stration 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.

cide 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. 5.2 blood pressure and heart rate increases 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) ] . 5.3 activation of mania or hypomania 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) ]. 5.4 somnolence and fatigue 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.

itiating 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) ]. 2.2 recommended dosage 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. 2.3 administration information 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. 2.4 dosage recommendations in patients with renal impairment 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) ] .

n rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. the safety of qelbree has been evaluated in 1118 pediatric patients (6 to 17 years of age) with adhd exposed to one or more doses in short-term (6 to 8 week), randomized, double-blind, placebo-controlled trials. a total of 682 pediatric patients 6 to 17 years of age were treated for at least 6 months, and 347 pediatric patients 6 to 17 years of age for at least 12 months with qelbree. the safety of qelbree has been evaluated in 189 adult patients (18 to 60 years of age) with adhd exposed to one or more doses in a short-term (6 week), randomized, double-blind, placebo-controlled trial. a total of 277 adult patients with adhd have been exposed to one or more doses of qelbree. eighty-four adult patients were treated for at least 6 months, and 22 adult patients for at least 12 months. pediatric patients (6 to 17 years of age) the data described below reflect exposure to qelbree in 826 pediatric patients (6 to 17 years) who participated in randomized, double-blind, placebo-controlled trials with doses ranging from 100 mg to 400 mg. the population (n=826) was 65% male, 35% female, 54% white, 41% black, 4% multiracial, and 1% other races. adverse reactions leading to discontinuation of qelbree treatment : approximately 3% (n=27) of the 826 patients receiving qelbree in clinical studies discontinued treatment due to an adverse reaction. the adverse reactions most commonly associated with discontinuation of qelbree were somnolence (n=5), nausea (n=3), headache (n=2), irritability (n=2), tachycardia (n=2), fatigue (n=2), and decreased appetite (n=2). most common adverse reactions (occurring at ≥5% and at least twice the placebo rate for any dose) : somnolence, decreased appetite, fatigue, nausea, vomiting, insomnia, and irritability. table 1 lists adverse reactions that occurred in at least 2% of patients treated with qelbree and more frequently in qelbree-treated patients than in placebo-treated patients. table 1 data represents pooled data from pediatric patients 6 to 17 years of age who were enrolled in randomized, placebo-controlled trials of qelbree. table 1. adverse reactions reported in ≥2% of pediatric patients (6 to 17 years of age) treated with qelbree and at a rate greater than placebo-treated patients in placebo-controlled adhd studies qelbree body system adverse reaction placebo n=463 (%) 100mg n=154 (%) 200mg n=367 (%) 400mg n=305 (%) all qelbree n=826 (%) nervous system disorders somnolence the following terms were combined: somnolence: somnolence, lethargy, sedation headache: headache, migraine, migraine with aura, tension headache upper respiratory tract infection: nasopharyngitis, pharyngitis, sinusitis, upper respiratory tract infection, viral sinusitis, viral upper respiratory tract infection abdominal pain: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper insomnia: initial insomnia, insomnia, middle insomnia, poor quality sleep, sleep disorder, terminal insomnia 4 12 16 19 16 headache 7 10 11 11 11 metabolic and nutritional disorders decreased appetite 0.4 5 8 8 7 infections and infestations upper respiratory tract infection 6 5 7 8 7 body as a whole - general disorders fatigue 2 4 5 9 6 pyrexia 0.2 3 2 1 2 gastrointestinal system disorders abdominal pain 4 3 6 7 5 nausea 3 1 4 7 5 vomiting 2 5 3 6 4 psychiatric disorders insomnia 1 2 5 5 4 irritability 1 3 2 5 3 effects on weight: in short–term, controlled studies (6 to 8 weeks), qelbree-treated patients 6 to 11 years of age gained an average of 0.2 kg, compared to a gain of 1 kg in same-aged patients who received placebo. qelbree-treated patients 12 to 17 years of age lost an average of 0.2 kg, compared to a weight gain of 1.5 kg in same-aged patients who received placebo. in a long-term open-label extension safety trial, 1097 patients received at least 1 dose of qelbree. among the 338 patients evaluated at 12 months, the mean change from baseline in weight-for-age z-score was -0.2 (standard deviation of 0.5). in the absence of a control group, it is unclear whether the weight change observed in the long-term open-label extension was attributable to the effect of qelbree. adults the data described below reflect exposure to qelbree in 189 adults with adhd who participated in the flexible-dose, randomized, double-blind, placebo-controlled trial with doses ranging from 200 mg to 600 mg. the population (n=189) was 56% male, 44% female, 81% white, 12% black, 3% asian, 3% other races and 1% multiracial. adverse reactions leading to discontinuation of qelbree treatment : approximately 9% of the 189 patients receiving qelbree in clinical studies discontinued treatment due to an adverse reaction. the adverse reactions most commonly associated with discontinuation of qelbree were fatigue (n=4), insomnia (n=3), constipation (n=3), and headache (n=2). most common adverse reactions (occurring at ≥5% and at least twice the placebo rate of qelbree): insomnia, headache, somnolence, fatigue, nausea, decreased appetite, dry mouth, and constipation. table 2 lists adverse reactions that occurred in at least 2% of patients treated with qelbree and more frequently in qelbree-treated patients than in placebo-treated patients. table 2 represents data from adults with adhd who were enrolled in a flexible-dose, randomized, placebo-controlled trial of qelbree at doses of 200 mg to 600 mg. table 2. adverse reactions reported in ≥2% of adults treated with qelbree and at a rate greater than placebo-treated patients in a flexible-dose placebo-controlled adhd study body system adverse reaction placebo n=183 (%) qelbree (200 mg to 600 mg) n=189 (%) psychiatric disorders insomnia the following terms were combined: somnolence: somnolence, lethargy, sedation headache: headache, migraine, migraine with aura, tension headache insomnia: initial insomnia, insomnia, middle insomnia, poor quality sleep, sleep disorder, terminal insomnia 7 23 irritability 3 4 nervous system disorders headache 7 17 somnolence 2 6 dizziness 2 4 gastrointestinal system disorders nausea 3 12 dry mouth 2 10 constipation 1 6 vomiting 1 4 gastrooesophageal reflux disease 1 2 body as a whole - general disorders fatigue 3 12 metabolic and nutritional disorders decreased appetite 3 10 cardiac disorders tachycardia 1 4

