Qelbree
viloxazine
Species
RatDog
Longest study
78 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“There are substantial species differences in the metabolism of viloxazine between the nonclinical species (rats and dogs) and humans.”
Why that species
Parent drug and major human metabolite exposures adequately represented in rat despite metabolic differences
“It should be noted that despite the differences in the metabolic profiles, the exposure level to both the parent drug and its major human metabolite (glucuronidated-5-hydroxy-viloxazine) are adequately represented and characterized in rat”
Surrogate molecule
No surrogate; the clinical compound was tested
“Viloxazine did not increase the incidence of tumors in rats treated for 2 years at oral doses of 30/22, 87/65/43, and 217/130/87 mg/kg/day.”
Species: general tox
Rat and dog (also mouse)
“In all three species (rat, mouse, and dog), repeat administration of viloxazine caused dose-dependent hepatocellular hypertrophy and/or vacuolation in the liver.”
Species: DART
Rat and rabbit (EFD); rat and mouse (pregnancy and lactation)
“oral administration of viloxazine during the period of organogenesis caused fetal toxicities and delayed fetal development in the rat and maternal toxicities in the rabbit at doses approximately equal to the maximum recommended human dose (MRHD) of 600 mg in adults, based on mg/m 2 .Oral administration of viloxazine to pregnant rats and mice during pregnancy and lactation caused maternal toxicities and deaths and fetal toxicities”
Species: carcinogenicity
Wistar rat (2-year) and rasH2 transgenic mouse (6-month)
“One Two Year Oral Gavage Carcinogenicity Study in Wistar Rats and One Six-Month Oral Gavage Carcinogenicity Study in rasH2 Transgenic Mice.”
Surrogate used in
No surrogate used; viloxazine itself tested
“Viloxazine did not increase the incidence of tumors in rats treated for 2 years at oral doses of 30/22, 87/65/43, and 217/130/87 mg/kg/day.”
Study lengthopen answer page →
Longest pivotal study
78 (18-month rat)
“Study title: An 18-Month Chronic Oral Toxicity in Rats”
Pivotal GLP studies
13-week and 18-month rat repeat-dose studies
“drug-induced hepatocellular hypertrophy and/or vacuolation were observed at comparable doses in previous 13-week and 18-month repeat-dose studies in rats of both sexes.”
Route in tox
Oral (gavage and dietary administration)
“It should be noted that viloxazine was administered via dietary intake in this study; therefore, the exposure profile is expected to be different from oral gavage studies”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration and rat bone marrow micronucleus assays
“It was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in the in vitro mammalian chromosomal aberration assay (human peripheral blood) or the in vivo rat bone marrow micronucleus assay.”
Carcinogenicity
2-year rat and 26-week Tg.rasH2 mouse: no increase in tumors
“Viloxazine did not increase the incidence of tumors in rats treated for 2 years at oral doses of 22, 43, and 87 mg/kg/day. The high dose of 87 mg/kg/day is approximately equal to the MRHD of 600 mg in adults, based on mg/m 2 . Viloxazine did not increase the incidence of tumors in Tg.rasH2 mice treated for 26 weeks at oral doses of 4.3, 13, and 43 mg/kg/day.”
Reproductive & developmental
Rat EFD: resorptions, delayed development and low-incidence malformations at 82 mg/kg/day
“However, at a dose of 82 mg/kg/day, viloxazine increased early and late resorptions, delayed fetal development, and caused low incidences of fetal malformations or anomalies (craniorachischisis, missing cervical vertebrae, and morphological changes associated with hydranencephaly).”
Safety pharmacology
No ECG (including QTcF) or blood pressure changes in telemetered dogs up to 50 mg/kg
“In telemetry-instrumented male conscious dogs (Study 809V-Tox2007-031, GLP), after a single oral dose (capsule) of viloxazine at 0 (control, empty capsule), 5, 25, and 50 mg/kg (n=4, Latin square design) there were no drug-related changes in ECG (PR, QRS, QT, or QTcF) or blood pressure”
Genotox: Ames
Negative (Ames)
“It was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in the in vitro mammalian chromosomal aberration assay (human peripheral blood) or the in vivo rat bone marrow micronucleus assay.”
