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  • CLASSES

    ADHD Agents, Non-stimulant

    BOXED WARNING

    Bipolar disorder, depression, mania, suicidal ideation

    In clinical trials, higher rates of suicidal ideation and behavior were reported in pediatric patients treated with viloxazine than in patients treated with placebo (0.9% vs. 0.4%). Closely monitor all viloxazine-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. Noradrenergic drugs, such as viloxazine, may also induce a manic or mixed episode in patients with bipolar disorder. Prior to initiating treatment with viloxazine, 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. Patients treated with viloxazine 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 depression, 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 should be observed for the emergence of such symptoms. Consider changing the therapeutic regimen, including possibly discontinuing viloxazine, 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 health care provider.

    DEA CLASS

    Rx

    DESCRIPTION

    Selective norepinephrine reuptake inhibitor
    Used in pediatric patients 6 to 17 years of age for attention deficit hyperactivity disorder (ADHD)
    Boxed Warning for risk of suicidal thoughts and behavior in this age group; particularly in early therapy or with dosage changes

    COMMON BRAND NAMES

    QELBREE

    HOW SUPPLIED

    QELBREE/Viloxazine Oral Cap ER: 100mg, 150mg, 200mg

    DOSAGE & INDICATIONS

    For the treatment of attention-deficit hyperactivity disorder (ADHD).
    Oral dosage
    Children and Adolescents 12 to 17 years

    200 mg PO once daily, initially. May titrate dosage after 1 week by 200 mg, depending on response and tolerability. Max: 400 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Pharmacological treatment of ADHD may be needed for extended periods. Periodically reevaluate long-term use of viloxazine and adjust dosage as needed.

    Children 6 to 11 years

    100 mg PO once daily, initially. May titrate dosage in 100 mg increments at weekly intervals depending on response and tolerability. Max: 400 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Pharmacological treatment of ADHD may be needed for extended periods. Periodically reevaluate long-term use of viloxazine and adjust dosage as needed.

    MAXIMUM DOSAGE

    Adults

    Safety and efficacy have not been established.

    Geriatric

    Safety and efficacy have not been established.

    Adolescents

    400 mg/day PO.

    Children

    6 to 12 years: 400 mg/day PO.
    1 to 5 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Viloxazine is not recommended in patients with hepatic impairment; the effect of hepatic impairment on the pharmacokinetics of viloxazine is unknown.

    Renal Impairment

    eGFR 30 mL/minute/1.73 m2 or more: No dosage adjustment is necessary.
    eGFR less than 30 mL/minute/1.73 m2: Initially, 100 mg PO once daily. May titrate dosage in weekly increments of 50 to 100 mg once daily, up to a maximum of 200 mg PO once daily.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Extended-release capsules:
    May be administered with or without food.
    Do not cut, crush, or chew the capsules.
    Have the patient swallow the capsule whole. If swallowing is difficult, the capsule may be opened and the contents sprinkled over 1 teaspoon (5 mL) of applesauce. The entire sprinkled applesauce should be consumed without chewing within 2 hours of preparation; do not store for future use.

    STORAGE

    QELBREE:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    MAOI therapy

    Viloxazine is contraindicated in patients receiving monoamine oxidase inhibitor (MAOI) therapy or patients who have received MAOI therapy within the past 14 days due to an increased risk of hypertensive crisis.

    Bipolar disorder, depression, mania, suicidal ideation

    In clinical trials, higher rates of suicidal ideation and behavior were reported in pediatric patients treated with viloxazine than in patients treated with placebo (0.9% vs. 0.4%). Closely monitor all viloxazine-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. Noradrenergic drugs, such as viloxazine, may also induce a manic or mixed episode in patients with bipolar disorder. Prior to initiating treatment with viloxazine, 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. Patients treated with viloxazine 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 depression, 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 should be observed for the emergence of such symptoms. Consider changing the therapeutic regimen, including possibly discontinuing viloxazine, 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 health care provider.

    Hypertension, tachycardia, ventricular arrhythmias

    Use viloxazine with caution in patients with cardiac conditions (i.e., hypertension, tachycardia, ventricular arrhythmias) that would be expected to deteriorate from significant increases in blood pressure or heart rate. Viloxazine increases heart rate and diastolic blood pressure. Increases in heart rate of 20 beats per minute (bpm) or more were reported more frequently in viloxazine-treated patients (22% to 34%) than placebo-treated patients (9% to 23%) in clinical trials (n = 826). In patients receiving viloxazine 400 mg once daily, 25% experienced a 15 mmHg or higher increase in diastolic blood pressure compared with 13% of patients receiving placebo. Monitor heart rate and blood pressure prior to initiating treatment with viloxazine, following dosage increases, and periodically while on therapy.

    Renal failure, renal impairment

    Renal excretion is the primary route of excretion of viloxazine. Dosage reduction is recommended in patients with severe renal impairment or renal failure (eGFR of less than 30 mL/minute/1.73 m2). No dosage adjustment is needed in those patients with mild to moderate renal impairment.

    Driving or operating machinery

    The use of viloxazine may cause somnolence and fatigue and impair the ability of a patient to participate in activities that require mental alertness, such as driving or operating machinery. Patients should not perform activities requiring coordination and concentration, such as gymnastics, riding a bicycle, or for older adolescents, operation of vehicles, until they are aware of how this medication affects them.

    Hepatic disease

    Viloxazine is not recommended in patients with hepatic impairment (hepatic disease). The effect of hepatic impairment on the pharmacokinetics of viloxazine is unknown.

    Pregnancy

    Viloxazine may cause maternal harm when used during pregnancy based on findings from animal reproduction studies. Discontinue viloxazine 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 or higher 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/m2, 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. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to viloxazine during pregnancy. Health care providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at www.womensmentalhealth.org/preg. The effect of viloxazine on labor and delivery is unknown.

    Breast-feeding

    There are no data on the presence of viloxazine in human milk, the effects on the breastfed 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 also be present in human milk. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for viloxazine and any potential adverse effects on the breastfed child from viloxazine or from the underlying maternal condition. Consider if an alternate drug would be preferred, especially while the woman is nursing a newborn or preterm infant. Although methylphenidate may be considered as an alternative to other ADHD medications during lactation and breast-feeding due to low excretion into breastmilk, the medical use of stimulant medications during breast-feeding has not been formally evaluated. The nursing infant should be monitored for signs of potential toxicity, such as poor feeding, irritability, or changes in sleep patterns.

    Geriatric

    The pharmacokinetics, safety and efficacy regarding the use of viloxazine in the geriatric population have not been evaluated in controlled clinical trials.

