DEFERASIROX (Page 3 of 11)

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

Deferasirox tablets are 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 [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/kg.

Pediatric Patients (ages 2 years-17 years):

Reduce the dose by 7 mg/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):

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/kg, or reduce by 50% if the dose is 7 or 14 mg/kg.
Pediatric Patients (ages 10 years -17 years):
Reduce the dose by 3.5 mg/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 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):
Discontinue therapy for eGFR less than 40 mL/min/1.73 m2 [see Contraindications (4)].

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, 2.2), Drug Interactions (7.5)].

Bile Acid Sequestrants

Concomitant use of bile acid sequestrants decreases systemic exposure. Avoid the concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol). If you must administer 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, 2.2), Drug Interactions (7.6)].

3 DOSAGE FORMS AND STRENGTHS

Deferasirox tablets 90 mg tablets are light blue oval biconvex film-coated tablet with beveled edges, debossed with ‘S102’ on one side and plain on the other side.
Deferasirox tablets 180 mg tablets are medium blue oval biconvex film-coated tablet with beveled edges, debossed with ‘S103’ on one side and plain on the other side.
Deferasirox tablets 360 mg tablets are dark blue oval biconvex film-coated tablet with beveled edges, debossed with ‘S104’ on one side and plain on the other side.

4 CONTRAINDICATIONS

Deferasirox tablets are 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 tablets [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 tablets are 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/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)]. For patients with renal impairment (eGFR 40–60 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 tablets 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, 2.2)].

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 tablets 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)].

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