Brand name: Qelbree
Drug class: Central Nervous System Agents, Miscellaneous
Chemical name: (2R)-2-[(2-ethoxyphenoxy)methyl]morpholine;(2S)-2-[(2-ethoxyphenoxy)methyl]morpholine;dihydrochloride
Molecular formula: C26H40Cl2N2O6
Suicidal Thoughts and Behaviors:
In clinical trials, higher rates of suicidal thoughts and behavior were reported in pediatric patients treated with viloxazine hydrochloride than in patients treated with placebo. Closely monitor for worsening and emergence of suicidal thoughts and behaviors.
See full prescribing information for complete boxed warning.
Viloxazine hydrochloride, a selective norepinephrine reuptake inhibitor, is a CNS agent.
Uses for Viloxazine
Viloxazine hydrochloride has the following uses:
Viloxazine hydrochloride is a selective norepinephrine reuptake inhibitor indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in pediatric patients 6 to 17 years of age.
Viloxazine Dosage and Administration
Viloxazine hydrochloride is available in the following dosage form(s) and strength(s):
Extended-release capsules: 100 mg, 150 mg, and 200 mg.
It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:
Capsules may be swallowed whole or opened and entire contents sprinkled onto a teaspoonful of applesauce. If sprinkled on applesauce, consume within 2 hours without chewing.
Pediatric patients 6 to 11 years of age: Recommended starting dosage is 100 mg orally once daily. May titrate in increments of 100 mg at weekly intervals to the maximum recommended dosage of 400 mg once daily, depending on response and tolerability.
Pediatric patients 12 to 17 years of age: Recommended starting dosage is 200 mg orally once daily. After 1 week, may titrate by an increment of 200 mg to the maximum recommended dosage of 400 mg once daily, depending on response and tolerability.
Severe renal impairment (eGFR <30 mL/min/1.73m2): Initial dosage is 100 mg orally once daily. May titrate in weekly increments of 50–100 mg once daily to a maximum recommended dosage of 200 mg once daily.
Cautions for Viloxazine
Concomitant administration of monoamine oxidase inhibitors (MAOI), or within 14 days after discontinuing an MAOI.
Concomitant administration of sensitive CYP1A2 substrates or CYP1A2 substrates with a narrow therapeutic range.
Suicidal Thoughts and Behaviors
In clinical studies, higher rates of suicidal thoughts and behavior were reported in pediatric patients with ADHD treated with viloxazine hydrochloride than in patients treated with placebo. Among 1019 patients exposed to viloxazine hydrochloride 100 mg to 400 mg in short-term trials, a total of nine patients (0.9%) reported suicidal ideation (N=6), behavior (N=1), or both (N=2). Eight patients reported suicidal ideation or behavior on the Columbia Suicide Severity Rating Scale (C-SSRS), a validated scale that assesses suicide risk. An additional patient treated with viloxazine hydrochloride reported suicidal behavior during the clinical trials, but did not report it on the C-SSRS. Among 463 patients treated with placebo in these studies, two patients (0.4%) reported suicidal ideation on the C-SSRS. No patients treated with placebo reported suicidal behavior. No completed suicides occurred in these trials.
Patients treated with viloxazine hydrochloride had higher rates of insomnia and irritability. Although a causal link between the emergence of such symptoms and the emergence of suicidal impulses has not been established, there is a concern that these and other symptoms such as depressed mood, anxiety, agitation, akathisia, mania, hypomania, panic attacks, impulsive behavior, and aggression may represent precursors to emerging suicidal ideation or behavior. Thus, patients being treated with viloxazine hydrochloride should be observed for the emergence of such symptoms.
Closely monitor all viloxazine hydrochloride-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Consider changing the therapeutic regimen, including possibly discontinuing viloxazine hydrochloride, in patients who are experiencing emergent suicidal thoughts and behaviors or symptoms that might be precursors to emerging suicidal ideation or behavior, especially if these symptoms are severe or abrupt in onset, or were not part of the patient's presenting symptoms. Advise family members or caregivers of patients to monitor for the emergence of suicidal ideation or behavior, and to report such symptoms immediately to the healthcare provider.
Blood Pressure and Heart Rate Increases
Viloxazine hydrochloride can cause an increase in heart rate and diastolic blood pressure.
In a clinical study in patients 6 to 11 years of age, 34/154 (22%) of patients treated with viloxazine hydrochloride 100 mg daily had a ≥20 beat per minute (bpm) increase in heart rate at any time point in the clinical trial, compared to 15/159 (9%) of patients who received placebo. This finding was observed in 84/268 (31%) who received the 200 mg daily dosage, compared to 39/262 (15%) of patients in the placebo group, and in 28/100 (28%) of patients who received the 400 mg daily dosage, compared to 24/103 (23%) of patients who received placebo.