    ADVERSE REACTIONS

    Severe

    suicidal ideation / Delayed / 0.9-0.9

    Moderate

    mania / Early / Incidence not known
    hypertension / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known

    Mild

    drowsiness / Early / 16.0-16.0
    headache / Early / 11.0-11.0
    anorexia / Delayed / 7.0-7.0
    infection / Delayed / 7.0-7.0
    fatigue / Early / 6.0-6.0
    abdominal pain / Early / 5.0-5.0
    nausea / Early / 5.0-5.0
    insomnia / Early / 4.0-4.0
    vomiting / Early / 4.0-4.0
    irritability / Delayed / 3.0-3.0
    fever / Early / 2.0-2.0
    lethargy / Early / Incidence not known
    weight loss / Delayed / Incidence not known
    sinusitis / Delayed / Incidence not known
    pharyngitis / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of viloxazine is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and viloxazine is a CYP1A2 inhibitor.
    Acetaminophen; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of viloxazine is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and viloxazine is a CYP1A2 inhibitor.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with viloxazine may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of viloxazine could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If viloxazine is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4; viloxazine is a dual weak 2D6 and weak 3A4 inhibitor. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of viloxazine is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and viloxazine is a CYP1A2 inhibitor.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of viloxazine is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and viloxazine is a CYP1A2 inhibitor.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of viloxazine is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and viloxazine is a CYP1A2 inhibitor.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with viloxazine may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of viloxazine could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If viloxazine is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Viloxazine is a dual weak CYP2D6 and weak CYP3A4 inhibitor. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Acetaminophen; Dextromethorphan: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with viloxazine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of viloxazine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If viloxazine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6 and CYP3A; viloxazine is a weak CYP2D6 and weak CYP3A inhibitor.
    Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of viloxazine is necessary. If viloxazine is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like viloxazine can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If viloxazine is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of viloxazine is necessary. If viloxazine is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like viloxazine can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If viloxazine is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
    Alosetron: (Contraindicated) Concomitant use of viloxazine and alosetron is contraindicated due to the increased risk for alosetron-related adverse effects and exposure. Alosetron is a CYP1A2 substrate and viloxazine is a strong CYP1A2 inhibitor. Coadministration of another strong CYP1A2 inhibitor increased the mean alosetron AUC by about 6-fold and prolonged the half-life by 3-fold.
    Alprazolam: (Major) Avoid coadministration of alprazolam and viloxazine due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with viloxazine, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and viloxazine is a weak CYP3A4 inhibitor. Coadministration with another weak CYP3A4 inhibitor increased alprazolam maximum concentration by 82%, decreased clearance by 42%, and increased half-life by 16%.
    Amitriptyline: (Moderate) Monitor for tricyclic antidepressant-related adverse reactions if coadministration with viloxazine is necessary; a dose reduction of tricyclic antidepressants may be necessary if clinically indicated. Concurrent use may increase exposure of tricyclic antidepressants; tricyclic antidepressants are CYP2D6 substrates and viloxazine is a weak CYP2D6 inhibitor.
    Amoxapine: (Major) Lower doses of amoxapine may be required during concurrent use of viloxazine due to the potential for increased amoxapine exposure. If viloxazine is discontinued, an increased dose of amoxapine may be necessary. Amoxapine is a CYP2D6 substrate; viloxazine is a CYP2D6 inhibitor.
    Anagrelide: (Moderate) Monitor for cardiovascular events including QT prolongation, torsade de pointes (TdP), and vasodilation and titrate the anagrelide dose accordingly if concomitant use of viloxazine is necessary. Concomitant use may increase anagrelide exposure; anagrelide is a CYP1A2 substrate and viloxazine is a strong CYP1A2 inhibitor.
    Aripiprazole: (Major) Monitor for aripiprazole-related adverse reactions during concurrent use of viloxazine. Reduce the oral aripiprazole dosage to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving viloxazine for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio. Aripiprazole is a substrate for CYP2D6 and CYP3A; viloxazine is a weak CYP2D6 and weak CYP3A inhibitor.
    Asenapine: (Moderate) Monitor for increased asenapine-related adverse effects, such as extrapyramidal symptoms and QT prolongation, if concomitant use of viloxazine is necessary; dosage reduction of asenapine may be necessary. Concomitant use may increase the exposure of asenapine; asenapine is a CYP1A2 substrate and viloxazine is a strong CYP1A2 inhibitor.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of viloxazine is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and viloxazine is a CYP1A2 inhibitor.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with viloxazine may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of viloxazine could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If viloxazine is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Viloxazine is a dual weak CYP2D6 and weak CYP3A4 inhibitor. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of viloxazine is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and viloxazine is a CYP1A2 inhibitor.
    Aspirin, ASA; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of viloxazine is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and viloxazine is a CYP1A2 inhibitor.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with viloxazine may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of viloxazine could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If viloxazine is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4; viloxazine is a dual weak 2D6 and weak 3A4 inhibitor. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of viloxazine is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and viloxazine is a CYP1A2 inhibitor.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of viloxazine is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and viloxazine is a CYP1A2 inhibitor.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with viloxazine may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of viloxazine could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If viloxazine is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Viloxazine is a dual weak CYP2D6 and weak CYP3A4 inhibitor. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of viloxazine is necessary. If viloxazine is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like viloxazine can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If viloxazine is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Atomoxetine: (Major) Avoid concomitant use of atomoxetine and viloxazine. This combination may represent duplicate therapy and additive toxicities may occur. Additionally, atomoxetine exposure may increase. Atomoxetine is a CYP2D6 substrate and viloxazine is a weak CYP2D6 inhibitor.
    Avanafil: (Moderate) Monitor for an increase in avanafil-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase avanafil exposure; viloxazine is a weak CYP3A inhibitor and avanafil is a CYP3A substrate.
    Bendamustine: (Major) Consider the use of an alternative therapy if viloxazine treatment is needed in patients receiving bendamustine. Concomitant use of viloxazine may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and viloxazine is a CYP1A2 inhibitor.
    Benzhydrocodone; Acetaminophen: (Moderate) Consider a reduced dose of benzhydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of viloxazine is necessary. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like viloxazine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of benzhydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If viloxazine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to benzhydrocodone.
    Betrixaban: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if betrixaban and selective norepinephrine reuptake inhibitors (SNRIs) are used concomitantly. Coadministration of betrixaban and SNRIs may increase the risk of bleeding.
    Brimonidine; Timolol: (Moderate) Monitor for increased timolol-related adverse reactions, including bradycardia and hypotension, during coadministration with viloxazine. Concomitant use may increase timolol exposure. Timolol is a CYP2D6 substrate and viloxazine is a weak CYP2D6 inhibitor.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with viloxazine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of viloxazine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If viloxazine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6 and CYP3A; viloxazine is a weak CYP2D6 and weak CYP3A inhibitor.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with viloxazine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of viloxazine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If viloxazine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6 and CYP3A; viloxazine is a weak CYP2D6 and weak CYP3A inhibitor.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Bupivacaine; Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with viloxazine is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP1A2 and CYP3A substrate and viloxazine is a strong CYP1A2 and weak CYP3A inhibitor. Coadministration of another CYP1A2 inhibitor increased lidocaine exposure by 71%.
