Drug Interactions between digoxin and lansoprazole / naproxen

MONITOR: Nonsteroidal anti-inflammatory drugs (NSAIDs) may increase plasma digoxin concentrations and half-life. The exact mechanism is unknown, but may be related to reduced renal clearance of digoxin. Data have been conflicting. The interaction has been reported with indomethacin and ibuprofen, but data for other NSAIDs are not available.

MANAGEMENT: Patients who require concomitant therapy should be monitored for altered pharmacologic effects of digoxin and for increased plasma levels. The digoxin dosage may require adjustment. Patients should be advised to notify their physician if they experience nausea, anorexia, visual changes, slow pulse, or irregular heartbeats.

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.

MONITOR: Proton pump inhibitors may increase the bioavailability of digoxin. The mechanism may involve a pH-dependent increase in gastrointestinal absorption of digoxin and/or inhibition by PPIs of the P-glycoprotein-mediated intestinal transport of digoxin. In pharmacokinetic studies, digoxin systemic exposure (AUC) increased by an average of 10% to 20% when administered with omeprazole, pantoprazole, or rabeprazole. These changes are generally not considered clinically significant. However, a case report describes a 65-year-old patient who exhibited signs of digoxin toxicity and ECG changes three months after starting treatment with omeprazole 20 mg/day. Her digoxin level was 3.9 ng/mL, and she was treated with digoxin immune Fab.

MONITOR: Coadministration with proton pump inhibitors (PPIs) for prolonged periods may increase the risk of digoxin toxicity. Chronic use of PPIs can induce hypomagnesemia. In patients with hypomagnesemia, toxicity may occur despite serum digoxin concentrations below 2.0 ng/mL because magnesium depletion sensitizes the myocardium to digoxin. The mechanism via which hypomagnesemia may occur during long-term PPI use is unknown, although changes in intestinal absorption of magnesium may be involved. Hypomagnesemia has been reported rarely in patients treated with PPIs for at least three months, but in most cases, after a year or more. Serious adverse events include tetany, seizures, tremor, carpopedal spasm, atrial fibrillation, supraventricular tachycardia, and abnormal QT interval; however, patients do not always exhibit these symptoms. In approximately 25% of the cases of PPI-associated hypomagnesemia reviewed by the U.S. Food and Drug Administration, the condition did not resolve with magnesium supplementation alone but also required discontinuation of the PPI. Both positive dechallenge as well as positive rechallenge (i.e., resolution of hypomagnesemia with PPI cessation and recurrence with PPI resumption) were reported in some cases. After discontinuing the PPI, the median time required for magnesium levels to normalize was one week. After restarting the PPI, the median time for hypomagnesemia to recur was two weeks.

MANAGEMENT: Caution is advised if digoxin is prescribed in combination with PPIs. Pharmacologic response and serum digoxin levels should be monitored more closely following the addition or discontinuation of PPI therapy, and the digoxin dosage adjusted as necessary. Patients should be advised to notify their physician if they experience potential signs and symptoms of digoxin toxicity such as nausea, anorexia, visual disturbances, slow pulse, or irregular heartbeats. Monitoring of serum magnesium levels is recommended prior to initiation of PPI therapy and periodically thereafter if prolonged treatment is anticipated or when combined with other agents that can cause hypomagnesemia (e.g., diuretics, aminoglycosides, cation exchange resins, amphotericin B, cetuximab, cisplatin, cyclosporine, foscarnet, panitumumab, pentamidine, tacrolimus). Patients should be advised to seek immediate medical attention if they develop potential signs and symptoms of hypomagnesemia such as palpitations, arrhythmia, muscle spasm, tremor, or convulsions. In children, abnormal heart rates may cause fatigue, upset stomach, dizziness, and lightheadedness. Magnesium replacement as well as discontinuation of the PPI may be required in some patients.