In a clinical study in patients 12 to 17 years of age, 22/99 (22%) of patients treated with viloxazine hydrochloride 200 mg daily had a ≥20 bpm increase in heart rate at any time point in the clinical trial, compared to 15/104 (14%) of patients who received placebo. This finding was observed in 69/205 (34%) who received the 400 mg daily dosage, compared to 35/201 (17%) of patients in the placebo group. In patients 12 to 17 years of age, 52/205 (25%) of patients treated with viloxazine hydrochloride 400 mg daily had a ≥15 mmHg increase in diastolic blood pressure at any time in the clinical trial, compared to 26/201 (13%) of patients in the placebo group.
Assess heart rate and blood pressure prior to initiating treatment with viloxazine hydrochloride, following increases in dosage, and periodically while on therapy.
Activation of Mania or Hypomania
Noradrenergic drugs, such as viloxazine hydrochloride, may induce a manic or mixed episode in patients with bipolar disorder. Prior to initiating treatment with viloxazine hydrochloride, screen patients to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a personal or family history of suicide, bipolar disorder, and depression.
Somnolence and Fatigue
Viloxazine hydrochloride can cause somnolence and fatigue. In the short-term, placebo-controlled clinical trials in pediatric patients with ADHD, somnolence (including lethargy and sedation) was reported in 16% of viloxazine hydrochloride-treated patients compared to 4% of placebo-treated patients. Fatigue was reported in 6% of viloxazine hydrochloride-treated patients, compared to 2% of placebo-treated patients.
Patients should not perform activities requiring mental alertness, such as operating a motor vehicle or operating hazardous machinery until they know how they will be affected by viloxazine hydrochloride.
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to viloxazine hydrochloride during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 866-961-2388 or visiting online at [Web].
Risk Summary: Based on findings from animal reproduction studies, viloxazine may cause maternal harm when used during pregnancy. Discontinue viloxazine hydrochloride when pregnancy is recognized unless the benefits of therapy outweigh the potential risk to the mother. Available data from case series with viloxazine use in pregnant women are insufficient to determine a drug-associated risk of major birth defects, miscarriage, or adverse maternal outcomes.
In animal reproduction studies, oral administration of viloxazine to pregnant rats and rabbits during the period of organogenesis did not cause significant maternal toxicity, but caused fetal toxicities and delayed fetal development in the rat at doses up to 2 times the maximum recommended human dose (MRHD) of 400 mg, based on mg/m2. In the rabbit, viloxazine caused maternal toxicity without significant fetal toxicity at doses ≥7 times the MRHD based on mg/m2. The no observed adverse effect levels (NOAELs) for fetal toxicity are approximately equal to and 11 times the MRHD, based on mg/m2 in the rat and rabbit, respectively. Oral administration of viloxazine to pregnant rats and mice during pregnancy and lactation caused maternal toxicities and deaths at doses approximately 2 and 1 time the MRHD, based on mg/m 2, respectively. At these maternally toxic doses, viloxazine caused offspring toxicities. The NOAEL for maternal and developmental toxicity is approximately equal to or less than the MRHD, based on mg/m2, in the rat and mouse, respectively.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Animal Data: Viloxazine was administered orally to pregnant rats during the period of organogenesis at doses of 13, 33, and 82 mg/kg/day, which are less than, equal to, and 2 times the MRHD of 400 mg, based on mg/m2, respectively. Viloxazine did not cause maternal toxicity at doses up to 82 mg/kg/day. Viloxazine at 82 mg/kg/day increased early and late resorption, delayed fetal development, and possibly caused low incidences of fetal malformations or anomalies (craniorachischisis, missing cervical vertebrae, and morphological changes associated with hydranencephaly). The NOAEL for fetal toxicity and malformation is 33 mg/kg/day, which is approximately equal to the MRHD, based on mg/m2.
Viloxazine was administered orally to pregnant rabbits during the period of organogenesis at doses of 43, 87, and 130 mg/kg/day, which are approximately 4, 7, and 11 times the MRHD of 400 mg, based on mg/m2, respectively. Viloxazine decreased maternal body weight, weight gain, or food consumption at doses ≥87 mg/kg/day but did not cause fetal toxicity at doses up to 130 mg/kg/day. The NOAELs for maternal and fetal toxicity is 43 and 130 mg/kg/day, respectively, which is approximately 4 and 11 times the MRHD, based on mg/m2, respectively.
Viloxazine was administered orally to pregnant rats during gestation and lactation at doses of 43, 87, and 217 mg/kg/day, which are approximately 1, 2, and 5 times the MRHD of 400 mg, based on mg/m2, respectively. Viloxazine caused maternal toxicity of decreased body weight, weight gain, and food consumption at doses ≥87 mg/kg/day and maternal deaths near term at 217 mg/kg/day. At these maternally toxic doses, viloxazine caused lower live birth, decreased viability, and delayed growth and sexual maturation without affecting learning and memory in the offspring. The NOAEL for maternal and developmental toxicity is 43 mg/kg/day, which is approximately equal to the MRHD, based on mg/m2.
