Exjade Side Effects

Generic Name: deferasirox

Please note - some side effects for Exjade may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Exjade - for the Consumer

Exjade

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Exjade:

Diarrhea; nausea; stomach pain; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur when using Exjade:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, throat, or tongue; unusual hoarseness); bloody, black, or tarry stools; change in the amount of urine produced; decreased hearing, hearing loss, or other hearing problems; symptoms of infection (eg, fever, chills, persistent sore throat or cough); symptoms of liver problems (eg, yellowing of the skin or eyes; dark urine; pale stools; severe or persistent nausea, stomach pain, or loss of appetite); unusual bruising or bleeding; unusual tiredness or fatigue; vision changes (eg, blurred or cloudy vision, decreased vision); vomit that looks like coffee grounds.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Exjade Side Effects - for the Professional

Exjade

Clinical Trials Experience

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

Renal Failure [see Warnings and Precautions (5.1)]. Hepatic Failure [see Warnings and Precautions (5.2)]. Fatal and non-fatal Gastrointestinal Bleedings [see Warnings and Precautions (5.3)]. Cytopenias [see Warnings and Precautions (5.4)].

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.

A total of 700 adult and pediatric patients were treated with Exjade (deferasirox) for 48 weeks in premarketing studies. These included 469 patients with ß-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 the sickle cell patients was 51 weeks. Of the 700 patients treated, 469 (403 ß-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 β-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 (ß-Thalassemia)		Study 3 (Sickle Cell Disease)
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 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.

In Study 1, a total of 113 (38%) patients treated with Exjade had increases in serum creatinine >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 Exjade 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 and Precautions (5.2)]. 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 Schönlein purpura, hyperactivity/insomnia, drug fever, and cataract (1 patient each).

In Study 3, a total of 48 (36%) 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 (ß-Thalassemia)			Study 3 (Sickle Cell Disease)
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

Proteinuria

In clinical studies, urine protein was measured monthly. Intermittent proteinuria (urine protein/creatinine ratio >0.6 mg/mg) occurred in 18.6% of Exjade-treated patients compared to 7.2% of deferoxamine-treated patients in Study 1. Although no patients were discontinued from Exjade in clinical studies up to 1 year due to proteinuria, monthly monitoring is recommended. The mechanism and clinical significance of the proteinuria are uncertain.

Other Adverse Reactions

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, 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.

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.

Skin and subcutaneous tissue disorders: leukocytoclastic vasculitis, urticaria, alopecia

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

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Side Effects by Body System - for Healthcare Professionals

General

General side effects including pyrexia (18.9%), headache (15.9%), abdominal pain (13.9%), influenza (10.8%), upper abdominal pain (7.8%), and fatigue (6.1%) have been reported.

Respiratory

Respiratory side effects including cough (13.9%), nasopharyngitis (13.2%), pharyngolaryngeal pain (10.5%), respiratory tract infection (9.5%), bronchitis (9.1%), pharyngitis (7.8%), and rhinitis (6.1%) have been reported.

Gastrointestinal

Gastrointestinal side effects including diarrhea (11.8%), nausea (10.5%), vomiting (10.1%), and upper gastrointestinal ulceration and hemorrhage have been reported.

Renal

Nonprogressive increases in serum creatinine have been noted in 38% of deferasirox-treated patients and appear to be dose related. These increases were within the normal range in 94% of patients. Deferasirox dosages had been adjusted once serum creatinine elevations were detected during the study. Dose reduction, interruption, or discontinuation should be considered for elevations in serum creatinine. If there is a progressive increase in serum creatinine beyond the age-appropriate upper limit of normal, deferasirox should be interrupted. Once the creatinine has returned to within the normal range, therapy with deferasirox may be reinitiated at a lower dose followed by gradual dose escalation, if the clinical benefit is expected to outweigh potential risks.

Intermittent proteinuria (urine protein/creatinine ratio greater than 0.6 mg/mg) has been reported in 18.6% of deferasirox treated patients. Monthly monitoring is recommended.

Renal side effects including increased creatinine, intermittent proteinuria, and renal tubulopathy have been reported. Cases of acute renal failure have also been reported in the context of severe complications relating to the underlying disease.

Dermatologic

Dermatologic side effects including rash (8.4%), urticaria (3.7%), and leukocytoclastic vasculitis have been reported.

Musculoskeletal

Musculoskeletal side effects including arthralgia (7.4%) and back pain (5.7%) have been reported.

Immunologic

Immunologic side effects including acute tonsillitis (6.4%) have been reported.

Other

Other side effects including ear infection (5.4%), high-frequency hearing loss, and decreased hearing have been reported.

Hepatic

Hepatic side effects have included two patients with drug-induced hepatitis and two patients with increased serum transaminases who discontinued use of deferasirox because of these hepatic abnormalities. There have been postmarketing reports of hepatic failure, some with a fatal outcome, in patients treated with deferasirox. Most of these events occurred in patients greater than 55 years of age. Seventeen of the patients in the clinical trials developed elevations in SGPT/ALT levels greater than five times the upper limit of normal at two consecutive visits.

Most reports of hepatic failure involved patients with significant comorbidities, including liver cirrhosis and multiorgan failure.

Increases in transaminases were not dose related.

Hematologic

Although most of these patients had preexisting hematologic disorders that are frequently associated with bone marrow failure, a contributory role for deferasirox could not be excluded.

Hematologic side effects have included cytopenias such as agranulocytosis, neutropenia, and thrombocytopenia.

Hypersensitivity

If reactions are severe, deferasirox should be discontinued and appropriate medical intervention instituted.

Hypersensitivity side effects including anaphylaxis and angioedema have been reported.

Ocular

Ocular side effects including lens opacities, cataracts, elevations in intraocular pressure, and retinal disorders have been reported with deferasirox therapy in less than 1% of patients in clinical trials.

Ophthalmic testing (including slit lamp examinations and dilated fundoscopy) are recommended before the start of deferasirox treatment and thereafter every 12 months.

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