Drug Interaction Report

GENERALLY AVOID: Theoretically, proton pump inhibitors may decrease the gastrointestinal absorption of enteric-coated naproxen, which requires an acidic environment for dissolution. The proposed mechanism is an increase in gastric pH (i.e. decreased gastric acidity) induced by proton pump inhibitors. In patients treated with proton pump inhibitors, the possibility of a reduced or subtherapeutic response to enteric-coated naproxen should be considered.

MANAGEMENT: Concomitant use of these drugs is generally not recommended.

GENERALLY AVOID: Coadministration of ceftriaxone with lansoprazole has been associated with prolongation of the QT interval and increased risk of ventricular arrhythmia, cardiac arrest, and death in hospitalized patients. The precise mechanism of interaction has not been established, although ceftriaxone and lansoprazole in combination have been shown in patch-clamp electrophysiologic experiments to block the human ether-a-go-go-related gene (hERG) potassium channel at clinically relevant concentrations, which is a common mechanism for drug-induced QT prolongation. In a single-center retrospective cohort study consisting of 380,000 patients, investigators found the combination of ceftriaxone and lansoprazole was associated with significant prolongation of the corrected QT (QTc) interval, and patients treated with the combination were 1.4 times more likely to have a QTc interval greater than 500 msec relative to treatment with either drug alone. On average, QTc intervals were 12 msec longer in men and 9 msec longer in women who were receiving ceftriaxone and lansoprazole concurrently compared with patients receiving either drug alone. These observations were not reported for cefuroxime and lansoprazole, the negative control used in the study. In another retrospective cohort study of 31,152 patients receiving ceftriaxone therapy with a proton pump inhibitor (PPI) in 13 hospitals in Ontario, Canada, over a 7 year period, concomitant use of lansoprazole (n=3747; 12%) was associated with adjusted absolute risk increases of 1.7% for ventricular arrhythmia or cardiac arrest and 7.4% for all-cause in-hospital mortality compared with use of other PPIs (n=27,405; 88%). Overall, ventricular arrhythmia or cardiac arrest occurred in 126 patients (3.4%) in the lansoprazole group and 319 patients (1.2%) in the other PPI group, while in-hospital mortality occurred in 746 patients (19.9%) in the lansoprazole group and 2762 patients (10.1%) in the other PPI group. However, these events could not be definitively linked to QTc interval prolongation, since QTc intervals on electrocardiograms were not captured in the study. The interaction was also independently reported in a patient receiving ceftriaxone 2 gm/day for pneumonia who developed QTc prolongation following the addition of lansoprazole 30 mg/day for epigastralgia. The patient's QTc interval was 422 msec on admission and 417 msec three days after starting ceftriaxone, but increased to 475 msec after two days of combined treatment despite no changes in electrolytes, echocardiography findings, or further drug use. Two days after lansoprazole was stopped and replaced with pantoprazole, QTc returned to normal at 424 msec while ceftriaxone was continued.

MANAGEMENT: Until more information is available, prescribers should consider avoiding the concomitant use of ceftriaxone and lansoprazole when possible, particularly in the elderly and patients with underlying risk factors for QT prolongation such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). Patients coadministered these medications should have renal function, serum electrolytes, and electrocardiograms monitored.

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.

MONITOR: Smoking cessation may lead to elevated plasma concentrations and enhanced pharmacologic effects of drugs that are substrates of CYP450 1A2 (and possibly CYP450 1A1) and/or certain drugs with a narrow therapeutic index (e.g., flecainide, pentazocine). One proposed mechanism is related to the loss of CYP450 1A2 and 1A1 induction by polycyclic aromatic hydrocarbons in tobacco smoke; when smoking cessation agents are initiated and smoking stops, the metabolism of certain drugs may decrease leading to increased plasma concentrations. The mechanism by which smoking cessation affects narrow therapeutic index drugs that are not known substrates of CYP450 1A2 or 1A1 is unknown. The clinical significance of this interaction is unknown as clinical data are lacking.

MANAGEMENT: Until more information is available, caution is advisable if smoking cessation agents are used concomitantly with drugs that are substrates of CYP450 1A2 or 1A1 and/or those with a narrow therapeutic range. Patients receiving smoking cessation agents may require periodic dose adjustments and closer clinical and laboratory monitoring of medications that are substrates of CYP450 1A2 or 1A1.