Drug Interactions between deferasirox and Excedrin PM Headache

MONITOR CLOSELY: Coadministration with nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of gastrointestinal bleeding associated with the use of deferasirox. Fatal gastrointestinal hemorrhages have been reported during deferasirox therapy, especially in elderly patients with advanced hematologic malignancies and/or low platelet counts. Non-fatal upper gastrointestinal irritation, ulceration, and hemorrhage have also been reported, including in children and adolescents.

MONITOR CLOSELY: Theoretical concerns exist regarding the potential for increased risk of renal impairment during coadministration of deferasirox with other nephrotoxic agents, including NSAIDs when used chronically or in high dosages. 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 haematological 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 NSAIDs. Patients should be advised to contact their physician if they develop potential signs and symptoms of gastrointestinal injury such as abdominal pain, bloating, dizziness, lightheadedness, vomiting blood, anorexia, or black, tarry stools. 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.

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MONITOR: Coadministration with deferasirox may increase the plasma concentrations of drugs that are substrates of the CYP450 1A2 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 1A2 activity by deferasirox. In a study of healthy volunteers, administration of the CYP450 1A2 substrate theophylline (120 mg single dose) in combination with deferasirox (repeated dosing of 30 mg/kg/day) resulted in an approximate doubling of theophylline systemic exposure (AUC) and elimination half-life.

MANAGEMENT: Caution is advised if deferasirox must be used concurrently with medications that undergo metabolism by CYP450 1A2, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever deferasirox is added to or withdrawn from therapy.

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