Drug Interactions between dasatinib and Yosprala

MONITOR CLOSELY: Coadministration of dasatinib and drugs that interfere with platelet function or coagulation may potentiate the risk of bleeding complications. Treatment with dasatinib is associated with severe thrombocytopenia. In addition, dasatinib has been shown to induce platelet dysfunction in vitro. Severe central nervous system hemorrhages, including fatalities, occurred in 1% of patients receiving dasatinib in clinical trials. Severe gastrointestinal hemorrhage occurred in 7% of patients and generally required treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 4% of patients. Most bleeding events were associated with severe thrombocytopenia.

MANAGEMENT: Concomitant use of other medications that interfere with platelet function or coagulation should be considered cautiously in patients treated with dasatinib. Close clinical and laboratory observation for bleeding complications is recommended during therapy. A complete blood count (CBC) with differential and platelet count should be obtained prior to and at least weekly for the first 2 months, then monthly thereafter or as clinically indicated. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

GENERALLY AVOID: Nonclinical data indicate that the solubility of dasatinib is pH-dependent. Therefore, long-term suppression of gastric acid secretion by H2-receptor antagonists or inhibitors of the proton pump (PPIs or potassium-competitive acid blockers [PCABs]) is likely to reduce dasatinib systemic exposure. In 24 healthy study subjects, administration of a 50 mg dose of dasatinib 10 hours after famotidine was associated with an approximately 60% reduction in dasatinib peak plasma concentration (Cmax) and systemic exposure (AUC). In 14 healthy study subjects, administration of a single 100 mg dose of dasatinib 22 hours following a 40 mg dose of omeprazole at steady state reduced the Cmax and AUC of dasatinib by over 40% each.

MANAGEMENT: Concomitant use of dasatinib with H2-receptor antagonists or inhibitors of the proton pump is not recommended. If gastric acidity management is necessary, antacids should be considered in place of these agents. However, patients treated with dasatinib should avoid taking antacids or oral medications that contain antacids (e.g., didanosine buffered tablets or pediatric oral solution) for at least two hours before and two hours after administration of dasatinib.

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.