DailyMed Label: QELBREE

DailyMed Label: QELBREE

2023

DailyMed Prescription

QELBREE

viloxazine hydrochloride

Supernus Pharmaceuticals, Inc

NDC: 17772-131

NDC: 17772-132

NDC: 17772-133

NDC: 17772-131

NDC: 17772-132

NDC: 17772-133

NDC: 17772-131

NDC: 17772-132

NDC: 17772-133

NDC: 17772-131

NDC: 17772-132

NDC: 17772-133

NDC: 17772-131

NDC: 17772-132

NDC: 17772-133

NDC: 17772-131

NDC: 17772-132

NDC: 17772-133

NDC: 17772-131

NDC: 17772-132

NDC: 17772-133

NDC: 17772-131

NDC: 17772-132

NDC: 17772-133

NDC: 17772-131

NDC: 17772-131

NDC: 17772-132

NDC: 17772-132

NDC: 17772-133

NDC: 17772-133

Qelbree contains viloxazine, a selective norepinephrine reuptake inhibitor, in the form of viloxazine hydrochloride which is (±)-2-[(2-ethoxyphenoxy)methyl]morpholine hydrochloride. The molecular formula is C 13 H 20 NO 3 Cl and its molecular weight is 273.8 (HCl salt) with the following structural formula: Viloxazine hydrochloride is a white to off-white powder. Viloxazine hydrochloride is soluble in water, 0.1N HCl and aqueous solutions of pH 9.5 and lower. Viloxazine hydrochloride is sparingly soluble in methanol, very slightly soluble in acetonitrile, acetic acid and isopropyl alcohol, and practically insoluble in ethyl acetate. Qelbree extended-release capsules are intended for oral administration. Each extended-release capsule contains 100 mg, 150 mg, and 200 mg of viloxazine free base equivalent to 115mg, 173mg, and 231mg, respectively, of viloxazine hydrochloride salt. The inactive ingredients are: Ammonium hydroxide, black iron oxide, butyl alcohol, corn starch, ethylcellulose, FD&C Blue #1, FD&C Red #28, FD&C Yellow #5, FD&C Yellow #6, FD&C Yellow #10, gelatin, hypromellose, isopropyl alcohol, lactose monohydrate, medium chain triglycerides, oleic acid, polyethylene glycol, potassium hydroxide, propylene glycol, shellac, strong ammonia solution, sucrose, talc, triacetin, titanium dioxide. Chemical Structure

Qelbree is indicated for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD) in adults and pediatric patients 6 years and older. Qelbree is a selective norepinephrine reuptake inhibitor indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in adults and pediatric patients 6 years and older ( 1 )

Pediatric patients 6 to 11 years of age : Recommended starting dosage is 100 mg once daily. May titrate in increments of 100 mg weekly to the maximum recommended dosage of 400 mg once daily ( 2.2 ) Pediatric patients 12 to 17 years of age : Recommended starting dosage is 200 mg once daily. May titrate after 1 week, by an increment of 200mg, to the maximum recommended dosage of 400 mg once daily ( 2.2 ) Adult patients : Recommended starting dosage is 200 mg once daily. May titrate in increments of 200 mg weekly, to maximum recommended dosage of 600 mg once daily ( 2.2 ) Capsules may be swallowed whole or opened and the entire contents sprinkled onto applesauce or pudding ( 2.3 ) Severe Renal Impairment : Initial dosage is 100 mg once daily. Titrate in weekly increments of 50 mg to 100 mg to a maximum recommended dosage of 200 mg once daily ( 2.4 , 8.6 ) Assess heart rate and blood pressure prior to initiating treatment with Qelbree, following increases in dosage, and periodically while on therapy [see Warnings and Precautions (5.2) ] . Prior to initiating treatment with Qelbree, screen patients for a personal or family history of suicide, bipolar disorder, and depression [see Warnings and Precautions (5.3) ]. Pediatric patients The recommended starting dosage for pediatric patients 6 to 11 years of age is 100 mg orally once daily. Dosage may be titrated in increments of 100 mg at weekly intervals to the maximum recommended dosage of 400 mg once daily, depending on response and tolerability. The recommended starting dosage for pediatric patients 12 to 17 years of age is 200 mg orally once daily. After 1 week, dosage may be titrated by an increment of 200 mg to the maximum recommended dosage of 400 mg once daily, depending on response and tolerability. Adult patients The recommended starting dosage for adults is 200 mg orally once daily. Dosage may be titrated in increments of 200 mg weekly to the maximum recommended dosage of 600 mg once daily, depending on response and tolerability. Pharmacological treatment of ADHD may be needed for extended periods. Periodically reevaluate the long-term use of Qelbree and adjust dosage as needed. Administer Qelbree orally with or without food [see Clinical Pharmacology (12.3) ] . Do not cut, crush, or chew the capsules. Swallow Qelbree capsules whole, or open the capsule and sprinkle the entire contents over a teaspoonful or tablespoonful of pudding or applesauce. Consume the food mixture in its entirety, without chewing, within 15 minutes for pudding, or within 2 hours for applesauce; do not store for future use. In patients with severe renal impairment (eGFR < 30 mL/min/1.73m 2 ), the recommended starting dosage is 100 mg once daily. Dosage may be titrated in weekly increments of 50 to 100 mg once daily, to a maximum recommended dosage of 200 mg once daily. No dosage adjustment is recommended in patients with mild to moderate (eGFR of 30 to 89 mL/min/1.73m 2 ) renal impairment [see Use in Specific Populations (8.6) ] .

