Drug Interactions between celecoxib / tramadol and deferasirox

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.

MONITOR: Coadministration with celecoxib may increase the plasma concentrations of drugs that are substrates of the CYP450 2D6 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 2D6 activity by celecoxib.

MANAGEMENT: Caution is advised if celecoxib must be used concurrently with medications that undergo metabolism by CYP450 2D6, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever celecoxib is added to or withdrawn from therapy.

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of tramadol, which is primarily metabolized by CYP450 3A4 and 2D6. Reduced opioid efficacy can occur, including opioid withdrawal in physically dependent patients. After discontinuing a CYP450 3A4 inducer, the tramadol plasma concentration will increase, which could increase and/or prolong opioid efficacy and adverse reactions, including seizures, serotonin syndrome, and respiratory depression. In addition, when two or more medications with similar adverse effect profiles are given concurrently, the likelihood of experiencing these adverse reactions may be increased. For example, coadministration with other agents that can prolong the QT interval (e.g., apalutamide, encorafenib, enzalutamide) may result in additive effects and an increased risk of ventricular arrhythmias like torsade de pointes.

MANAGEMENT: Caution is advised when tramadol is used with CYP450 3A4 inducers. Patients should be monitored for opioid efficacy and signs of withdrawal. If the CYP450 3A4 inducer also carries a risk of prolonging the QT interval, then obtaining more frequent electrocardiograms (ECGs) to monitor the QT interval may be advisable. Patients should be counseled to seek immediate medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, syncope, palpitations, irregular heartbeat, and/or shortness of breath. If a CYP450 3A4 inducer is discontinued, monitor for seizures, serotonin syndrome, sedation, and respiratory depression. The prescribing information for the concomitant CYP450 3A4 inducers should be consulted for specific recommendations.