Drug Interaction Report

MONITOR CLOSELY: Aspirin (ASA; acetylsalicylic acid ) may potentiate the risk of bleeding in patients treated with dabigatran etexilate. The pharmacologic effects of ASA that contribute to this interaction include prolongation of prothrombin time and inhibition of platelet adhesion and aggregation. Aspirin at dosages of 81 to 325 mg daily has been shown to increase the risk of bleeding when given concomitantly with dabigatran etexilate at dosages above 220 mg/day. In a phase 3 clinical trial of dabigatran etexilate for the prevention of stroke and systemic embolism in patients with atrial fibrillation, coadministration of oral antiplatelet agents including ASA and clopidogrel increased the risk of bleeding by about twofold. However, there is no evidence that the addition of ASA or clopidogrel to dabigatran, or its comparator warfarin, improved outcomes with respect to stroke.

MANAGEMENT: Caution is advised if dabigatran is used in combination with aspirin. Close clinical and laboratory observation for hematologic complications is recommended. 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.

MONITOR: Patients with gastrointestinal conditions may have an increased risk of gastrointestinal bleeding during concomitant treatment with dabigatran etexilate and proton pump inhibitors or H2 blockers. In addition, pantoprazole resulted in an approximately 30% decrease in dabigatran systemic exposure (AUC). Diminished clinical effect may occur, although no dosage adjustment is recommended for dabigatran etexilate. The pharmacokinetics of pantoprazole were not significantly altered by dabigatran. Pantoprazole and other proton pump inhibitors were also coadministered with dabigatran in clinical trials for the prevention of venous thromboembolic events after hip- or knee-replacement surgery, and no effects on bleeding or efficacy were observed. Ranitidine had no significant effects on the absorption of dabigatran.

MANAGEMENT: Patients should be monitored for signs of gastrointestinal bleeding and advised to promptly report any symptoms to their physician, such as abdominal pain, dizziness, lightheadedness, vomiting blood, anorexia, and/or black, tarry stools.

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.

GENERALLY AVOID: The concurrent use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) and ethanol may lead to gastrointestinal (GI) blood loss. The mechanism may be due to a combined local effect as well as inhibition of prostaglandins leading to decreased integrity of the GI lining.

MANAGEMENT: Patients should be counseled on this potential interaction and advised to refrain from alcohol consumption while taking aspirin or NSAIDs.

One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.