Qelbree (viloxazine extended-release capsules) are available as: 100 mg: yellow opaque body and cap (printed "SPN" on the cap, "100" on the body) 150 mg: lavender opaque body and cap (printed "SPN" on the cap, "150" on the body) 200 mg: light green opaque body and cap (printed "SPN" on the cap, "200" on the body) Extended-release capsules: 100 mg, 150 mg and 200 mg ( 3 )

Qelbree is contraindicated in patients: receiving concomitant treatment with monoamine oxidase inhibitors (MAOI), or within 14 days following discontinuing an MAOI, because of an increased risk of hypertensive crisis [see Drug Interactions (7.1) ] . receiving concomitant administration of sensitive CYP1A2 substrates or CYP1A2 substrates with a narrow therapeutic range [see Drug Interactions (7.1) ]. Concomitant administration of monoamine oxidase inhibitors (MAOI), or dosing within 14 days after discontinuing an MAOI ( 4 , 7.1 ) Concomitant administration of sensitive CYP1A2 substrates or CYP1A2 substrates with a narrow therapeutic range ( 4 , 7.1 )

Blood Pressure and Heart Rate Increases: Assess heart rate and blood pressure prior to initiating treatment, following increases in dosage, and periodically while on therapy ( 5.2 ) Activation of Mania or Hypomania: Screen patients for bipolar disorder ( 5.3 ) Somnolence and Fatigue: Advise patients to use caution when driving or operating hazardous machinery due to potential somnolence (including sedation and lethargy) and fatigue ( 5.4 ) Higher rates of suicidal thoughts and behaviors were reported in pediatric and adult patients with ADHD treated with Qelbree than in patients treated with placebo. Among 1019 pediatric patients exposed to Qelbree 100 mg to 400 mg in short-term trials, a total of nine patients (0.9%) reported suicidal ideation (N=6), behavior (N=1) or both (N=2). Eight patients reported suicidal ideation or behavior on the Columbia Suicide Severity Rating Scale (C-SSRS), a validated scale that assesses suicide risk. An additional patient treated with Qelbree reported suicidal behavior during the clinical trials, but did not report it on the C-SSRS. Among 463 patients treated with placebo in these studies, two patients (0.4%) reported suicidal ideation on the C-SSRS. No patients treated with placebo reported suicidal behavior. No completed suicides occurred in these trials. Among 189 adults treated with Qelbree, a total of three patients (1.6%) reported suicidal ideation on the C-SSRS, versus 0 of 183 adults treated with placebo. No adults treated with either Qelbree or placebo reported suicidal behavior on the C-SSRS in the study. No attempted or completed suicides occurred in the trial. Patients treated with Qelbree had higher rates of insomnia and irritability [see Adverse Reactions (6.1) ] . Although a causal link between the emergence of insomnia and irritability and the emergence of suicidal impulses has not been established, there is a concern that these and other symptoms such as depressed mood, anxiety, agitation, akathisia, mania, hypomania, panic attacks, impulsive behavior, and aggression may represent precursors to emerging suicidal ideation or behavior. Thus, patients being treated with Qelbree should be observed for the emergence of precursor symptoms. Closely monitor all Qelbree-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Consider changing the therapeutic regimen, including possibly discontinuing Qelbree, in patients who are experiencing emergent suicidal thoughts and behaviors or symptoms that might be precursors to emerging suicidal ideation or behavior, especially if these symptoms are severe or abrupt in onset, or were not part of the patient's presenting symptoms. Advise family members or caregivers of patients to monitor for the emergence of suicidal ideation or behavior, and to report such symptoms immediately to the healthcare provider. Qelbree can cause an increase in heart rate and diastolic blood pressure. Pediatric Patients In a clinical study in pediatric patients 6 to 11 years of age, 34/154 (22%) of patients treated with Qelbree 100 mg daily had a ≥20 beat per minute (bpm) increase in heart rate at any time point in the clinical trial, compared to 15/159 (9%) of patients who received placebo. This finding was observed in 84/268 (31%) who received the 200 mg daily dosage, compared to 39/262 (15%) of patients in the placebo group, and in 28/100 (28%) of patients who received the 400 mg daily dosage, compared to 24/103 (23%) of patients who received placebo. In a clinical study in pediatric patients 12 to 17 years of age, 22/99 (22%) of patients treated with Qelbree 200 mg daily had a ≥20 bpm increase in heart rate at any time point in the clinical trial, compared to 15/104 (14%) of patients who received placebo. This finding was observed in 69/205 (34%) who received the 400 mg daily dosage, compared to 35/201 (17%) of patients in the placebo group. In pediatric patients 12 to 17 years of age, 52/205 (25%) of patients treated with Qelbree 400 mg daily had a ≥ 15 mmHg increase in diastolic blood pressure at any time in the clinical trial, compared to 26/201 (13%) of patients in the placebo group. Adult Patients In a clinical study in adult patients (18 to 60 years of age), 52/178 (29%) of patients treated daily with Qelbree (200 mg to 600 mg) had a ≥20 beat per minute (bpm) increase in heart rate at any time point in the clinical trial, compared to 23/181 (13%) of patients who received placebo. Of patients treated daily with Qelbree (200 to 600 mg), 23/178 (13%) had a ≥ 15 mmHg increase in diastolic blood pressure at any time in the clinical trial, compared to 16/181 (9%) of patients in the placebo group. Assess heart rate and blood pressure prior to initiating treatment with Qelbree, following increases in dosage, and periodically while on therapy [see Dosage and Administration (2.1) ] . Noradrenergic drugs, such as Qelbree, may induce a manic or mixed episode in patients with bipolar disorder. Prior to initiating treatment with Qelbree, 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 [see Dosage and Administration (2.1) ]. Qelbree can cause somnolence and fatigue. In the short-term, placebo-controlled clinical trials in pediatric patients (6 to 17 years) with ADHD, somnolence (including lethargy and sedation) was reported in 16% of Qelbree-treated patients compared to 4% of placebo-treated patients. Fatigue was reported in 6% of Qelbree-treated patients, compared to 2% of placebo-treated patients [see Adverse Reactions (6.1) ] . In adults, somnolence was reported in 6% of Qelbree-treated patients versus 2% in placebo-treated patients. Fatigue was reported in 12% of Qelbree-treated patients versus 3% of placebo-treated patients. Patients should not perform activities requiring mental alertness, such as operating a motor vehicle or operating hazardous machinery until they know how they will be affected by Qelbree.

The following serious adverse reactions are described in other sections of the labeling:

