fe/g dry weight in patients treated with deferoxamine.
    Reduction of LIC and serum ferritin was observed with deferasirox tablet for oral suspension doses of 20 to 30 mg per kg per day. Deferasirox tablets for oral suspension doses below 20 mg per kg per day failed to provide consistent lowering of LIC and serum ferritin levels (Figure 1). Therefore, a starting dose of 20 mg per kg per day is recommended [see Dosage and Administration (2.1)].

    Figure 1. Changes in Liver Iron Concentration and Serum Ferritin Following Deferasirox Tablets for Oral Suspension (5 to 30 mg per kg per day) in Study 1

    figure

    Study 2 (NCT00061763) was an open-label, noncomparative trial of efficacy and safety of deferasirox tablets for oral suspension given for 1 year to patients with chronic anemias and transfusional hemosiderosis. Similar to Study 1, patients received 5, 10, 20, or 30 mg per kg per day of deferasirox tablets for oral suspension based on baseline LIC.
    A total of 184 patients were treated in this study: 85 patients with beta-thalassemia and 99 patients with other congenital or acquired anemias (myelodysplastic syndromes, n=47; Diamond-Blackfan syndrome, n=30; other, n=22). Nineteen percent of patients were less than 16 years of age and 16% were greater than or equal to 65 years of age. There was a reduction in the absolute LIC from baseline to end of study (-4.2 mg Fe/g dry weight).
    Study 3 (NCT00067080) was a multicenter, open-label, randomized trial of the safety and efficacy of deferasirox tablets for oral suspension relative to deferoxamine given for 1 year in patients with sickle cell disease and transfusional hemosiderosis. Patients were randomized to deferasirox tablets for oral suspension at doses of 5, 10, 20, or 30 mg per kg per day or subcutaneous deferoxamine at doses of 20 to 60 mg per kg per day for 5 days per week according to baseline LIC.
    A total of 195 patients were treated in this study: 132 with deferasirox tablets for oral suspension and 63 with deferoxamine. Forty-four percent (44%) of patients were less than 16 years of age and 91% were black. At end of study, the mean change in LIC (as measured by magnetic susceptometry by a superconducting quantum interference device) in the per protocol-1 (PP-1) population, which consisted of patients who had at least 1 post-baseline LIC assessment, was -1.3 mg Fe/g dry weight for patients receiving deferasirox tablets for oral suspension (n=113) and -0.7 mg Fe/g dry weight for patients receiving deferoxamine (n=54).
    One-hundred five (105) patients with thalassemia major and cardiac iron overload were enrolled in a study assessing the change in cardiac MRI T2* value [(measured in milliseconds, (ms)] before and after treatment with deferasirox. Cardiac T2* values at baseline ranged from 5 to less than 20 ms. The geometric mean of cardiac T2* in the 68 patients who completed 3 years of deferasirox tablets for oral suspension therapy increased from 11.98 ms at baseline to 17.12 ms at 3 years. Cardiac T2* values improved in patients with severe cardiac iron overload (less than10 ms) and in those with mild to moderate cardiac iron overload (greater than or equal to 10 to less than 20 ms). The clinical significance of these observations is unknown.
    Six hundred twenty-seven patients with MDS were enrolled across 5 uncontrolled trials. Two hundred thirty- nine of the 627 patients were enrolled in trials that limited enrollment to patients with IPSS Low or Intermediate 1 risk MDS, and the remaining 388 patients were enrolled in trials that did not specify MDS risk stratification but required a life expectancy of greater than 1 year. Planned duration of treatment in these trials ranged from 1-year (365 patients) to 5-years (47 patients). These trials evaluated the effects of deferasirox tablets for oral suspension therapy on parameters of iron overload, including LIC (125 patients) and serum ferritin (627 patients).The Percent of patients completing planned duration of treatment was 51% in the largest 1 year study, 52% in the 3-year study and 22% in the 5 year study. The major causes for treatment discontinuation were withdrawal of consent, adverse reaction, and death. Over 1 year of follow-up across these pooled studies, mean change in serum ferritin was -332.8 (±2615.59) mcg/L (n=593) and mean change in LIC was -5.9 (±8.32) mg Fe/g dw (n=68). Results of these pooled studies in 627 patients with MDS suggest a progressive decrease in serum ferritin and LIC beyond 1 year in those patients who are able to continue deferasirox tablets for oral suspension.

    Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s JADENU® (deferasirox) tablets. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Deferasirox 90 mg tablets are yellow colored, film coated oval, biconvex tablets with beveled edges debossed with 'D' on one side and '90' on another side.
    They are available in bottles of 30 tablets (NDC: 43598-853-30).
    They are available in bottles of 1000 tablets (NDC: 43598-853-10).
    Deferasirox 360 mg tablets are yellow colored, film coated oval, biconvex tablets with beveled edges debossed with 'D' on one side and '360' on another side.
    They are available in bottles of 30 tablets   (NDC: 43598-851-30).
    They are available in bottles of 1000 tablets (NDC: 43598-851-10).
    Store deferasirox tablets at 20°C to 25°C (68°F to 77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from moisture.

  • 17 PATIENT COUNSELING INFORMATION

    Dosing Instructions
    Advise patients to take deferasirox tablets with water or other liquids. Advise patients to swallow deferasirox tablets once daily with water or other liquids, preferably at the same time each day. Advise patients to take deferasirox 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). For patients who have difficulty swallowing whole tablets, deferasirox tablets may be crushed and mixed with soft foods (e.g., yogurt or applesauce) immediately prior to use and administered orally. Advise against the use of commercial crushers with serrated surfaces for crushing a single 90 mg tablet. Advise patients to immediately and completely consume the dose and not store it for future use [see Dosage and Administration (2.3)].

    Blood Testing
    Advise patients that blood tests will be performed frequently to check for damage to kidneys, liver, or blood cells [see Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5)].

    Acute Kidney Injury, Including Acute Renal Failure
    Caution patients about the potential for kidney toxicity when taking deferasirox tablets. 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 [see Warnings and Precautions (5.1)].

    Hepatic Toxicity and Failure
    Caution patients about the potential for hepatic toxicity when taking deferasirox tablets. 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 [see Warnings and Precautions (5.2)].

    Gastrointestinal Ulceration and Hemorrhage
    Caution patients about the potential for the development of GI ulcers or bleeding when taking deferasirox in combination with drugs that have ulcerogenic or hemorrhagic potential, 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 (5.3)].

    Allergic Reactions
    Serious allergic reactions (which include swelling of the throat) have been reported in patients taking-deferasirox, usually within the first month of treatment. If reactions are severe, advise patients to stop taking deferasirox immediately and seek immediate medical attention [see Warnings and Precautions (5.7)].

    Severe Skin Reactions
    Severe skin reactions have been reported in patients taking deferasirox tablets. Inform patients of the signs and symptoms of severe skin reactions. If reactions are severe, advise patients to stop taking deferasirox tablets immediately and seek immediate medical attention [see Warnings and Precautions (5.8)].

    Skin Rash
    Skin rashes may occur during deferasirox treatment. If the skin rash is severe, advise patients to stop taking deferasirox and seek medical attention [ see Warnings and Precautions (5.9)].

    Pediatric Patients with Acute Illness
    Instruct pediatric patients and their caregivers to contact their healthcare provider during episodes of acute illness, especially if the patient has not been drinking fluids or the patient has volume depletion due to fever, vomiting, or diarrhea [see Warnings and Precautions (5.1)].

    Auditory and Ocular Testing
    Because auditory and ocular disturbances have been reported with deferasirox, conduct auditory testing and ophthalmic testing before starting deferasirox treatment and thereafter at regular intervals. Advise patients to contact their healthcare provider if they develop visual or auditory changes during treatment [see Warnings and Precautions (5.10)].

