b'placebo-treated patients. Fatigue was reported in 6% of Qelbree-treated Drugs Having Clinically Important Interactions with Qelbree (continued) Lactationpatients compared to 2% of placebo-treated patients. Moderate Sensitive CYP1A2 Substrate (continued) Risk SummaryPatients should not perform activities requiring mental alertness, such as Examples: Clozapine, pirfenidone There are no data on the presence of viloxazine in human milk, the effects on the operating a motor vehicle or operating hazardous machinery until they know breastfed infant, or the effects on milk production. Viloxazine is likely present in rat how they will be affected by Qelbree. CYP2D6 Substrates milk. When a drug is present in animal milk, it is likely that the drug will be present ADVERSE REACTIONS Clinical Impact: Viloxazine is a weak inhibitor of CYP2D6, and increases thein human milk.Clinical Trials Experience exposure of CYP2D6 substrates when coadministered. The developmental and health benefits of breastfeeding should be considered Qelbree (viloxazine extended-release capsules), for oral useThe safety of Qelbree has been evaluated in 1118 patients (6 to 17 years ofIntervention: Monitor patients for adverse reactions and adjust dosages ofalong with the mothers clinical need for Qelbree and any potential adverse effects BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION age) with ADHD exposed to one or more doses in short-term (6 to 8 week),CYP2D6 substrates, as clinically indicated. on the breastfed child from Qelbree or from the underlying maternal condition.randomized, double-blind, placebo-controlled trials. Examples: Atomoxetine, desipramine, dextromethorphan, nortriptyline,Pediatric UseFor full prescribing information see package insert. A total of 682 pediatric patients were treated for at least 6 months, and 347metoprolol, nebivolol, perphenazine, tolterodine, venlafaxine, and risperidone The safety and effectiveness of Qelbree in pediatric patients ages 6 to 17 years of pediatric patients for at least 12 months with Qelbree. CYP3A4 Substrates age with ADHD have been established based on randomized, placebo-controlled WARNING: SUICIDAL THOUGHTS AND BEHAVIORS The data described below reflect exposure to Qelbree in 826 patients whoClinical Impact: Viloxazine is a weak inhibitor of CYP3A4 which increases thestudies in pediatric patients.In clinical studies, higher rates of suicidal thoughts and behavior participated in randomized, double-blind, placebo-controlled trials with dosesexposure of CYP3A4 substrates when coadministered. The safety and effectiveness of Qelbree have not been established in pediatric were reported in pediatric patients with ADHD treated with Qelbreeranging from 100 mg to 400 mg. The population (N=826) was 65% male, Intervention: Monitor patients for adverse reactions and adjust dosages ofpatients younger than 6 years old.than in patients treated with placebo. Closely monitor all Qelbree- 35% female, 54% White, 41% Black, 4% multiracial, and 1% other races.CYP3A4 substrates, as clinically indicated. Patients treated with Qelbree should be monitored for suicidal thoughts and treated patients for clinical worsening, and for emergence of suicidalAdverse Reactions Leading to Discontinuation of Qelbree Treatment: Examples: Alfentanil, avanafil, buspirone, conivaptan, darifenacin, darunavir,behavior, and for changes in weight.thoughts and behaviors. Approximately 3% of the 826 patients receiving Qelbree in clinical studiesebastine, everolimus, ibrutinib, lomitapide, lovastatin, midazolam, naloxegol,Juvenile Animal Toxicity Data discontinued treatment due to an adverse reaction. The adverse reactions mostnisoldipine, saquinavir, simvastatin, sirolimus, tacrolimus, tipranavir, triazolam,Viloxazine was administered orally to juvenile rats from postnatal day (PND) CONTRAINDICATIONS commonly associated with discontinuation of Qelbree were somnolence, nausea,vardenafil, and lurasidone 23 through PND 79 at doses of 43, 130, and 217 mg/kg/day, which are Qelbree is contraindicated in patients receiving concomitant treatment withheadache, irritability, tachycardia, fatigue, and decreased appetite. USE IN SPECIFIC POPULATIONS approximately 1, 2, and 3 times the MRHD of 400 mg, based on mg/m 2in monoamine oxidase inhibitors (MAOI), or within 14 days following discontinuing Most Common Adverse Reactions (occurring at 5% and at least twice thePregnancy children, respectively. Viloxazine decreased body weight, weight gain, and food an MAOI, because of an increased risk of hypertensive crisis. placebo rate for any dose): somnolence, decreased appetite, fatigue, nausea,Pregnancy Exposure Registry consumption in both sexes at 217 mg/kg/day. Sexual maturation, reproductive Qelbree should not be taken when receiving concomitant administration ofvomiting, insomnia, and irritability. Report pregnancies to the National