    Buprenorphine: (Moderate) Concomitant use of buprenorphine and viloxazine can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when viloxazine is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping viloxazine, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If viloxazine is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and viloxazine is a CYP3A4 inhibitor.
    Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine and viloxazine can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when viloxazine is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping viloxazine, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If viloxazine is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and viloxazine is a CYP3A4 inhibitor.
    Buspirone: (Moderate) Monitor for an increase in buspirone-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase buspirone exposure; viloxazine is a weak CYP3A inhibitor and buspirone is a CYP3A substrate.
    Butalbital; Acetaminophen; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of viloxazine is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and viloxazine is a CYP1A2 inhibitor.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with viloxazine may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of viloxazine could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If viloxazine is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Viloxazine is a dual weak CYP2D6 and weak CYP3A4 inhibitor. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of viloxazine is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and viloxazine is a CYP1A2 inhibitor.
    Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of viloxazine is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and viloxazine is a CYP1A2 inhibitor.
    Caffeine; Sodium Benzoate: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of viloxazine is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and viloxazine is a CYP1A2 inhibitor.
    Carbamazepine: (Moderate) Monitor carbamazepine concentrations closely during coadministration of viloxazine; carbamazepine dose adjustments may be needed. Concomitant use may increase carbamazepine concentrations. Carbamazepine is a CYP3A4 substrate and viloxazine is a CYP3A4 inhibitor.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with viloxazine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of viloxazine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If viloxazine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6 and CYP3A; viloxazine is a weak CYP2D6 and weak CYP3A inhibitor.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with viloxazine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of viloxazine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If viloxazine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6 and CYP3A; viloxazine is a weak CYP2D6 and weak CYP3A inhibitor.
    Celecoxib; Tramadol: (Moderate) Concurrent use of tramadol with viloxazine may produce unpredictable effects, including prolonged opioid-related adverse reactions, such as fatal respiratory depression, a withdrawal syndrome in those with physical dependence to opioid agonists, seizures, or serotonin syndrome. Consider dose adjustments of tramadol until stable drug effects are achieved. Monitor patients closely for respiratory depression and sedation at frequent intervals. Tramadol is primarily metabolized by CYP2D6 to the active metabolite M1, and by CYP3A4; viloxazine is a dual weak CYP2D6 and weak CYP3A4 inhibitor. CYP3A4 inhibitors may increase tramadol-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Chlordiazepoxide; Amitriptyline: (Moderate) Monitor for tricyclic antidepressant-related adverse reactions if coadministration with viloxazine is necessary; a dose reduction of tricyclic antidepressants may be necessary if clinically indicated. Concurrent use may increase exposure of tricyclic antidepressants; tricyclic antidepressants are CYP2D6 substrates and viloxazine is a weak CYP2D6 inhibitor.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with viloxazine may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of viloxazine could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If viloxazine is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Viloxazine is a dual weak CYP2D6 and weak CYP3A4 inhibitor. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Chlorpheniramine; Dextromethorphan: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with viloxazine may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of viloxazine could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If viloxazine is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4; viloxazine is a dual weak 2D6 and weak 3A4 inhibitor. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with viloxazine may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of viloxazine could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If viloxazine is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4; viloxazine is a dual weak 2D6 and weak 3A4 inhibitor. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with viloxazine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of viloxazine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If viloxazine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6 and CYP3A; viloxazine is a weak CYP2D6 and weak CYP3A inhibitor.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with viloxazine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of viloxazine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If viloxazine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6 and CYP3A; viloxazine is a weak CYP2D6 and weak CYP3A inhibitor.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with viloxazine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of viloxazine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If viloxazine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6 and CYP3A; viloxazine is a weak CYP2D6 and weak CYP3A inhibitor.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with viloxazine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of viloxazine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If viloxazine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6 and CYP3A; viloxazine is a weak CYP2D6 and weak CYP3A inhibitor.
    Chlorpromazine: (Moderate) Monitor for an increase in chlorpromazine-related adverse reactions, including QT prolongation, anticholinergic effects, orthostasis, and somnolence, if coadministration with viloxazine is necessary. Concomitant use may increase chlorpromazine exposure. Chlorpromazine is a CYP2D6 substrate and viloxazine is a weak CYP2D6 inhibitor.
    Clomipramine: (Moderate) Monitor for tricyclic antidepressant-related adverse reactions if coadministration with viloxazine is necessary; a dose reduction of tricyclic antidepressants may be necessary if clinically indicated. Concurrent use may increase exposure of tricyclic antidepressants; tricyclic antidepressants are CYP2D6 substrates and viloxazine is a weak CYP2D6 inhibitor.
    Clozapine: (Major) Reduce the clozapine dose to one-third of the original dose when coadministered with viloxazine. If viloxazine is discontinued, increase the clozapine dose to the original dose. Concomitant use may increase the plasma concentrations of clozapine, resulting in adverse reactions. Clozapine is a CYP1A2, CYP2D6, and CYP3A substrate; viloxazine is a strong CYP1A2, weak CYP2D6, and weak CYP3A inhibitor. Coadministration of another strong CYP1A2 inhibitor increased mean trough concentrations of clozapine and its metabolites, N-desmethylclozapine and clozapine N-oxide, were elevated about three-fold compared to baseline steady-state concentrations.
    Codeine: (Moderate) Concomitant use of codeine with viloxazine may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of viloxazine could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If viloxazine is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Viloxazine is a dual weak CYP2D6 and weak CYP3A4 inhibitor. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with viloxazine may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of viloxazine could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If viloxazine is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Viloxazine is a dual weak CYP2D6 and weak CYP3A4 inhibitor. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with viloxazine may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of viloxazine could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If viloxazine is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Viloxazine is a dual weak CYP2D6 and weak CYP3A4 inhibitor. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with viloxazine may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of viloxazine could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If viloxazine is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Viloxazine is a dual weak CYP2D6 and weak CYP3A4 inhibitor. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with viloxazine may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of viloxazine could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If viloxazine is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Viloxazine is a dual weak CYP2D6 and weak CYP3A4 inhibitor. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Conivaptan: (Moderate) Monitor for an increase in conivaptan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase conivaptan exposure; viloxazine is a weak CYP3A inhibitor and conivaptan is a CYP3A substrate.
    Cyclosporine: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with viloxazine is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A4 substrate and viloxazine is a weak CYP3A4 inhibitor.
