Viloxazine increased plasma levels of phenytoin by an average of 37%. It also was known to significantly increase plasma levels of theophylline and decrease its clearance from the body, sometimes resulting in accidental overdose of theophylline.
Mechanism of action
Viloxazine, like imipramine, inhibited norepinephrine reuptake in the hearts of rats and mice; unlike imipramine, it did not block reuptake of norepinephrine in either the medullae or the hypothalami of rats. As for serotonin, while its reuptake inhibition was comparable to that of desipramine, viloxazine did potentiate serotonin-mediated brain functions in a manner similar to amitriptyline and imipramine, which are relatively potent inhibitors of serotonin reuptake. Unlike any of the other drugs tested, it did not exhibit any anticholinergic effects. It was also found to up-regulate GABAB receptors in the frontal cortex of rats.
Viloxazine was discovered by scientists at Imperial Chemical Industries when they recognized that some beta blockers inhibited serotonin reuptake inhibitor activity in the brain at high doses. To improve the ability of their compounds to cross the blood brain barrier, they changed the ethanolamineside chain of beta blockers to a morpholine ring, leading to the synthesis of viloxazine. The drug was first marketed in 1976. It was never approved by the FDA, but the FDA granted it an orphan designation for cataplexy and narcolepsy in 1984. It was withdrawn from markets worldwide in 2002 for business reasons. As of 2015, Supernus Pharmaceuticals was developing formulations of viloxazine as a treatment for ADHD and major depressive disorder under the names SPN-809 and SPN-812.
Research
Viloxazine has undergone two randomized controlled trials for nocturnal enuresis in children, both of those times versus imipramine. By 1990, it was seen as a less cardiotoxic alternative to imipramine, and to be especially effective in heavy sleepers. In narcolepsy, viloxazine has been shown to suppress auxiliary symptoms such as cataplexy and also abnormal sleep-onset REM without really improving daytime somnolence. In a cross-over trial viloxazine significantly reduced EDS and cataplexy. Viloxazine has also been studied for the treatment of alcoholism, with some success. While viloxazine may have been effective in clinical depression, it did relatively poorly in a double-blind randomized controlled trial versus amisulpride in the treatment of dysthymia. A long-acting version of the drug is also under investigation as a treatment for attention deficit hyperactivity disorder.