Genotox: in vitro mammalian
Chromosomal aberration (human peripheral blood): negative
“It was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in the in vitro mammalian chromosomal aberration assay (human peripheral blood) or the in vivo rat bone marrow micronucleus assay.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“It was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in the in vitro mammalian chromosomal aberration assay (human peripheral blood) or the in vivo rat bone marrow micronucleus assay.”
Carcinogenicity model
2-year rat and 26-week Tg.rasH2 mouse: no increase in tumors
“Viloxazine did not increase the incidence of tumors in rats treated for 2 years at oral doses of 22, 43, and 87 mg/kg/day. The high dose of 87 mg/kg/day is approximately equal to the MRHD of 600 mg in adults, based on mg/m 2 . Viloxazine did not increase the incidence of tumors in Tg.rasH2 mice treated for 26 weeks at oral doses of 4.3, 13, and 43 mg/kg/day.”
Carcinogenicity timing
2-year Wistar rat and 6-month rasH2 mouse studies completed and reviewed in the NDA
“One Two Year Oral Gavage Carcinogenicity Study in Wistar Rats and One Six-Month Oral Gavage Carcinogenicity Study in rasH2 Transgenic Mice.”
hERG / QT
Dog telemetry: no ECG (PR, QRS, QT, QTcF) or blood pressure changes up to 50 mg/kg
“In telemetry-instrumented male conscious dogs (Study 809V-Tox2007-031, GLP), after a single oral dose (capsule) of viloxazine at 0 (control, empty capsule), 5, 25, and 50 mg/kg (n=4, Latin square design) there were no drug-related changes in ECG (PR, QRS, QT, or QTcF) or blood pressure”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Qelbree don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Dose-dependent hepatocellular hypertrophy and/or vacuolation in rat, mouse and dog (FDA integrated review, p. 68)
NOAEL / key findings
Dose-dependent hepatocellular hypertrophy and/or vacuolation in rat, mouse and dog
“In all three species (rat, mouse, and dog), repeat administration of viloxazine caused dose-dependent hepatocellular hypertrophy and/or vacuolation in the liver.”
Risksopen answer page →
Immune & cytokine safety
Decreased thymus weight, considered secondary to stress and poor condition; reversible
“thymus with correlative decreased thymus weight in both sexes and arterial inflammation or degeneration in males. These findings were most likely secondary to the stress and poor condition of the animals, rather than a direct drug effect, and were reversible after recovery.”
Biodistribution & persistence
No skin accumulation; reversible melanin binding in the uveal tract with rapid elimination
“These data suggest that viloxazine or its metabolites do not preferentially distribute to or accumulate in the skin; viloxazine and its metabolites reversibly bind to melanin in the uveal tract but are rapidly dissociated or eliminated.”
Modality-specific risk
Seizures/convulsions in multiple species at therapeutically relevant doses
“Viloxazine caused seizures/convulsions in multiple animal species (rat, dog, and mouse) at therapeutically relevant doses, suggesting a potential risk for seizures with chronic use of viloxazine.”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Label warnings
Boxed warning: Suicidal thoughts and behaviors
- Suicidal Thoughts and Behaviors
- Blood Pressure and Heart Rate Increases
- Activation of Mania or Hypomania
- Somnolence and Fatigue
PsychiatricCardiovascular
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Qelbree don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Dose-dependent hepatocellular hypertrophy and/or vacuolation in rat, mouse and dog (FDA integrated review, p. 68)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
18-month dietary rat study (pre-GLP era) with 6-week recovery; longest GLP studies 13-week rat and dog with 4-week recovery
“18-month main study: n=22/sex/group, from which n=5/sex in the control and HD groups were evaluated after a 6-week recovery”
Pivotal GLP studies
13-week and 18-month rat repeat-dose studies
“drug-induced hepatocellular hypertrophy and/or vacuolation were observed at comparable doses in previous 13-week and 18-month repeat-dose studies in rats of both sexes.”