Viloxazine was administered orally to pregnant mice during gestation and lactation at doses of 13, 33, and 82 mg/kg/day, which are approximately less than or equal to the MRHD of 400 mg, based on mg/m2, respectively. Viloxazine treatment at 82 mg/kg/day during the gestation period caused maternal deaths and decreased body weight in the offspring. The NOAEL for both maternal and developmental toxicity is 33 mg/kg/day, which is less than the MRHD, based on mg/m2.
Risk Summary: There are no data on the presence of viloxazine in human milk, the effects on the breast-fed infant, or the effects on milk production. Viloxazine is likely present in rat milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk.
The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for viloxazine hydrochloride and any potential adverse effects on the breast-fed child from viloxazine hydrochloride or from the underlying maternal condition.
The safety and effectiveness of viloxazine hydrochloride in pediatric patients 6 to 17 years of age with ADHD have been established based on randomized, placebo-controlled studies in pediatric patients.
The safety and effectiveness of viloxazine hydrochloride have not been established in pediatric patients younger than 6 years old.
Patients treated with viloxazine hydrochloride should be monitored for suicidal thoughts and behavior, and for changes in weight.
Juvenile Animal Toxicity Data: Viloxazine was administered orally to juvenile rats from postnatal day (PND) 23 through PND 79 at doses of 43, 130, and 217 mg/kg/day, which are approximately 1, 2, and 3 times the MRHD of 400 mg, based on mg/m2 in children, respectively. Viloxazine decreased body weight, weight gain, and food consumption in both sexes at 217 mg/kg/day. Sexual maturation, reproductive capacity, and learning and memory were not affected. The NOAEL for juvenile toxicity is 130 mg/kg/day, which is approximately 2 times the MRHD, based on mg/m2 in children.
Clinical trials of viloxazine hydrochloride in the treatment of ADHD did not include sufficient numbers of patients aged 65 and older to determine whether or not they respond differently from younger patients.
Dosage reduction is recommended in patients with severe (eGFR of <30 mL/min/1.73m2 [MDRD]) renal impairment.
No dosage adjustment of viloxazine hydrochloride is recommended in patients with mild to moderate (eGFR of 30 to 89 mL/min/1.73m2 [MDRD]) renal impairment.
The exposure of viloxazine increases in patients with renal impairment.
The effect of hepatic impairment on the pharmacokinetics of viloxazine is unknown Viloxazine hydrochloride is not recommended in patients with hepatic impairment.
Common Adverse Effects
Most commonly observed adverse reactions (≥5% and at least twice the rate of placebo) were: somnolence, decreased appetite, fatigue, nausea, vomiting, insomnia, and irritability.
It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:
Moderate sensitive CYP1A2 substrates: Not recommended for coadministration with viloxazine hydrochloride. Dose reduction may be warranted.
Mechanism of Action
The mechanism of action of viloxazine in the treatment of ADHD is unclear; however, it is thought to be through inhibiting the reuptake of norepinephrine.
Advice to Patients
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Suicidal Thoughts and Behaviors
Advise patients and caregivers to monitor for the emergence of suicidal thoughts or behaviors or symptoms that might be precursors to emerging suicidal ideation or behavior, especially early during treatment and when the dosage is adjusted up or down. Instruct patients and caregivers to report such symptoms to the healthcare provider.
Concomitant Use with Monoamine Oxidase Inhibitors (MAOI)
Caution patients about the concomitant use of viloxazine hydrochloride and monoamine oxidase inhibitors (MAOI), or within 14 days after discontinuing an MAOI, because of an increased risk of hypertensive crisis.
Blood Pressure and Heart Rate Increases
Instruct patients that viloxazine hydrochloride can cause elevations of their blood pressure and pulse rate and they should be monitored for such effects.
Activation of Mania/Hypomania
Advise patients and their caregivers to look for signs of activation of mania/hypomania.
Somnolence and Fatigue
Advise patients about the potential for somnolence (including sedation and lethargy) and fatigue. Advise patients to use caution when performing activities requiring mental alertness, such as driving a motor vehicle or operating hazardous machinery, until they know how they will be affected by viloxazine hydrochloride.
Effects on Weight
Advise patients and their caregivers that viloxazine hydrochloride may affect weight and that weight should be monitored while using viloxazine hydrochloride
Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to viloxazine hydrochloride during pregnancy. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy and to discuss if viloxazine hydrochloride should be discontinued.
Advise patients to take the capsule whole or sprinkled on a teaspoonful of applesauce and consume within 2 hours. Do not cut, chew, or crush the capsule.
AHFSfirstRelease™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Capsule, Extended Release
AHFS Drug Information. © Copyright 2023, Selected Revisions May 10, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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