Deferasirox: Package Insert and Label Information

DEFERASIROX — deferasirox tablet
Xiromed, LLC

WARNING: RENAL FAILURE, HEPATIC FAILURE, AND GASTROINTESTINAL 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 & 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.

1.2 Treatment of Chronic Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes

Deferasirox tablets are indicated for the treatment of chronic iron overload in patients 10 years of age and older with non-transfusion-dependent thalassemia (NTDT) syndromes and with a liver iron concentration (LIC) of at least 5 milligrams of iron per gram of liver dry weight (mg Fe/g dw) and a serum ferritin greater than 300 mcg/L. This indication is approved under accelerated approval based on a reduction of liver iron concentrations (to less than 5 mg Fe/g dw) and serum ferritin levels [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

1.3 Limitations of Use


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

2 DOSAGE & ADMINISTRATION

2.1 Transfusional Iron Overload

Deferasirox 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 1000 mcg/L.

Prior to starting therapy, or increasing dose, evaluate:

  • Serum ferritin level
  • Baseline renal function:
    • Obtain serum creatinine in duplicate (due to variations in measurements)
    • Calculate the estimated glomerular filtration rate (eGFR). Use a prediction equation appropriate for adult patients (e.g., CKD-EPI, MDRD method) and in pediatric patients (e.g., Schwartz equations).
    • Obtain urinalyses and serum electrolytes to evaluate renal tubular function [see Dosage and Administration (2.4), Warnings and Precautions (5.1)].
  • Serum transaminases and bilirubin [see Dosage and Administration (2.4), Warnings and Precautions (5.2)]
  • Baseline auditory and ophthalmic examinations [see Warnings and Precautions (5.10)]

Initiating Therapy:

The recommended initial dose of deferasirox 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, 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 2500 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 1000 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 deferasirox 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 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)].

2.2 Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes

Deferasirox therapy should only be considered when a patient with NTDT syndrome has an LIC of at least 5 mg Fe/g dw and a serum ferritin greater than 300 mcg/L.

Prior to starting therapy, obtain:

  • LIC by liver biopsy or by an FDA-cleared or approved method for identifying patients for treatment with deferasirox therapy

  • Serum ferritin level on at least 2 measurements 1-month apart [see Clinical Studies (14)]

  • Baseline renal function:

    • Obtain serum creatinine in duplicate (due to variations in measurements)
    • Calculate the estimated glomerular filtration rate (eGFR). Use a prediction equation appropriate for adult patients (e.g., CKD-EPI, MDRD method) and in pediatric patients (e.g., Schwartz equations).
    • Obtain urinalyses and serum electrolytes to evaluate renal tubular function [see Dosage and Administration (2.4), Warnings and Precautions (5.1)].
  • Serum transaminases and bilirubin [see Dosage and Administration (2.4), Warnings and Precautions (5.2)]

  • Baseline auditory and ophthalmic examinations [see Warnings and Precautions (5.10)]

Initiating Therapy:

  • The recommended initial dose of deferasirox for patients with eGFR greater than 60 mL/min/1.73 m2 is 7 mg per kg body weight orally once daily. Calculate doses (mg per kg per day) to the nearest whole tablet.

  • If the baseline LIC is greater than 15 mg Fe/g dw, consider increasing the dose to 14 mg/kg/day after 4 weeks.

During Therapy:

  • Monitor serum ferritin monthly. Interrupt treatment when serum ferritin is less than 300 mcg/L and obtain an LIC to determine whether the LIC has fallen to less than 3 mg Fe/g dw.

  • Use the minimum effective dose to achieve a trend of decreasing ferritin.

  • Monitor LIC every 6 months.

  • After 6 months of therapy, if the LIC remains greater than 7 mg Fe/g dw, increase the dose of deferasirox to a maximum of 14 mg/kg/day. Do not exceed a maximum of 14 mg/kg/day.

  • If after 6 months of therapy, the LIC is 3 to 7 mg Fe/g dw, continue treatment with deferasirox at no more than 7 mg/kg/day.

