Jadenu (Page 3 of 8)

5.3 Gastrointestinal (GI) Ulceration, Hemorrhage, and Perforation

GI hemorrhage, including deaths, has been reported, especially in elderly patients who had advanced hematologic malignancies and/or low platelet counts. Nonfatal upper GI irritation, ulceration and hemorrhage have been reported in patients, including children and adolescents, receiving deferasirox [see Adverse Reactions (6.1)]. Monitor for signs and symptoms of GI ulceration and hemorrhage during JADENU therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. The risk of gastrointestinal hemorrhage may be increased when administering JADENU in combination with drugs that have ulcerogenic or hemorrhagic potential, such as nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, oral bisphosphonates, or anticoagulants. There have been reports of ulcers complicated with gastrointestinal perforation (including fatal outcome) [see Adverse Reactions (6.2)].

5.4 Bone Marrow Suppression

Neutropenia, agranulocytosis, worsening anemia, and thrombocytopenia, including fatal events, have been reported in patients treated with deferasirox. Preexisting hematologic disorders may increase this risk. Monitor blood counts in all patients. Interrupt treatment with JADENU in patients who develop cytopenias until the cause of the cytopenia has been determined. JADENU is contraindicated in patients with platelet counts below 50 x 10 9 /L.

5.5 Increased Risk of Toxicity in the Elderly

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

5.6 Hypersensitivity

JADENU 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 JADENU and institute appropriate medical intervention. JADENU 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.

5.7 Severe Skin Reactions

Severe skin reactions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and erythema multiforme, have been reported during deferasirox therapy [see Adverse Reactions (6.2)]. The risk of other skin reactions including DRESS (drug reaction with eosinophilia and systemic symptoms) cannot be excluded. If severe skin reactions are suspected, discontinue JADENU immediately and do not reintroduce JADENU therapy.

5.8 Skin Rash

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

5.9 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. Perform auditory and ophthalmic testing (including slit lamp examinations and dilated fundoscopy) before starting JADENU treatment and thereafter at regular intervals (every 12 months). If disturbances are noted, monitor more frequently. Consider dose reduction or interruption.

5.10 Overchelation

For patients with transfusional iron overload, measure serum ferritin monthly to assess for possible overchelation of iron. If the serum ferritin falls below 500 mcg/L, consider interrupting therapy with JADENU, since overchelation may increase JADENU toxicity [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 JADENU 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 JADENU and obtain a confirmatory LIC [see Clinical Studies (14)].

6 ADVERSE REACTIONS

The following adverse reactions are also discussed in other sections of the labeling:

  • Renal Toxicity, Renal Failure, and Proteinuria [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 (5.6)]
  • Severe Skin Reactions [see Warnings and Precautions (5.7)]
  • Skin Rash [see Warnings and Precautions (5.8)]
  • Auditory and Ocular Abnormalities [see Warnings and Precautions (5.9)]

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. JADENU was evaluated in healthy volunteer trials. Currently, there are no clinical data in patients with JADENU tablets and JADENU Sprinkle granules. JADENU 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 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 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* Occurring in >5% of Deferasirox-treated Patients in Study 1, Study 3, and MDS Pool
*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. Also see Table 2.
Study 1 (Beta-thalassemia) Study 3 (Sickle Cell Disease) MDS Pool
Preferred Term Deferasirox N=296 n (%) Deferoxamine N=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)

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.

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 postbaseline visits 113 (38) 41 (14) 48 (36) 14 (22) 229 (37)
Creatinine increase >33% and >ULN at 2 consecutive postbaseline visits 7 (2) 1 (0) 3 (2) 2 (3) 126 (20)
SGPT/ALT
SGPT/ALT >5 x ULN at 2 postbaseline visits 25 (8) 7 (2) 2 (2) 0 9 (1)
SGPT/ALT >5 x ULN at 2 consecutive postbaseline visits 17 (6) 5 (2) 5 (4) 0 5 (1)

Non-Transfusion-Dependent Thalassemia Syndromes

In Study 4, 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 5, 130 of the patients who completed Study 4 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 displays adverse reactions occurring in greater than 5% in any group. The most frequent adverse reactions with a suspected relationship to study drug were nausea, rash, and diarrhea.

Table 3. Adverse Reactions Occurring in >5% in NTDT Patients
Study 4 Study 5
Deferasirox Placebo Deferasirox
N=110 N=56 N=130
n (%) n (%) n (%)
Any adverse reaction 31 (28) 9 (16) 27 (21)
Nausea 7 (6) 4 (7) 2 (2)
Rash 7 (6) 1 (2) 2 (2)
Diarrhea 5 (5) 1 (2) 7 (5)

In Study 4, 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 4.

Table 4. Number (%) of NTDT Patients with Increases in Serum Creatinine or SGPT/ALT
Study 4 Study 5
Deferasirox Placebo Deferasirox
N=110 N=56 N=130
Laboratory Parameter n (%) n (%) n (%)
Serum creatinine (>33% increase from baseline and >ULN at ≥2 consecutive postbaseline values) 3 (3) 0 2 (2)
SGPT/ALT (>5 x ULN and >2 x baseline) 1 (1) 1 (2) 2 (2)

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, gastrointestinal hemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, renal tubular disorder (Fanconi’s 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, and erythema multiforme. 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.

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