Drug Interactions between acalabrutinib and aspirin / omeprazole

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.

GENERALLY AVOID: Coadministration of acalabrutinib in its capsule formulation with proton pump inhibitors may significantly decrease the oral bioavailability of acalabrutinib and reduce its concentrations in plasma. The solubility of acalabrutinib is pH-dependent and decreases with increasing pH. According to the product labeling, acalabrutinib is freely soluble in water at pH below 3 and practically insoluble at pH above 6. Coadministration of acalabrutinib capsules with omeprazole 40 mg for 5 days decreased acalabrutinib systemic exposure (AUC) by 43% in healthy subjects. Due to the long-lasting effect of proton pump inhibitors, separation of dosing may not eliminate the interaction with acalabrutinib capsules. By contrast, no clinically significant differences in the pharmacokinetics of acalabrutinib were observed when the tablet formulation, which contains acalabrutinib maleate, was coadministered with the proton pump inhibitor, rabeprazole.

MANAGEMENT: No adjustments to therapy are required when using the tablet formulation containing acalabrutinib maleate. However, concomitant use of acalabrutinib capsules with proton pump inhibitors should generally be avoided. If gastric acid reducing agents are required during treatment with acalabrutinib capsules, antacids and/or H2-receptor antagonists should be considered, with dosing separated by a couple hours from acalabrutinib dosing as suggested in the manufacturer's labeling.

Coadministration with proton pump inhibitors may decrease the oral bioavailability of aspirin and other salicylates. The interaction has been studied with omeprazole and aspirin, although data are conflicting. In one study, pretreatment with omeprazole (20 mg/day for 2 days) in 11 healthy volunteers led to a significant and progressively greater reduction in the mean serum salicylate level at 30, 60, and 90 minutes after administration of aspirin (650 mg single dose). The investigators suggest that acid suppression may reduce the lipophilic nature of aspirin, thereby adversely affecting its absorption from the gastrointestinal tract. Another study found no effect of omeprazole pretreatment (20 mg/day for 4 days) on plasma salicylate and aspirin levels, skin bleeding times, or antiplatelet effect of low-dose aspirin (125 mg single dose) in 14 healthy volunteers. However, these results do not exclude the possibility that omeprazole might interfere with the analgesic, antipyretic, or anti-inflammatory effects of aspirin, which has been demonstrated in rats.

Proton pump inhibitors may enhance the release rate of salicylates from enteric-coated formulations due to premature disruption of the coating and intragastric release of the drug secondary to an increase in gastric pH. In eight healthy volunteers, omeprazole pretreatment (20 mg/day for 4 days) did not affect the bioavailability of salicylate from uncoated aspirin tablets but significantly increased the absorption rate of salicylate from enteric-coated sodium salicylate tablets. The clinical significance of this interaction is unknown. Theoretically, it may increase the risk of gastric adverse effects associated with salicylates.