    Darifenacin: (Moderate) Monitor for an increase in darifenacin-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase darifenacin exposure; viloxazine is a weak CYP3A inhibitor and darifenacin is a CYP3A substrate.
    Darunavir: (Moderate) Monitor for an increase in darunavir-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase darunavir exposure; viloxazine is a weak CYP3A inhibitor and darunavir is a CYP3A substrate.
    Darunavir; Cobicistat: (Moderate) Monitor for an increase in darunavir-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase darunavir exposure; viloxazine is a weak CYP3A inhibitor and darunavir is a CYP3A substrate.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for an increase in darunavir-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase darunavir exposure; viloxazine is a weak CYP3A inhibitor and darunavir is a CYP3A substrate.
    Desipramine: (Moderate) Monitor for tricyclic antidepressant-related adverse reactions if coadministration with viloxazine is necessary; a dose reduction of tricyclic antidepressants may be necessary if clinically indicated. Concurrent use may increase exposure of tricyclic antidepressants; tricyclic antidepressants are CYP2D6 substrates and viloxazine is a weak CYP2D6 inhibitor.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Dextromethorphan: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Dextromethorphan; Guaifenesin: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Dextromethorphan; Quinidine: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with viloxazine is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and viloxazine is a CYP3A4 inhibitor.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with viloxazine may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of viloxazine could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If viloxazine is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4; viloxazine is a dual weak 2D6 and weak 3A4 inhibitor. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with viloxazine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of viloxazine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If viloxazine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6 and CYP3A; viloxazine is a weak CYP2D6 and weak CYP3A inhibitor.
    Disopyramide: (Moderate) Monitor for an increase in disopyramide-related adverse reactions if coadministration with viloxazine is necessary as concurrent use may increase disopyramide exposure. Disopyramide is a CYP3A4 substrate and viloxazine is a weak CYP3A4 inhibitor. Although specific drug interaction studies have not been done for disopyramide, cases of life-threatening interactions have been reported when disopyramide was coadministered with moderate and strong CYP3A4 inhibitors.
    Dofetilide: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with viloxazine is necessary as concurrent use may increase dofetilide exposure. viloxazine is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Dorzolamide; Timolol: (Moderate) Monitor for increased timolol-related adverse reactions, including bradycardia and hypotension, during coadministration with viloxazine. Concomitant use may increase timolol exposure. Timolol is a CYP2D6 substrate and viloxazine is a weak CYP2D6 inhibitor.
    Doxepin: (Moderate) Monitor for tricyclic antidepressant-related adverse reactions if coadministration with viloxazine is necessary; a dose reduction of tricyclic antidepressants may be necessary if clinically indicated. Concurrent use may increase exposure of tricyclic antidepressants; tricyclic antidepressants are CYP2D6 substrates and viloxazine is a weak CYP2D6 inhibitor.
    Duloxetine: (Contraindicated) Concomitant use of viloxazine and duloxetine is contraindicated due to the increased risk for duloxetine-related adverse effects and exposure. Duloxetine is a CYP1A2 and CYP2D6 substrate and viloxazine is a strong CYP1A2 inhibitor and weak CYP2D6 inhibitor. Coadministration with another strong CYP1A2 inhibitor increased duloxetine exposure by approximately 6-fold.
    Edoxaban: (Major) Coadministration of edoxaban with other drugs that affect hemostasis, such as selective norepinephrine reuptake inhibitors (SNRIs), increases the risk of bleeding. If these drugs are administered together, instruct patients to monitor for signs and symptoms of bleeding, and to promptly report any bleeding events to their practitioner.
    Eliglustat: (Major) Coadministration of eliglustat and viloxazine is not recommended in poor CYP2D6 metabolizers (PMs). In normal (extensive) CYP2D6 metabolizers with mild hepatic impairment, coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. Viloxazine is a weak CYP3A and weak CYP2D6 inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration of eliglustat with CYP3A inhibitors may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
    Enalapril; Felodipine: (Moderate) Concurrent use of felodipine and viloxazine should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and viloxazine is a weak CYP3A4 inhibitor. Concurrent use of another weak CYP3A4 inhibitor increased felodipine AUC and Cmax by approximately 50%.
    Ergotamine; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of viloxazine is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and viloxazine is a CYP1A2 inhibitor.
    Erlotinib: (Major) Avoid coadministration of erlotinib with viloxazine if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP1A2; viloxazine is a weak CYP3A4 and strong CYP1A2 inhibitor. Coadministration with a moderate CYP3A4/CYP1A2 inhibitor increased erlotinib exposure by 39% and increased the erlotinib Cmax by 17%.
    Everolimus: (Moderate) Monitor for an increase in everolimus-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase everolimus exposure; viloxazine is a weak CYP3A inhibitor and everolimus is a CYP3A substrate.
    Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse effects, like myopathy, if concomitant use of viloxazine is necessary. Concomitant use may increase simvastatin exposure; viloxazine is a weak CYP3A inhibitor and simvastatin is a CYP3A substrate.
    Felodipine: (Moderate) Concurrent use of felodipine and viloxazine should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and viloxazine is a weak CYP3A4 inhibitor. Concurrent use of another weak CYP3A4 inhibitor increased felodipine AUC and Cmax by approximately 50%.
    Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of viloxazine is necessary. If viloxazine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like viloxazine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If viloxazine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
    Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or viloxazine; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and viloxazine is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased overall exposure to finerenone by 21%.
    Flecainide: (Moderate) Monitor for an increase in flecainide-related adverse reactions, including QT prolongation, if coadministration with viloxazine is necessary. Flecainide is a CYP2D6 substrate and viloxazine is a weak CYP2D6 inhibitor. Plasma concentrations of flecainide may increase, especially in normal (extensive) CYP2D6 metabolizers.
    Flibanserin: (Moderate) The concomitant use of flibanserin and multiple weak CYP3A4 inhibitors, including viloxazine, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the potential outcomes of combination therapy with multiple weak CYP3A4 inhibitors and flibanserin should be discussed with the patient.
    Fluoxetine: (Moderate) Monitor for increased fluoxetine-related adverse effects if coadministered with viloxazine. Concomitant use may increase fluoxetine exposure. Fluoxetine is a CYP2D6 substrate and viloxazine is a weak CYP2D6 inhibitor.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with viloxazine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of viloxazine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If viloxazine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6 and CYP3A; viloxazine is a weak CYP2D6 and weak CYP3A inhibitor.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with viloxazine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of viloxazine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If viloxazine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6 and CYP3A; viloxazine is a weak CYP2D6 and weak CYP3A inhibitor.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with viloxazine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of viloxazine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If viloxazine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6 and CYP3A; viloxazine is a weak CYP2D6 and weak CYP3A inhibitor.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with viloxazine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of viloxazine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If viloxazine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6 and CYP3A; viloxazine is a weak CYP2D6 and weak CYP3A inhibitor.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with viloxazine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of viloxazine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If viloxazine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6 and CYP3A; viloxazine is a weak CYP2D6 and weak CYP3A inhibitor.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with viloxazine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of viloxazine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If viloxazine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6 and CYP3A; viloxazine is a weak CYP2D6 and weak CYP3A inhibitor.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with viloxazine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of viloxazine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If viloxazine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6 and CYP3A; viloxazine is a weak CYP2D6 and weak CYP3A inhibitor.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with viloxazine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of viloxazine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If viloxazine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6 and CYP3A; viloxazine is a weak CYP2D6 and weak CYP3A inhibitor.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with viloxazine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of viloxazine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If viloxazine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6 and CYP3A; viloxazine is a weak CYP2D6 and weak CYP3A inhibitor.
