Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

QELBREE (NDA-211964)

(VILOXAZINE HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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01/23/2025 (SUPPL-13)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

Available data from a lactation study in 15 women indicate that viloxazine and its metabolite, 5-HVLX-gluc, are present in breastmilk. The estimated daily infant dose of viloxazine and 5-HVLX-gluc is 0.085 mg/kg and 0.00595 mg/kg (using a nominal infant body weight of 6 kg), respectively, and the relative infant dose (RID) is approximately 1% and 0.07%, respectively, the weight-normalized maternal daily dose (8.58 mg/kg) of viloxazine. These data support that transfer of viloxazine into breastmilk is low (see Data). There are no data on the effects of viloxazine on the breastfed infant or the effects on milk production.

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.

Data

A multi-dose (600 mg daily for three days) milk and plasma lactation study was conducted in 15 healthy lactating women. The geometric mean of the total excreted amounts of viloxazine and 5-HVLX-gluc in breast milk over a period of 24 hours at steady-state were 0.511 mg and 0.0357 mg, respectively. The RID of viloxazine and 5- HVLX-gluc were approximately 1% and 0.07%, respectively, of the weight-normalized maternal daily dose (8.58 mg/kg) of viloxazine.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

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Before taking QELBREE, tell your healthcare provider about all your or your child’s medical conditions, including if you or your child:

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are breastfeeding or plan to breastfeed.QELBREE passes into your breastmilk. Talk to your healthcare provider about the best way to feed the baby during treatment with QELBREE.

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04/29/2022 (SUPPL-3)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Suicidal Thoughts and Behaviors

Additions underlined

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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.

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5.2 Blood Pressure and Heart Rate Increases

Additions underlined

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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 greater than or equal to 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 greater than or equal to 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.

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5.4 Somnolence and Fatigue

Additions underlined

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.

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6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive additions, please refer to label for complete information.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined

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Risk Summary

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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/m2.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/m2, respectively (see Data).

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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/m2. 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/m2.

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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/m2, respectively. Viloxazine caused maternal toxicity of decreased body weight, weight gain, and food consumption at doses greater than or equal to 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/m2.

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/m2,. 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/m2.

8.4 Pediatric Use

Additions underlined

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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/m2, 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/m2.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions underlined

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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)].

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MEDICATION GUIDE

Additions underlined

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What is the most important information I should know about QELBREE? QELBREE can cause serious side effects, including:

Increased risk of suicidal thoughts or actions. QELBREE may increase suicidal thoughts or actions in children and adults with attention deficit hyperactivity disorder (ADHD), especially within the first few months of treatment or when the dose is changed.
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What is QELBREE?
QELBREE is a prescription medicine used to treat attention deficit hyperactivity disorder (ADHD) in adults and children 6 years of age and older.
It is not known if QELBREE is safe and effective in children less than 6 years of age.
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How should I take QELBREE?
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If QELBREE capsules cannot be swallowed whole, the capsule may be opened and the entire contents sprinkled onto a teaspoonful or tablespoonful of pudding or applesauce.
Swallow all the food mixture right away, without chewing, or within 15 minutes of mixing for pudding, or within 2 hours of mixing for applesauce.
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The most common side effects of QELBREE in children 6 to 17 years of age include:
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The most common side effects of QELBREE in adults include:

insomnia
headache
sleepiness
tiredness
nausea
decreased appetite
dry mouth
constipation

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