Pregnancy Registry capacity, and learning and memory were not affected. The NOAEL for juvenile toxicity is 130 mg/kg/day, which is approximately 2 times the MRHD, based on sensitive CYP1A2 substrates or CYP1A2 substrates with a narrow therapeuticListed here are adverse reactions that occurred in at least 2% of patientsfor Psychiatric Medications at 1-866-961-2388, and at the website mg/m 2in children.range. treated with Qelbree and more frequently in the Qelbree-treated patients than(www.womensmentalhealth.org/preg).WARNINGS AND PRECAUTIONSin the placebo-treated patients. Data represents pooled data from pediatricRisk SummaryGeriatric Usepatients ages 6 to 17 years who were enrolled in randomized, placebo- Clinical trials of Qelbree in the treatment of ADHD did not include sufficient Suicidal Thoughts and Behaviors (See Above) controlled trials of Qelbree.Based on findings from animal reproduction studies, viloxazine may causenumbers of patients aged 65 and older to determine whether or not they respond Among 1019 patients exposed to Qelbree 100 mg to 400 mg in short-term trials,maternal harm when used during pregnancy. Discontinue Qelbree whendifferently from younger patients. a total of nine patients (0.9%) reported suicidal ideation (N=6), behavior (N=1) orAdverse Reactions Reported in 2% of Pediatric Patients pregnancy is recognized unless the benefits of therapy outweigh the potential both (N=2). Eight patients reported suicidal ideation or behavior on the Columbia(Ages 6 to 17 Years) Treated with Qelbree and at a Greater Rate thanrisk to the mother. Available data from case series with viloxazine use inRenal ImpairmentSuicide Severity Rating Scale (C-SSRS), a validated scale that assesses suicide(N=463); All Qelbree (N=826). Nervous system disorders: Somnolence*;birth defects, miscarriage or adverse maternal outcomes.Dosage reduction is recommended in patients with severePlacebo-Treated Patients in Placebo-Controlled ADHD Studies Placebopregnant women are insufficient to determine a drug-associated risk of major2risk. An additional patient treated with Qelbree reported suicidal behavior during(eGFR of 30 mL/min/1.73m [MDRD]) renal impairment.the clinical trials, but did not report it on the C-SSRS. Among 463 patients treatedHeadache*. Metabolic and nutritional disorders: Decreased appetite.No dosage adjustment of Qelbree is recommended in patients with mild to with placebo in these studies, two patients (0.4%) reported suicidal ideation Infections and infestations: Upper respiratory tract infection*. Body as aIn animal reproduction studies, oral administration of viloxazine to pregnant ratsmoderate (eGFR of 30 to 89 mL/min/1.73m 2[MDRD]) renal impairment.on the C-SSRS. No patients treated with placebo reported suicidal behavior. Whole - General disorders: Fatigue; Pyrexia. Gastrointestinal systemand rabbits during the period of organogenesis did not cause significant maternalThe exposure of viloxazine increases in patients with renal impairment.No completed suicides occurred in these trials.disorders: Abdominal Pain*; Nausea; Vomiting. Psychiatric disorders:toxicity but caused fetal toxicities and delayed fetal development in the rat at Insomnia*; Irritability.doses up to 2 times the maximum recommended human dose (MRHD) of Hepatic ImpairmentPatients treated with Qelbree had higher rates of insomnia and irritability. Although400 mg, based on mg/m 2 . In the rabbit, viloxazine caused maternal toxicityThe effect of hepatic impairment on the pharmacokinetics of viloxazine is a causal link between the emergence of such symptoms and the emergence of*The following terms were combined: Somnolence: somnolence, lethargy,without significant fetal toxicity at doses7 times the MRHD based on mg/ unknown. Qelbree is not recommended in patients with hepatic impairment.suicidal impulses has not been established, there is a concern that these andsedation; Headache: headache, migraine, migraine with aura, tension headache;m 2 . The no observed adverse effect levels (NOAELs) for fetal toxicity are other symptoms such as depressed mood, anxiety, agitation, akathisia, mania,Upper respiratory tract infection: nasopharyngitis, pharyngitis, sinusitis,approximately equal to and 11 times the MRHD, based on mg/m 2in the rat andOVERDOSAGEhypomania, panic attacks, impulsive behavior, and aggression may representupper respiratory tract infection, viral sinusitis, viral upper respiratory tract rabbit, respectively. Oral administration of viloxazine to pregnant rats and miceHuman Experienceprecursors to emerging suicidal ideation or behavior. Thus, patients being treatedinfection; Abdominal pain: abdominal discomfort, abdominal pain, abdominalduring pregnancy and lactation caused maternal toxicities and deaths at dosesThe pre-market clinical trials with Qelbree do not provide information regarding with Qelbree should be