Moderate sensitive CYP1A2 substrates : Not recommended for coadministration with Qelbree. Dose reduction may be warranted ( 7.1 ) Table 3: Clinically Important Drug Interactions with Qelbree Monoamine Oxidase Inhibitors (MAOI) Clinical Impact Concomitant use of Qelbree with an MAOI may lead to a potentially life-threatening hypertensive crisis. Intervention Concomitant use of Qelbree with an MAOI or within 2 weeks after discontinuing an MAOI is contraindicated [see Contraindications (4) ] . Sensitive CYP1A2 Substrates or CYP1A2 Substrates with a Narrow Therapeutic Range Clinical Impact Viloxazine is a strong CYP1A2 inhibitor. Concomitant use of viloxazine significantly increases the total exposure, but not peak exposure, of sensitive CYP1A2 substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions associated with these CYP1A2 substrates. Intervention Coadministration with Qelbree is contraindicated [see Contraindications (4) ] . Moderate Sensitive CYP1A2 Substrate Clinical Impact Viloxazine is a strong CYP1A2 inhibitor. Concomitant use of viloxazine significantly increases the total, but not peak, exposure of sensitive CYP1A2 substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions associated with these CYP1A2 substrates. Intervention Not recommended for coadministration with Qelbree. Dose reduction may be warranted if coadministered. CYP2D6 Substrates Clinical Impact Viloxazine is a weak inhibitor of CYP2D6, and increases the exposure of CYP2D6 substrates when coadministered [see Clinical Pharmacology (12.3) ] . Intervention Monitor patients for adverse reactions and adjust dosages of CYP2D6 substrates, as clinically indicated. CYP3A4 Substrates Clinical Impact Viloxazine is a weak inhibitor of CYP3A4 which increases the exposure of CYP3A4 substrates when coadministered [see Clinical Pharmacology (12.3) ]. Intervention Monitor patients for adverse reactions and adjust dosages of CYP3A4 substrates, as clinically indicated.

Pregnancy : May cause maternal harm; discontinue when pregnancy is recognized ( 8.1 ) Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed Qelbree during pregnancy. Healthcare 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. Risk Summary Based on findings from animal reproduction studies, viloxazine may cause maternal harm when used during pregnancy. Discontinue Qelbree 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 during the period of organogenesis caused fetal toxicities and delayed fetal development in the rat and maternal toxicities in the rabbit at doses approximately equal to the maximum recommended human dose (MRHD) of 600 mg in adults, based on mg/m 2 .Oral administration of viloxazine to pregnant rats and mice during pregnancy and lactation caused maternal toxicities and deaths and fetal toxicities at doses equal to or less than the MRHD of 600 mg in adults, based on mg/m 2 , respectively (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Viloxazine was administered orally to pregnant rats during the period of organogenesis at doses of 13, 33, and 82 mg/kg/day. The high dose is approximately equal to the MRHD of 600 mg in adults, based on mg/m 2 . Viloxazine did not cause maternal toxicity up to the high dose. Viloxazine at the high dose increased early and late resorption, delayed fetal development, and possibly caused low incidences of fetal malformations or anomalies (craniorachischisis, missing cervical vertebrae, and morphological changes associated with hydranencephaly). The NOAEL for fetal toxicity and malformation is 33 mg/kg/day, which is less than the MRHD of 600 mg in adults, based on mg/m 2 . Viloxazine was administered orally