Drug Interactions between Dexone LA and lopinavir / ritonavir

GENERALLY AVOID: Coadministration with protease inhibitors may increase the plasma concentration and pharmacologic effects of dexamethasone. The proposed mechanism is protease inhibitor-mediated inhibition of CYP450 3A4, the isoenzyme involved in the metabolic clearance of dexamethasone. Ritonavir has been reported to increase dexamethasone systemic exposure (AUC) by more than threefold. In one case report, an HIV patient who had been receiving long-term dexamethasone therapy for thrombotic thrombocytopenia purpura developed spinal epidural lipomatosis four months following the initiation of ritonavir. Although the patient was already cushingoid as a result of chronic dexamethasone administration, he did not have symptoms of myelopathy until after ritonavir was added. The effect of dexamethasone on the clearance of protease inhibitors has not been established. Theoretically, plasma levels of protease inhibitors may decrease due to dexamethasone induction of their metabolism by CYP450 3A4. This may lead to a loss of therapeutic effect and development of resistance to protease inhibitor-containing antiretroviral regimens; however, data are not available. These interactions may also be seen with cobicistat, a potent CYP450 3A4 inhibitor that solely acts as a pharmacokinetic booster in antiretroviral treatment regimen; however, data are not available.

MONITOR: Corticosteroids such as dexamethasone may cause hypokalemia and potentiate the risk of QT and/or PR interval prolongation associated with the use of certain protease inhibitors such as atazanavir, lopinavir-ritonavir, and saquinavir-ritonavir. The risk of torsade de pointes arrhythmia, bradycardia, and heart block may be increased.

MANAGEMENT: Caution is advised if dexamethasone must be used concomitantly with protease inhibitors or cobicistat. Some authorities advise against concomitant use unless the potential benefit outweighs the risk. Adrenal function should be monitored regularly during chronic use of these agents, and dexamethasone dosage adjusted as necessary. Patients should be monitored for symptoms of hypercorticism (e.g., acne, easy bruising, moon face, edema, hirsutism, buffalo hump, skin striae, glucose intolerance, and irregular menstruations), immunosuppression, and osteoporosis. In addition, it may be appropriate to monitor patients for potentially reduced antiretroviral response following initiation or any dosage increase of dexamethasone. Serum potassium and ECG monitoring should also be considered during coadministration of dexamethasone with certain protease inhibitors in accordance with the product labeling.

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MONITOR: Coadministration of lopinavir-ritonavir with inducers of CYP450 3A4 may decrease the plasma concentrations of lopinavir, which is primarily metabolized by the isoenzyme. Clinical studies have shown that potent CYP450 3A4 inducers such as rifampin and phenytoin can significantly alter the plasma concentrations of lopinavir, possibly by overriding some of the inhibiting effects of ritonavir and enhancing the clearance of both lopinavir and ritonavir. In 22 healthy, HIV-negative subjects, administration of lopinavir-ritonavir (400 mg-100 mg twice daily for 20 days) with rifampin (600 mg once daily for 10 days) decreased lopinavir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 55%, 75% and 99%, respectively. In another study of 12 healthy volunteers, coadministration of lopinavir-ritonavir (400 mg-100 mg twice daily for 22 days) and phenytoin (300 mg once daily on days 11 thru 22) resulted in decreases in Cmax, AUC and Cmin of lopinavir by 24%, 33% and 46%, respectively. Ritonavir Cmax, AUC and Cmin were also reduced by 20%, 28% and 47%, respectively, although only the change in Cmin was statistically significant. The extent to which other, less potent inducers of CYP450 3A4 may interact with lopinavir-ritonavir is unknown.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, caution is advised if lopinavir-ritonavir is prescribed with CYP450 3A4 inducers. Close clinical and laboratory monitoring of antiretroviral response is recommended.

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