stration 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.

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 . 8.2 lactation 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. 8.4 pediatric use 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 . 8.5 geriatric use 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. 8.6 renal impairment 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) ].

t 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 .

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 .

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.

tration 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.

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 . 13.2 animal toxicology and/or pharmacology 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 .

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 .

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) --

¦..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).

monitored for such effects [see warnings and precautions (5.2) ] . activation of mania/hypomania advise patients and their caregivers to look for signs of activation of mania/hypomania [see warnings and precautions (5.3) ] . somnolence and fatigue advise patients about the potential for somnolence (including sedation and lethargy) and fatigue. advise patients to use caution when performing activities requiring mental alertness, such as driving a motor vehicle or operating hazardous machinery, until they know how they will be affected by qelbree [see warnings and precautions (5.4) ]. effects on weight advise patients and their caregivers that qelbree may affect weight and that weight should be monitored while using qelbree [see adverse reactions (6.1) ]. pregnancy advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to qelbree during pregnancy. advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy to discuss if qelbree should be discontinued [see use in specific populations (8.1) ]. administration instructions advise patients to take the capsule whole or sprinkled over a teaspoonful or tablespoonful of applesauce or pudding and consume within 15 minutes when mixed with pudding or within 2 hours when mixed with applesauce. do not cut, chew or crush the capsule [see dosage and administration (2.3) ] .