Drug Interactions between acalabrutinib and dexamethasone / ketorolac / moxifloxacin

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.

MONITOR CLOSELY: Coadministration of acalabrutinib 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 acalabrutinib therapy. In the combined safety database of 1040 patients with hematologic malignancies treated with acalabrutinib monotherapy, major hemorrhage (serious or >= Grade 3 bleeding events or any central nervous system bleeding) occurred in 3.6% of patients, with fatalities occurring in 0.1% of patients. Overall, bleeding events of any grade, including bruising and petechiae, occurred in 46% of patients. The mechanism is not well understood, as bleeding events have occurred in patients both with and without thrombocytopenia. In clinical trials, major hemorrhagic events were experienced by 3% of patients taking acalabrutinib without concurrent antithrombotic agents. The addition of antithrombotic agents increased this percentage to 4.3%.

MANAGEMENT: Concomitant use of acalabrutinib with antithrombotic agents or other drugs that increase bleeding risk 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. Refer to the product labeling for guidance on acalabrutinib dosage adjustments in patients with concurrent Grade 3 thrombocytopenia and bleeding.

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 inducers of CYP450 3A4 may decrease the plasma concentrations of acalabrutinib, which is primarily metabolized by the isoenzyme. When acalabrutinib was administered with the potent CYP450 3A4 inducer rifampin (600 mg once daily for 9 days) in 24 healthy subjects, acalabrutinib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 68% and 77%, respectively. Reduced efficacy of acalabrutinib may occur. The interaction has not been studied with other, less potent inducers.

MANAGEMENT: The potential for diminished pharmacologic effects of acalabrutinib should be considered during coadministration with CYP450 3A4 inducers. Alternative treatments may be required if an interaction is suspected.

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.