DART package
Species: DART
Rat and rabbit (EFD); rat and mouse (pregnancy and lactation)
“oral administration of viloxazine during the period of organogenesis caused fetal toxicities and delayed fetal development in the rat and maternal toxicities in the rabbit at doses approximately equal to the maximum recommended human dose (MRHD) of 600 mg in adults, based on mg/m 2 .Oral administration of viloxazine to pregnant rats and mice during pregnancy and lactation caused maternal toxicities and deaths and fetal toxicities”
Reproductive & developmental
Rat EFD: resorptions, delayed development and low-incidence malformations at 82 mg/kg/day
“However, at a dose of 82 mg/kg/day, viloxazine increased early and late resorptions, delayed fetal development, and caused low incidences of fetal malformations or anomalies (craniorachischisis, missing cervical vertebrae, and morphological changes associated with hydranencephaly).”
PPND / ePPND: when
Rat PPND completed and reviewed in the NDA (maternal toxicity and deaths at high dose)
“Viloxazine caused maternal toxicity of decreased body weight, weight gain, and food consumption at doses ≥87 mg/kg/day and maternal death at 217 mg/kg/day.”
Carcinogenicity
Species: carcinogenicity
Wistar rat (2-year) and rasH2 transgenic mouse (6-month)
“One Two Year Oral Gavage Carcinogenicity Study in Wistar Rats and One Six-Month Oral Gavage Carcinogenicity Study in rasH2 Transgenic Mice.”
Carcinogenicity model
2-year rat and 26-week Tg.rasH2 mouse: no increase in tumors
“Viloxazine did not increase the incidence of tumors in rats treated for 2 years at oral doses of 22, 43, and 87 mg/kg/day. The high dose of 87 mg/kg/day is approximately equal to the MRHD of 600 mg in adults, based on mg/m 2 . Viloxazine did not increase the incidence of tumors in Tg.rasH2 mice treated for 26 weeks at oral doses of 4.3, 13, and 43 mg/kg/day.”
Carcinogenicity timing
2-year Wistar rat and 6-month rasH2 mouse studies completed and reviewed in the NDA
“One Two Year Oral Gavage Carcinogenicity Study in Wistar Rats and One Six-Month Oral Gavage Carcinogenicity Study in rasH2 Transgenic Mice.”
Safety marginopen answer page →
Safety margin at NOAEL
No safety margin between NOAEL exposures for seizures in animals and clinical blood levels
“The Agency expressed concern over the lack of a safety margin between the no observed adverse effect level (NOAEL) exposures for seizures in animals and the blood levels already attained in clinical trials.”
NOAEL / key findings
Dose-dependent hepatocellular hypertrophy and/or vacuolation in rat, mouse and dog
“In all three species (rat, mouse, and dog), repeat administration of viloxazine caused dose-dependent hepatocellular hypertrophy and/or vacuolation in the liver.”
Efficacy evidenceopen answer page →
Efficacy evidence
Normal rats: increased brain norepinephrine (and 5-HT, DA) levels
“In vivo administration of viloxazine to the rat increased brain norepinephrine levels, as well as serotonin (5-HT) and dopamine (DA) levels.”
Why that model
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reviewer's view of the efficacy data
FDA: NE reuptake inhibition and increased brain NE shown; evidence inadequate for a clear serotonin-receptor effect
“In summary (Table 87), pharmacology studies showed that viloxazine inhibits NE reuptake and increases the brain NE level by inhibiting NET; however, the evidence is inadequate to support a clear drug effect on serotonin receptors.”
Flexibilityopen answer page →
Flexibility accepted
GLPAcceptedBeyond the letter
General and reproductive toxicity largely from 1970s legacy studies not in full GLP compliance, many without toxicokinetics
Why: No significant issues compromising study quality or data interpretation found on review · Other reason
“Many of the nonclinical legacy general toxicity and reproductive and developmental toxicity studies were completed in the 1970s, before the good laboratory practice (GLP) regulation was implemented; therefore, they are not in full compliance with GLP.”
“Nevertheless, after evaluating the study reports, I did not identify any significant issues that would compromise the quality of the studies or the interpretation of the data; therefore, these studies are considered adequate and acceptable for the NDA review.”
Safety marginCriticised but acceptedBeyond the letter
No safety margin between animal NOAEL exposures for seizures and clinical blood levels
Why: Published clinical literature showed no clear seizure risk in humans · Human data
“The Agency expressed concern over the lack of a safety margin between the no observed adverse effect level (NOAEL) exposures for seizures in animals and the blood levels already attained in clinical trials.”
“The Agency agreed after review of the submitted data that there did not appear to be a clear seizure risk associated with viloxazine in humans.”
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