Exjade (Deferasirox) - Side Effects and Adverse Reactions

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

A total of 700 adult and pediatric patients were treated with Exjade (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 <16 years of age. In the sickle cell disease population, 89% of patients were Black. Median treatment duration among these 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 88-205 weeks.

Table 1 displays adverse reactions occurring in >5% of Exjade-treated beta-thalassemia patients (Study 1) and sickle cell disease patients (Study 3) with a suspected relationship to study drug. Abdominal pain, nausea, vomiting, diarrhea, skin rashes, and increases in serum creatinine were the most frequent adverse reactions reported with a suspected relationship to Exjade. Gastrointestinal symptoms, increases in serum creatinine, and skin rash were dose related.

Table 1. Adverse Reactions Occurring in >5% of Exjade-treated Patients in Study 1 and Study 3*

	Study 1 ( Ÿ -Thalassemia)		Study 3 ( S ickle C ell D isease)
Preferred Term	EXJADE N=296 n (%)	Deferoxamine N=290 n (%)	EXJADE N=132 n (%)	Deferoxamine N=63 n (%)
Abdominal Pain**	63 (21.3)	41 (14.1)	37 (28.0)	9 (14.3)
Diarrhea	35 (11.8)	21 (7.2)	26 (19.7)	3 (4.8)
Creatinine Increased***	33 (11.1)	0 (0)	9 (6.8)	0
Nausea	31 (10.5)	14 (4.8)	30 (22.7)	7 (11.1)
Vomiting	30 (10.1)	28 (9.7)	28 (21.2)	10 (15.9)
Rash	25 (8.4)	9 (3.1)	14 (10.6)	3 (4.8)
* Adverse r eaction frequencie s are based on a dverse e vents report ed 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.

In Study 1, a total of 113 patients treated with Exjade had increases in serum creatinine >33% above baseline on 2 separate occasions (Table 2) and 25 patients required dose reductions. Increases in serum creatinine appeared to be dose related [ See Warnings a nd Precautions (5.1)]. In this study, 17 patients developed elevations in SGPT/ALT levels >5 times the upper limit of normal at 2 consecutive visits. Of these, 2 patients had liver biopsy proven drug-induced hepatitis and both discontinued Exjade therapy [ See Warnings a nd Precautions (5.3) ]. An additional 2 patients, who did not have elevations in SGPT/ALT >5 times the upper limit of normal, discontinued Exjade 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 Sch¶nlein purpura, hyperactivity/insomnia, drug fever, and cataract (1 patient each).  

In Study 3, a total of 48 patients treated with Exjade had increases in serum creatinine >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 Exjade-treated patients required dose reductions. In this study, 5 patients in the Exjade group developed elevations in SGPT/ALT levels >5 times the upper limit of normal at 2 consecutive visits and 1 patient subsequently had Exjade permanently discontinued. Four additional patients discontinued Exjade due to adverse reactions with a suspected relationship to study drug, including diarrhea, pancreatitis associated with gallstones, atypical tuberculosis, and skin rash.

Table 2. Number (%) of Patients with Increases in Serum Creatinine or SGPT/ALT in Study 1 and Study 3

	Study 1 ( Ÿ -Thalassemia)		Study 3 ( S ickle C ell D isease)
Laboratory Parameter	EXJADE N=296 n (%)	Deferoxamine N=290 n (%)	EXJADE N=132 n (%)	Deferoxamine N=63 n (%)
Serum Creatinine
Creatinine increase >33% and <ULN at 2 consecutive postbaseline visits	113 (38.2)	41 (14.1)	48 (36.4)	14 (22.2)
Creatinine increase >33% and >ULN at 2 consecutive postbaseline visits	7 (2.4)	1 (0.3)	3 (2.3)	2 (3.2)
SGPT/ALT
SGPT/ALT >5 x ULN at 2 postbaseline visits	25 (8.4)	7 (2.4)	2 (1.5)	0
SGPT/ALT >5 x ULN at 2 consecutive postbaseline visits	17 (5.7)	5 (1.7)	5 (3.8)	0

In the population of more than 5,000 patients who have been treated with Exjade 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, pharyngolaryngeal pain, early cataract, hearing loss, gastrointestinal hemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, and renal tubulopathy (Fanconi’s syndrome). Adverse reactions occurring in 0.01% to 0.1% of patients included optic neuritis and esophagitis. 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.

6.2 Postmarketing Experience

The following adverse reactions have been spontaneously reported during postapproval use of Exjade. Because these reactions are reported voluntarily from a population of uncertain size, in which patients may have received concomitant medication, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure .

There have been reports of cytopenias, including agranulocytosis, neutropenia and thrombocytopenia, in patients treated with Exjade. Although most of these patients had preexisting hematologic disorders that are frequently associated with bone marrow failure, a contributory role for Exjade cannot be excluded. Cases of acute renal failure have been reported in the context of severe complications relating to the underlying disease. There have been postmarketing reports of hepatic failure, some with a fatal outcome, in patients treated with Exjade. Most of these events occurred in patients greater than 55 years of age. Most reports of hepatic failure involved patients with significant comorbidities, including liver cirrhosis and multiorgan failure [ See Warnings a nd Precautions (5.3) ].

Skin and subcutaneous tissue disorders:   leukocytoclastic vasculitis, urticaria.

Immune system disorders: hypersensitivity reactions (including anaphylaxis and angioedema).

REPORTS OF SUSPECTED EXJADE SIDE EFFECTS / ADVERSE REACTIONS

Possible Exjade side effects / adverse reactions in 38 year old female

Reported by a pharmacist from United States on 2011-10-04

Patient: 38 year old female

Reactions: Liver Injury

Adverse event resulted in: hospitalization

Suspect drug(s):
Exjade

Possible Exjade side effects / adverse reactions in 72 year old male

Reported by a physician from Japan on 2011-10-04

Patient: 72 year old male weighing 56.0 kg (123.2 pounds)

Reactions: Pneumonia, Neoplasm Malignant, Hyperthermia, Diarrhoea, Neoplasm Progression, Enteritis Infectious, Serum Ferritin Increased

Adverse event resulted in: death

Suspect drug(s):
Exjade
    Dosage: 1000 mg, daily
    Administration route: Oral
    Start date: 2010-11-26
    End date: 2010-12-02

Exjade
    Dosage: 1000 mg, daily
    Administration route: Oral
    Start date: 2010-12-08
    End date: 2010-12-10

Exjade
    Dosage: 1000 mg, daily
    Administration route: Oral
    Indication: Iron Overload
    Start date: 2010-11-03
    End date: 2010-11-07

Other drugs received by patient: Neutrogin; Aldactone; Magmitt; Magmitt; Ciprofloxacin HCL; Vancomycin; Glakay; Lasix; Ciprofloxacin HCL; Vancomycin; Primobolan-Depot INJ; Omeprazole; Lasix; Itraconazole; Zolpidem; Funguard; Potassium Gluconate TAB; Adona; Omegacin; Herbessor R; Lasix; Sandoglobulin; Potassium Gluconate TAB; Rocephin

Possible Exjade side effects / adverse reactions in 13 year old female

Reported by a health professional (non-physician/pharmacist) from United Kingdom on 2011-10-07

Patient: 13 year old female

Reactions: Weight Decreased, Vomiting, Nausea, Serum Ferritin Increased, Abdominal Pain Upper, Decreased Appetite

Adverse event resulted in: hospitalization

Suspect drug(s):
Exjade
    Dosage: 30 mg/kg, daily

Exjade
    Dosage: 20 mg/kg, daily