Deferasirox (Page 4 of 10)

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 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 Abmormalities

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 events irrespective of causality was increased among pediatric patients, who received deferasirox tablets for oral suspension 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:

6.1Clinical 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 deferasirox tablets for oral suspension. The following adverse reactions have been reported with deferasirox 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 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 at the completion of the study.

Table 1. Adverse Reactions* 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(%) DeferoxamineN=290 n(%) Deferasirox N=132 n(%) Deferoxamine N=63 n(%) Deferasirox 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)

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 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 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.

[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 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)

Abbreviations: ALT, alanine transaminase; MDS, myelodysplastic syndrome; SGPT, serum glutamic-pyruvic transaminase; ULN, upper limit of normal.

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