DRUG INTERACTIONS-(summary )

 Moderate sensitive CYP1A2 substrates: Not recommended for coadministration with Qelbree. Dose reduction may be warranted

BRIEF SUMMARY

QELBREE- (Apr -2021)

Indn-  For the treatment of attention deficit                                                                                hyperactivity disorder  

Comp-   Extended-release capsules: 100 mg, 150 mg and 200 mg                         

  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

 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 

ADR-  Most commonly observed adverse reactions and at least twice the rate of placebo) were: somnolence, decreased appetite, fatigue, nausea, vomiting, insomnia, and irritability

CI- Concomitant administration of monoamine oxidase inhibitors (MAOI), or dosing within 14 days after discontinuing an MAOI

Concomitant administration of sensitive CYP1A2 substrates or CYP1A2 substrates with a narrow therapeutic rang

WARNINGS -

 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

Pat Inform-

Suicidal Thoughts and Behaviors -   Advise patients and caregivers to monitor for the emergence of suicidal thoughts or behaviors or symptoms that might be precursors to emerging suicidal ideation or behavior, especially early during treatment and when the dosage is adjusted up or down

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U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 15

Name of the Drug-    QELBREE

Active Ingredient -   Viloxazine

Pharmacological Classification-   For the treatment of attention deficit                                                                                hyperactivity disorder                                                                                                                                                                                     

Date of Approval-          4/2/2021

HIGHLIGHTS OF PRESCRIBING INFORMATION-                                                 

 These highlights do not include all the information needed to use                         QELBREE™ safely and effectively.                                                                               See full prescribing information for QELBREE™. QELBREE™ (viloxazine extended-release capsules), for oral use

Initial U.S. Approval: 2021

WARNING:                                                                                                            SUICIDAL THOUGHTS AND BEHAVIORS                                                                         See full prescribing information for complete boxed warning.

In clinical trials, higher rates of suicidal thoughts and behavior were reported in pediatric patients treated with Qelbree than in patients treated with placebo.

Closely monitor for worsening and emergence of suicidal thoughts and behaviors

INDICATIONS AND USAGE-

 Qelbree is a selective norepinephrine reuptake inhibitor indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients 6 to 17 years of age

DOSAGE AND ADMINISTRATION

 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

 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 

 Capsules may be swallowed whole or opened and the entire contents sprinkled onto applesauce (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)

DOSAGE FORMS AND STRENGTHS-

 Extended-release capsules: 100 mg, 150 mg and 200 mg 

ADVERSE REACTIONS

 Most commonly observed adverse reactions (=5% and at least twice the rate of placebo) were: somnolence, decreased appetite, fatigue, nausea, vomiting, insomnia, and irritability

CONTRAINDICATIONS-

 Concomitant administration of monoamine oxidase inhibitors (MAOI), or dosing within 14 days after discontinuing an MAOI

Concomitant administration of sensitive CYP1A2 substrates or CYP1A2 substrates with a narrow therapeutic rang

WARNINGS AND PRECAUTIONS-

 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

 Activation of Mania or Hypomania: Screen patients for bipolar disorder

Somnolence and Fatigue: Advise patients to use caution when driving or operating hazardous machinery due to potential somnolence (including sedation and lethargy) and fatigue

DOSAGE AND ADMINISTRATION

 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

 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 

 Capsules may be swallowed whole or opened and the entire contents sprinkled onto applesauce

 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 

DOSAGE FORMS AND STRENGTHS-

 Extended-release capsules: 100 mg, 150 mg and 200 mg 

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Suicidal Thoughts and Behaviors -                                                                         Advise patients and caregivers to monitor for the emergence of suicidal thoughts or behaviors or symptoms that might be precursors to emerging suicidal ideation or behavior, especially early during treatment and when the dosage is adjusted up or down. Instruct patients and caregivers to report such symptoms to the healthcare provider

Concomitant Use with Monoamine Oxidase Inhibitors (MAOI) -                                 Caution patients about the concomitant use of Qelbree and monoamine oxidase inhibitors (MAOI), or within 14 days after discontinuing an MAOI, because of an increased risk of hypertensive crisis

Blood Pressure and Heart Rate Increases -                                                                   Instruct patients that Qelbree can cause elevations of their blood pressure and pulse rate and they should be monitored for such effects

Activation of Mania/Hypomania -                                                                             Advise patients and their caregivers to look for signs of activation of mania/hypomania 

Somnolence and Fatigue-                                                                                               Advise patients about the potential for somnolence (including sedation and lethargy) and fatigue.

