Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 2D6 may increase the plasma concentrations of nebivolol, which is primarily metabolized by the isoenzyme The mechanism is decreased clearance due to inhibition of CYP450 2D6 activity. Several studies have shown that coadministration of CYP450 2D6 inhibitors increases the peak plasma concentration (Cmax) and systemic exposure (AUC) of nebivolol. When the potent CYP450 2D6 inhibitor paroxetine (20-40 mg daily) was coadministered with nebivolol (5 mg) in 23 healthy subjects, nebivolol's Cmax and AUC increased by 5.7-fold and 6.1-fold, respectively. Similarly, when bupropion (300 mg), a potent CYP450 2D6 inhibitor, was coadministered with nebivolol in 18 healthy volunteers, the Cmax and AUC increased by 2.3-fold and 7.2-fold, respectively. Fluoxetine (20 mg daily), a potent CYP450 2D6 inhibitor, increased nebivolol's Cmax and AUC by approximately 2.3-fold and 6-fold in 10 patients. Fluvoxamine, a mild CYP450 2D6 inhibitor, increased Cmax and AUC by 1.41-fold and 1.44-fold in 18 healthy volunteers. However, no data resulted in significant changes to heart rate or blood pressure.

MANAGEMENT: Caution is advised when nebivolol is used concomitantly with CYP450 2D6 inhibitors. Additional caution and monitoring are advised if the coadministered CYP450 2D6 inhibitor may potentiate the blood pressure lowering effects of nebivolol (e.g., phenothiazines, tricyclic antidepressants (TCAs), and some antipsychotic (neuroleptic) agents). Patients should be monitored closely for adverse effects such as bradycardia, diarrhea, nausea, fatigue, chest pain, peripheral edema, headache, dizziness, insomnia, dyspnea and rash, and the nebivolol dose should be adjusted according to blood pressure response.

GENERALLY AVOID: Taking stiripentol on an empty stomach may reduce its oral bioavailability. Stiripentol degrades rapidly when exposed to gastric acid in an empty stomach.

GENERALLY AVOID: Alcohol may potentiate the depressant effects of stiripentol on the central nervous system. Concomitant use may result in increased sedation and dizziness as well as impairment of psychomotor skills.

GENERALLY AVOID: It is not known whether stiripentol may reduce theophylline and caffeine metabolism, as data on the potential for inhibition of CYP450 1A2 are limited. Consumption of foods and nutritional products such as cola drinks (which contain significant quantities of caffeine) and chocolate (which contains caffeine and trace amounts of theophylline) may be unsafe during treatment with stiripentol, particularly in children.

MANAGEMENT: Stiripentol should be taken during a meal for optimal absorption; however, it should not be taken with milk, dairy products (e.g., yogurt, soft cream cheese), fruit juice, or carbonated beverages. Patients should be advised to avoid or limit consumption of alcohol and to avoid activities requiring mental alertness such as driving or operating hazardous machinery until they know how the medication affects them. Food and beverages that may contain caffeine or theophylline such as colas, chocolate, coffee, tea, or energy drinks should also be avoided during treatment with stiripentol.