    Ibrutinib: (Moderate) Monitor for an increase in ibrutinib-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase ibrutinib exposure; viloxazine is a weak CYP3A inhibitor and ibrutinib is a CYP3A substrate.
    Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of viloxazine is necessary. If viloxazine is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like viloxazine can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If viloxazine is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Imipramine: (Moderate) Monitor for tricyclic antidepressant-related adverse reactions if coadministration with viloxazine is necessary; a dose reduction of tricyclic antidepressants may be necessary if clinically indicated. Concurrent use may increase exposure of tricyclic antidepressants; tricyclic antidepressants are CYP2D6 substrates and viloxazine is a weak CYP2D6 inhibitor.
    Iobenguane I 131: (Major) Discontinue selective norepinephrine reuptake inhibitors for at least 5 half-lives before the administration of the dosimetry dose or a therapeutic dose of iobenguane I-131. Do not restart selective norepinephrine reuptake inhibitors until at least 7 days after each iobenguane I-131 dose. Drugs that reduce catecholamine uptake or deplete catecholamine stores, such as selective norepinephrine reuptake inhibitors, may interfere with iobenguane I-131 uptake into cells and interfere with dosimetry calculations resulting in altered iobenguane I-131 efficacy.
    Isocarboxazid: (Contraindicated) The use of selective norepinephrine reuptake inhibitors with monoamine oxidase inhibitors (MAOIs) is contraindicated. At least 2 weeks should elapse between the discontinuation of a drug with MAO inhibiting activity and the start of selective norepinephrine reuptake inhibitors, or vice-versa. Selective norepinephrine reuptake inhibitors potentiate certain catecholamines by inhibiting neuronal reuptake. Reactions with MAOIs may include confusion, seizures, and severe hypertension as well as less severe symptoms.
    Isradipine: (Minor) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with viloxazine is necessary. Concomitant use may increase isradipine exposure. Isradipine is a CYP3A substrate and viloxazine is a weak CYP3A inhibitor.
    Ixabepilone: (Moderate) Frequently monitor peripheral blood counts between cycles of ixabepilone, and for other acute ixabepilone-related adverse reactions if coadministration with viloxazine is necessary; consider the use of an alternative agent to viloxazine that does not inhibit CYP3A4. Ixabepilone is a CYP3A4 substrate and viloxazine is a weak CYP3A4 inhibitor. The effect of weak CYP3A4 inhibitors on exposure to ixabepilone has not been studied.
    Lemborexant: (Major) Limit the dose of lemborexant to 5 mg PO once daily if coadministered with viloxazine as concurrent use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; viloxazine is a weak CYP3A4 inhibitor. Coadministration with a weak CYP3A4 inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
    Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with viloxazine is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP1A2 and CYP3A substrate and viloxazine is a strong CYP1A2 and weak CYP3A inhibitor. Coadministration of another CYP1A2 inhibitor increased lidocaine exposure by 71%.
    Lidocaine; Epinephrine: (Moderate) Monitor for lidocaine toxicity if coadministration with viloxazine is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP1A2 and CYP3A substrate and viloxazine is a strong CYP1A2 and weak CYP3A inhibitor. Coadministration of another CYP1A2 inhibitor increased lidocaine exposure by 71%.
    Lidocaine; Prilocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with viloxazine is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP1A2 and CYP3A substrate and viloxazine is a strong CYP1A2 and weak CYP3A inhibitor. Coadministration of another CYP1A2 inhibitor increased lidocaine exposure by 71%.
    Lofexidine: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and viloxazine. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; viloxazine is a CYP2D6 inhibitor. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
    Lomitapide: (Major) Decrease the dose of lomitapide by one-half not to exceed 30 mg/day PO if coadministration with viloxazine is necessary. Concomitant use may significantly increase the serum concentration of lomitapide. Viloxazine is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors.
    Lonafarnib: (Major) Avoid coadministration of lonafarnib and viloxazine; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Lonafarnib is a sensitive CYP3A4 substrate and viloxazine is a weak CYP3A4 inhibitor.
    Lovastatin: (Moderate) Monitor for an increase in lovastatin-related adverse effects, like myopathy, if concomitant use of viloxazine is necessary. Concomitant use may increase lovastatin exposure; viloxazine is a weak CYP3A inhibitor and lovastatin is a CYP3A substrate.
    Lovastatin; Niacin: (Moderate) Monitor for an increase in lovastatin-related adverse effects, like myopathy, if concomitant use of viloxazine is necessary. Concomitant use may increase lovastatin exposure; viloxazine is a weak CYP3A inhibitor and lovastatin is a CYP3A substrate.
    Lurasidone: (Moderate) Monitor for an increase in lurasidone-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase lurasidone exposure; viloxazine is a weak CYP3A inhibitor and lurasidone is a CYP3A substrate.
    Maprotiline: (Moderate) Monitor for an increase in maprotiline-related adverse reactions if coadministration with viloxazine is necessary; a dose reduction of maprotiline may be necessary. Concurrent use may increase exposure of maprotiline. Maprotiline is a CYP2D6 substrate and viloxazine is a CYP2D6 inhibitor.
    Meclizine: (Moderate) Monitor for meclizine-related adverse effects, such as drowsiness and anticholinergic effects, when coadministered with viloxazine. Concomitant use may increase the exposure to meclizine. Meclizine is a CYP2D6 substrate and viloxazine is a CYP2D6 inhibitor.
    Mefloquine: (Moderate) Use mefloquine with caution if coadministration with viloxazine is necessary as concurrent use may increase mefloquine exposure and mefloquine-related adverse events. Mefloquine is a substrate of CYP3A4 and viloxazine is a weak CYP3A4 inhibitor.
    Melatonin: (Moderate) Monitor for an increase in melatonin-related adverse reactions if concomitant use of viloxazine is necessary. Concomitant use may increase melatonin exposure; melatonin is a CYP1A2 substrate and viloxazine is a strong CYP1A2 inhibitor. In some cases, a dose reduction of melatonin might be needed.
    Meperidine: (Moderate) Consider a reduced dose of meperidine with frequent monitoring for respiratory depression and sedation if concurrent use of viloxazine is necessary. If viloxazine is discontinued, meperidine plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to meperidine. Meperidine is a substrate of CYP3A4 and viloxazine is a weak CYP3A4 inhibitor. Concomitant use with viloxazine can increase meperidine exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of meperidine.
    Meperidine; Promethazine: (Moderate) Consider a reduced dose of meperidine with frequent monitoring for respiratory depression and sedation if concurrent use of viloxazine is necessary. If viloxazine is discontinued, meperidine plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to meperidine. Meperidine is a substrate of CYP3A4 and viloxazine is a weak CYP3A4 inhibitor. Concomitant use with viloxazine can increase meperidine exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of meperidine.
    Methadone: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of viloxazine is necessary. If viloxazine is discontinued, methadone plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Methadone is a substrate of CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; viloxazine is a weak CYP3A and weak CYP2D6 inhibitor. Concomitant use with viloxazine can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone.
    Metoprolol: (Moderate) Monitor for increased metoprolol-related adverse reactions, including bradycardia and hypotension, during coadministration with viloxazine. Concomitant use may increase metoprolol exposure and thus enhance the beta-blocking properties of metoprolol. Metoprolol is a CYP2D6 substrate and viloxazine is a weak CYP2D6 inhibitor.
    Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased metoprolol-related adverse reactions, including bradycardia and hypotension, during coadministration with viloxazine. Concomitant use may increase metoprolol exposure and thus enhance the beta-blocking properties of metoprolol. Metoprolol is a CYP2D6 substrate and viloxazine is a weak CYP2D6 inhibitor.
    Midazolam: (Moderate) Use caution when midazolam is coadministered with viloxazine. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A4 substrate and viloxazine is a weak CYP3A4 inhibitor.
    Monoamine oxidase inhibitors: (Contraindicated) The use of selective norepinephrine reuptake inhibitors with monoamine oxidase inhibitors (MAOIs) is contraindicated. At least 2 weeks should elapse between the discontinuation of a drug with MAO inhibiting activity and the start of selective norepinephrine reuptake inhibitors, or vice-versa. Selective norepinephrine reuptake inhibitors potentiate certain catecholamines by inhibiting neuronal reuptake. Reactions with MAOIs may include confusion, seizures, and severe hypertension as well as less severe symptoms.
    Naloxegol: (Moderate) Monitor for an increase in naloxegol-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase naloxegol exposure; viloxazine is a weak CYP3A inhibitor and naloxegol is a CYP3A substrate.
