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Included as part of the PRECAUTIONS section.

Renal

Acute renal failure, fatal in some patients and requiring dialysis in others, has been reported following the postmarketing use of Exjade (deferasirox). Most fatalities occurred in patients with multiple comorbidities and who were in advanced stages of their hematological disorders. Monitor serum creatinine and/or creatinine clearance in patients who: are at increased risk of complications, have preexisting renal conditions, are elderly, have comorbid conditions, or are receiving medicinal products that depress renal function. Closely monitor the renal function of patients with creatinine clearances between 40 and less than 60 mL/min, particularly in situations where patients have additional risk factors that may further impair renal function such as concomitant medications, dehydration, or severe infections.

Assess serum creatinine and/or creatinine clearance in duplicate before initiating therapy to establish a reliable pretreatment baseline, due to variations in measurements. Monitor serum creatinine and/or creatinine clearance monthly thereafter. In patients with additional renal risk factors (see above), monitor serum creatinine and/or creatinine clearance weekly during the first month after initiation or modification of therapy and monthly thereafter.

Consider dose reduction, interruption, or discontinuation for increases in serum creatinine. If there is a progressive increase in serum creatinine beyond the age-appropriate upper limit of normal, interrupt Exjade use. Once the creatinine has returned to within the normal range, therapy with Exjade may be reinitiated at a lower dose followed by gradual dose escalation, if the clinical benefit is expected to outweigh potential risks [see Dose Modifications].

In the clinical studies, for increases of serum creatinine on 2 consecutive measures ( > 33% in patients > 15 years of age or > 33% and greater than the age-appropriate upper limit of normal in patients < 15 years of age), the daily dose of Exjade was reduced by 10 mg/kg. Patients with baseline serum creatinine above the upper limit of normal were excluded from clinical studies.

In the clinical studies, Exjade-treated patients experienced dose-dependent increases in serum creatinine. These increases occurred at a greater frequency compared to deferoxamine-treated patients (38% vs. 14%, respectively, in Study 1 and 36% vs 22%, respectively, in Study 3). Most of the creatinine elevations remained within the normal range [see ADVERSE REACTIONS]. There have also been reports of renal tubulopathy in patients treated with Exjade. The majority of these patients were children and adolescents with β-thalassemia and serum ferritin levels < 1500 mcg/L.

Hepatic Dysfunction and Failure

Avoid the use of Exjade in patients with severe (Child-Pugh C) hepatic impairment. For patients with moderate (Child-Pugh B) hepatic impairment, a 50% reduction in the starting dose is recommended [see DOSAGE AND ADMINISTRATION, and Use In Specific Populations]. Closely monitor patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment for efficacy and adverse reactions that may require dose titration.

In Study 1, 4 patients discontinued Exjade because of hepatic abnormalities (drug-induced hepatitis in 2 patients and increased serum transaminases in 2 additional patients). 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. Serum transaminases and bilirubin should be monitored before the initiation of treatment, every 2 weeks during the first month and monthly thereafter. Consider dose modifications or interruption of treatment for severe or persistent elevations.

Gastrointestinal

Fatal GI hemorrhages, especially in elderly patients who had advanced hematologic malignancies and/or low platelet counts, have been reported. Non-fatal upper GI irritation, ulceration and hemorrhage have been reported in patients, including children and adolescents, receiving Exjade [see ADVERSE REACTIONS]. Physicians and patients should remain alert for signs and symptoms of GI ulceration and hemorrhage during Exjade therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. Use caution when administering Exjade in combination with drugs that have ulcerogenic or hemorrhagic potential, such as non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, oral bisphosphonates, or anticoagulants.

Cytopenias

There have been postmarketing reports (both spontaneous and from clinical trials) of cytopenias, including agranulocytosis, neutropenia and thrombocytopenia, in patients treated with Exjade. Some of these patients died. The relationship of these episodes to treatment with Exjade is uncertain. Most of these patients had preexisting hematologic disorders that are frequently associated with bone marrow failure [see ADVERSE REACTIONS]. Monitor blood counts regularly. Consider interrupting treatment with Exjade in patients who develop unexplained cytopenia. Reintroduction of therapy with Exjade may be considered, once the cause of the cytopenia has been elucidated.

Hypersensitivity

Serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving Exjade, with the onset of the reaction occurring in the majority of cases within the first month of treatment [see ADVERSE REACTIONS]. If reactions are severe, discontinue Exjade and institute appropriate medical intervention.

Rash

Rashes may occur during Exjade (deferasirox) treatment. For rashes of mild to moderate severity, Exjade may be continued without dose adjustment, since the rash often resolves spontaneously. In severe cases, Exjade may be interrupted. Reintroduction at a lower dose with escalation may be considered in combination with a short period of oral steroid administration. Erythema multiforme has been reported during Exjade treatment.

Co-morbidities

Clinical trials to demonstrate increased survival or to confirm clinical benefit have not been completed. Exjade has been shown to decrease serum ferritin and liver iron concentration in clinical trials. Consider the importance of these factors as well as individual patient factors and the prognosis associated with any underlying conditions before initiation of Exjade therapy [see CONTRAINDICATIONS].

In postmarketing experience, there have been reports of serious adverse reactions, some with a fatal outcome, in patients taking Exjade therapy, predominantly when the drug was administered to patients with advanced age, complications from underlying conditions or very advanced disease. Most of these deaths occurred within six months of Exjade initiation and generally involved worsening of the underlying condition. The reports do not rule out the possibility that Exjade may have contributed to the deaths.

