Drug Interactions between ombitasvir / paritaprevir / ritonavir and Symbyax

MONITOR: Fluoxetine may raise the plasma concentration of ritonavir by inhibiting its metabolism. A 19% increase has been observed in the mean area under the plasma concentration-time curve of ritonavir. One pharmacokinetic study concluded that no ritonavir dose adjustment was necessary. Also, ritonavir appears to be a moderately competitive inhibitor of the enzyme CYP450 2D6. Elevated serum fluoxetine levels are therefore possible.

MANAGEMENT: If fluoxetine and ritonavir must be used concurrently, the patient should be monitored for fluoxetine toxicity (nausea, vomiting, dizziness, confusion, vertigo, tremor, and gait abnormalities). A reduction in fluoxetine dosage may be necessary.

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MONITOR: It is uncertain whether olanzapine causes clinically significant prolongation of the QT interval. In pooled studies of adults as well as pooled studies of adolescents, there were no significant differences between olanzapine and placebo in the proportion of patients experiencing potentially important changes in ECG parameters, including QT, QTcF (Fridericia-corrected), and PR intervals. In clinical trials, clinically meaningful QTc prolongations (QTcF >=500 msec at any time post-baseline in patients with baseline QTcF <500 msec) occurred in 0.1% to 1% of patients treated with olanzapine, with no significant differences in associated cardiac events compared to placebo. Published studies have generally reported no significant effect of olanzapine on QTc interval, although both QTc prolongation and QTc shortening have also been reported. There have been a few isolated case reports of QT prolongation in patients receiving olanzapine. However, causality is difficult to establish due to confounding factors such as concomitant use of drugs that cause QT prolongation and underlying conditions that may predispose to QT prolongation (e.g., hypokalemia, congenital long QT syndrome, preexisting conduction abnormalities).

MANAGEMENT: Some authorities recommend caution when olanzapine is used with drugs that are known to cause QT prolongation. ECG monitoring may be advisable in some cases, such as in patients with a history of cardiac arrhythmias or congenital or family history of long QT syndrome. 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.

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MONITOR: Coadministration with ritonavir may significantly decrease the plasma concentrations of olanzapine. The mechanism is ritonavir induction of CYP450 1A2 and uridine 5' diphosphate glucuronosyltransferase, the enzymes responsible for the metabolic clearance of olanzapine. In 14 healthy, nonsmoking volunteers, ritonavir (300 mg titrated to 500 mg orally twice a day over 11 days) decreased the mean peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and half-life of olanzapine (10 mg single oral dose) by 40%, 53% and 50%, respectively, compared to administration of olanzapine alone. Oral clearance increased by 115%. All but one subject reported less sedation with olanzapine after ritonavir administration than before.

MANAGEMENT: Patients treated concomitantly with ritonavir may require a higher dosage of olanzapine to control psychotic symptoms. Pharmacologic response to olanzapine should be monitored more closely whenever ritonavir is added to or withdrawn from therapy in patients stabilized on their antipsychotic regimen, and the olanzapine dosage adjusted as necessary.

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