Drug Interaction Report

ADJUST DOSE: Coadministration with voriconazole may increase the blood concentrations of cyclosporine. The mechanism is voriconazole inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of cyclosporine. In seven renal transplant recipients stabilized on their cyclosporine regimen, voriconazole (200 mg every 12 hours for 7.5 days) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of cyclosporine by 13% and 70%, respectively, compared to placebo. Six other subjects were discontinued from the study during voriconazole exposure due to safety concerns (elevated cyclosporine levels) and drug-related adverse effects that included elevated liver function tests, asthenia, dyspnea, and peripheral edema. These subjects had a mean 2.5-fold increase in cyclosporine plasma trough concentration (Cmin) compared to a mean increase of 1.7-fold in subjects who were not discontinued from the study. Although not serious, most causality-related adverse events occurred during voriconazole exposure and were attributable to elevated cyclosporine concentrations.

MANAGEMENT: Caution is advised if cyclosporine must be used concomitantly with voriconazole. Patients who are already receiving cyclosporine should have the dosage reduced to one-half the original dosage upon initiation of voriconazole therapy. Close monitoring of renal function and cyclosporine blood levels is recommended both following initiation and withdrawal of voriconazole therapy, and the cyclosporine dosage adjusted as necessary.

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ADJUST DOSE: Coadministration with cyclosporine may significantly increase the plasma concentrations of letermovir. The proposed mechanism is cyclosporine inhibition of the OATP1B1-mediated hepatic uptake of letermovir. Cyclosporine exposure may also increase due to inhibition of CYP450 3A4-mediated metabolism by letermovir. According to the product labeling, letermovir peak plasma concentration (Cmax), systemic exposure (AUC) and concentration at 24 hours postdose (C24h) increased by an average of 48%, 111% and 106%, respectively, when letermovir (240 mg orally once daily) was coadministered with cyclosporine (200 mg single oral dose). Cyclosporine Cmax, AUC and C24h increased by an average of 8%, 66% and 119%, respectively, when a 50 mg single oral dose was coadministered with letermovir 240 mg orally once daily. In pharmacokinetic studies, median steady-state AUC of letermovir was 34,400 ng*h/mL when dosed at 480 mg orally once daily without cyclosporine, compared to 60,800 ng*h/mL when dosed at 240 mg orally once daily with cyclosporine. Likewise, a median value of 100,000 ng*h/mL was reported when letermovir was given intravenously at 480 mg once daily without cyclosporine, compared to 70,300 ng*h/mL when given intravenously at 240 mg once daily with cyclosporine. In hematopoietic stem cell transplant patients, the bioavailability of letermovir was 35% at a dosage of 480 mg orally once daily without cyclosporine, compared to 85% at a dosage of 240 mg orally once daily with cyclosporine.

MANAGEMENT: The dosage of letermovir should be decreased to 240 mg orally or intravenously once daily when coadministered with cyclosporine. If cyclosporine is initiated during letermovir prophylaxis therapy, letermovir dosage should be decreased to 240 mg once daily beginning with the next dose. If cyclosporine is discontinued, letermovir dosage should be increased to 480 mg once daily beginning with the next dose. No dosage adjustment of letermovir is needed if cyclosporine dosing is interrupted due to high cyclosporine levels. Cyclosporine whole blood concentrations should also be monitored frequently during treatment and after discontinuation of letermovir, and the dosage adjusted accordingly. In addition, clinicians should be aware that the magnitude of CYP450 3A- and OATP1B1/3-mediated drug interactions with coadministered drugs may be different when letermovir is used with cyclosporine. The combined effect of the two drugs on CYP450 3A may be similar to that of a strong CYP450 3A inhibitor, hence clinicians should refer to the prescribing information for dosing recommendations of the CYP450 3A substrate with a strong CYP450 3A inhibitor. Similarly, letermovir and cyclosporine may demonstrate some additive effects on OATP1B1 inhibition, although cyclosporine by itself is already a strong OATP1B1/3 inhibitor.

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MONITOR: Coadministration with letermovir may decrease the plasma concentrations of drugs that are metabolized by CYP450 2C9 and/or 2C19. The interaction has been studied with voriconazole, a substrate of CYP450 2C9 and 2C19. According to the product labeling, voriconazole peak plasma concentration (Cmax), systemic exposure (AUC) and concentration at 12 hours postdose (C12hr) decreased by an average of 39%, 44% and 51%, respectively, when voriconazole 200 mg orally twice daily was coadministered with letermovir 480 mg orally once daily.

MANAGEMENT: Caution is advised when letermovir is used concomitantly with drugs that are substrates of CYP450 2C9 and/or 2C19, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever letermovir is added to or withdrawn from therapy.

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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: Food reduces the oral absorption and bioavailability of voriconazole. According to the product labeling, administration of multiple doses of voriconazole with high-fat meals decreased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) by 34% and 24%, respectively, when the drug is administered as a tablet, and by 58% and 37%, respectively, when administered as the oral suspension.

MANAGEMENT: To ensure maximal oral absorption, voriconazole tablets and oral suspension should be taken at least one hour before or after a meal.

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