Viloxazine

Mechanism of Action

Research indicates that the mechanism of action of viloxazine is closely associated with inhibiting the reuptake of norepinephrine. However, it is noteworthy that viloxazine does not affect the release of norepinephrine. Studies have demonstrated that viloxazine can effectively inhibit norepinephrine transport, leading to increased norepinephrine levels in the amygdala, nucleus accumbens, and prefrontal cortex through reuptake inhibition. Furthermore, viloxazine has been found to moderately increase dopamine levels in the prefrontal cortex, amygdala, and, to a lesser extent, in the nucleus accumbens. This phenomenon is attributed to the norepinephrine transporter, which is also responsible for dopamine reuptake. Owing to its minimal impact on dopamine transmission in the nucleus accumbens, viloxazine may have a lower potential for misuse than other drugs currently used to treat ADHD.[1] Notably, the (S) stereoisomer of viloxazine exhibits 10 times greater potency than the (R) stereoisomer.[6]

Increased dopamine activity in the D1 pathway within the nucleus accumbens has been associated with addiction-related pathways. In early studies involving the self-administration of viloxazine to rhesus monkeys, the drug exhibited poor reinforcement and showed no physical drug dependence, indicating a low addictive potential.[3] Furthermore, studies revealed that viloxazine might be a weak inhibitor of adrenergic alpha and beta receptors.[1]

Early studies of viloxazine also suggest that the drug 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.[1]

Conversely, Viloxazine enhanced the brain's sensitivity to serotonin, leading to increased 5-hydroxytryptophan levels, heightened hind limb extensor reflex, and intensified 5-hydroxytryptophan-induced behavioral symptoms. These effects are likely due to increased serotonin receptor activation. In vivo studies have revealed that viloxazine can increase serotonin levels in the amygdala, nucleus accumbens, and prefrontal cortex. Furthermore, some suggested mechanisms of viloxazine include weak antagonism at the 5HT7, 5HT2C, and 5HT2B receptors. The antagonism of the 5HT2B gamma-aminobutyric acid (GABA) interneurons moderates the function of inhibitory neurons, ultimately resulting in increased serotonin levels in the prefrontal cortex.[7]

Finally, unlike other antidepressants, viloxazine exhibits low inhibition levels at H1 and H2 histamine receptors and M1-M4 muscarinic receptors. In addition, the drug displays low levels of cholinergic activity and slight inhibition of monoamine oxidases (MAO) A and B. The ability of viloxazine to increase serotonin levels in the brain may also contribute to its antidepressive effects. These properties also facilitate the utilization of viloxazine as an antidepressant therapy in Europe, particularly for its immediate-release formulation, which was popular during the early 1970s.[3]

Administration

Viloxazine's extended-release formula, approved to treat ADHD in children aged 6 to 17 and adults, is administered once daily.[8] This formulation is available in 100 mg, 150 mg, and 200 mg extended-release capsules, which can be administered orally. Viloxazine tablets can be administered orally, either whole or by opening and sprinkling them over applesauce, as long as they are consumed within 2 hours. However, it is crucial not to crush or chew the capsule contents, as this would compromise the extended-release mechanism of the medication.[8]

Adult Dosage

For ADHD treatment, the recommended adult dosage of viloxazine is mentioned below.

•  Adult dosage ranges from 200 to 600 mg orally per day. 
  • Doctors recommend starting the medication with a daily dose of 200 mg and gradually increasing it each week by 200 mg until a maximum dosage of 600 mg per day is reached. 

Pediatric Dosage

For ADHD treatment, the recommended pediatric dosage of viloxazine is mentioned below.

• In patients between the ages of 6 and 11: The dosage ranges from 100 to 400 mg orally daily.
  • Doctors recommend starting the medication with a daily dose of 100 mg and gradually increasing it each week by 100 mg until a maximum dosage of 400 mg per day is reached.
• In patients between the ages of 12 and 17: The dosage ranges from 200 to 400 mg orally daily.
  • Doctors recommend starting the medication with a daily dose of 200 mg and gradually increasing it after a week until a maximum dosage of 400 mg per day is reached.

