Continuing Education Activity
Viloxazine was marketed as an antidepressant as an immediate-release formulation in Europe for over two decades before being proposed as a potential treatment for patients with ADHD (attention deficit hyperactivity disorder). In 1971, viloxazine was first endorsed in the United Kingdom before being recognized by numerous other nations as an antidepressant. In April of 2021, the United States Food and Drug Administration (FDA) approved the use of viloxazine in children and adolescents with ADHD, specifically viloxazine extended-release capsules. This activity summarizes the indications, administration, doses, contraindications, activity, adverse events, and other critical elements of viloxazine therapy in the clinical setting related to the crucial points required by members of an interprofessional team managing the care of patients with ADHD.
- Describe the mechanism of action of viloxazine extended-release as an FDA-approved non-stimulant alternative in the treatment of ADHD.
- Explain the indications for extended-release viloxazine therapy.
- Review the potential adverse events associate4d with viloxazine therapy.
- Summarize the necessary monitoring for specific populations on viloxazine therapy.
Viloxazine was first discovered when scientists tried to synthesize compounds with propranolol-like structures with CNS modulating properties. The S stereoisomer is ten times as potent as the R stereoisomer.
The history of viloxazine began in 1970 when it was first marketed to adults in Europe and the United Kingdom in an immediate-release formulation as an antidepressant medication used to treat depression. Viloxazine has since been reformulated as an extended-release formula. Most recently, the drug has received FDA approval for use in the pediatric population between the ages of 6 to 17 to treat attention deficit hyperactive disorder (ADHD).
The exact mechanism of action of viloxazine is unclear, but research suggests it may behave as a serotonin-norepinephrine modulating agent. In addition to norepinephrine transport inhibition, viloxazine has been shown to increase 5HT levels in the prefrontal cortex. Specifically, it behaves as an agonist at the 5HT2C receptor and antagonist at the 5HT2B receptor.
Viloxazine was shown to have some epileptogenic properties in some patients. Caution should be used when prescribing to patients with a history of seizures or neurological disorders. Numerous studies have shown the lack of anticholinergic side effects in viloxazine compared to other tricyclic antidepressants. Lack of anticholinergic side effects makes this a possible candidate for treating depression in elderly populations. However, it does not have FDA approval for that indication in the USA. It also has no adult indications approved by the FDA.
This article focuses on the FDA-approved extended-release formulation, which was approved by the FDA for ADHD therapy in April of 2021.
Mechanism of Action
Research suggests the mechanism of action of viloxazine seems to be closely related to the reuptake inhibition of norepinephrine. However, viloxazine does not affect the release of norepinephrine. Studies have shown viloxazine can inhibit norepinephrine transport and increase norepinephrine levels in the amygdala, nucleus accumbens, and prefrontal cortex via reuptake inhibition. Viloxazine has also been shown to moderately increase dopamine levels in the prefrontal cortex, amygdala, and very little in the nucleus accumbens. This appears to result from the norepinephrine transporter, which is also responsible for dopamine reuptake. Because viloxazine has very little effect on dopamine transmission in the nucleus accumbens, it may have a low potential for abuse compared to other drugs currently used to treat ADHD.
Increased dopamine activity in the D1 pathway in the nucleus accumbens has been linked to pathways related to addiction. Some early studies involving the self-administering of viloxazine to rhesus monkeys showed poor reinforcement and no physical drug dependence showing the addictive potential of the drug is low. Studies also reveal viloxazine may be a weak inhibitor of adrenergic alpha and adrenergic beta receptors.
Early studies of viloxazine also suggest that it does not inhibit serotonin uptake in the brain and platelets. However, some other studies have shown increased serotonin release from rat neuronal slices after exposure to viloxazine.
Viloxazine did, however, increase the brain's sensitivity to serotonin resulting in 5-hydroxytryptophan, induced hind limb extensor reflex, and 5-hydroxytryptophan induced behavioral symptoms. These may be results of increased serotonin receptor activation. Studies performed in vivo demonstrated that viloxazine could also boost serotonin levels in the amygdala, nucleus accumbens, and prefrontal cortex, respectively. Some other suggested mechanisms of viloxazine include weak antagonism at the 5HT7 receptor, 5HT2C receptors, and the 5HT2B receptor. Antagonism of the 5HT2B GABA interneurons removes inhibition of inhibitory neurons, ultimately leading to increased serotonin levels in the prefrontal cortex.
Finally, unlike other antidepressants, viloxazine has weak inhibition at H1 and H2 histamine receptors, M1-M4 muscarinic receptors, very little cholinergic activity, and weak inhibition of both MAO-A and B. The ability of viloxazine to increase serotonin levels in the brain may also contribute to its antidepressive effects. This may be why it was used as an antidepressant therapy in Europe in an immediate-release formulation during the early 1970s.
Viloxazine's once-daily extended-release formula has been approved to treat ADHD in children ages 6 to 17. This formulation can be taken orally and is available in 100 mg, 150 mg, and 200 mg formulations. Viloxazine tablets can be taken as a whole orally or opened and poured over applesauce as long as it is eaten within 2 hours.
In patients between the age of 6 to 11, the suggested dose is 100 mg PO daily. If needed, this dosage can be increased by 100 mg weekly until a maximum dose of 400 mg is reached.
