Drug Interactions between dexamethasone / ketorolac / moxifloxacin and zanubrutinib

MONITOR CLOSELY: Concomitant administration of corticosteroids may potentiate the risk of tendinitis and tendon rupture associated with fluoroquinolone treatment. The mechanism is unknown. Tendinitis and tendon rupture have most frequently involved the Achilles tendon, although cases involving the rotator cuff (the shoulder), the hand, the biceps, and the thumb have also been reported. Some have required surgical repair or resulted in prolonged disability. Tendon rupture can occur during or up to several months after completion of fluoroquinolone therapy.

MANAGEMENT: Caution is recommended if fluoroquinolones are prescribed in combination with corticosteroids, particularly in patients with other concomitant risk factors (e.g., age over 60 years; recipient of kidney, heart, and/or lung transplant). Patients should be advised to stop taking the fluoroquinolone, avoid exercise and use of the affected area, and promptly contact their physician if they experience pain, swelling, or inflammation of a tendon. In general, fluoroquinolones should only be used to treat conditions that are proven or strongly suspected to be caused by bacteria and only if the benefits outweigh the risks.

GENERALLY AVOID: Coadministration with moderate inducers of CYP450 3A4 may significantly decrease the plasma concentrations of zanubrutinib, which is primarily metabolized by the isoenzyme. In healthy subjects, coadministration of multiple doses of rifabutin, a moderate CYP450 3A4 inducer, decreased zanubrutinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 48% and 44%, respectively. Based on pharmacokinetic modeling, coadministration with multiple doses of efavirenz, another moderate CYP450 3A4 inducer, is predicted to decrease zanubrutinib Cmax and AUC by 58% and 60%, respectively. Reduced efficacy of zanubrutinib may occur.

MANAGEMENT: Concomitant use of zanubrutinib with moderate CYP450 3A4 inducers should generally be avoided. If coadministration is required, the manufacturer recommends increasing the dosage of zanubrutinib to 320 mg twice daily. Following discontinuation of the inducer, the previous dosage of zanubrutinib should be restarted.

MONITOR CLOSELY: Coadministration of zanubrutinib and drugs that interfere with platelet function or coagulation may potentiate the risk of bleeding complications. Serious and fatal hemorrhagic events have been reported during zanubrutinib therapy. Grade 3 or higher bleeding events including intracranial and gastrointestinal hemorrhage, hematuria, and hemothorax have been reported in up to 4% of patients treated with zanubrutinib monotherapy, with fatalities occurring in 0.3% of patients. Overall, bleeding events of any grade, including purpura and petechiae, occurred in nearly 55% of patients, both with and without concomitant antiplatelet or anticoagulation therapy. The mechanism for the bleeding events is not well understood, although treatment with zanubrutinib commonly causes thrombocytopenia. Grade 3 or 4 thrombocytopenia was reported in up to 11.5% of patients treated with zanubrutinib monotherapy.

MANAGEMENT: Concomitant use of zanubrutinib in patients receiving other medications that interfere with platelet function or coagulation should be approached with caution. Close clinical and laboratory monitoring for bleeding complications is recommended during therapy. Patients should be advised to promptly report any signs and symptoms of bleeding to their physician. Discontinue zanubrutinib if intracranial hemorrhage of any grade occurs. Refer to the product labeling for dose adjustment or discontinuation of therapy recommendations if Grade 3 or higher adverse reactions occur.

MONITOR: The combined use of corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the potential for serious gastrointestinal (GI) toxicity, including inflammation, bleeding, ulceration, and perforation. In a large, case-control study of elderly patients, those who used corticosteroids and NSAIDs concurrently had an estimated relative risk (RR) for peptic ulcer disease and GI hemorrhage of 14.6 compared to those who used neither. Corticosteroid use was associated with a doubling of the risk (estimated RR = 2.0), but the risk was confined to those who also used NSAIDs. It is possible that both categories of agents are ulcerogenic and have additive effects on the GI mucosa during coadministration. Some investigators have also suggested that the primary effect of corticosteroids in this interaction is to delay healing of erosions caused by NSAIDs rather than cause de novo ulcerations.

MANAGEMENT: Caution is advised if corticosteroids and NSAIDs are used together, especially in patients with a prior history of peptic ulcer disease or GI bleeding and in elderly and debilitated patients. During concomitant therapy, patients should be advised to take the medications with food and to immediately report signs and symptoms of GI ulceration and bleeding such as severe abdominal pain, dizziness, lightheadedness, and the appearance of black, tarry stools. The selective use of prophylactic anti-ulcer therapy (e.g., antacids, H2-antagonists) may be considered.

MONITOR: Coadministration with nonsteroidal anti-inflammatory drugs (NSAIDs) may potentiate the risk of central nervous system toxicity sometimes associated with fluoroquinolone use. The interaction has been reported most often with enoxacin. It may occur with other fluoroquinolones as well, but is poorly documented. The exact mechanism of interaction is unknown. Some investigators suggest that the piperazine ring of fluoroquinolones may inhibit the binding of gamma-aminobutyric acid (GABA) to brain receptors and that NSAIDs may synergistically add to this effect. Patients with a history of seizures may be at greater risk.

MANAGEMENT: Clinical monitoring for signs of CNS stimulation such as tremors, involuntary muscle movements, hallucinations, or seizures is recommended if fluoroquinolone antibiotics are prescribed in combination with NSAIDs.