Drug Interactions between Cymbalta and vemurafenib

MONITOR: Coadministration with inhibitors of CYP450 1A2 may increase the plasma concentrations of duloxetine, which is a substrate of the isoenzyme. In 14 male study subjects, coadministration with 100 mg fluvoxamine, a potent CYP450 1A2 inhibitor, resulted in a 2.5-fold increase in duloxetine peak plasma concentration (Cmax), a nearly 6-fold increase in duloxetine systemic exposure (AUC), and an approximately 3-fold increase in duloxetine half-life. The interaction has not been studied with less potent CYP450 1A2 inhibitors such as mexiletine, propafenone, and zileuton. Theoretically, high plasma levels of duloxetine may increase the risk of serious adverse effects such as hypertension, hypertensive crisis, increased heart rate, orthostatic hypotension, syncope, and serotonin syndrome. Serotonin syndrome is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. Symptoms may include mental status changes such as irritability, altered consciousness, confusion, hallucinations, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea.

MANAGEMENT: Caution is advised if duloxetine is used in combination with CYP450 1A2 inhibitors. Pharmacologic response to duloxetine should be monitored more closely whenever a CYP450 1A2 inhibitor is added to or withdrawn from therapy, and the dosage adjusted as necessary.

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