Chemical formula: C₁₅H₁₅N Molecular mass: 209.12 g/mol PubChem compound: 16095349
Available data from the clinical development program with centanafadine use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In embryo-fetal developmental studies, pregnant rats and rabbits received oral centanafadine during gestation. In rats, decreased maternal body weight and body weight gain and decreased fetal body weight were observed at exposures lower than the human exposure at the Maximum Recommended Human Dose (MRHD) of 280 mg. An increase in the incidence of fetal skeletal variations was observed at exposures approximately 4 times the human exposure at the MRHD of 280 mg. In rabbits, centanafadine did not result in any effects on embryo-fetal survival or development at any dose. In a rat pre- and post-natal developmental study, oral administration of centanafadine during gestation and lactation resulted in decreased maternal body weight gain during gestation and a slight increase in the incidence of early postnatal pup mortality at exposures lower than the human exposure at the MRHD of 280 mg.
The 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 risks of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
There are no data on the presence of centanafadine or its metabolite in either human or animal milk, the effects 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 centanafadine and any potential adverse effects on the breastfed child from centanafadine or from the underlying maternal condition.
Centanafadine did not increase the incidence of tumors in rats treated for up to 91 weeks at any of the oral doses tested, up to 20 mg/kg/day in males and 30 mg/kg/day in females, which are less than the human exposure at the maximum recommended human dose (MRHD) of 280 mg based on AUC. Centanafadine did not increase the incidence of tumors in rasH2 mice treated for 26 weeks at oral doses of up to 10 mg/kg/day.
Centanafadine was not genotoxic in a battery of genotoxicity tests. Centanafadine was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay, or clastogenic in the in vitro mammalian chromosomal aberration assay or in vivo in the rat bone marrow micronucleus test.
Centanafadine did not impact rat fertility or reproduction at doses of 3, 10, or 30 mg/kg/day, with the highest dose tested being lower than the human exposure at the MRHD of 280 mg based on AUC.
Because clinical trials are conducted under widely varying conditions, adverse reaction 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 centanafadine is based on studies in:
The most common adverse reactions (≥5% and greater than placebo) in the double-blind clinical trials were:
The most common adverse reactions associated with discontinuation (≥1%) in the pediatric and adult double-blind clinical trials were rash, decreased appetite, nausea, and somnolence.
The safety data below are from pediatric patients aged 6 to 17 years in Studies 1 and 2 who received centanafadine 280 mg (or weight-based equivalent) once daily.
Table 1 presents adverse reactions reported in 2% or more of centanafadine-treated pediatric patients aged 6 to 12 years and more frequently than placebo-treated patients in Study 1.
Table 1. Adverse Reactions in ≥2% of Pediatric Patients 6 to 12 Years of Age Treated with Centanafadine and Greater than Placebo in 6-Week Placebo-Controlled ADHD Study (Study 1):
| Placebo (N=153) | Centanafadine High dose* (N=157) | |
| Rasha | 0% | 9% |
| Decreased appetite | 3% | 8% |
| Fatigueb | 0% | 4% |
| Abdominal painc | 2% | 4% |
| Nausea | 1% | 3% |
| Pharyngitis streptococcal | 2% | 3% |
| Diarrhea | 0% | 2% |
| Influenza | 0% | 2% |
* Weight-based equivalent dose (targeting adult exposures at 280 mg/day)
a Rash includes: drug eruption, macular rash, maculo-papular rash, morbilliform rash, papular rash, and other related terms
b Fatigue includes: lethargy
c Abdominal pain includes: upper abdominal pain, abdominal discomfort
Table 2 presents adverse reactions reported in 2% or more of centanafadine-treated pediatric patients aged 13 to 17 years and more frequently than placebo-treated patients in Study 2.
Table 2. Adverse Reactions in ≥2% of Pediatric Patients 13 to 17 Years of Age Treated with Centanafadine and Greater than Placebo in 6-Week Placebo-Controlled ADHD Study (Study 2):
| Placebo (N=147) | Centanafadine 280 mg/day (N=151) | |
| Decreased appetite | 2% | 15% |
| Nausea | 3% | 10% |
| Rasha | 1% | 8% |
| Headacheb | 6% | 7% |
| Abdominal painc | 0% | 5% |
| Somnolenced | 3% | 4% |
| Fatiguee | 1% | 3% |
| Dizziness | 0% | 3% |
| Nasopharyngitis | 1% | 3% |
| Insomniaf | 1% | 3% |
| Irritability | 1% | 3% |
| Dry mouth | 0% | 2% |
| Weight decreased | 1% | 2% |
a Rash includes: drug eruption, macular rash, maculo-papular rash, morbilliform rash, papular rash, and other related terms.
b Headache includes: migraine
c Abdominal pain includes: abdominal discomfort, upper abdominal pain, abdominal tenderness, gastrointestinal pain; lower abdominal pain
d Somnolence includes: sedation
e Fatigue includes: lethargy
f Insomnia includes: initial insomnia
The safety data below are based on pooled data from Studies 3 and 4 in adult patients with ADHD treated with another formulation of centanafadine for 6 weeks.
