Drug Interactions between avapritinib and Yosprala

MONITOR CLOSELY: Coadministration of avapritinib 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 avapritinib therapy, including gastrointestinal, hepatic, tumor, ocular, and intracranial hemorrhages. In clinical studies, intracranial hemorrhage (e.g., subdural hematoma, cerebral hemorrhage, cerebral hematoma) occurred in 1% to 3% of patients, with onset ranging from 1.7 to 19.3 months after initiating avapritinib. Overall, 0.9% of patients receiving avapritinib required permanent discontinuation for an intracranial hemorrhage, and 1.2% required treatment interruption followed by dosage reduction. The mechanism for the bleeding events is not well understood, although treatment with avapritinib commonly causes thrombocytopenia.

MANAGEMENT: Concomitant use of avapritinib with other drugs that increase the risk of bleeding 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. Patients should also seek immediate medical attention if they experience neurological signs and symptoms that may be associated with intracranial hemorrhage such as severe headache, vision problems, somnolence, or focal weakness. Brain imaging by magnetic resonance imaging (MRI) or computed tomography (CT) may be performed at the discretion of the physician based on severity and clinical presentation. For patients with observed intracranial hemorrhage during treatment with avapritinib, some authorities recommend that avapritinib be discontinued permanently regardless of Grade. Others suggest withholding avapritinib for Grade 1 or 2 reactions until resolution, then resuming at a reduced dosage. However, avapritinib should be permanently discontinued upon recurrence of Grade 1 or 2 reactions or first occurrence of Grade 3 or 4 reactions.

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.