Drug Interaction Report

MONITOR CLOSELY: Theoretical concerns exist regarding the potential for increased risk of renal impairment during coadministration of deferasirox with other nephrotoxic agents. The use of deferasirox has been associated with postmarketing reports of acute renal failure, in some cases resulting in dialysis or even fatality. Most fatalities occurred in patients with multiple comorbidities and who were in advanced stages of their hematological disorders. In clinical studies, patients treated with deferasirox experienced dose-dependent increases in serum creatinine. These increases occurred at a greater frequency than in deferoxamine-treated patients (38% vs. 14%, respectively, in one study and 36% vs. 22%, respectively, in another study). Most of the creatinine elevations remained within the normal range. There have also been reports of renal tubulopathy in patients treated with deferasirox. The majority of these patients were children and adolescents with beta-thalassemia and serum ferritin levels below 1500 mcg/L. Deferasirox has not been studied for use in patients with baseline serum creatinine above the upper limit of normal.

MANAGEMENT: Caution is advised if deferasirox is used in combination with other potentially nephrotoxic agents (e.g., aminoglycosides; polypeptide, glycopeptide, and polymyxin antibiotics; amphotericin B; adefovir; cidofovir; tenofovir; foscarnet; cisplatin; gallium nitrate; lithium; mesalamine; certain immunosuppressants; intravenous bisphosphonates; intravenous pentamidine; high intravenous dosages of methotrexate; high dosages and/or chronic use of nonsteroidal anti-inflammatory agents). Serum creatinine and/or creatinine clearance should be closely monitored (e.g., prior to initiation of deferasirox therapy, then weekly during the first month after initiation or modification of therapy and monthly thereafter), especially in the elderly and patients with preexisting renal impairment, comorbid conditions, dehydration, or severe infections. Dosage reduction, interruption, or discontinuation should be considered in the presence of creatinine elevations. A progressive increase in serum creatinine beyond the age-appropriate upper limit of normal may warrant an interruption of therapy. Once the creatinine has returned to within the normal range, therapy may be reinitiated at a lower dose followed by a gradual dose escalation according to the product labeling, provided the clinical benefit is expected to outweigh potential risks. In clinical studies, the daily dosage of deferasirox was reduced by 10 mg/kg for increases of serum creatinine on two consecutive measures (i.e., >33% in patients older than 15 years of age, or >33% and greater than the age-appropriate upper limit of normal in patients younger than 15 years of age). Care should be taken to maintain adequate hydration in patients who develop diarrhea or vomiting.

ADJUST DOSING INTERVAL: Consumption of food has led to a 27% decrease in the bioavailability of orally administered tacrolimus.

MANAGEMENT: Tacrolimus should be administered at least one hour before or two hours after meals.

GENERALLY AVOID: Grapefruit juice has been reported to increase tacrolimus trough concentrations. Data are limited, but inhibition of the CYP450 enzyme system appears to be involved.

MANAGEMENT: The clinician may want to recommend that the patient avoid ingesting large amounts of grapefruit juice while taking tacrolimus.

ADJUST DOSING INTERVAL: According to product labeling, the bioavailability of deferasirox was variably increased when taken with a meal.

MANAGEMENT: To ensure consistent plasma drug levels, deferasirox should be taken on an empty stomach 30 minutes before eating preferably at the same time everyday.