Jadenu (Page 2 of 8)

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 JADENU tablets or JADENU Sprinkle granules [see Warnings and Precautions (5.2), Use in Specific Populations (8.7)].

Patients with Baseline Renal Impairment

For patients with CLcr 40 to 60 mL/min, reduce the starting dose by 50% [see Use in Specific Populations (8.6)]. Do not use JADENU in patients with serum creatinine greater than two times the age-appropriate upper limit of normal (ULN) or CLcr less than 40 mL/min [see Contraindications (4)].

2.5 Dose Modifications for Increases in Serum Creatinine

For serum creatinine increases while receiving JADENU [see Warnings and Precautions (5.1)] modify the dose as follows:

Transfusional Iron Overload

Adults and Adolescents (ages 16 years and older):

  • 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 to 15 years):

  • Reduce the dose by 7 mg per kg if serum creatinine increases to greater than 33% above the average baseline measurement and greater than the age appropriate upper limit of normal (ULN).

All Patients (regardless of age):

  • Discontinue therapy for serum creatinine greater than two times the age-appropriate ULN or for creatinine clearance less than 40 mL/min. [see Contraindications (4)]

Non-Transfusion-Dependent Thalassemia Syndromes

Adults and Adolescents (ages 16 years and older):

  • 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 to 15 years):

  • Reduce the dose by 3.5 mg per kg if serum creatinine increases to greater than 33% above the average baseline measurement and greater than the age appropriate ULN.

All Patients (regardless of age):

  • Discontinue therapy for serum creatinine greater than 2 times the age-appropriate ULN or for creatinine clearance less than 40 mL/min [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 JADENU tablets or JADENU Sprinkle granules 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 JADENU tablets or JADENU Sprinkle granules 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

  • 90 mg JADENU tablets
    Light blue oval biconvex film-coated tablet with beveled edges, debossed with ‘NVR’ on one side and ‘90’ on a slight upward slope in between two debossed curved lines on the other side.
  • 180 mg JADENU tablets
    Medium blue oval biconvex film-coated tablet with beveled edges, debossed with ‘NVR’ on one side and ‘180’ on a slight upward slope in between two debossed curved lines on the other side.
  • 360 mg JADENU tablets
    Dark blue oval biconvex film-coated tablet with beveled edges, debossed with ‘NVR’ on one side and ‘360’ on a slight upward slope in between two debossed curved lines on the other side.
  • 90 mg JADENU Sprinkle granules
    Supplied in cartons containing 30 child resistant foil sachets. Each sachet contains 162 mg of white to almost white granules, equivalent to 90 mg deferasirox.
  • 180 mg JADENU Sprinkle granules
    Supplied in cartons containing 30 child resistant foil sachets. Each sachet contains 324 mg of white to almost white granules, equivalent to 180 mg deferasirox.
  • 360 mg JADENU Sprinkle granules Supplied in cartons containing 30 child resistant foil sachets. Each sachet contains 648 mg of white to almost white granules, equivalent to 360 mg deferasirox.

4 CONTRAINDICATIONS

JADENU is contraindicated in patients with:

  • Serum creatinine greater than two times the age-appropriate upper limit of normal or creatinine clearance less than 40 mL/min [see Warnings and Precautions (5.1)] ;
  • Poor performance status;
  • High-risk myelodysplastic syndromes;
  • Advanced malignancies;
  • Platelet counts less than 50 x 10 9 /L;
  • Known hypersensitivity to deferasirox or any component of JADENU [see Warnings and Precautions (5.6), Adverse Reactions (6.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Renal Toxicity, Renal Failure, and Proteinuria

JADENU can cause acute renal failure, fatal in some patients and requiring dialysis in others. Postmarketing experience showed that most fatalities occurred in patients with multiple comorbidities and who were in advanced stages of their hematological disorders. In the clinical trials, deferasirox-treated patients experienced dose-dependent increases in serum creatinine. In patients with transfusional iron overload, these increases in creatinine occurred at a greater frequency compared to deferoxamine-treated patients (38% versus 14%, respectively, in Study 1 and 36% versus 22%, respectively, in Study 3) [see Adverse Reactions (6.1, 6.2)].

Measure serum creatinine in duplicate (due to variations in measurements) and determine the CLcr (estimated by the Cockcroft-Gault method) before initiating therapy in all patients in order to establish a reliable pretreatment baseline. Monitor serum creatinine weekly during the first month after initiation or modification of therapy and at least monthly thereafter. Monitor serum creatinine and/or CLcr more frequently if creatinine levels are increasing. Dose reduction, interruption, or discontinuation based on increases in serum creatinine may be necessary [see Dosage and Administration (2.5)].

JADENU is contraindicated in patients with CLcr less than 40 mL/minute or serum creatinine greater than 2 times the age appropriate ULN.

Renal tubular damage, including Fanconi’s Syndrome, has been reported in patients treated with deferasirox, most commonly in children and adolescents with beta-thalassemia and serum ferritin levels less than 1500 mcg/L.

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. In clinical trials in patients with transfusional iron overload, deferasirox was temporarily withheld until the urine protein/creatinine ratio fell below 0.6 mg/mg. Monthly monitoring for proteinuria is recommended. The mechanism and clinical significance of the proteinuria are uncertain [see Adverse Reactions (6.1)].

5.2 Hepatic 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)].

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 JADENU 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.

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