The FDA has issued a complete response letter (CRL) in reply to a supplemental new drug application requesting permission to include new data in the clinical trials section of the U.S. label of vortioxetine (Brintellix, Takeda/Lundbeck) for treating certain aspects of cognitive dysfunction in adults with major depressive disorder (MDD). The FDA approved vortioxetine in September 2013 for the treatment of MDD in adults. The CRL does not apply to the use of vortioxetine in MDD.
Takeda Pharmaceuticals and H. Lundbeck expressed surprise at the decision, since the FDA’s Psychopharmacologic Drugs Advisory Committee (PDAC) voted 8 to 2 that the companies had presented substantial evidence to support a claim of effectiveness for vortioxetine in treating certain aspects of cognitive dysfunction in adults with MDD. The two companies are reviewing the contents of the letter with the FDA to determine the appropriate path forward.
The mechanism of the antidepressant effect of vortioxetine is not fully understood. It is an inhibitor of serotonin (5-HT) reuptake, and that is thought to be involved in its mechanism of action. It is also an agonist at 5-HT1A receptors, a partial agonist at 5-HT1B receptors, and an antagonist at 5-HT1D, 5-HT3, and 5-HT7 receptors. The contribution of each of these activities to the antidepressant effect of vortioxetine has not been established. While it is considered to be the only compound with this combination of pharmacodynamic activity, the clinical relevance of this is unknown.
The most commonly observed adverse events in MDD patients treated with vortioxetine in six- and eight-week placebo-controlled studies included nausea, constipation, and vomiting. Overall, 5% to 8% of the patients who received vortioxetine 5 to 20 mg per day in short-term trials discontinued treatment because of adverse events, the most common being nausea, compared with 4% of placebo-treated patients in these studies.
In clinical trials, vortioxetine had no significant effect on body weight, as measured by the mean change from baseline in six- and eight-week placebo-controlled studies. In the six-month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to vortioxetine during the initial 12-week, open-label phase, there was no significant effect on body weight in vortioxetine-treated patients compared with those given placebo. Vortioxetine has not been associated with clinically significant effects on vital signs, including systolic and diastolic blood pressure and heart rate, as measured in placebo-controlled studies.
Vortioxetine is available as 5-mg, 10-mg, and 20-mg tablets. The recommended starting dosage of vortioxetine is 10 mg once daily without regard to meals. The dosage should then be increased to 20 mg per day, as tolerated, because higher doses demonstrated better treatment effects in trials conducted in the U.S. A dosage reduction to 5 mg per day may be considered for patients who cannot tolerate higher doses.
Source: Takeda Pharmaceuticals U.S.A.; March 29, 2016.