Drug Interactions between amoxicillin / omeprazole / rifabutin and cyclosporine

MONITOR CLOSELY: The coadministration with rifamycins, particularly rifampin, may decrease the blood concentrations and pharmacologic effects of cyclosporine. The mechanism probably involves reduced absorption as well as accelerated clearance of cyclosporine due to induction of both intestinal P-glycoprotein drug efflux pumps and hepatic/intestinal CYP450 3A4 isoenzymes by rifamycins. In a study of six healthy volunteers, rifampin (600 mg orally at bedtime for 11 days) increased the average blood clearance of cyclosporine (10 mg/kg orally and 3 mg/kg intravenously) by 40% and decreased its oral bioavailability from 27% to 10%. There have also been case reports of transplant patients whose cyclosporine blood levels dropped significantly, often below assay detection limits, as early as two days following the initiation of rifampin. The decreases were associated with acute rejection episodes in many cases, subsequently requiring discontinuation of rifampin or substantial increases in cyclosporine dosage. This interaction is likely to occur with other rifamycins but to a lesser extent. In vitro and in vivo enzyme studies have suggested rifapentine induction potential to be less than that of rifampin but greater than that of rifabutin.

MANAGEMENT: Given the risk of organ rejection associated with inadequate immunosuppressant levels, caution is advised if cyclosporine must be coadministered with rifamycins, particularly rifampin. Cyclosporine blood levels should be closely monitored and the dosage adjusted accordingly, particularly following initiation or discontinuation of rifamycin therapy in patients who are stabilized on their anti-rejection regimen.

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 cyclosporine. 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.

MONITOR: Coadministration with omeprazole may alter the blood concentrations of cyclosporine in some patients. The mechanism of interaction is unknown. Both increased and decreased cyclosporine levels have been described in isolated case reports of patients treated concomitantly with omeprazole 40 mg/day. Moreover, one retrospective study found that the cyclosporine dosage required to achieve a certain therapeutic level was 28% lower in heart transplant patients who received omeprazole (n=21) than in those who did not (n=139). In contrast, two pharmacokinetic studies have found no significant interaction between these two agents. In 10 male kidney transplant patients with stable renal function receiving maintenance cyclosporine therapy, omeprazole administered at 20 mg once daily for two weeks had no clinically or statistically significant effect on the whole blood concentrations of cyclosporine and its metabolites relative to placebo. In addition, no adverse event and no clinically significant changes in laboratory values were noted during administration of omeprazole. Likewise, no significant changes in cyclosporine levels were observed in eight kidney transplant patients administered omeprazole 20 mg/day for six days compared to controls.

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 cyclosporine. 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. A potential interaction with omeprazole should also be considered when cyclosporine levels are altered and no other causes can be identified. Occasionally, a dosage adjustment of cyclosporine may be necessary.