    Drug Interactions
    Caution patients not to take aluminum containing antacids and deferasirox tablets simultaneously [see Drug Interactions (7.1)].
    Caution patients about potential loss of effectiveness of drugs metabolized by CYP3A4 (e.g., cyclosporine, simvastatin, hormonal contraceptive agents) when deferasirox is administered with these drugs [see Drug Interactions (7.2)].
    Caution patients about potential loss of effectiveness of deferasirox when administered with drugs that are potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir). Based on serum ferritin levels and clinical response, consider increases in the dose of deferasirox when concomitantly used with potent UGT inducers [see Drug Interactions (7.5)].
    Caution patients about potential loss of effectiveness of deferasirox when administered with drugs that are bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol). Based on serum ferritin levels and clinical response, consider increases in the dose of deferasirox when concomitantly used with bile acid sequestrants [see Drug Interactions (7.6)].
    Caution patients with diabetes to monitor their glucose levels more frequently when repaglinide is used concomitantly with deferasirox [see Drug Interactions (7.3)].

    Handling Instructions
    Advise patients to store deferasirox in a dry, room-temperature environment [see How Supplied/Storage and Handling (16)].

    Driving and Using Machines
    Caution patients experiencing dizziness to avoid driving or operating machinery [see Adverse Reactions (6.1)].

  • MEDICATION GUIDE


    Deferasirox (de fer a sir ox)
    tablets

    What is the most important information I should know about deferasirox tablets?

    Deferasirox tablets can cause serious side effects, including:

    Kidney problems: Deferasirox tablets can cause can cause sudden (acute) kidney problems, including kidney failure that may require treatment with dialysis, and may cause death. Deaths have happened mostly in people who also have other health problems and had a blood disorder that was in an advanced stage. Adults and children who already have kidney problems and are taking certain medicines with deferasirox tablets may also have an increased risk of sudden kidney problems. Be sure to tell your healthcare provider about all the medicines you take during treatment with deferasirox tablets.
    Your healthcare provider should do blood and urine tests to check your or your child’s kidney function before and during treatment with deferasirox tablets. Call your healthcare provider right away if:
     your child becomes sick with fever, vomiting, or diarrhea and cannot drink fluids normally during treatment with deferasirox tablets. Your child may be dehydrated. Your healthcare provider may need to temporarily stop treatment with deferasirox tablets and treat your child for dehydration to help prevent kidney problems. Your healthcare provider may monitor your child’s kidney function more closely.
     you notice that you or your child are passing less urine than usual during treatment with deferasirox tablets.

    Liver problems. Deferasirox tablets can cause liver problems, including liver failure that can sometimes cause death. Liver problems with deferasirox tablets may be more common in people who are over 55 years of age but can also happen in children. Liver failure has happened more often in people with cirrhosis of the liver and failure of other organs. Liver failure has also happened along with kidney problems in certain children who become dehydrated. See “Kidney problems” above.
    Your healthcare provider should do blood tests to check your liver function before you start and regularly during treatment with deferasirox tablets. Call your healthcare provider right away, if you develop any of the following signs and symptoms:
     drowsiness                                                     yellowing or increased yellowing of your skin or eyes
     upper right stomach-area (abdomen) pain     dark urine

    Bleeding, ulcers and tears of the stomach or intestine. Severe stomach and intestine bleeding (hemorrhage) that have caused death have happened in some people treated with deferasirox tablets, especially in elderly people who have advanced blood cancers or low platelet counts. Some people have also had ulcers of the stomach or intestine, sometimes with tears (perforation) that have caused death. In some people who have taken deferasirox tablets, including children and adolescents, irritation of the upper gastrointestinal tract, ulcers, and bleeding have happened, but did not cause death.
    Your risk of severe bleeding (hemorrhage) may be increased if you take deferasirox tablets along with other medicines that can cause ulcers or bleeding, such as:
     nonsteroidal anti-inflammatory drugs (NSAIDs)    certain osteoporosis medicines called oral bisphosphonates
     corticosteroids,                                                     blood thinner medicines

    Before you start taking deferasirox tablets, tell your healthcare provider if you are taking one of these medicines. Ask your healthcare provider if you are not sure. If you develop an ulcer of the stomach or intestine, or severe bleeding, your healthcare provider may stop deferasirox tablets.
    Elderly people may be at a higher risk of developing serious side effects and death due to serious side effects with deferasirox tablets Your healthcare provider may need to monitor you more closely during treatment with deferasirox tablets.
     Tell your healthcare provider if you get heartburn during treatment with deferasirox tablets.
     Get emergency medical help right away if you vomit blood or pass black or bloody stools, or if you have severe stomach-area (abdomen) pain during treatment with deferasirox tablets.
    See "What are possible side effects of deferasirox tablets?" for more information about side effects.

