Deferasirox (Page 4 of 9)

5.5 Age-Related Risk of Toxicity

Elderly Patients

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

Pediatric Patients

Deferasirox 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 Exjade^® doses in the 20-40 mg/kg/day range equivalent to 14-28 mg/kg/day deferasirox when body iron burden was approaching or in the normal range. Interrupt deferasirox in patients with volume depletion, and resume deferasirox when renal function and fluid volume have normalized. Monitor liver and renal function more frequently during volume depletion and in patients receiving deferasirox in the 14-28 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 the patient’s response to therapy and minimize the risk of overchelation. An analysis of pediatric patients treated with Exjade^® in pooled clinical trials (n = 158), found a higher rate of renal adverse reactions among patients receiving doses greater than 25 mg/kg/day equivalent to 17.5 mg/kg/day deferasirox, 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 Reactions (6.1), Use in Specific Populations (8.4)].

If the serum ferritin falls below 1,000 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 therapy with deferasirox 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 in the 14 to 28 mg/kg/day range, when the body iron burden is approaching or within the normal range can result in life threatening adverse reactions [see Dosage and Administration (2.1)].

For patients with NTDT, measure LIC by liver biopsy or by using an FDA-cleared or approved method for monitoring patients receiving deferasirox therapy every 6 months on treatment. Interrupt deferasirox administration when the LIC is less than 3 mg Fe/g dw. Measure serum ferritin monthly, and if the serum ferritin falls below 300 mcg/L, interrupt deferasirox and obtain a confirmatory LIC [see Clinical Studies (14)].

5.7 Hypersensitivity

Deferasirox 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 and institute appropriate medical intervention. Deferasirox is 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 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 immediately and do not reintroduce deferasirox therapy.

5.9 Skin Rash

Rashes may occur during deferasirox treatment [see Adverse Reactions (6.1)]. For rashes of mild to moderate severity, deferasirox may be continued without dose adjustment, since the rash often resolves spontaneously. In severe cases, interrupt treatment with deferasirox. 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 therapy in the clinical studies. The frequency of auditory adverse reactions was increased among pediatric patients, who received Exjade^® doses greater than 25 mg/kg/day equivalent to 17.5 mg/kg/day deferasirox 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 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), (5.6)]
• Hepatic Toxicity and Failure [see Warnings and Precautions (5.2), (5.6)]
• 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. Deferasirox was evaluated in healthy volunteer trials. Currently, there are no clinical data in patients with deferasirox tablets. Deferasirox contains the same active ingredient as Exjade^® (deferasirox) tablets for oral suspension. The following adverse reactions have been reported with Exjade^® tablets for oral suspension.

Transfusional Iron Overload

A total of 700 adult and pediatric patients were treated with 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 myelodysplastic syndrome (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% (Adverse Events (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 at the completion of the study.

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

Table 1. Adverse Reactions^a Occurring in > 5% of Deferasirox-treated Patients in Study 1, Study 3, and MDS Pool

	Study 1 (Beta-thalassemia)		Study 3 (Sickle Cell Disease)		MDS Pool
Adverse Reactions	Deferasirox N = 296 n (%)	Deferoxamine N = 290 n (%)	Deferasirox N = 132 n (%)	Deferoxamine N = 63 n (%)	Deferasirox N = 627 n (%)
Abdominal Painb	63 (21)	41 (14)	37 (28)	9 (14)	145 (23)
Diarrhea	35 (12)	21 (7)	26 (20)	3 (5)	297 (47)
CreatinineIncreasedc	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)
Abbreviation: MDS, myelodysplastic syndrome.a Adverse reaction frequencies are based on AEs reported regardless of relationship to study drug.b Includes ‘abdominal pain’, ‘abdominal pain lower’, and ‘abdominal pain upper’.c Includes ‘blood creatinine increased’ and ‘blood creatinine abnormal’. See also Table 2.

In Study 1, a total of 113 (38%) patients treated with deferasirox 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 developed elevations in serum glutamic-pyruvic transaminase (SGPT)/ALT levels greater than 5 times the upper limit of normal (ULN) at 2 consecutive visits. Of these, 2 patients had liver biopsy proven drug-induced hepatitis and both discontinued deferasirox 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 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 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-treated patients required dose reductions. In this study, 5 patients in the deferasirox group developed elevations in SGPT/ALT levels greater than 5 times the ULN at 2 consecutive visits and 1 patient subsequently had deferasirox permanently discontinued. Four additional patients discontinued 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 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 N = 296 n (%)	Deferoxamine N = 290 n (%)	Deferasirox N = 132 n (%)	Deferoxamine N = 63 n (%)	Deferasirox 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 xULN at 2 post- baseline visits	25 (8)	7 (2)	2 (2)	0	9 (1)
SGPT/ALT > 5 xULN at 2 consecutive post-baseline visits	17 (6)	5 (2)	5 (4)	0	5 (1)
Abbreviations: ALT, alanine transaminase; MDS, myelodysplastic syndrome; SGPT, serum glutamic-pyruvic transaminase; ULN, upper limit of normal.