Specific Patient Population

Pregnant patients: Clinicians must carefully consider the risks versus benefits of viloxazine therapy during pregnancy. Currently, the available data from human studies is limited regarding the effects of viloxazine on pregnant patients. Some conflicting studies suggest a potential risk of fetal toxicity based on animal studies. If the therapy is continued, patients should be enrolled in the National Registry for Psychiatric Medications for monitoring and further assessment.

Breastfeeding considerations: Clinicians should carefully evaluate the risks versus benefits of breastfeeding while on viloxazine therapy. Currently, there is insufficient human research data available on the effects of viloxazine on infants or milk production to determine any potential risks associated with its use. There is a possibility that viloxazine may be secreted in breast milk based on its drug properties.

Renal impairment: For patients with severe kidney disease (estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m²), doctors recommend starting the medication with an initial daily dose of 100 mg and gradually increasing it by 50 to 100 mg each subsequent week until a maximum dosage of 200 mg per day is reached.[9]

Hepatic impairment: There is currently no defined dosing regimen for viloxazine in patients with hepatic impairment.

Older patients: For patients with advanced age, refer to the renal impairment dosing guidelines for appropriate dosage adjustments.

Adverse Effects

Viloxazine is considered a relatively safe drug. A case study demonstrated that overdoses of viloxazine ranging from 100 mg to 4 g resulted in fewer severe adverse effects, particularly related to arrhythmias and QT prolongations, than tricyclic antidepressants or MAO inhibitor overdoses. The most significant adverse effect observed in viloxazine overdose was convulsing seizures, with one case reporting extrapyramidal symptoms, loss of consciousness, and CNS depression.

In a 5-week double-blind study, 2 groups of patients suffering from depression were administered either 50 mg of viloxazine sustained-release 3 times daily or a single dose of 50 mg imipramine, respectively. Both groups reported significant improvement in depressive symptoms, as evidenced by the Beck and Hamilton rating scores, with no statistically significant difference between them. The drug dosages were increased after the initial week, and the patients were monitored for the following 4 weeks. During this period, viloxazine exhibited modest-to-significant drug intolerance, whereas imipramine did not show similar issues. Notably, the group receiving viloxazine experienced a weight reduction, whereas the group taking imipramine experienced a weight gain.[10] In addition, in clinical studies, pediatric patients taking viloxazine exhibited higher rates of suicidal ideation and behavior compared to those on a placebo.[1]

Severe adverse reactions, including suicidality and mania, have been reported in individuals using viloxazine.

Common reactions to viloxazine include increased heart rate and blood pressure, insomnia, somnolence, nausea, anorexia, abdominal pain, vomiting, constipation, gastroesophageal reflux disease (GERD), and weight loss with long-term use.

Contraindications

Viloxazine undergoes metabolism by the hepatic enzyme CYP2D6. A study investigated potential interactions between viloxazine and paroxetine, a CYP2D6 inhibitor. The study results revealed no severe drug interactions or adverse effects when both drugs were coadministered.[11]

The CYP1A2 enzyme also metabolizes viloxazine. Caution should be exercised when coadministering viloxazine with other drugs metabolized by CYP1A2.[8][11] For instance, a study examined the effects of viloxazine on plasma levels of phenytoin, and the results revealed significant increases in serum phenytoin concentrations.[12] Viloxazine should not be used concomitantly with other drugs such as linezolid, duloxetine, and MAO inhibitors. This is not an exhaustive list; therefore, it is essential to refer to the package insert for a complete list of contraindicated medications.