to pregnant rabbits during the period of organogenesis at doses of 43, 87, and 130 mg/kg/day, which are approximately 1, 3, and 4 times the MRHD of 600 mg in adults, based on mg/m 2 , respectively. Viloxazine decreased maternal body weight, weight gain, or food consumption at doses ≥ 87 mg/kg/day but did not cause fetal toxicity at doses up to 130 mg/kg/day. The NOAELs for maternal and fetal toxicity is 43 and 130 mg/kg/day, respectively, which is approximately 1 and 4 times the MRHD, based on mg/m 2 , respectively. Viloxazine was administered orally to pregnant rats during gestation and lactation at doses of 43, 87, and 217 mg/kg/day, which are less than, equal to , and 4 times the MRHD of 600 mg in adults, based on mg/m 2 , respectively. Viloxazine caused maternal toxicity of decreased body weight, weight gain, and food consumption at doses ≥ 87 mg/kg/day and maternal deaths near term at 217 mg/kg/day. At these maternally toxic doses, viloxazine caused lower live birth, decreased viability, and delayed growth and sexual maturation without affecting learning and memory in the offspring. The NOAEL for maternal and developmental toxicity is 43 mg/kg/day, which is less than the MRHD of 600 mg in adults, based on mg/m 2 . Viloxazine was administered orally to pregnant mice during gestation and lactation at doses of 13, 33, and 82 mg/kg/day, which are less than the MRHD of 600 mg in adults, based on mg/m 2 ,. Viloxazine treatment at 82 mg/kg/day during the gestation period caused maternal deaths and decreased body weight in the offspring. The NOAEL for both maternal and developmental toxicity is 33 mg/kg/day, which is less than the MRHD of 600 mg in adults, based on mg/m 2 . Risk Summary 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 be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Qelbree and any potential adverse effects on the breastfed child from Qelbree or from the underlying maternal condition. The safety and effectiveness of Qelbree in pediatric patients 6 to 17 years of age with ADHD have been established based on randomized, placebo-controlled studies in pediatric patients [see Adverse Reactions (6.1) and Clinical Studies (14) ] . The safety and effectiveness of Qelbree have not been established in pediatric patients younger than 6 years old. Patients treated with Qelbree should be monitored for suicidal thoughts and behavior [see Warnings and Precautions (5.1) ] , and for changes in weight [see Adverse Reactions (6.1) ]. Juvenile Animal Toxicity Data Viloxazine was administered orally to juvenile rats from postnatal day (PND) 23 through PND 79 at doses of 43, 130, and 217 mg/kg/day, which are approximately 1, 2, and 3 times the MRHD of 400 mg in children, based on mg/m 2 , respectively. Viloxazine decreased body weight, weight gain, and food consumption in both sexes at 217 mg/kg/day. Sexual maturation, reproductive capacity, and learning and memory were not affected. The NOAEL for juvenile toxicity is 130 mg/kg/day, which is approximately 2 times the MRHD of 400 mg in children, based on mg/m 2 . Clinical trials of Qelbree in the treatment of ADHD did not include sufficient numbers of patients aged 65 and older to determine whether or not they respond differently from younger patients. Dosage reduction is recommended in patients with severe (eGFR of < 30 mL/min/1.73m 2 [MDRD]) renal impairment [see Dosage and Administration (2.4) ] . No dosage adjustment of Qelbree is recommended in patients with mild to moderate (eGFR of 30 to 89 mL/min/1.73m 2 [MDRD]) renal impairment. The exposure of viloxazine increases in patients with renal impairment [see Clinical Pharmacology (12.3) ].