  • When the LIC is less than 3 mg Fe/g dw, interrupt treatment with deferasirox and continue to monitor the LIC.

  • Monitor blood counts, liver function, renal function and ferritin monthly [see Warnings and Precautions (5.1, 5.2, 5.4)].

  • Increase monitoring frequency for pediatric patients who have acute illness, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake. Consider dose interruption until oral intake and volume status are normal [see Dosage and Administration (2.4, 2.5), Warnings and Precautions (5.1), Use in Specific Populations (8.4), Clinical Pharmacology (12.3)].

Restart treatment when the LIC rises again to more than 5 mg Fe/g dw.

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 Exjade® tablets for oral suspension and converting to deferasirox, 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.

EXJADE ® Tablets for oral suspension (white round tablet) Deferasirox Tablets (film coated blue oval tablet)
Transfusion-Dependent Iron Overload
Starting Dose 20 mg/kg/day 14 mg/kg/day
Titration Increments 5-10 mg/kg 3.5-7 mg/kg
Maximum Dose 40 mg/kg/day 28 mg/kg/day
Non-Transfusion-Dependent Thalassemia Syndromes
Starting Dose 10 mg/kg/day 7 mg/kg/day
Titration Increments 5-10 mg/kg 3.5-7 mg/kg
Maximum Dose 20 mg/kg/day 14 mg/kg/day

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 in adult or pediatric patients with eGFR less than 40 mL/min/1.73 m2 [see Dosage and Administration (2.5), Contraindications (4)].

For patients with renal impairment (eGFR 40-60 mL/min/1.73 m2), reduce the starting dose by 50% [see Use in Specific Populations (8.6)].

Exercise caution in pediatric patients with eGFR between 40 and 60 mL/minute/1.73 m2. If treatment is needed, use the minimum effective dose and monitor renal function frequently. Individualize dose titration based on improvement in renal injury [see Use in Specific Populations (8.6)].

2.5 Dose Modifications for Decreases in Renal Function while on Deferasirox

Deferasirox 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 [see Warnings and Precautions (5.1)] , modify the dose as follows:

Transfusional Iron Overload

Adults:

  • If the serum creatinine increases by 33% or more above the average baseline measurement, repeat the serum creatinine within 1 week, and if still elevated by 33% or more, reduce the dose by 7 mg per kg.

Pediatric Patients (ages 2 years-17 years):

  • Reduce the dose by 7 mg per kg if eGFR decreases by greater than 33% below the average baseline measurement and repeat eGFR within 1 week
  • Interrupt deferasirox 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 use. Use the minimum effective deferasirox 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 to prevent severe and irreversible renal injury [see Warnings and Precautions (5.1)].

All Patients (regardless of age):

  • Discontinue therapy for eGFR less than 40 mL/min/1.73 m2 [see Contraindications (4)].

Non-Transfusion-Dependent Thalassemia Syndromes

Adults:

  • If the serum creatinine increases by 33% or more above the average baseline measurement, repeat the serum creatinine within 1 week, and if still elevated by 33% or more, interrupt therapy if the dose is 3.5 mg per kg, or reduce by 50% if the dose is 7 or 14 mg per kg.

Pediatric Patients (ages 10 years -17 years):

  • Reduce the dose by 3.5 mg per kg if eGFR decreases by greater than 33% below the average baseline measurement and repeat the eGFR within 1 week.

  • Increase monitoring frequency for pediatric patients who have acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake. Consider dose interruption until oral intake and volume status are normal. Avoid use of other nephrotoxic drugs [see Warnings and Precautions (5.1)].

  • In the setting of decreased renal function, evaluate the risk benefit profile of continued deferasirox use. Use the minimum effective deferasirox 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 to prevent severe and irreversible renal injury [see Warnings and Precautions (5.1)].

All Patients (regardless of age):

  • Discontinue therapy for eGFR less than 40 mL/min/1.73 m2 [see Contraindications (4)].

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