A small study comprising 2 groups of individuals compared the effects of viloxazine on children with ADHD to those who received a placebo. The study results revealed that the group treated with viloxazine reported several negative symptoms, including suicidal thoughts, anxiety, irritability, aggression, panic attacks, and impulsive behavior.[8] Children should be monitored for these adverse effects during viloxazine treatment. Moreover, it is essential to avoid prescribing viloxazine alongside another MAO inhibitor or within 2 weeks after discontinuing an MAO inhibitor to mitigate the risk of serotonin syndrome. 

Furthermore, viloxazine may lead to increased diastolic blood pressure and heart rate due to its impact on norepinephrine levels in the brain. As a result, patients with hypertension or tachycardia should be carefully considered for alternative therapy options. Viloxazine has the potential to trigger manic episodes in patients with a history of bipolar disorders. Clinical studies have also demonstrated that viloxazine may induce nausea, vomiting, and drowsiness. Patients operating heavy machinery or driving vehicles should exercise caution and be mindful of these effects while on viloxazine therapy.[13]

Box Warning

Studies have indicated a higher rate of suicidality in pediatric patients treated for ADHD with viloxazine compared to those on a placebo. As a result, children receiving this drug require close monitoring for any signs of clinical deterioration and suicidality. Healthcare professionals must counsel families and caregivers of patients about the potential risk associated with viloxazine, emphasizing the importance of promptly communicating any changes or concerns regarding patients' behavior to the prescribing clinician.

Monitoring

Serum creatinine levels should be measured at baseline. In addition, blood pressure and heart rate should be recorded at baseline, following dosage increases, and periodically thereafter.

Although viloxazine intoxication is uncommon, children should be closely monitored during treatment, as several studies have reported significant adverse effects in children with ADHD. (Refer to the Box Warning above.) This monitoring should be especially vigilant following therapy initiation or dose changes.[14][15]

Toxicity

Research conducted when the drug was first introduced recommended gastric lavage as a measure for toxic ingestion of viloxazine. However, as viloxazine is rapidly absorbed in the body, to counter the effects of the drug effectively, it is important to administer the procedure promptly after ingestion. As viloxazine is primarily eliminated through the kidneys, patients should undergo diuresis to enhance the elimination of the drug as much as possible.[16]

There is no established therapeutic index of viloxazine in humans. However, clinical studies have determined safe dosage ranges. Viloxazine is generally considered a safe drug when administered within 50 to 600 mg daily, with minimal adverse effects observed, primarily limited to mild gastrointestinal discomfort. Over the last few decades, very few cases of viloxazine toxicity have been reported, and there have been no instances of severe toxicity. Although a report described 12 cases of viloxazine overdoses, none of the patients exhibited ECG abnormalities.[17]

Furthermore, the literature confirms that viloxazine demonstrates significantly fewer adverse effects than other antidepressants. No deaths were reported in a study where patients were administered various doses of viloxazine ranging from 100 mg to 4 g. The only observed complications included transitory loss of consciousness and 2 cases of convulsive seizures.[18]

Enhancing Healthcare Team Outcomes

Viloxazine is generally considered a safe medication that can be prescribed to treat ADHD in adults and children 6 or older. Primary care physicians, advanced practice practitioners, and psychiatrists are among the healthcare professionals who typically prescribe this drug. However, they should coordinate their decision to initiate therapy with other interprofessional healthcare team members only after thoroughly evaluating the patient and determining that viloxazine is an appropriate treatment option for them.

All members of the interprofessional healthcare team play a crucial role as frontline resources, providing patients with accurate dosage and safety information and addressing any questions about their medication regimen. This includes nursing staff and pharmacists, who are vital in monitoring and reporting any signs of adverse events to the prescriber. They also work closely with the patient, parents, and caregivers to address potential suicidality risks, particularly in children. Furthermore, pharmacists conduct medication reconciliation to identify and prevent possible drug-drug interactions. 

Interprofessional cooperation, open communication, and shared decision-making among the healthcare team are essential to ensure comprehensive patient care and maximize the benefits of viloxazine, resulting in favorable treatment outcomes with minimal adverse events.