    Nanoparticle Albumin-Bound Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with viloxazine is necessary. The dose of sirolimus may also need to be reduced with coadministration of viloxazine. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of viloxazine. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; viloxazine is a weak CYP3A inhibitor.
    Nebivolol: (Moderate) Monitor for increased nebivolol-related adverse reactions, including bradycardia and hypotension, during coadministration with viloxazine. Concomitant use may increase nebivolol exposure and thus enhance the beta-blocking properties. Nebivolol is a CYP2D6 substrate and viloxazine is a weak CYP2D6 inhibitor.
    Nebivolol; Valsartan: (Moderate) Monitor for increased nebivolol-related adverse reactions, including bradycardia and hypotension, during coadministration with viloxazine. Concomitant use may increase nebivolol exposure and thus enhance the beta-blocking properties. Nebivolol is a CYP2D6 substrate and viloxazine is a weak CYP2D6 inhibitor.
    Niacin; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse effects, like myopathy, if concomitant use of viloxazine is necessary. Concomitant use may increase simvastatin exposure; viloxazine is a weak CYP3A inhibitor and simvastatin is a CYP3A substrate.
    Nimodipine: (Moderate) Monitor blood pressure and reduce the dose of nimodipine as clinically appropriate if coadministration with viloxazine is necessary. Concurrent use may increase nimodipine exposure. Nimodipine is a CYP3A4 substrate and viloxazine is a weak CYP3A4 inhibitor.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with viloxazine due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and viloxazine is a CYP3A4 inhibitor. Coadministration with another CYP3A4 inhibitor increased the AUC of nisoldipine by 30% to 45%.
    Nortriptyline: (Moderate) Monitor for tricyclic antidepressant-related adverse reactions if coadministration with viloxazine is necessary; a dose reduction of tricyclic antidepressants may be necessary if clinically indicated. Concurrent use may increase exposure of tricyclic antidepressants; tricyclic antidepressants are CYP2D6 substrates and viloxazine is a weak CYP2D6 inhibitor.
    Olanzapine: (Moderate) Monitor for olanzapine-related adverse effects, including sedation, anticholinergic effects, hypotension, and QT prolongation, if concomitant use of viloxazine is necessary. A dose reduction of olanzapine may be necessary. Concomitant use may increase olanzapine exposure. Direct glucuronidation and CYP metabolism via CYP2D6 and CYP1A2 are the primary metabolic pathways for olanzapine. Viloxazine is a strong CYP1A2 inhibitor and weak CYP2D6.
    Olanzapine; Fluoxetine: (Moderate) Monitor for increased fluoxetine-related adverse effects if coadministered with viloxazine. Concomitant use may increase fluoxetine exposure. Fluoxetine is a CYP2D6 substrate and viloxazine is a weak CYP2D6 inhibitor. (Moderate) Monitor for olanzapine-related adverse effects, including sedation, anticholinergic effects, hypotension, and QT prolongation, if concomitant use of viloxazine is necessary. A dose reduction of olanzapine may be necessary. Concomitant use may increase olanzapine exposure. Direct glucuronidation and CYP metabolism via CYP2D6 and CYP1A2 are the primary metabolic pathways for olanzapine. Viloxazine is a strong CYP1A2 inhibitor and weak CYP2D6.
    Olanzapine; Samidorphan: (Moderate) Monitor for olanzapine-related adverse effects, including sedation, anticholinergic effects, hypotension, and QT prolongation, if concomitant use of viloxazine is necessary. A dose reduction of olanzapine may be necessary. Concomitant use may increase olanzapine exposure. Direct glucuronidation and CYP metabolism via CYP2D6 and CYP1A2 are the primary metabolic pathways for olanzapine. Viloxazine is a strong CYP1A2 inhibitor and weak CYP2D6.
    Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of viloxazine is necessary. If viloxazine is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like viloxazine can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If viloxazine is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Ozanimod: (Moderate) Monitor blood pressure if concomitant use of ozanimod and viloxazine is necessary. Hypertensive crisis has occurred with ozanimod alone and this risk may increase with concomitant use of viloxazine. Some ozanimod metabolites inhibit MAO-B which may potentiate the hypertensive effects of viloxazine.
    Perphenazine: (Moderate) Monitor for an increase in perphenazine-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase perphenazine exposure; viloxazine is a weak CYP2D6 inhibitor and perphenazine is a CYP2D6 substrate.
    Perphenazine; Amitriptyline: (Moderate) Monitor for an increase in perphenazine-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase perphenazine exposure; viloxazine is a weak CYP2D6 inhibitor and perphenazine is a CYP2D6 substrate. (Moderate) Monitor for tricyclic antidepressant-related adverse reactions if coadministration with viloxazine is necessary; a dose reduction of tricyclic antidepressants may be necessary if clinically indicated. Concurrent use may increase exposure of tricyclic antidepressants; tricyclic antidepressants are CYP2D6 substrates and viloxazine is a weak CYP2D6 inhibitor.
    Phenelzine: (Contraindicated) The use of selective norepinephrine reuptake inhibitors with monoamine oxidase inhibitors (MAOIs) is contraindicated. At least 2 weeks should elapse between the discontinuation of a drug with MAO inhibiting activity and the start of selective norepinephrine reuptake inhibitors, or vice-versa. Selective norepinephrine reuptake inhibitors potentiate certain catecholamines by inhibiting neuronal reuptake. Reactions with MAOIs may include confusion, seizures, and severe hypertension as well as less severe symptoms.
    Pimozide: (Major) Avoid concomitant use of pimozide and viloxazine. Concomitant use may result in elevated pimozide concentrations resulting in QT prolongation, ventricular arrhythmias, and sudden death. Pimozide is a CYP3A, 2D6 and 1A2 substrate, and viloxazine is a strong CYP1A2, weak CYP2D6, and weak CYP3A inhibitor.
    Pirfenidone: (Major) Avoid concomitant use of viloxazine and pirfenidone due to the increased risk for pirfenidone-related adverse effects and exposure. Pirfenidone is a CYP1A2 substrate and viloxazine is a strong CYP1A2 inhibitor.
    Promethazine; Dextromethorphan: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
    Propafenone: (Major) Avoid use of propafenone and viloxazine together as concurrent use may increase plasma concentrations of propafenone, which may lead to cardiac arrhythmias and exaggerated beta-blocking activity. Propafenone is a CYP2D6 and CYP3A4 substrate; viloxazine is a weak CYP2D6 and weak CYP3A4 inhibitor.
    Propranolol: (Moderate) Monitor for increased propranolol-related adverse reactions, including bradycardia and hypotension, during coadministration of viloxazine. Concurrent use may increase propranolol exposure. Propranolol is metabolized by CYP2D6, CYP1A2 and CYP2C19. Viloxazine is a strong CYP1A2 inhibitor and weak CYP2D6 inhibitor.
    Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased propranolol-related adverse reactions, including bradycardia and hypotension, during coadministration of viloxazine. Concurrent use may increase propranolol exposure. Propranolol is metabolized by CYP2D6, CYP1A2 and CYP2C19. Viloxazine is a strong CYP1A2 inhibitor and weak CYP2D6 inhibitor.
    Protriptyline: (Moderate) Monitor for tricyclic antidepressant-related adverse reactions if coadministration with viloxazine is necessary; a dose reduction of tricyclic antidepressants may be necessary if clinically indicated. Concurrent use may increase exposure of tricyclic antidepressants; tricyclic antidepressants are CYP2D6 substrates and viloxazine is a weak CYP2D6 inhibitor.
    Ramelteon: (Contraindicated) Concomitant use of viloxazine and ramelteon is contraindicated due to the increased risk for ramelteon-related adverse effects and exposure. Ramelteon is a CYP1A2 substrate and viloxazine is a strong CYP1A2 inhibitor. Coadministration with another strong CYP1A2 inhibitor increased ramelteon exposure by 190-fold.
    Rasagiline: (Contraindicated) Concurrent use of viloxazine with rasagiline or within two weeks after discontinuing rasagiline is contraindicated due to the risk for hypertensive crisis. If use is necessary, do not exceed a rasagiline dose of 0.5 mg once daily when coadministered with viloxazine. Coadministration may also result in increased rasagiline concentrations. Rasagiline is primarily metabolized by CYP1A2; viloxazine is a strong CYP1A2 inhibitor. When rasagiline was administered with a strong CYP1A2 inhibitor, the AUC of rasagiline increased by 83%.
    Riluzole: (Moderate) Coadministration of riluzole with viloxazine may increase the risk for riluzole-related adverse reactions, such as gastrointestinal symptoms and elevated hepatic enzymes. In vitro findings suggest an increase in riluzole exposure is likely. Riluzole is a CYP1A2 substrate and viloxazine is a strong CYP1A2 inhibitor.
    Risperidone: (Moderate) Monitor for an increase in risperidone-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase risperidone exposure. Viloxazine is a weak CYP2D6 inhibitor and risperidone is a CYP2D6 substrate.
    Rivaroxaban: (Major) Coadministration of rivaroxaban with other drugs that affect hemostasis, such as selective norepinephrine reuptake inhibitors (SNRIs), increases the risk of bleeding. If these drugs are administered together, instruct patients to monitor for signs and symptoms of bleeding, and to promptly report any bleeding events to their practitioner.
    Roflumilast: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with viloxazine is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A4 and CYP1A2 substrate and viloxazine is a strong CYP1A2 inhibitor and weak CYP3A4 inhibitor. Coadministration of roflumilast with other dual CYP3A4/CYP1A2 inhibitors increased the exposure of roflumilast by 85% to 156%.
