Deferasirox

DEFERASIROX — deferasirox tablet, for suspension
Alembic Pharmaceuticals Limited

WARNING: RENAL FAILURE, HEPATIC FAILURE, AND GASTROINTESTINAL HEMORRHAGE


Renal Failure
• Deferasirox tablets for oral suspension 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 tablets for oral suspension dosing in all patients. Deferasirox tablets for oral suspension are 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 tablets for oral suspension 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 tablets for oral suspension 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 tablets for oral suspension 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 tablets for oral suspension 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 for oral suspension 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 EXJADE® (deferasirox) tablets for oral suspension. 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 for oral suspension when administered with other iron chelation therapy have not been established.

2 DOSAGE AND ADMINISTRATION

2.1 Transfusional Iron Overload

Deferasirox tablets for oral suspension 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:
o Obtain serum creatinine in duplicate (due to variations in measurements) to establish accurate baseline
o 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).
o 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 tablets for oral suspension for patients 2 years of age and older with eGFR greater than 60 mL/min/1.73 m2 is 20 mg per kg body weight orally, once daily. Calculate doses (mg per kg per day) to the nearest whole tablet.

During therapy:
• Monitor serum ferritin monthly and adjust the dose of deferasirox tablets for oral suspension, 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 5 or 10 mg per kg and tailor adjustments to the individual patient’s response and therapeutic goals.
• In patients not adequately controlled with doses of 30 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 40 mg per kg may be considered. Doses above 40 mg per kg are not recommended [see Warnings and Precautions (5.6)].
• Adjust dose based on serum ferritin levels
o If the serum ferritin falls below 1000 mcg/L at 2 consecutive visits, consider dose reduction, especially if the dose is greater than 25 mg/kg/day [see Adverse Reactions (6.1)].
o If the serum ferritin falls below 500 mcg/L, interrupt deferasirox tablets for oral suspension and continue monthly monitoring.
o Evaluate the need for ongoing chelation therapy for patients whose conditions no longer require regular blood transfusions.
o 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 oral suspension 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 EXJADE® (deferasirox) tablets for oral suspension. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2.3 Administration

Do not chew tablets or swallow them whole.

Take deferasirox tablets for oral suspension once daily on an empty stomach at least 30 minutes before food, preferably at the same time each day. Completely disperse tablets by stirring in water, orange juice, or apple juice until a fine suspension is obtained. Disperse doses of less than 1 g in 3.5 ounces of liquid and doses of 1 g or greater in 7 ounces of liquid. After swallowing the suspension, resuspend any residue in a small volume of liquid and swallow. Do not take deferasirox tablets for oral suspension with aluminum-containing antacid products [see Drug Interactions (7.1)].

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 for oral suspension [see Warnings and Precautions (5.2), Use in Specific Populations (8.7)].

Patients with Baseline Renal Impairment

Do not use deferasirox tablets for oral suspension 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/min/1.73 m2. If treatment is needed, use the minimum effective dose and monitor renal function frequently. Individualize dose titration based on improvement in renal injury [see Use in Specific Populations (8.6)].

2.5 Dose Modifications for Decreases in Renal Function while on Deferasirox Tablets for Oral Suspension

Deferasirox tablets for oral suspension is contraindicated in patients with eGFR less than 40 mL/min/1.73 m2 [see Contraindications (4)].

For decreases in renal function while receiving deferasirox tablets for oral suspension [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 10 mg per kg.

Pediatric Patients (ages 2 to 17 years):

  • Reduce the dose by 10 mg/per/kg if eGFR decreases by greater than 33% below the average baseline measurement andrepeat the eGFR within 1 week.
  • Interrupt deferasirox tablets for oral suspension 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 for oral suspension use. Use the minimum effective deferasirox tablets for oral suspension 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 for oral suspension 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/1.73m2 [see Contraindications (4)].

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

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