Drug Interaction Report

MONITOR: Coadministration of proton pump inhibitors (PPIs) has been reported to reduce the antitumor efficacy of capecitabine, although available data are inconsistent and conflicting. Several retrospective studies and post-hoc analyses of randomized controlled trials have demonstrated an adverse impact of PPI use on disease progression, recurrence rates, and/or survival outcomes in patients receiving capecitabine-containing chemotherapy for the treatment of gastroesophageal and colorectal cancers. A reduction in dissolution and subsequent absorption of capecitabine due to PPI-induced elevations in gastric pH has been proposed as the underlying mechanism of interaction. However, three pharmacokinetic studies conducted with antacid (Maalox) and PPIs (esomeprazole, rabeprazole) failed to show significant effects on plasma concentrations of capecitabine and its metabolites. Additionally, the association between PPIs and poorer oncologic outcomes was not seen with concomitant use of other acid-suppressing agents such as H2-receptor antagonists in a retrospective post hoc analysis of data from six completed colorectal cancer clinical trials. Subgroup analyses in this investigation also did not find a significant negative association with survival for concomitant PPI use across 980 patients receiving capecitabine and oxaliplatin (CapOx) with or without bevacizumab. Meanwhile, one retrospective study reported positive effects of omeprazole on response rate and disease-free survival in advanced rectal cancer treated with CapOx chemoradiotherapy (CRT) for two cycles prior to surgery. In vitro data have shown that PPIs may possess direct antitumor effects and can also re-sensitize drug-resistant colon adenocarcinoma cell lines to cytotoxic drugs by inhibiting a membranous proton pump known as vacuolar-ATPase (V-ATPase), which is overexpressed in resistant cancer cells. It is possible that suppressing the activity of V-ATPases helps to modulate the abnormal pH gradients in tumor microenvironment associated with tumorigenesis, tumor progression, and drug resistance. More recently, some investigators have conducted systematic reviews and meta-analyses that have cast doubt on the occurrence of a significant interaction between PPIs and capecitabine based on existing clinical, pharmacokinetic, and in vitro evidence. It is also unclear whether the potential negative effects of PPI use reported during capecitabine treatment in gastroesophageal and colorectal cancers may occur in other cancers.

MANAGEMENT: Based on available data, it may be advisable to avoid PPI use during treatment with capecitabine when possible. Alternative acid suppressing agents such as antacids and H2-receptor antagonists may be preferable in some cases. If PPIs are required, patients should be monitored and evaluated at regular intervals to ascertain the continued need for their use.

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.