Drug Interactions between amoxicillin / clarithromycin / lansoprazole and tacrolimus

ADJUST DOSE: Coadministration with certain macrolide or ketolide antibiotics may significantly increase the oral bioavailability of tacrolimus. The proposed mechanism is inhibition of tacrolimus metabolism via intestinal CYP450 3A4. Inhibition of P-glycoprotein (P-gp) efflux transporter in gut wall may also contribute. There have been case reports of nephrotoxicity and other adverse effects (e.g., hyperkalemia, hyperglycemia, hemolytic anemia, hemolytic uremic syndrome, neurotoxicity) in association with significantly elevated tacrolimus blood levels within days following the addition of clarithromycin or erythromycin, which necessitated either a dosing adjustment or interruption of tacrolimus and/or discontinuation of the macrolide. Greater than 10-fold increases in tacrolimus blood levels have been observed in some cases. These reports are consistent with data derived from pharmacokinetic studies involving tacrolimus and other potent CYP450 3A4 inhibitors such as azole antifungal agents. Although data are not available for telithromycin, it is expected to interact similarly with tacrolimus due to its status as a potent CYP450 3A4/P-gp inhibitor.

MONITOR CLOSELY: Tacrolimus can cause concentration-dependent prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval such as macrolide and ketolide antibiotics may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution is advised when tacrolimus is used with macrolide or ketolide antibiotics that significantly inhibit CYP450 3A4 such as clarithromycin, erythromycin, josamycin, and telithromycin. A preemptive dosage reduction for tacrolimus may be appropriate in some cases. Frequent monitoring of tacrolimus whole blood levels should be performed during and after discontinuation of macrolide antibiotic therapy, and the tacrolimus dosage adjusted accordingly. In addition, patients should be closely monitored for development of serious adverse effects such as nephrotoxicity, lymphoma and other malignancies, infections, diabetes, neurotoxicity (tremor, paraesthesia, encephalopathy, delirium, coma), hyperkalemia, QT prolongation, myocardial hypertrophy, and hypertension. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

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.

MONITOR: Coadministration with clarithromycin may increase the plasma concentrations of lansoprazole. The proposed mechanism is clarithromycin inhibition of intestinal (first-pass) and hepatic metabolism of lansoprazole via CYP450 3A4. Although lansoprazole is primarily metabolized by CYP450 2C19 in the liver, 3A4-mediated metabolism is the predominant pathway in individuals who are 2C19-deficient (approximately 3% to 5% of the Caucasian and 17% to 20% of the Asian population). Additionally, inhibition of P-glycoprotein intestinal efflux transporter by clarithromycin may also contribute to the interaction, resulting in increased bioavailability of lansoprazole. In 18 healthy volunteers--six each of homozygous extensive metabolizers (EMs), heterozygous EMs, and poor metabolizers (PMs) of CYP450 2C19--clarithromycin (400 mg orally twice a day for 6 days) increased the peak plasma concentration (Cmax) of a single 60 mg oral dose of lansoprazole by 1.47, 1.71- and 1.52-fold, respectively, and area under the concentration-time curve (AUC) by 1.55-, 1.74- and 1.80-fold, respectively, in each of these groups compared to placebo. The AUC ratio of lansoprazole to lansoprazole sulphone, which is considered an index of CYP450 3A4 activity, was significantly increased by clarithromycin in all three groups. However, elimination half-life of lansoprazole was prolonged by 1.54-fold only in PMs. Mild diarrhea was reported in two subjects and mild abdominal disturbance in six subjects during clarithromycin coadministration. These side effects continued until day 6 and ameliorated the day after discontinuation of clarithromycin, whereas no adverse events were reported during placebo administration or after lansoprazole plus placebo. In another study, clarithromycin induced dose-dependent increases in the plasma concentration of lansoprazole in a group of 20 patients receiving treatment for H. pylori eradication. Mean 3-hour plasma lansoprazole concentration was 385 ng/mL for the control subjects who received lansoprazole 30 mg and amoxicillin 750 mg twice a day for 7 days; 696 ng/mL for patients coadministered clarithromycin 200 mg twice a day; and 947 ng/mL for patients coadministered clarithromycin 400 mg twice a day.

MANAGEMENT: Although lansoprazole is generally well tolerated, caution may be advised during coadministration with clarithromycin, particularly if higher dosages of one or both drugs are used. Dosage adjustment may be necessary in patients who experience excessive adverse effects of lansoprazole.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.