observed for the emergence of such symptoms.pain lower, abdominal pain upper; Insomnia: initial insomnia, insomnia, middleapproximately 2 and 1 time the MRHD, based on mg/m 2 , respectively (see Data).symptoms of overdose.Consider changing the therapeutic regimen, including possibly discontinuinginsomnia, poor quality sleep, sleep disorder, terminal insomnia.At these maternally toxic doses, viloxazine caused offspring toxicities. The NOAELLiterature reports from post marketing experience with immediate-release Effects on Weight: In shortterm, controlled studies (6 to 8 weeks), Qelbree- for maternal and developmental toxicity is approximately equal to or less than viloxazine include cases of overdosage from 1000 mg to 6500 mg (2.5 to 16.25 Qelbree, in patients who are experiencing emergent suicidal thoughts andtreated patients 6 to 11 years of age gained an average of 0.2 kg, compared tothe MRHD, based on mg/m 2 , in the rat and mouse, respectively (see Data). times the maximum recommended daily dose). The most reported symptom was behaviors or symptoms that might be precursors to emerging suicidal ideationa gain of 1 kg in same-aged patients who received placebo. Qelbree-treateddrowsiness. Impaired consciousness, diminished reflexes, and increased heart or behavior, especially if these symptoms are severe or abrupt in onset, orpatients 12 to 17 years of age lost an average of 0.2 kg, compared to a weightData rate have also been reported. were not part of the patients presenting symptoms. Advise family membersgain of 1.5 kg in same-aged patients who received placebo. In a long-term Animal Dataor caregivers of patients to monitor for the emergence of suicidal ideation oropen-label extension safety trial, 1097 patients received at least 1 dose ofViloxazine was administered orally to pregnant rats during the period ofTreatment and Managementbehavior, and to report such symptoms immediately to the healthcare provider. organogenesis at doses of 13, 33, and 82 mg/kg/day, which are less than, equalThere is no specific antidote for Qelbree overdose. Administer symptomatic and Qelbree. Among the 338 patients evaluated at 12 months, the mean change fromto, and 2 times the MRHD of 400 mg, based on mg/m 2 , respectively. Viloxazinesupportive treatment as appropriate. In case of overdose, consult a Certified Effects on Blood Pressure and Heart Ratebaseline in weight-for-age z-score was -0.2 (standard deviation of 0.5). In the Qelbree can cause an increase in heart rate and diastolic blood pressure.absence of a control group, it is unclear whether the weight change observed indid not cause maternal toxicity at doses up to 82 mg/kg/day. Viloxazine at Poison Control Center (1-800-222-1222 or www.poison.org).In a clinical study in patients 6 to 11 years of age, 34/154 (22%) of patients treatedthe long-term open-label extension was attributable to the effect of Qelbree. 82 mg/kg/day increased early and late resorption, delayed fetal development,NON-CLINICAL TOXICOLOGYwith Qelbree 100 mg daily had a 20 beat per minute (bpm) increase in heartand possibly caused low incidences of fetal malformations or anomaliesCarcinogenesis, Mutagenesis, and Impairment of Fertilityrate at any time point in the clinical trial, compared to 15/159 (9%) of patients whoDRUG INTERACTIONS (craniorachischisis, missing cervical vertebrae, and morphological changesCarcinogenesisDrugs Having Clinically Important Interactions with Qelbreeassociated with hydranencephaly). The NOAEL for fetal toxicity and malformation received placebo. This finding was observed in 84/268 (31%) who received theis 33 mg/kg/day, which is approximately equal to the MRHD, based on mg/m 2 . Viloxazine did not increase the incidence of tumors in rats treated for 2 years 200 mg dose, compared to 39/262 (15%) of patients in the placebo group, andMonoamine Oxidase Inhibitors (MAOI) at oral doses of 22, 43, and 87 mg/kg/day. The high dose of 87 mg/kg/day is in 28/100 (28%) of patients who received the 400 mg dose, compared to 24/103Clinical Impact: Concomitant use of Qelbree with an MAOI may lead to aViloxazine was administered orally to pregnant rabbits during the period ofapproximately equal to the MRHD of 400 mg, based on mg/m 2in children. (23%) of patients who received placebo. potentially life-threatening hypertensive crisis. organogenesis at doses of 43, 87, and 130 mg/kg/day, which are approximately 4, 7, and 11 times the MRHD of 400 mg, based on mg/m 2 , respectively. ViloxazineViloxazine did not increase the incidence of tumors in Tg.rasH2 mice treated for In a clinical study in patients 12 to 17 years of age, 22/99 (22%) of patients treatedIntervention: Concomitant use of Qelbree with an MAOI or within2 weeks afterdecreased maternal body weight, weight gain, or food consumption at doses 26 weeks at oral doses of 4.3, 13, and 43 mg/kg/day.with Qelbree 200 mg daily had a 20 