Advise patients to use caution when performing activities requiring mental alertness, such as driving a motor vehicle or operating hazardous machinery, until they know how they will be affected by Qelbree

Effects on Weight-                                                                                                          Advise patients and their caregivers that Qelbree may affect weight and that weight should be monitored while using Qelbree

 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

Administration-                                                                                                       Instructions -                                                                                                                 Advise patients to take the capsule whole or sprinkled on a teaspoonful of applesauce and consume within 2 hours.

Do not cut, chew or crush the capsule.

Qelbree is manufactured by: Catalent Pharma Solutions, LLC, 1100 Enterprise Drive Winchester, KY 40391.

Distributed by: Supernus Pharmaceuticals, Inc. Rockville, MD 20850 USA Qelbree is a trademark of Supernus Pharmaceuticals, Inc. Reference ID: 4772843 RA-QEL-V1-202104 © Supernus Pharmaceuticals Inc. 2021

 CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                                  The mechanism of action of viloxazine in the treatment of ADHD is unclear; however, it is thought to be through inhibiting the reuptake of norepinephrine.

2. Pharmacodynamics-                                                                                                Viloxazine binds to the norepinephrine transporter (NET, Ki= 0.63 µM) and inhibits the reuptake of norepinephrine (IC50=0.2 µM).

Cardiac Electrophysiology- At a dose 4.5 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.

3. Pharmacokinetics-                                                                                                    Viloxazine Cmax

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 (Tmax) 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 Cmax and AUC by about 9% and 8%, respectively. Viloxazine Tmax increased by about 2 hours after administration with a high-fat meal. Sprinkling the contents of a capsule on applesauce decreased viloxazine Cmax 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 Cmax and AUC0-t of viloxazine and its major metabolite, at doses ranging from 100 mg to 400 mg, were approximately 40-50% higher in pediatric patients 6 to 11 years of age than in pediatric patients 12 to 17 years of age.

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 Renal Impairment- Exposures of viloxazine in patients with renal impairment are summarized in Figure 1 [see Dosage and Administration (2.4) and Use in Specific Populations (

Effect of Renal Impairment on Viloxazine Pharmacokinetics Patients with Hepatic Impairment The pharmacokinetics of viloxazine have not been evaluated in hepatic impairment 

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 Cmax and AUC0-24 were 21% and 26%, respectively, higher in CYP2D6 PMs compared to EMs.

Drug Interaction- Studies- Alcohol: There was no significant effect on viloxazine Cmax 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, Cmax and AUC of viloxazine decreased by about 32% and 19%, respectively .

In Vitro Studies Based on in vitro data, drugs that inhibit CYP isozymes 1A1, 1A2, 2B6, 2D6, 2C8, 2C9, 2C19, and 2E1 are not expected to have significant impact on the pharmacokinetic profile of viloxazine.

Viloxazine does not inhibit CYP2C8, 2C9 or 2C19 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 a 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.

8 USE IN SPECIFIC POPULATIONS

1. Pregnancy 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.

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.

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.

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

3. 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  and Clinical Studies]. 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 .

Juvenile Animal Toxicity Data- Viloxazine was administered orally to juvenile rats from postnatal day (PND) 23 through PND 79 at doses of 43, 130, and 217 mg/kg/day, which are approximately 1, 2, and 3 times the MRHD of 400 mg, based on mg/m2 in  children, respectively.                                                                                                                  Viloxazine decreased body weight, weight gain, and food consumption in both sexes at 217 mg/kg/day. Sexual maturation, reproductive capacity, and learning and memory were not affected. The NOAEL for juvenile toxicity is 130 mg/kg/day, which is approximately 2 times the MRHD, based on mg/m2 in children.

4. 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.

5. Renal Impairment Dosage reduction is recommended in patients with severe (eGFR of < 30 mL/min/1.73m2 [MDRD]) renal impairment . No dosage adjustment of Qelbree is recommended in patients with mild to moderate (eGFR of 30 to 89 mL/min/1.73m2 [MDRD]) renal impairment. The exposure of viloxazine increases in patients with renal impairment 

6. Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of viloxazine is unknown [see Clinical Pharmacology (12.3)]. Qelbree is not recommended in patients with hepatic impairment.

10 OVERDOSAGE -                                                                                                      Human Experience -The pre-market clinical trials with Qelbree do not provide information regarding symptoms of overdose. Literature reports from post marketing experience with immediate-release viloxazine include cases of overdosage from 1000 mg to 6500 mg (2.5 to 16.25 times the maximum recommended daily dose).

The most reported symptom was drowsiness. Impaired consciousness, diminished reflexes, and increased heart rate have also been reported.

Treatment and Management-                                                                                           There is no specific antidote for Qelbree overdose. Administer symptomatic and supportive treatment as appropriate. In case of overdose, consult a Certified Poison Control Center (1-800-222-1222 or www.poison.org).