    Ropinirole: (Moderate) A dose adjustment of ropinirole may be needed when therapy with viloxazine is initiated or discontinued. Concomitant use of ropinirole and viloxazine may increase the exposure of ropinirole. Ropinirole is a CYP1A2 substrate and viloxazine is a strong CYP1A2 inhibitor. Coadministration with another strong CYP1A2 inhibitor increased ropinirole exposure by 84%.
    Ropivacaine: (Moderate) Use caution when ropivacaine is coadministered with viloxazine. Concomitant use may lead to increased ropivacaine concentrations. Ropivacaine is a CYP1A2 substrate and viloxazine is a strong CYP1A2 inhibitor. Coadministration with another strong CYP1A2 inhibitor decreased the clearance of ropivacaine by 70%.
    Safinamide: (Contraindicated) Concurrent use of viloxazine with safinamide or within two weeks after discontinuing safinamide is contraindicated due to the risk for hypertensive crisis.
    Saquinavir: (Moderate) Monitor for an increase in saquinavir-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase saquinavir exposure; viloxazine is a weak CYP3A inhibitor and saquinavir is a CYP3A substrate.
    Selegiline: (Contraindicated) Selective norepinephrine reuptake inhibitors are contraindicated for use with selegiline because of a possible increased risk of hypertensive crisis. At least 14 days should elapse between discontinuation of selegiline and initiation of treatment with a selective norepinephrine reuptake inhibitor. After stopping treatment with the reuptake inhibitor, a time period equal to 4 to 5 half-lives of the reuptake inhibitor or any active metabolite should elapse before starting therapy with selegiline.
    Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse effects, like myopathy, if concomitant use of viloxazine is necessary. Concomitant use may increase simvastatin exposure; viloxazine is a weak CYP3A inhibitor and simvastatin is a CYP3A substrate.
    Simvastatin; Sitagliptin: (Moderate) Monitor for an increase in simvastatin-related adverse effects, like myopathy, if concomitant use of viloxazine is necessary. Concomitant use may increase simvastatin exposure; viloxazine is a weak CYP3A inhibitor and simvastatin is a CYP3A substrate.
    Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 if coadministration with viloxazine is necessary. The dose of sirolimus may also need to be reduced with coadministration of viloxazine. Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions with coadministration of viloxazine. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; viloxazine is a weak CYP3A inhibitor.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if viloxazine must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of viloxazine is necessary. Sufentanil is a CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like viloxazine can increase sufentanil exposure resulting in increased or prolonged opioid effects.
    Tacrolimus: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with viloxazine is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; viloxazine is a weak CYP3A4 inhibitor.
    Tapentadol: (Major) Caution is advised when tapentadol is coadministered with selective norepinephrine reuptake inhibitors. The combined use of these drugs may result in excessive concentrations of norepinephrine, increasing the risk of adverse cardiac effects. If concomitant treatment is clinically warranted, careful observation of the patient is advised, especially during initiation of the second therapy and after dosage adjustments (increases) of either agent.
    Tasimelteon: (Contraindicated) Concomitant use of viloxazine and tasimelteon is contraindicated due to the increased risk for tasimelteon-related adverse effects and exposure. Tasimelteon is a CYP1A2 substrate and viloxazine is a strong CYP1A2 inhibitor. Coadministration with another strong CYP1A2 inhibitor increased tasimelteon exposure by 7-fold.
    Theophylline, Aminophylline: (Contraindicated) Concomitant use of viloxazine and aminophylline is contraindicated due to the increased risk for aminophylline-related adverse effects and exposure. Theophylline is a CYP1A2 substrate and viloxazine is a strong CYP1A2 inhibitor. (Contraindicated) Concomitant use of viloxazine and theophylline is contraindicated due to the increased risk for theophylline-related adverse effects and exposure. Theophylline is a CYP1A2 substrate and viloxazine is a strong CYP1A2 inhibitor.
    Thioridazine: (Contraindicated) Coadministration of thioridazine and viloxazine is contraindicated due to the potential for increased thioridazine exposure. Increased plasma concentrations of thioridazine are expected to increase the prolongation of the QTc interval associated with thioridazine and may increase the risk of serious, potentially fatal, cardiac arrhythmias, such as torsade de pointes type arrhythmias. Thioridazine is a CYP2D6 substrate and viloxazine is a weak CYP2D6 inhibitor.
    Timolol: (Moderate) Monitor for increased timolol-related adverse reactions, including bradycardia and hypotension, during coadministration with viloxazine. Concomitant use may increase timolol exposure. Timolol is a CYP2D6 substrate and viloxazine is a weak CYP2D6 inhibitor.
    Tipranavir: (Moderate) Monitor for an increase in tipranavir-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase tipranavir exposure; viloxazine is a weak CYP3A inhibitor and tipranavir is a CYP3A substrate. The clinical significance of this interaction is unclear as the level of tipranavir metabolites is low at steady-state.
    Tizanidine: (Contraindicated) Concomitant use of viloxazine and tizanidine is contraindicated due to the increased risk for tizanidine-related adverse effects and exposure. Tizanidine is a CYP1A2 substrate and viloxazine is a strong CYP1A2 inhibitor. Coadministration with other strong CYP1A2 inhibitors increased the exposure of tizanidine by 10 and 33-fold.
    Tolterodine: (Moderate) Monitor for an increase in tolterodine-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase tolterodine exposure; viloxazine is a weak CYP2D6 inhibitor and tolterodine is a CYP2D6 substrate.
    Tramadol: (Moderate) Concurrent use of tramadol with viloxazine may produce unpredictable effects, including prolonged opioid-related adverse reactions, such as fatal respiratory depression, a withdrawal syndrome in those with physical dependence to opioid agonists, seizures, or serotonin syndrome. Consider dose adjustments of tramadol until stable drug effects are achieved. Monitor patients closely for respiratory depression and sedation at frequent intervals. Tramadol is primarily metabolized by CYP2D6 to the active metabolite M1, and by CYP3A4; viloxazine is a dual weak CYP2D6 and weak CYP3A4 inhibitor. CYP3A4 inhibitors may increase tramadol-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Tramadol; Acetaminophen: (Moderate) Concurrent use of tramadol with viloxazine may produce unpredictable effects, including prolonged opioid-related adverse reactions, such as fatal respiratory depression, a withdrawal syndrome in those with physical dependence to opioid agonists, seizures, or serotonin syndrome. Consider dose adjustments of tramadol until stable drug effects are achieved. Monitor patients closely for respiratory depression and sedation at frequent intervals. Tramadol is primarily metabolized by CYP2D6 to the active metabolite M1, and by CYP3A4; viloxazine is a dual weak CYP2D6 and weak CYP3A4 inhibitor. CYP3A4 inhibitors may increase tramadol-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Tranylcypromine: (Contraindicated) The use of selective norepinephrine reuptake inhibitors with monoamine oxidase inhibitors (MAOIs) is contraindicated. At least 2 weeks should elapse between the discontinuation of a drug with MAO inhibiting activity and the start of selective norepinephrine reuptake inhibitors, or vice-versa. Selective norepinephrine reuptake inhibitors potentiate certain catecholamines by inhibiting neuronal reuptake. Reactions with MAOIs may include confusion, seizures, and severe hypertension as well as less severe symptoms.
    Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with viloxazine and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A substrate and viloxazine is a weak CYP3A inhibitor
    Tricyclic antidepressants: (Moderate) Monitor for tricyclic antidepressant-related adverse reactions if coadministration with viloxazine is necessary; a dose reduction of tricyclic antidepressants may be necessary if clinically indicated. Concurrent use may increase exposure of tricyclic antidepressants; tricyclic antidepressants are CYP2D6 substrates and viloxazine is a weak CYP2D6 inhibitor.
    Trimipramine: (Moderate) Monitor for tricyclic antidepressant-related adverse reactions if coadministration with viloxazine is necessary; a dose reduction of tricyclic antidepressants may be necessary if clinically indicated. Concurrent use may increase exposure of tricyclic antidepressants; tricyclic antidepressants are CYP2D6 substrates and viloxazine is a weak CYP2D6 inhibitor.
    Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with viloxazine. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; viloxazine is a weak CYP3A4 inhibitor.
    Vardenafil: (Moderate) Monitor for an increase in vardenafil-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase vardenafil exposure; viloxazine is a weak CYP3A inhibitor and vardenafil is a CYP3A substrate.
    Venlafaxine: (Moderate) Monitor for an increase in venlafaxine-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase venlafaxine exposure; viloxazine is a weak CYP2D6 inhibitor and venlafaxine is a CYP2D6 substrate. Since both drugs may increase blood pressure via blocking of norepinephrine reuptake, blood pressure and heart rate should be monitored periodically.
    Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with viloxazine is necessary. Vinorelbine is a CYP3A4 substrate and viloxazine is a weak CYP3A4 inhibitor.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with viloxazine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP1A2 and CYP3A substrate; viloxazine is a strong CYP1A2 and weak CYP3A inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.