Special Senses

Auditory disturbances (high frequency hearing loss, decreased hearing), and ocular disturbances (lens opacities, cataracts, elevations in intraocular pressure, and retinal disorders) have been reported at a frequency of < 1% with Exjade therapy in the clinical studies. Auditory and ophthalmic testing (including slit lamp examinations and dilated fundoscopy) are recommended before starting Exjade treatment and thereafter at regular intervals (every 12 months). If disturbances are noted, consider dose reduction or interruption.

Laboratory Tests

Measure serum ferritin monthly to assess response to therapy and to evaluate for the possibility of overchelation of iron. If the serum ferritin falls consistently below 500 mcg/L, consider temporarily interrupting therapy with Exjade [see DOSAGE AND ADMINISTRATION].

In the clinical studies, the correlation coefficient between the serum ferritin and LIC was 0.63. Therefore, changes in serum ferritin levels may not always reliably reflect changes in LIC.

Perform laboratory monitoring of renal and hepatic function.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 104-week oral carcinogenicity study in Wistar rats showed no evidence of carcinogenicity from deferasirox at doses up to 60 mg/kg per day (0.48 times the MRHD (Maximum Recommended Human Dose) on a mg/m² basis). A 26-week oral carcinogenicity study in p53 (+/-) transgenic mice has shown no evidence of carcinogenicity from deferasirox at doses up to 200 mg/kg per day (0.81 times the MRHD on a mg/m² basis) in males and 300 mg/kg per day (1.21 times the MRHD on a mg/m² basis) in females.

Deferasirox was negative in the Ames test and chromosome aberration test with human peripheral blood lymphocytes. It was positive in 1 of 3 in-vivo oral rat micronucleus tests.

Deferasirox at oral doses up to 75 mg/kg per day (0.6 times the MRHD on a mg/m² basis) was found to have no adverse effect on fertility and reproductive performance of male and female rats.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies with Exjade in pregnant women. Administration of deferasirox to animals during pregnancy and lactation resulted in decreased offspring viability and an increase in renal anomalies in male offspring at exposures that were less than the recommended human exposure. Exjade should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In embryofetal developmental studies, pregnant rats and rabbits received oral deferasirox during the period of organogenesis at doses up to (100 mg/kg/day in rats and 50 mg/kg/day in rabbits) 0.8 times the MRHD (Maximum Recommended Human Dose) on a mg/m² basis. These doses resulted in maternal toxicity but no fetal harm was observed.

In a prenatal and postnatal developmental study, pregnant rats received oral deferasirox daily from organogenesis through lactation day 20 at doses (10, 30, and 90 mg/kg/day) 0.08, 0.2, and 0.7 times the MRHD on a mg/m² basis. Maternal toxicity, loss of litters, and decreased offspring viability occurred at 0.7 times the MRHD on a mg/m² basis, and increases in renal anomalies in male offspring occurred at 0.2 times the MRHD on a mg/m² basis.

Nursing Mothers

It is not known whether Exjade is excreted in human milk. Deferasirox and its metabolites were excreted in rat milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from deferasirox and its metabolites, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Of the 700 patients who received Exjade during clinical studies, 292 were pediatric patients 2 - < 16 years of age with various congenital and acquired anemias, including 52 patients age 2 - < 6 years, 121 patients age 6 - < 12 years and 119 patients age 12 - < 16 years. Seventy percent of these patients had β-thalassemia. Children between the ages of 2 - < 6 years have a systemic exposure to Exjade approximately 50% of that of adults [see CLINICAL PHARMACOLOGY]. However, the safety and efficacy of Exjade in pediatric patients was similar to that of adult patients, and younger pediatric patients responded similarly to older pediatric patients. The recommended starting dose and dosing modification are the same for children and adults [see Clinical Studies, INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION].

Growth and development were within normal limits in children followed for up to 5 years in clinical trials.

Geriatric Use

Four hundred and thirty-one (431) patients ≥ 65 years of age have been studied in clinical trials of Exjade. The majority of these patients had myelodysplastic syndrome (MDS) (n=393). In these trials, elderly patients experienced a higher frequency of adverse reactions than younger patients. Closely monitor elderly patients for early signs or symptoms of adverse reactions that may require a dose adjustment. Elderly patients are at increased risk for Exjade toxicity due to the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Renal Impairment

Exjade has not been studied in patients with renal impairment [see WARNINGS AND PRECAUTIONS].

Hepatic Impairment

In a single dose (20 mg/kg) study in patients with varying degrees of hepatic impairment, deferasirox exposure was increased compared to patients with normal hepatic function. The average total (free and bound) AUC of deferasirox increased 16% in 6 subjects with mild (Child-Pugh A) hepatic impairment, and 76% in 6 subjects with moderate (Child-Pugh B) hepatic impairment compared to 6 subjects with normal hepatic function. The impact of severe (Child-Pugh C) hepatic impairment was assessed in only one subject.

Avoid the use of Exjade in patients with severe (Child-Pugh C) hepatic impairment. For patients with moderate (Child-Pugh B) hepatic impairment, the starting dose should be reduced by 50%. Closely monitor patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment for efficacy and adverse reactions that may require dose titration [See DOSAGE AND ADMINISTRATION, and WARNINGS AND PRECAUTIONS].

Last reviewed on RxList: 8/19/2011
This monograph has been modified to include the generic and brand name in many instances.