Drug Interactions between lansoprazole / naproxen and tacrolimus

MONITOR CLOSELY: Coadministration of macrolide immunosuppressants with other nephrotoxic agents may increase the risk and/or severity of renal impairment due to additive adverse effects on the kidney. No formal interaction studies have been performed. However, clinical experience in coadministration with cyclosporine indicates increased renal toxicity as evidenced by increased serum creatinine and decreased glomerular filtration rate. An interaction with ibuprofen resulting in acute renal failure was suspected in two liver transplant patients who had been stabilized on tacrolimus.

MANAGEMENT: Caution is advised when macrolide immunosuppressants is used in patients who have recently received or are receiving treatment with other potentially nephrotoxic drugs (e.g., aminoglycosides; polypeptide, glycopeptide, and polymyxin antibiotics; amphotericin B; adefovir; cidofovir; tenofovir; foscarnet; cisplatin; cyclosporine; deferasirox; gallium nitrate; lithium; mesalamine; intravenous bisphosphonates; intravenous pentamidine; high intravenous dosages of methotrexate; high dosages and/or chronic use of nonsteroidal anti-inflammatory agents). Renal function should be closely monitored both during and after discontinuation of therapy. Patients should be advised to seek medical attention if they experience symptoms that may indicate nephrotoxicity such as decreased urine output, sudden weight gain, fluid retention, edema, or shortness of breath.

MONITOR CLOSELY: Coadministration with some proton pump inhibitors (PPIs) may significantly increase the whole blood concentrations of tacrolimus, particularly in patients with CYP450 2C19 mutant alleles. The interaction has been reported primarily with lansoprazole and omeprazole, but may occur with other PPIs that have a similar metabolic profile such as dexlansoprazole and esomeprazole. The proposed mechanism is competitive inhibition of tacrolimus metabolism via intestinal and hepatic CYP450 3A4. Although these PPIs are primarily metabolized by CYP450 2C19, CYP450 3A4 is the major metabolic pathway in individuals who are CYP450 2C19-deficient (i.e., CYP450 2C19 poor metabolizers), 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 various case reports of patients with such mutations who developed significant increases in tacrolimus trough levels within several days after the addition of a PPI, usually lansoprazole or omeprazole. Their levels normalized only after tacrolimus dosage was reduced and the PPI was discontinued or replaced with either famotidine or rabeprazole. Studies have indicated that the interaction does not occur with rabeprazole, presumably because it is metabolized by a nonenzymatic pathway in addition to the CYP450 pathways. Available data also suggest that pantoprazole does not significantly interact with tacrolimus, although the reason is unclear, since pantoprazole is similarly metabolized as the other PPIs.

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 3% to 5% of Caucasians and individuals of African descent and 17% to 23% of Asians are poor metabolizers with minimal CYP450 2C19 functional capacity. Since 2C19 genotype information is not frequently available for patients, caution is advised whenever tacrolimus is coadministered with 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.

MONITOR CLOSELY: 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 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: Monitoring of serum magnesium levels is recommended prior to initiation of therapy and periodically thereafter if prolonged treatment with a PPI 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.

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.