How Supplied Qelbree (viloxazine extended-release capsules) are available in the following strengths and colors: 100mg (yellow capsule printed with "SPN" on capsule cap and "100" on capsule body with edible black ink). Bottles of 100 capsules………………..…….NDC 17772-131-01 Bottles of 90 capsules……………………….NDC 17772-131-90 Bottles of 60 capsules……………………….NDC 17772-131-60 Bottles of 30 capsules……………………….NDC 17772-131-30 150mg (lavender capsule printed with "SPN" on capsule cap and "150" on capsule body with edible black ink). Bottles of 100 capsules………………………NDC 17772-132-01 Bottles of 90 capsules………………………..NDC 17772-132-90 Bottles of 60 capsules………………………..NDC 17772-132-60 Bottles of 30 capsules………………………..NDC 17772-132-30 200mg (light green capsule printed with "SPN" on capsule cap and "200" on capsule body with edible black ink). Bottles of 100 capsules…………………..…NDC 17772-133-01 Bottles of 90 capsules………………………NDC 17772-133-90 Bottles of 60 capsules………………………NDC 17772-133-60 Bottles of 30 capsules………………………NDC 17772-133-30 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).

The mechanism of action of viloxazine in the treatment of ADHD is unclear; however, it is thought to be through inhibiting the reuptake of norepinephrine. Viloxazine binds to the norepinephrine transporter (NET, Ki= 0.63 µM) and inhibits the reuptake of norepinephrine (IC 50 =0.2 µM). Cardiac Electrophysiology At a dose 3 times the maximum recommended dose, Qelbree did not prolong the QT interval to any clinically relevant extent. There was no effect of Qelbree on the PR interval or QRS duration in healthy volunteers. However, nonclinical studies suggest the potential for Qelbree to inhibit cardiac sodium channels. Viloxazine C max and AUC increase proportionally over a dosage range from 100 mg to 600 mg once daily. Steady-state was reached after two days of once-daily administration, and no accumulation was observed. Absorption The relative bioavailability of viloxazine extended-release relative to an immediate-release formulation was about 88%. The median (range) time to peak plasma concentration of viloxazine (T max ) was approximately 5 hours, with a range of 3 to 9 hours, following a single 200 mg dose. Effect of Food Administration of 200 mg viloxazine extended-release with a high-fat meal (800 to 1000 calories) decreased viloxazine C max and AUC by about 9% and 8%, respectively. Viloxazine T max increased by about 2 hours after administration with a high-fat meal. Sprinkling the contents of a capsule on applesauce decreased viloxazine C max and AUC by about 10% and 5%, respectively. Distribution Viloxazine is 76-82% bound to human plasma proteins over the blood concentration range of 0.5 mcg/mL to 10 mcg/mL. Elimination The mean (± SD) half-life of viloxazine was 7.02 ± (4.74 hours). Metabolism Viloxazine is primarily metabolized by CYP2D6, UGT1A9, and UGT2B15. The major metabolite detected in plasma is 5-hydroxy-viloxazine glucuronide. Excretion 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 is excreted in the feces. Specific Populations Geriatric Patients No studies were conducted to evaluate pharmacokinetics in the geriatric population. Pediatric Patients The estimated steady-state C max and AUC 0-t of viloxazine and its major metabolite, at doses ranging from 200 mg to 400 mg, was approximately 130-250% and 60-140% higher in pediatric patients 6 to 11 and 12 to 17 years of age, respectively, compared to adults. Male or Female Patients and Racial or Ethnic Groups No clinically significant differences in the pharmacokinetics of viloxazine was observed based on race and sex. Patients with Hepatic and Renal Impairment Exposures of viloxazine in patients with hepatic and renal impairment are summarized in Figure 1 [see Dosage and Administration (2.4) and Use in Specific Populations (8.6) ] Figure 1: Effect of Hepatic and Renal Impairment on Viloxazine Pharmacokinetics Figure 1 CYP2D6 Metabolism A multiple-dose study was conducted with Qelbree 900 mg once-daily in healthy volunteers to compare the effect of CYP2D6 poor metabolizers (PMs) and extensive metabolizers (EMs) on the PK of viloxazine. At steady state, viloxazine geometric means for C max and AUC 0-24 were 21% and 26%, respectively, higher in CYP2D6 PMs compared to EMs. Drug Interaction Studies Alcohol : There was no significant effect on viloxazine C max and AUC when 200 mg viloxazine ER was administered with orange juice containing 4% and 20% alcohol. However, when administered with orange juice containing 40% alcohol, C max and AUC of viloxazine decreased by about 32% and 19%, respectively. The effect of other drugs on the pharmacokinetics of viloxazine is presented in Figure 2. Figure 2: Effects of Other Drugs on Viloxazine Pharmacokinetics The effect of viloxazine on the pharmacokinetics of other drugs is presented in Figure 3 [see Drug Interactions (7.1) ] . Figure 3: Effect of Viloxazine on the Pharmacokinetics of Other Drugs Figure 2 Figure 3 In Vitro Studies Based on in vitro data, drugs that inhibit CYP isozymes, 1A2, 2B6, 2D6, 2C8, 2C9, 2C19, 2E1 and 3A4 are not expected to have significant impact on the pharmacokinetic profile of viloxazine. Viloxazine does not inhibit CYP2C8, 2C9 or 2C19 activities. Viloxazine is a reversible inhibitor of P450-1A2, 2B6, 2D6 and 3A4/5. Viloxazine is a potential inducer of CYP1A2 and CYP2B6. Viloxazine is not an inhibitor of P-gp, BCRP, MATE2-K, OATP1B1*1a, and OATP1B3 transporters. Viloxazine appears to be a weak inhibitor of the MATE1. Viloxazine is not a substrate of either OATP1B1*1a or OATP1B3 transporters.

