Deferasirox (Page 3 of 8)

5.4 Bone Marrow Suppression

Neutropenia, agranulocytosis, worsening anemia, and thrombocytopenia, including fatal events, have been reported in patients treated with deferasirox tablets for oral suspension. Preexisting hematologic disorders may increase this risk. Monitor blood counts in all patients. Interrupt treatment with deferasirox tablets for oral suspension in patients who develop cytopenias until the cause of the cytopenia has been determined. Deferasirox tablets for oral suspension are contraindicated in patients with platelet counts below 50 x 109 /L.

5.5 Age-Related Risk of Toxicity

Elderly Patients

Deferasirox tablets for oral suspension have been associated with serious and fatal adverse reactions in the postmarketing setting among adults, predominantly in elderly patients. Monitor elderly patients treated with deferasirox tablets for oral suspension more frequently for toxicity [see Use in Specific Populations (8.5)].

Pediatric Patients

Deferasirox tablets for oral suspension 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 when body iron burden was approaching or in the normal range. Interrupt deferasirox tablets for oral suspension in patients with volume depletion, and resume deferasirox tablets for oral suspension when renal function and fluid volume have normalized. Monitor liver and renal function more frequently during volume depletion and in patients receiving deferasirox tablets for oral suspension in the 20 to 40 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 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 Reaction (6.1), Use in Specific Populations (8.4)].

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)]. If the serum ferritin falls below 500 mcg/L, interrupt therapy with deferasirox tablets for oral suspension 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 tablets for oral suspension in the 20 to 40 mg/kg/day range when the body iron burden is approaching or within the normal range has resulted in life-threatening adverse events [see Dosage and Administration (2.1)].
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.

5.7 Hypersensitivity

Deferasirox tablets for oral suspension 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 tablets for oral suspension and institute appropriate medical intervention. Deferasirox tablets for oral suspension are 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 tablets for oral suspension 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 tablets for oral suspension immediately and do not reintroduce deferasirox tablets for oral suspension therapy.

5.9 Skin Rash

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

5.10 Auditory and Ocular Abnormalities

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 tablets for oral suspension 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 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 tablets for oral suspension 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:

  • Acute Kidney Injury, Including Acute Renal Failure Requiring Dialysis, and Renal Tubular Toxicity Including Fanconi Syndrome [see Warnings and Precautions (5.1)]
  • Hepatic Toxicity and Failure [see Warnings and Precautions (5.2)]
  • Gastrointestinal (GI) Hemorrhage [see Warnings and Precautions (5.3)]
  • Bone Marrow Suppression [see Warnings and Precautions (5.4)]
  • Hypersensitivity [see Warnings and Precautions (5.7)]
  • Severe Skin Reactions [see Warnings and Precautions (5.8)]
  • Skin Rash [see Warnings and Precautions (5.9)]
  • Auditory and Ocular Abnormalities [see Warnings and Precautions (5.10)]

6.1 Clinical 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.

Transfusional Iron Overload
A total of 700 adult and pediatric patients were treated with deferasirox tablets for oral suspension (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 (627) 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 tablets for oral suspension at the completion of the study.

Table 1 displays adverse reactions occurring in greater than 5% of deferasirox tablets for oral suspension-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 tablets for oral suspension. Gastrointestinal symptoms, increases in serum creatinine, and skin rash were dose related.

Table 1. Adverse Reactions* Occurring in Greater Than 5% of Deferasirox Tablets for Oral Suspension-treated Patients in Study 1, Study 3, and MDS Pool

Study 1 (Beta-thalassemia) Study 3 (Sickle Cell Disease) MDS Pool
Adverse Reactions Deferasirox Tablets for Oral Suspension N=296 n (%) Deferoxamine N=290 n (%) Deferasirox Tablets for Oral Suspension N=132 n (%) Deferoxamine N=63 n (%) Deferasirox Tablets for Oral Suspension N=627 n (%)
Abdominal Pain** 63 (21) 41 (14) 37 (28) 9 (14) 145 (23)
Diarrhea 35 (12) 21 (7) 26 (20) 3 (5) 297 (47)
Creatinine Increased*** 33 (11) 0 (0) 9 (7) 0 89 (14)
Nausea 31 (11) 14 (5) 30 (23) 7 (11) 161 (26)
Vomiting 30 (10) 28 (10) 28 (21) 10 (16) 83 (13)
Rash 25 (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’, and ‘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 tablets for oral suspension 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 tablets for oral suspension 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 tablets for oral suspension 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 tablets for oral suspension 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 tablets for oral suspension 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 tablets for oral suspension-treated patients required dose reductions. In this study, 5 patients in the deferasirox tablets for oral suspension group developed elevations in SGPT/ALT levels greater than 5 times the ULN at 2 consecutive visits and 1 patient subsequently had deferasirox tablets for oral suspension permanently discontinued. Four additional patients discontinued deferasirox tablets for oral suspension 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 tablets for oral suspension 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 Tablets for Oral Suspension N=296 n (%) Deferoxamine N=290 n (%) Deferasirox Tablets for Oral Suspension N=132 n (%) Deferoxamine N=63 n (%) Deferasirox Tablets for Oral Suspension 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 tablets for oral suspension-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 tablets for oral suspension 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 starting at 20 mg/kg/day (95% CI: 1.08 to 1.48).

- A 25% increased risk for acute kidney injury was observed with each 250 mcg/L decrease in serum ferritin starting at 1250 mcg/L (95% CI: 1.01 to 1.56).

- Among pediatric patients with a serum ferritin <1000 mcg/L, those who received deferasirox tablets for oral suspension dosage >30 mg/kg/day, compared to those who received lower dosages, had a higher risk for acute kidney injury (OR=4.47, 95% CI: 1.25 to 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 when their serum ferritin was <1000 mcg/L (n=158) had a 6-fold greater rate of renal adverse events (IRR = 6, 95% CI: 1.75 to 21.36) and a 2-fold greater rate of dose interruptions (IRR= 2.06, 95% CI: 1.33 to 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 to 3.48) [see Warnings and Precautions (5.6)].

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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