Drug Interaction Report

GENERALLY AVOID: Coadministration of tacrolimus and cyclosporine may increase the risk and severity of nephrotoxicity due to additive effects on the kidney. Clinical experience indicates that the combination is associated with increased renal toxicity as evidenced by increased serum creatinine and decreased glomerular filtration rate. In vitro and animal data also suggest that tacrolimus may inhibit the intestinal first-pass metabolism of cyclosporine via CYP450 3A4, resulting in significantly increased bioavailability of the latter.

MANAGEMENT: To avoid undue nephrotoxicity, tacrolimus and cyclosporine should not be used simultaneously. Tacrolimus or cyclosporine should be discontinued for at least 24 hours prior to initiating the other. In the presence of elevated tacrolimus or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

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MONITOR: Coadministration of amlodipine with cyclosporine may increase the plasma concentrations and the risk of adverse effects of both drugs. The proposed mechanism by which amlodipine increases cyclosporine exposure has not been clearly delineated, but may involve inhibition of CYP450 3A4 and/or P-glycoprotein; cyclosporine may increase amlodipine exposure by inhibiting its metabolism via the CYP450 3A4 enzymatic pathway. Studies have revealed that coadministration of amlodipine with cyclosporine in renal transplant patients resulted in variable increases in trough concentrations of cyclosporine (average 0% to 40%).

MANAGEMENT: Although the interaction has not been studied, caution is advised if amlodipine and cyclosporine are used in combination, particularly in renal transplant patients. Cyclosporine blood levels and renal function should be monitored more closely whenever amlodipine is added to or withdrawn from therapy, and the cyclosporine dosage adjusted as necessary. Similarly, dosage adjustments as well as clinical and laboratory monitoring of amlodipine should be considered whenever cyclosporine is added to or withdrawn from therapy. During concomitant treatment, patients should be advised to notify their physician if they experience signs and symptoms of cyclosporine toxicity such as nausea, vomiting, diarrhea, abdominal pain, dizziness, fatigue, headache, tremors, and convulsions or adverse effects associated with amlodipine such as hypotension or edema. In addition, concurrent use may also increase the risk of gingival overgrowth.

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MONITOR: Coadministration with amlodipine may increase the blood concentrations of tacrolimus. The exact mechanism of interaction is unknown but may involve inhibition of the CYP450 3A5 metabolism of tacrolimus. Isolated case reports and one crossover study involving healthy subjects have demonstrated that the AUC of tacrolimus may increase by 2.3-fold or more when taken concomitantly with amlodipine.

MANAGEMENT: Caution is advised if tacrolimus is administered concomitantly with amlodipine. Tacrolimus blood levels should be monitored frequently and the dosage adjusted accordingly, particularly following initiation or discontinuation of amlodipine therapy in patients who are stabilized on their tacrolimus regimen. Patients should be advised to contact their physician if they experience potential signs and symptoms of tacrolimus toxicity such as fever, infection, diarrhea, tremor, headache, fatigue, lethargy, and changes in motor function, mental status, or sensory function.

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GENERALLY AVOID: Administration with grapefruit juice (compared to water or orange juice) has been shown to increase blood concentrations of cyclosporine with a relatively high degree of interpatient variability. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

GENERALLY AVOID: Administration with red wine or purple grape juice may decrease blood concentrations of cyclosporine. In 12 healthy volunteers, 12 ounces total of a merlot consumed 15 minutes prior to and during cyclosporine administration (single 8 mg/kg dose of Sandimmune) decreased cyclosporine peak blood concentration (Cmax) and systemic exposure (AUC) by 38% and 30%, respectively, compared to water. The time to reach peak concentration (Tmax) doubled, and oral clearance increased 50%. Similarly, one study were 12 healthy patients were administered purple grape juice and a single dose of cyclosporine showed a 30% and a 36% decrease in cyclosporine systemic exposure (AUC) and peak blood concentration (Cmax), respectively. The exact mechanism of interaction is unknown but may involve decreased cyclosporine absorption.

MONITOR: Food has been found to have variable effects on the absorption of cyclosporine. There have been reports of impaired, unchanged, and enhanced absorption during administration with meals relative to the fasting state. The mechanisms are unclear. Some investigators found an association with the fat content of food. In one study, increased fat intake resulted in significantly increased cyclosporine bioavailability and clearance. However, the AUC and pharmacodynamics of cyclosporine were not significantly affected, thus clinical relevance of these findings may be minimal.

MANAGEMENT: Patients receiving cyclosporine therapy should be advised to either refrain from or avoid fluctuations in the consumption of grapefruits and grapefruit juice. Until more data are available, the consumption of red wine or purple grape juice should preferably be avoided or limited. All oral formulations of cyclosporine should be administered on a consistent schedule with regard to time of day and relation to meals so as to avoid large fluctuations in plasma drug levels.

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ADJUST DOSING INTERVAL: Consumption of food has led to a 27% decrease in the bioavailability of orally administered tacrolimus.

MANAGEMENT: Tacrolimus should be administered at least one hour before or two hours after meals.

GENERALLY AVOID: Grapefruit juice has been reported to increase tacrolimus trough concentrations. Data are limited, but inhibition of the CYP450 enzyme system appears to be involved.

MANAGEMENT: The clinician may want to recommend that the patient avoid ingesting large amounts of grapefruit juice while taking tacrolimus.

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MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia.

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MONITOR: Calcium-containing products may decrease the effectiveness of calcium channel blockers by saturating calcium channels with calcium. Calcium chloride has been used to manage acute severe verapamil toxicity.

MANAGEMENT: Management consists of monitoring the effectiveness of calcium channel blocker therapy during coadministration with calcium products.

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The consumption of grapefruit juice may slightly increase plasma concentrations of amlodipine. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Data have been conflicting and the clinical significance is unknown. Monitoring for calcium channel blocker adverse effects (e.g., headache, hypotension, syncope, tachycardia, edema) is recommended.

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