Carcinogenesis Viloxazine did not increase the incidence of tumors in rats treated for 2 years at oral doses of 22, 43, and 87 mg/kg/day. The high dose of 87 mg/kg/day is approximately equal to the MRHD of 600 mg in adults, based on mg/m 2 . Viloxazine did not increase the incidence of tumors in Tg.rasH2 mice treated for 26 weeks at oral doses of 4.3, 13, and 43 mg/kg/day. Mutagenesis Viloxazine was not genotoxic in a battery of genotoxicity tests. It was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in the in vitro mammalian chromosomal aberration assay or in the in vivo rat bone marrow micronucleus assay. Impairment of Fertility Viloxazine was orally administered to male and female rats prior to and throughout mating and continued until completion of the second littering at doses of 13, 33, and 82 mg/kg/day. Viloxazine did not affect male or female fertility parameters. The NOAEL for male and female fertility is 82 mg/kg/day, which is approximately equal to the MRHD of 600 mg in adults, based on mg/m 2 . In animal studies, viloxazine treatment caused dose-dependent convulsions at oral doses of ≥ 130, ≥ 173, and ≥ 39 mg/kg/day in the rat, mouse, and dog, respectively, which are approximately equal to or slightly higher than the MRHD of 600 mg in adults, based on mg/m 2 .