    What are deferasirox tablets?
    Deferasirox tablets are prescription medicines that are used to treat:
     people 2 years of age and older who have an increased amount of iron in their blood for a long period of time (chronic), caused by repeated blood transfusions
    It is not known if deferasirox tablets are safe and effective when used with other medicines to treat an increased amount of iron in the blood.
    It is not known if deferasirox tablets are safe and effective for treating children under 2 years of age who have an increased amount of iron in their blood for a long period of time (chronic) caused by repeated blood transfusions.

    Do not take deferasirox tablets if you:
     have certain kidney problems
     have high-risk myelodysplastic syndrome (MDS)
     have advanced cancer 
     have a low platelet count
     are allergic to deferasirox or any of the ingredients in deferasirox tablets. See the end of this leaflet for a list of the ingredients in deferasirox tablets.

    Ask your healthcare provider if you are not sure if you have any of the medical conditions listed above.

    Before taking deferasirox tablets tell your healthcare provider about all of your medical conditions, including if you:
     have kidney problems
     have liver problems
     have advanced cancer. See “Do not take deferasirox tablets if you?”
     have a blood disorder that may increase your risk for bleeding
     are pregnant or plan to become pregnant. It is not known if deferasirox tablets can harm your unborn baby. Hormonal forms of birth control may not be as effective if used during treatment with deferasirox tablets. You could become pregnant. Talk to your healthcare provider about other birth control options that you can use during this time. Tell your healthcare provider right away if you become pregnant during treatment with deferasirox tablets.
     are breastfeeding or plan to breastfeed. It is not known if deferasirox passes into your breast milk and can harm your baby. You and your healthcare provider should decide if you will take deferasirox tablets or breastfeed. You should not do both.

    Tell your healthcare provider about all the medicines you take, including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements. Some medicines may affect how deferasirox tablets works, and deferasirox tablets may affect how other medicines work. Also, your risk of sudden kidney problems or severe bleeding may be increased if you take deferasirox tablets with certain medicines. See‘What is the most important information I should know about deferasirox tablets?”
     Avoid taking the following medicines during treatment with deferasirox tablets:
    o antacid products (medicines used to treat heartburn) that contain aluminum
    o theophylline
    o certain medicines to lower your cholesterol, called bile acid sequestrants.
    Ask your healthcare provider if you are not sure if you take one of these medicines.
    Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.
    How should I take deferasirox tablets?
     Take deferasirox tablets exactly as your healthcare provider tells you.
     Do not change your dose of deferasirox tablets or stop taking unless your healthcare provider tells you to.
     Deferasirox tablets comes as tablets.
    o You may take deferasirox tablets on an empty stomach or with a light meal. Examples of a light meal include:
     1 whole wheat English muffin, 1 packet of jelly (0.5 ounce), and skim milk (8 fluid ounces), or
     A turkey sandwich (2 ounces of turkey on whole wheat bread with lettuce, tomato, and 1 packet of mustard)