bpm increase in heart rate at any time pointdiscontinuing an MAOI is contraindicated.87 mg/kg/day but did not cause fetal toxicity at doses up to 130 mg/kg/day.Mutagenesisin the clinical trial, compared to 15/104 (14%) of patients who received placebo. Examples: Selegiline, isocarboxazid, phenelzine, tranylcypromine, safinamide,The NOAELs for maternal and fetal toxicity is 43 and 130 mg/kg/day, respectively, This finding was observed in 69/205 (34%) who received the 400 mg dose,rasagiline which is approximately 4 and 11 times the MRHD, based on mg/m 2 , respectively. Viloxazine was not genotoxic in a battery of genotoxicity tests. It was not compared to 35/201 (17%) of patients in the placebo group. mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic In patients ages 12 to 17 years, 52/205 (25%) of patients treated with Qelbree Sensitive CYP1A2 Substrates or CYP1A2 Substrates with a NarrowViloxazine was administered orally to pregnant rats during gestation and lactationin the in vitro mammalian chromosomal aberration assay or in the in vivo rat bone Therapeutic Range at doses of 43, 87, and 217 mg/kg/day, which are approximately 1, 2, and 5 timesmarrow micronucleus assay.400 mg daily had a15 mmHg increase in diastolic blood pressure at any time Clinical Impact: Viloxazine is a strong CYP1A2 inhibitor. Concomitant use ofthe MRHD of 400 mg, based on mg/m 2 , respectively. Viloxazine caused maternal in the clinical trial, compared to 26/201 (13%) of patients in the placebo group.viloxazine significantly increases the total exposure, but not peak exposure, oftoxicity of decreased body weight, weight gain, and food consumption at dosesImpairment of FertilityAssess heart rate and blood pressure prior to initiating treatment with Qelbree,sensitive CYP1A2 substrates, which may increase the risk of adverse reactions 87 mg/kg/day and maternal deaths near term at 217 mg/kg/day. At theseViloxazine was orally administered to male and female rats prior to and throughout following increases in dosage, and periodically while on therapy. associated with these CYP1A2 substrates. maternally toxic doses, viloxazine caused lower live birth, decreased viability,mating and continued until completion of the second littering at doses of 13, 33, and 82 mg/kg/day, which are less than, equal to, and 2 times the MRHD of 400 mg, Activation of Mania or HypomaniaIntervention: Coadministration with viloxazine is contraindicated. and delayed growth and sexual maturation without affecting learning andbased on mg/m 2 , respectively. Viloxazine did not affect male or female fertility Noradrenergic drugs, such as Qelbree, may induce a manic or mixed episodememory in the offspring. The NOAEL for maternal and developmental toxicityExamples: Alosetron, duloxetine, ramelteon, tasimelteon, tizanidine, theophylline 2 parameters in the rat. The NOAEL for male and female fertility is 82 mg/kg/day, in patients with bipolar disorder. Prior to initiating treatment with Qelbree, screenis 43 mg/kg/day, which is approximately equal to the MRHD, based on mg/m.which is approximately 2 times the MRHD, based on mg/m 2 .patients to determine if they are at risk for bipolar disorder; such screening shouldModerate Sensitive CYP1A2 Substrate Viloxazine was administered orally to pregnant mice during gestation and include a detailed psychiatric history, including a personal or family history of Clinical Impact: Viloxazine is a strong CYP1A2 inhibitor. Concomitant use oflactation at doses of 13, 33, and 82 mg/kg/day, which are approximatelyAnimal Toxicology and/or Pharmacologysuicide, bipolar disorder, and depression. viloxazine significantly increases the total, but not peak, exposure of sensitiveless than or equal to the MRHD of 400 mg, based on mg/m 2 , respectively.In animal studies, viloxazine treatment caused dose-dependent convulsions CYP1A2, which may increase the risk of adverse reactions associated withViloxazine treatment at 82 mg/kg/day during the gestation period causedat oral doses of130,173, and39 mg/kg/day in the rat, mouse, and dog, Somnolence and Fatiguerespectively, which are approximately equal to or slightly higher than the MRHDQelbree can cause somnolence and fatigue. In the short-term, placebo-controlledthese CYP1A2 substrates. maternal deaths and decreased body weight in the offspring. The NOAEL of 400 mg, based on mg/m 2in children. clinical trials in pediatric patients with ADHD, somnolence (including lethargy andIntervention: Not recommended for coadministration with viloxazine. Dosefor both maternal and developmental toxicity is 33 mg/kg/day, which is less sedation) was reported in 16% of Qelbree-treated patients compared to 4% ofreduction may be warranted if coadministered. than the MRHD, based on mg/m 2 . RA-812-BS-HCP-V1 Revised: 04/2021 Based on: PI 04/2021QBE.2021-0102 HCP Girl Wordcloud Ad_USMed_M01.indd 3 11/22/21 7:17 AM'