ADHD Studies in Pediatric Patients The efficacy of Qelbree in the treatment of ADHD in pediatric patients 6 to 17 years of age was evaluated in three short-term, randomized, placebo-controlled monotherapy trials (Studies 1, 2, and 3). Study 1 (NCT03247530) was a multicenter, randomized, double-blind, three-arm placebo-controlled, parallel group monotherapy trial in patients 6 to 11 years of age with ADHD. Total duration of treatment was 6 weeks, including a 1-week titration period (starting at 100 mg once daily) and 5-week maintenance phase. Patients were randomized to receive 100 mg, 200 mg, or placebo, given once daily as a single dose. The primary endpoint was the change from baseline to the end of study on the total score on the ADHD Rating Scale (ADHD-RS-5), an 18-question scale that assesses hyperactivity, impulsivity, and inattentive symptoms. Higher ADHD-RS-5 scores reflect more severe symptoms. The Clinical Global Impression-Improvement (CGI-I) score at the end of the study was a secondary endpoint. A total of 477 patients were randomized in Study 1; 399 completed the study, and 78 discontinued. The change from baseline (reduction) in ADHD-RS-5 total score was statistically significantly greater in patients treated with Qelbree 100 mg or with Qelbree 200 mg than in patients on placebo (see Table 4 ). Compared with patients on placebo, a statistically significantly greater reduction (improvement) in CGI-I score at the end of the study was observed both in patients treated with Qelbree 100 mg and in patients treated with Qelbree 200 mg. Study 2 (NCT03247543) was a multicenter, randomized, double-blind, three-arm, placebo-controlled, parallel-group monotherapy trial in patients 6 to 11 years of age with ADHD. Total duration of treatment was 8 weeks, including a 3-week titration period (starting at 100 mg once daily), and a 5-week maintenance phase. Patients were randomized to receive Qelbree 200 mg, Qelbree 400 mg, or placebo, given once daily as a single dose. The primary endpoint was the change from baseline to the end of study on the total score on the ADHD Rating Scale (ADHD-RS-5). The Clinical Global Impression-Improvement (CGI-I) score at the end of the study was a secondary endpoint. A total of 313 patients were randomized in Study 2; 251 completed the study, and 62 discontinued. The change from baseline (reduction) in ADHD-RS-5 total score was statistically significantly greater in patients treated with Qelbree 200 mg or with Qelbree 400 mg than in patients on placebo (see Table 4 ). Compared with patients on placebo, a statistically significantly greater reduction (improvement) in CGI-I score at the end of the study was observed both in patients treated with Qelbree 200 mg and in patients treated with Qelbree 400 mg. Study 3 (NCT03247517) was a multicenter, randomized, double-blind, three-arm, placebo-controlled, parallel-group monotherapy trial in patients 12 to 17 years of age with ADHD. Total duration of treatment was 6 weeks, including 1-week titration period (starting at 200mg once daily) and a 5-week maintenance phase. Patients were randomized to receive Qelbree 200 mg, Qelbree 400 mg, or placebo, given once daily as a single dose. The primary endpoint was the change from baseline to the end of study on the total score on the ADHD Rating Scale (ADHD-RS-5). The Clinical Global Impression-Improvement (CGI-I) score at the end of the study was a secondary endpoint. A total of 310 patients were randomized in Study 3; 266 completed and 44 discontinued. The change from baseline (reduction) in ADHD-RS-5 total score was statistically significantly greater in patients treated with Qelbree 200 mg or with Qelbree 400 mg than in patients on placebo (see Table 4 ). Compared with patients on placebo, a statistically significantly