    PREGNANCY AND LACTATION

    Pregnancy

    Viloxazine may cause maternal harm when used during pregnancy based on findings from animal reproduction studies. Discontinue viloxazine 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 or higher 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/m2, 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. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to viloxazine during pregnancy. Health care providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at www.womensmentalhealth.org/preg. The effect of viloxazine on labor and delivery is unknown.

    There are no data on the presence of viloxazine in human milk, the effects on the breastfed 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 also be present in human milk. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for viloxazine and any potential adverse effects on the breastfed child from viloxazine or from the underlying maternal condition. Consider if an alternate drug would be preferred, especially while the woman is nursing a newborn or preterm infant. Although methylphenidate may be considered as an alternative to other ADHD medications during lactation and breast-feeding due to low excretion into breastmilk, the medical use of stimulant medications during breast-feeding has not been formally evaluated. The nursing infant should be monitored for signs of potential toxicity, such as poor feeding, irritability, or changes in sleep patterns.

    MECHANISM OF ACTION

    Viloxazine is a selective norepinephrine reuptake inhibitor. The mechanism of action of viloxazine in the treatment of attention-deficit hyperactivity disorder (ADHD) is unclear; however, it is thought to be through inhibiting the reuptake of norepinephrine.

    PHARMACOKINETICS

    Viloxazine is administered orally. It is 76% to 82% bound to human plasma proteins over the blood concentration range of 0.5 to 10 mcg/mL. The viloxazine Cmax and AUC increase proportionally over a dosage range from 100 mg to 400 mg once daily. Steady-state is reached after 2 days of once-daily administration, and no accumulation is observed. Viloxazine is primarily metabolized by CYP2D6, UGT1A9, and UGT2B15. The major metabolite detected in plasma is 5-hydroxy-viloxazine glucuronide. Renal excretion is the primary route of excretion of viloxazine. After administration of radiolabeled viloxazine, 90% of the dose was recovered in urine within the first 24 hours post-dose; less than 1% of the dose was excreted in the feces. The mean (+/- SD) half-life of viloxazine was 7.02 +/- (4.74 hours).
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP2D6, CYP3A4, CYP2B6, MATE1
    Viloxazine is a strong inhibitor of CYP1A2 and moderate inhibitor of CYP2D6 and CYP3A4. Viloxazine is a reversible inhibitor of these enzymes and CYP2B6. Because of viloxazine's inhibition of CYP1A2, this drug is contraindicated in patients receiving concomitant administration of sensitive CYP1A2 substrates or CYP1A2 substrates with a narrow therapeutic range. Viloxazine is a potential inducer of CYP1A2 and CYP2B6. Viloxazine is primarily metabolized by CYP2D6, UGT1A9, and UGT2B15. However, based on in vitro data, drugs that inhibit CYP2D6 are not expected to have a significant impact on the pharmacokinetics of viloxazine.
     
    Based on in vitro data, drugs that inhibit CYP450 isozymes 1A1, 1A2, 2B6, 2C8, 2C9, 2C19, and 2E1 are not expected to have significant impact on the pharmacokinetic profile of viloxazine. Viloxazine does not inhibit CYP2C8, 2C9 or 2C19. Viloxazine appears to be a weak inhibitor of the MATE1 transporter. The drug is not an inhibitor of P-glycoprotein (P-gp), BCRP, MATE2-K, OATP1B1 1a, or OATP1B3 transporters. Viloxazine is not a substrate of either OATP1B1 1a or OATP1B3 transporters.

    Oral Route

    The relative bioavailability of viloxazine extended-release capsules relative to an immediate-release formulation was about 88%. The median (range) time to peak plasma concentration of viloxazine (Tmax) was approximately 5 hours (range: 3 to 9 hours) following a single 200 mg dose. The administration of 200 mg viloxazine extended-release capsules with a high-fat meal (800 to 1,000 calories) decreased viloxazine Cmax and AUC by approximately 9% and 8%, respectively. Viloxazine Tmax increased by approximately 2 hours after administration with a high-fat meal. Sprinkling the contents of a capsule on applesauce decreased viloxazine Cmax and AUC by approximately 10% and 5%, respectively. The product can be taken with or without food.