    Taking deferasirox tablets:
    o Take deferasirox tablets by mouth with water or other liquids 1 time every day, preferably at the same time every day.
    o If you have trouble swallowing the tablets whole, you may crush deferasirox tablets and mix them with soft foods such as yogurt or apple sauce right before taking your dose.
    o Take the dose right away. Do not save any of the deferasirox tablets and soft food mixture for later use.
    Do not use store-bought pill crushers with serrated surfaces for crushing deferasirox tablets 90 mg tablets.
     Do not take deferasirox tablets with aluminum-containing antacid products. See “Before taking deferasirox tablets”
     Tell your healthcare provider if you or your child gain or lose any weight. Your or your child’s dose of deferasirox tablets may need to be adjusted.
     If you take the diabetes medicine repaglinide during treatment with deferasirox tablets you may need to test your blood sugar (glucose) levels more often. Follow your healthcare provider’s instructions about how often to test your blood sugar during this time.
     Your healthcare provider should do blood and urine tests before, and during treatment to check how you respond to deferasirox tablets, and to monitor you for side effects. Your healthcare provider may change your dose, temporarily or permanently stop deferasirox tablets if you have certain side effects.
     In people who have thalassemia, your healthcare provider will check the amount of iron in your liver before and during treatment with deferasirox tablets.
     If you or your child take too much deferasirox tablets, call your healthcare provider right away or go to the nearest hospital emergency room.

    What should I avoid while taking deferasirox tablets?
    Deferasirox tablets may cause dizziness. Avoid driving or operating machinery until you know how deferasirox tablets affects you. Do not drive or operate machinery if deferasirox tablets makes you dizzy.

    What are the possible side effects of deferasirox tablets?

    Deferasirox tablets can cause serious side effects, including:
     See "What is the most important information I should know about deferasirox tablets?"

     Effects on your bone marrow. Deferasirox tablets can affect your bone marrow and cause you to have low white blood cell count which can be serious, decreased platelets, or worsening of your anemia, and may lead to death. Your risk for effects on your bone marrow may be increased if you already have other blood disorders. Your healthcare provider will do blood tests to monitor your blood cell counts for these problems.
     Serious allergic reactions. Deferasirox tablets may cause serious allergic reactions, which usually start within the first month of treatment. Get medical help right away if you develop any of the following symptoms of a serious allergic reaction including:
    o difficulty in breathing or swallowing                o swelling of the face, lips, mouth, tongue or throat
    o chest pain                                                       o severe itching of the skin with a red rash or raised bumps
    o rapid heartbeat  
    o feeling faint                                                     o hives

     Skin rash and severe skin reactions. Skin rashes are common with deferasirox tablets. If you get a more severe rash, your healthcare provider may temporarily stop deferasirox tablets.

    Severe skin reactions can also happen with deferasirox tablets and can be life-threatening or lead to death. Get medical help right away if you develop any one or more of the following signs and symptoms of a severe skin reaction, including:
    o rash or red skin o skin peeling
    o blisters on your lips, or around your mouth or eyes  o high fever or flu-like symptoms
    o mouth sores  o enlarged lymph nodes

     Hearing and vision problems. Deferasirox tablets can cause decreased hearing and changes in your vision including cataracts, increased pressure in your eye, and problems with your retinas. Your healthcare provider should do hearing and vision tests before you start and then regularly during treatment. Your healthcare provider may decrease your dose or stop deferasirox tablets if you develop hearing or vision problems.

    The most common side effects in anyone who takes deferasirox tablets include: diarrhea and nausea.

    Other common side effects in people with too much iron in their blood due to repeated blood transfusions include: vomiting, stomach-area (abdomen) pain, and an abnormal kidney function blood test.

    These are not all the possible side effects of deferasirox tablets.

    Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    How should I store deferasirox tablets?
     Store deferasirox tablets at room temperature between 68°F to 77°F (20°C to 25°C).
     Keep the bottle closed tightly and away from moisture.
    Keep deferasirox tablets and all medicines out of the reach of children.

    General information about the safe and effective use of deferasirox tablets
    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use deferasirox tablets for a condition for which it was not prescribed. Do not give it to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for more information about deferasirox tablets.

    For more information, call Dr. Reddy’s Laboratories Inc., at 1-888-375-3784..

    What are the ingredients in deferasirox tablets?

    Deferasirox tablets:
    Active ingredient: deferasirox
    Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hydrogenated castor oil, lactose monohydrate, low substituted hydroxy propyl cellulose, microcrystalline cellulose, poloxamer (188), povidone (K30) and sodium stearyl fumarate. The film coating contains. hypromellose, titanium dioxide, propylene glycol, talc and iron oxide yellow.

    Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s JADENU® (deferasirox) tablets. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

    This Medication Guide has been approved by the U.S. Food and Drug Administration.

    To reorder additional Medication Guides, contact Dr. Reddy’s Customer Service at 1-866-733-3952.

    Rx Only


    Distributed by:

    Dr. Reddy’s Laboratories Inc.,

    Princeton, NJ 08540

    Made in India

    Issued: 10/2019

  • PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

    Deferasirox tablets-90mg-30s-container label:
    container1

  • PRINCIPAL DISPLAY PANEL

    Deferasirox tablets-360mg-30s-container label:

    container2

  • INGREDIENTS AND APPEARANCE
    DEFERASIROX 
    deferasirox tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 43598-853
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    DEFERASIROX (UNII: V8G4MOF2V9) (DEFERASIROX - UNII:V8G4MOF2V9) DEFERASIROX90 mg
    Inactive Ingredients
    Ingredient NameStrength
    CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)  
    CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
    HYDROXYPROPYL CELLULOSE, LOW SUBSTITUTED (UNII: 2165RE0K14)  
    POLOXAMER 188 (UNII: LQA7B6G8JG)  
    POVIDONE K30 (UNII: U725QWY32X)  
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    Silicon Dioxide (UNII: ETJ7Z6XBU4)  
    SODIUM STEARYL FUMARATE (UNII: 7CV7WJK4UI)  
    CASTOR OIL (UNII: D5340Y2I9G)  
    HYPROMELLOSES (UNII: 3NXW29V3WO)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    TALC (UNII: 7SEV7J4R1U)  
    FERRIC OXIDE YELLOW (UNII: EX438O2MRT)  
    PROPYLENE GLYCOL (UNII: 6DC9Q167V3)  
    Product Characteristics
    ColorYELLOWScoreno score
    ShapeOVALSize11mm
    FlavorImprint Code D;90
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 43598-853-3030 in 1 BOTTLE; Type 0: Not a Combination Product11/20/2019
    2NDC: 43598-853-101000 in 1 BOTTLE; Type 0: Not a Combination Product11/20/2019
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21094511/20/2019
    DEFERASIROX 
    deferasirox tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 43598-851
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    DEFERASIROX (UNII: V8G4MOF2V9) (DEFERASIROX - UNII:V8G4MOF2V9) DEFERASIROX360 mg
    Inactive Ingredients
    Ingredient NameStrength
    CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)  
    CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
    HYDROXYPROPYL CELLULOSE, LOW SUBSTITUTED (UNII: 2165RE0K14)  
    POLOXAMER 188 (UNII: LQA7B6G8JG)  
    POVIDONE K30 (UNII: U725QWY32X)  
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    Silicon Dioxide (UNII: ETJ7Z6XBU4)  
    SODIUM STEARYL FUMARATE (UNII: 7CV7WJK4UI)  
    CASTOR OIL (UNII: D5340Y2I9G)  
    HYPROMELLOSES (UNII: 3NXW29V3WO)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    TALC (UNII: 7SEV7J4R1U)  
    FERRIC OXIDE YELLOW (UNII: EX438O2MRT)  
    PROPYLENE GLYCOL (UNII: 6DC9Q167V3)  
    Product Characteristics
    ColorYELLOWScoreno score
    ShapeOVALSize17mm
    FlavorImprint Code D;360
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 43598-851-3030 in 1 BOTTLE; Type 0: Not a Combination Product11/20/2019
    2NDC: 43598-851-101000 in 1 BOTTLE; Type 0: Not a Combination Product11/20/2019
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21094511/20/2019
    Labeler - Dr. Reddy's Laboratories Inc (802315887)
    Establishment
    NameAddressID/FEIBusiness Operations
    MSN LABORATORIES PRIVATE LIMITED650786952analysis(43598-853, 43598-851) , manufacture(43598-853, 43598-851)

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