Non-Transfusion-Dependent Thalassemia Syndromes

In Study 5, 110 patients with NTDT received 1 year of treatment with deferasirox 5 or 10 mg/kg/day and 56 patients received placebo in a double-blind, randomized trial. In Study 6, 130 of the patients who completed Study 5 were treated with open-label deferasirox at 5, 10, or 20 mg/kg/day (depending on the baseline LIC) for 1 year [see Clinical Studies (14)]. Table 3 and 4 display the frequency of adverse reactions in patients with NTDT. Adverse reactions with a suspected relationship to study drug were included in Table 3 if they occurred at ≥ 5% of patients in Study 5.

Table 3. Adverse Reactions Occurring in Greater Than 5% Patients with NTDT

Any adverse reaction	Study 5		Study 6
	Deferasirox	Placebo	Deferasirox
	N = 110	N = 56	N = 130
	n (%)	n (%)	n (%)
	31 (28)	9 (16)	27 (21)
Nausea	7 (6)	4 (7)	2 (2)a
Rash	7 (6)	1 (2)	2 (2)a
Diarrhea	5 (5)	1 (2)	7 (5)
Abbreviation: NTDT, non-transfusion-dependent thalassemia.a The occurrence of nausea, and rash are included for Study 6. There were no additional adverse reactions with a suspected relationship to study drug occurring in >5% of patients in Study 6.

In Study 5, 1 patient in the placebo 10 mg/kg/day group experienced an ALT increase to greater than 5 times ULN and greater than 2 times baseline (Table 4). Three deferasirox-treated patients (all in the 10 mg/kg/day group) had 2 consecutive serum creatinine level increases greater than 33% from baseline and greater than ULN. Serum creatinine returned to normal in all 3 patients (in 1 spontaneously and in the other 2 after drug interruption). Two additional cases of ALT increase and 2 additional cases of serum creatinine increase were observed in the 1-year extension of Study 5. The number (%) of patients with NTDT with increase in serum creatinine or SGPT/ALT in Study 5 and Study 6 are presented in Table 4 below.

Table 4. Number (%) of Patients with NTDT with Increases in Serum Creatinine or SGPT/ALT

Laboratory Parameter	Study 5		Study 6
	Deferasirox	Placebo	Deferasirox
	N = 110	N = 56	N = 130
	n (%)	n (%)	n (%)
Serum creatinine (> 33% increase from baseline and > ULN at ≥ 2 consecutive post-baseline values)	3 (3)	0	2 (2)
SGPT/ALT (> 5 x ULN and > 2 x baseline)	1 (1)	1 (2)	2 (2)
Abbreviations: ALT, alanine transaminase; NTDT, non-transfusion-dependent thalassemia; SGPT, serum glutamic-pyruvic transaminase; ULN, upper limit of normal.

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-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 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, GI 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, GI 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 Exjade^® dosage equivalent to 3.5 mg/kg deferasirox, starting at 20 mg/kg/day equivalent to 14 mg/kg/day deferasirox (95% confidence interval (CI): 1.08-1.48).
• 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: 1.01-1.56).
• Among pediatric patients with a serum ferritin < 1,000 mcg/L, those who received Exjade^® dosage > 30 mg/kg/day, equivalent to 21 mg/kg/day deferasirox compared to those who received lower dosages, had a higher risk for acute kidney injury (Odds ratio (OR) = 4.47, 95% CI: 1.25-15.95), consistent with overchelation.

In addition, a cohort-based analysis of ARs was conducted in the deferasirox pediatric pooled clinical trial data. Pediatric patients who received Exjade^® dose > 25 mg/kg/day equivalent to 17.5 mg/kg/day deferasirox when their serum ferritin was < 1,000 mcg/L (n = 158), had a 6-fold greater rate of renal adverse reactions (Incidence Rate Ratio (IRR) = 6.00, 95% CI: 1.75-21.36), and a 2-fold greater rate of dose interruptions (IRR = 2.06, 95% CI: 1.33-3.17) compared to the time-period prior to meeting these simultaneous criteria. Adverse reactions of special interest (cytopenia, renal, hearing, and GI disorders) occurred 1.9-fold more frequently when these simultaneous criteria were met, compared to preceding time-periods (IRR = 1.91, 95% CI: 1.05-3.48) [see Warnings and Precautions (5.6)].