greater reduction (improvement) in CGI-I score at the end of the study was observed both in patients treated with Qelbree 200 mg and in patients treated with Qelbree 400 mg. Table 4. Primary Efficacy Results for Change from Baseline in ADHD-RS-5 Total Score in Pediatric Patients (6 to 17 years) with ADHD (Studies 1, 2, 3) Study Number (Age range) Treatment Group Primary Efficacy Measure: ADHD-RS-5 Total Score n Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline (95% CI) ADHD-RS-5 = Attention-Deficit/Hyperactivity Disorder Rating Scale 5 th Edition; n: sample size; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not adjusted for multiple comparisons Study 1 (6 to 11 years) 100 mg/day Doses that are statistically significantly superior to placebo after multiplicity adjustment 147 45.0 (6.53) -16.6 (1.16) -5.8 (-8.9, -2.6) 200 mg/day 158 44.0 (6.80) -17.7 (1.12) -6.9 (-10.0, -3.8) Placebo 155 43.6 (7.05) -10.9 (1.14) -- Study 2 (6 to 11 years) 200 mg/day 107 43.8 (6.54) -17.6 (1.43) -6.0 (-10.0, -1.9) 400 mg/day 97 45.0 (6.55) -17.5 (1.52) -5.8 (-9.9, -1.7) Placebo 97 43.5 (6.79) -11.7 (1.48) -- Study 3 (12 to 17 years) 200 mg/day 94 39.9 (7.22) -16.0 (1.45) -4.5 (-8.4, -0.6) 400 mg/day 103 39.4 (7.59) -16.5 (1.38) -5.1 (-8.9, -1.3) Placebo 104 40.5 (6.79) -11.4 (1.37) -- ADHD Study in Adults The efficacy of Qelbree in the treatment of ADHD in adults 18 to 65 years of age was evaluated in a short-term, randomized, placebo-controlled, flexible-dose monotherapy trial (Study 4). Study 4 (NCT04016779) was a multicenter, randomized, double-blind, placebo-controlled, flexible-dose, parallel-group monotherapy trial in adults 18 to 65 years of age with ADHD. Total duration of treatment was 6 weeks, starting at 200 mg once daily Week 1 and titrating up 400 mg once daily Week 2. Dose was adjusted by 200 mg per day once a week to a minimum of 200 mg once daily and maximum of 600 mg once daily thereafter. Patients were randomized to receive Qelbree (200 mg to 600 mg), or placebo, given once daily as a single dose. The primary endpoint was the change from baseline to the end of study on the total score on the ADHD Investigator Symptom Rating Scale (AISRS), an 18-item scale corresponding to 18 symptoms of ADHD. Higher AISRS scores reflect more severe symptoms. The change from baseline in the Clinical Global Impression-Severity of Illness (CGI-S) score at the end of the study was the key secondary endpoint. A total of 374 adult patients were randomized in Study 4; 267 completed and 107 discontinued. The average dose at end of study was 504 mg per day. The change from baseline (reduction) in the AISRS Total score was statistically significantly greater in adults treated with Qelbree than in adults on placebo (see Table 5 ). In addition, the change from baseline (reduction) in the CGI-S score was statistically significantly greater in adults treated with Qelbree than in adults on placebo. Table 5. Primary Efficacy Results for Change from Baseline AISRS Total Score in Adults (18 to 60 years of age) with ADHD (Study 4) Study Number (Population) Treatment Group n Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline (95% CI) AISRS: Attention-Deficit/Hyperactivity Disorder Investigator Symptom Rating Scale; n: sample size; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not adjusted for multiple comparisons Study 4 (Adults) Qelbree Treatment is statistically significantly superior to placebo (200 mg to 600 mg) 175 38.5 (6.56) -15.5 (0.91) -3.7 (-6.2, -1.2) Placebo 179 37.6 (6.62) -11.7 (0.90) --

30 Capsules NDC 17772-131-30 Qelbree ™ (viloxazine extended-release capsules) 100 mg Once daily For oral use ATTENTION PHARMACIST: Dispense the Accompanying Medication Guide to Each Patient Rx only PRINCIPAL DISPLAY PANEL - 100 mg Capsule Bottle Label