Renal

Cases of acute renal failure, some with a fatal outcome, have been reported following the postmarketing use of Exjade® (deferasirox). Most of the fatalities occurred in patients with multiple co-morbidities and who were in advanced stages of their hematological disorders. Particular attention should be given to monitoring serum creatinine in patients who: are at increased risk of complications, have preexisting renal conditions, are elderly, have co-morbid conditions, or are receiving medicinal products that depress renal function.

Serum creatinine should be assessed in duplicate before initiating therapy to establish a reliable pre-treatment baseline, due to variations in measurements. Serum creatinine should be monitored monthly thereafter. Patients with additional renal risk factors (see above) should be monitored weekly during the first month after initiation or modification of therapy, and monitored monthly thereafter.

Dose reduction, interruption, or discontinuation should be considered for increases in serum creatinine. If there is a progressive increase in serum creatinine beyond the age-appropriate upper limit of normal, Exjade should be interrupted. 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.

For adult patients, the daily dose of Exjade should be reduced by 10 mg/kg if a rise in serum creatinine to > 33% above the average of the pretreatment measurements is seen at two consecutive visits, and cannot be attributed to other causes. For pediatric patients, the dose should be reduced by 10 mg/kg if serum creatinine levels rise above the age-appropriate upper limit of normal at two consecutive visits.

In the clinical studies, for increases of serum creatinine on two 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.

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. Most of the creatinine elevations remained within the normal range.

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.

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.) In line with the standard clinical management of such hematological disorders, blood counts should be monitored regularly. Interruption of treatment with Exjade should be considered in patients who develop unexplained cytopenia. Reintroduction of therapy with Exjade may be considered, once the cause of the cytopenia has been elucidated.

Hepatic

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). Hepatic dysfunction associated with Exjade administration has been described in postmarketing reports. Liver function tests should be monitored monthly during Exjade treatment and dose modifications considered for severe or persistent elevations.

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, EXJADE should be discontinued and appropriate medical intervention instituted.

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, dose reduction or interruption should be considered.

General

Skin 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.

Laboratory Tests

Serum ferritin should be measured 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, consideration should be given to 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.

Laboratory monitoring of renal and hepatic function should be performed. (See WARNINGS.)

Carcinogenicity/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 (about 0.48 times the recommended human oral dose based on body surface area). 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 (about 0.81 times the recommended human oral dose based on body surface area) in males and 300 mg/kg per day (about 1.21 times the recommended human oral dose based on body surface area) 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 vivooral rat micronucleus tests.

Deferasirox at oral doses up to 75 mg/kg per day (about 0.6 times the recommended human oral dose based on body surface area) was found to have no adverse effect on fertility and reproductive performance of male and female rats.

Pregnancy

Teratogenic Effects: Pregnancy Category B

Reproduction studies have been performed in pregnant rats at oral doses up to 100 mg/kg per day (about 0.8 times the recommended human oral dose based on body surface area) and in pregnant rabbits at oral doses up to 50 mg/kg per day (about 0.8 times the recommended human oral dose based on body surface area). These studies have revealed no evidence of impaired fertility or harm to the fetus due to deferasirox. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, deferasirox should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether deferasirox is excreted in human milk. Deferasirox and its metabolites were excreted in breast milk of rats following a 10 mg/kg dose (about 0.08 times the recommended human oral dose based on body surface area). Because many drugs are excreted in human milk, caution should be exercised when deferasirox is administered to a nursing woman.

Pediatric Use

Of the 700 patients who received Exjade during clinical studies, 292 were pediatric patients 2 to < 16 years of age with various congenital and acquired anemias, including 52 patients age 2 to < 6 years, 121 patients age 6 to < 12 years and 119 patients age 12 to < 16 years. Seventy percent of these patients had β-thalassemia. Children between the ages of 2 to < 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.)

During the 1-year study, the growth and development were within normal limits.

Geriatric Use

Exjade clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently, or have a different adverse event profile, from younger subjects. Thirty patients ≥ 65 years of age were included in clinical studies of Exjade. The majority of these patients had myelodysplastic syndrome (MDS) (n=27). In general, caution should be used in elderly patients due to the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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