Drug interactions between Nexium and Prograf

tacrolimus ↔ esomeprazole

Applies to:Prograf (tacrolimus) and Nexium (esomeprazole)

MONITOR: Chronic use of proton pump inhibitors (PPIs) may induce hypomagnesemia, and the risk may be increased during concomitant use of other agents that can cause magnesium loss such as tacrolimus. 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. Hypomagnesemia can also cause impaired parathyroid hormone secretion, which may lead to hypocalcemia. In approximately 25% of the cases of PPI-associated hypomagnesemia reviewed by the FDA, 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: Monitoring of serum magnesium levels is recommended prior to initiation of therapy and periodically thereafter if prolonged treatment with a proton pump inhibitor is anticipated or when combined with other agents that can cause hypomagnesemia such as 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.

MONITOR: Coadministration with some PPIs may increase the blood concentrations of tacrolimus in patients with CYP450 2C19 mutant alleles. The proposed mechanism is competitive inhibition of tacrolimus metabolism via intestinal and hepatic CYP450 3A4. The interaction has been reported with lansoprazole. Although lansoprazole is primarily metabolized by CYP450 2C19, CYP450 3A4 is the major metabolic pathway in individuals who are CYP450 2C19-deficient, thereby increasing the risk of CYP450 3A4-mediated interactions. In a study of healthy volunteers, administration of a single 2 mg dose of tacrolimus in combination with lansoprazole (30 mg daily for 4 days) increased the tacrolimus systemic exposure (AUC) by 81% in subjects with CYP450 2C19 mutant alleles and by 29% in subjects without (i.e., CYP450 2C19 extensive metabolizers), whereas administration with rabeprazole (10 mg daily for 4 days) had minimal effect in either group. There have also been several case reports of patients with such mutations who developed significant increases in tacrolimus trough levels shortly (within 1 to 3 days) after the addition of lansoprazole. Their levels normalized only after tacrolimus dosage was reduced and lansoprazole was discontinued and replaced with either famotidine or rabeprazole. Theoretically, other proton pump inhibitors (PPIs) with a similar metabolic profile such as esomeprazole, omeprazole, and pantoprazole can also cause this interaction.

MANAGEMENT: Approximately 16% to 25% of Caucasians and 36% to 47% of Asians have gene mutations that result in varying degrees of reduced CYP450 2C19 enzyme activity. It has been further estimated that approximately 2% of Caucasians and 16% of Asians are poor metabolizers with minimal CYP450 2C19 functional capacity. Since 2C19 genotype information is not frequently available for patients, caution is advised if tacrolimus must be prescribed with lansoprazole or other similar PPIs. Pharmacologic response to tacrolimus and blood concentrations should be monitored more closely whenever the PPI is added to or withdrawn from therapy, and the tacrolimus dosage adjusted as necessary to prevent concentration-dependent adverse effects such as nephrotoxicity, neurotoxicity, posttransplant diabetes mellitus, infections, and myocardial hypertrophy. Clinicians should bear in mind that CYP450 2C19 deficiency can also be pharmacologically induced by drugs such as cimetidine, delavirdine, efavirenz, felbamate, fluconazole, fluoxetine, fluvoxamine, oxcarbazepine, ticlopidine, and voriconazole. To minimize the risk of interaction, alternatives such as famotidine, nizatidine, ranitidine, or rabeprazole should be considered for acid suppression therapy in patients treated with tacrolimus.