In patients between the ages of 12 to 17, the suggested dose is 200 mg PO daily. This dose can be increased after a week to 200 mg daily for a maximum dose of 400 mg.
In patients with severe kidney disease (eGFR <30 ml/min/1.73 m^2), dosing should begin at 100 mg daily and can be increased by 50 to 100 mg until reaching a maximum dose of 200 mg.
Viloxazine is a relatively safe drug. One case study showed that overdoses of viloxazine from 100 mg to 4 g showed less severe adverse effects compared to arrhythmias and QT prolongations normally seen in tricyclic antidepressants or Monoamine oxidase inhibitors overdose. The most severe adverse effect of viloxazine overdose was convulsing seizures, one seizure with extrapyramidal symptoms, loss of consciousness, and CNS depression.
In a 5-week double-blind study, 50 mg of viloxazine sustained-release three times daily compared to imipramine 50 mg single dose was given to patients suffering from depression. Both groups reported significant improvement in depressive symptoms using the Beck and Hamilton rating scores with no significant statistical difference. After the first week, doses of the drug were doubled, and patients were followed up for four weeks. Modest to major drug intolerance was seen with viloxazine but not imipramine. Of note, weight loss was noted with the group given viloxazine, but weight gain was seen with those on imipramine. In clinical studies, higher rates of suicidal ideation and behavior were seen in pediatric patients taking viloxazine versus a placebo.
Viloxazine has been shown to be metabolized by the hepatic enzyme CYP2D6. One study was performed to investigate if there were any interactions between viloxazine and paroxetine, a CYP2D6 inhibitor. The study reported no severe drug interactions or adverse effects when both drugs were co-administered.
Viloxazine is metabolized by the CYP1A2 enzyme. Care is necessary when it is co-administered with other drugs metabolized by this enzyme. For example, one study examined the effects of viloxazine on plasma levels of phenytoin and found significant increases. Other drugs contraindicated with viloxazine include linezolid, duloxetine, and MAO-inhibitors, among others.
In one study, a small percentage of children who were being treated with viloxazine for ADHD versus a placebo reported suicidal ideation in addition to anxiety, irritability, mania, aggression, panic attacks, and impulsive behavior. Children should be monitored for these adverse effects during treatment. Viloxazine should not be prescribed alongside another MOAI or within two weeks after stopping an MAOI.
In addition, the drug affects norepinephrine levels in the brain, increases diastolic blood pressure and heart rate, and can stimulate manic episodes in patients who have previously been diagnosed with bipolar disorders. The clinical study also shows that viloxazine induces nausea, vomiting, and drowsiness. Patients operating heavy machinery or driving a vehicle should exercise caution before performing these duties while taking viloxazine.
Finally, pregnant patients or those trying to become g pregnant should discontinue viloxazine. In animal studies, viloxazine resulted in fetus injury and poor development in the rat model at 400 mg. In another rabbit model, viloxazine caused maternal injury with fetal injury at seven times the maximum human dosage of 400 mg. Administration of viloxazine orally to pregnant and lactating mice caused maternal injury and death at 1 and 2 times the maximum human dosage of 400 mg. These dosages can lead to fetal injury.
Since the drug is primarily renally excreted, patients should undergo diuresis to eliminate as much of the drug as possible.
Even though viloxazine intoxication is extremely rare, close monitoring is necessary for children during treatment, as most of the viloxazine studies reported significant adverse side effects in ADHD children. Moreover, higher rates of suicidal ideation and behavior were seen in pediatric patients taking viloxazine versus a placebo. Therefore, closed monitoring is imperative in children who have been prescribed the medication.
There is no established therapeutic index of viloxazine in humans. However, studies show that safety dosage has been defined. Viloxazine can be safely administered and increased up to a maximum of 400 mg for two weeks. In patients with renal failure, the dosage can be increased up to a maximum of 200 mg.
Viloxazine is a relatively safe drug at daily doses between 50 mg to 400 mg with no adverse effects other than mild GI discomfort. In the last few decades, very few cases of viloxazine toxicity have been reported. There have not been any reported severe toxicity cases with viloxazine. One report showed viloxazine overdose in 12 patients. However, all 12 of these patients had no EKG abnormalities.
In addition, the literature confirms that viloxazine exhibits significantly fewer side effects compared to other antidepressants. One study administered various doses from 100 mg to 4 g of viloxazine to patients and monitored them for complications. As a result, no deaths occurred. The only complications were transitory loss of consciousness and two cases of convulsive seizures.
Enhancing Healthcare Team Outcomes
Viloxazine intoxication cases are rare and happen mostly in the psychiatric patient population, and the cases could be either accidental or intentional. Given that the demographic of patients prescribed anti-depressants is at high risk for overdose suicide, improved communication is needed between healthcare providers and family members to provide the appropriate dosage and monitoring information to patients. Also, patients should always consult with their primary doctor before taking viloxazine.
Viloxazine is a generally safe medication that can be obtained by prescription. Primary care clinicians and psychiatrists may act as frontline resources and provide patients with proper dosage and safety information. Other specialists and health care professionals, including nurses and pharmacists, can monitor and report any adverse medication events to the prescriber. Appropriate cooperation between all interprofessional team members is essential to ensure the patient receives the most effective care and optimal benefits from viloxazine, resulting in optimal outcomes with fewer adverse events.