Table 3 lists adverse reactions reported in ≥2% of adult patients treated with another formulation of centanafadine and more frequently than placebo-treated patients.
Table 3. Adverse Reactions in ≥2% of Adults Treated with Another Centanafadine Formulation and Greater than Placebo in 6-Week Placebo-Controlled ADHD Studies (Studies 3 and 4):
Placebo (N=290) | Another Centanafadine Formulation Low Dose* (N=294) | Another Centanafadine Formulation High Dose* (N=292) | |
| Headachea | 7% | 5% | 8% |
| Decreased appetite | 2% | 5% | 7% |
| Insomniab | 4% | 5% | 7% |
| Nausea | 2% | 2% | 7% |
| Dry mouth | 0% | 3% | 6% |
| Diarrhea | 1% | 2% | 5% |
| Irritability | 2% | 3% | 4% |
| Rashc | 2% | 2% | 4% |
| Abdominal paind | 1% | 2% | 4% |
| Parasomniae | 1% | 1% | 3% |
| Tachycardiaf | 1% | 1% | 2% |
| Depressed moodg | 0% | 3% | 2% |
| Anxietyh | 1% | 2% | 2% |
| Upper respiratory tract infection | 2% | 5% | 2% |
* There are no expected differences in the safety of centanafadine 210 mg and 280 mg once daily compared to the low and high doses of the other centanafadine formulation, respectively, for the treatment of ADHD in adults.
a Headache includes: cervicogenic headache, migraine with aura, migraine without aura, sinus headache, head discomfort, tension headache, migraine, and other related terms
b Insomnia includes: initial insomnia, middle insomnia, poor quality sleep, terminal insomnia, and other related terms.
c Rash includes: erythematous rash, maculo-papular rash, morbilliform rash, papular rash, pruritic rash, and other related terms.
d Abdominal pain includes: abdominal discomfort, upper abdominal pain, lower abdominal pain, abdominal tenderness, gastrointestinal pain, and other related terms.
e Parasomnia includes: abnormal dreams, sleep terror, nightmare, somnambulism, and other related terms.
f Tachycardia includes: sinus tachycardia, supraventricular tachycardia, postural orthostatic tachycardia syndrome, increased orthostatic heart rate response, increased heart rate, and other related terms.
g Depressed mood includes: depressive symptom, depression, major depressive disorder, major depression, dysphoria, and other related terms.
h Anxiety includes: nervousness, panic attack, and other related terms.
In Study 1, 6% (10/157) of centanafadine-treated patients aged 6 to 12 years discontinued due to adverse reactions versus 1% (2/153) of placebo-treated patients. The most frequently reported adverse reaction associated with discontinuation (1% or more and twice rate of placebo) was rash (2.5%).
In Study 2, 8% (12/151) of centanafadine-treated patients aged 13 to 17 years discontinued due to adverse reactions versus 0% (0/147) of placebo-treated patients. The most frequently reported adverse reactions (1% or more and twice rate of placebo) associated with discontinuation were rash (2%), decreased appetite (2%), nausea (2%), and somnolence (1%).
In Studies 3 and 4, 6% (18/292) of adult patients treated with the high dose of another formulation of centanafadine discontinued due to adverse reactions versus 5% (14/294) of patients treated with the low dose and 1% (4/290) of placebo-treated patients. The most frequently reported adverse reaction associated with discontinuation (1% or more and twice rate of placebo) was rash (2%).
In the 6-week study in pediatric patients aged 6 to 12 years (Study 1), suicide attempt was reported in 0.7% (2/304) of centanafadine-treated patients versus 0% in placebo (0/153). In the long-term open-label trial in pediatric patients aged 6 to 17 years, suicidal ideation was reported in 0.8% (5/620) of patients, leading to discontinuation in 0.6% (4/620).
Compared to placebo, short-term (6-week) treatment (Study 1) with centanafadine in patients 6 to 12 years of age was associated with differences, ranging from +0.1 to +2.8 mmHg, in the mean absolute change from baseline systolic blood pressure (SBP) and with differences, ranging from -0.2 mmHg to +1.6 mmHg, in the mean absolute change from baseline diastolic blood pressure (DBP).
Patients enrolled in the long-term open-label study had mean absolute changes in baseline SBP ranging from +0.7 to +2.7 mmHg and in baseline DBP ranging from +0.5 to +2.8 mmHg through Week 88.
During the 6-week trial (Study 2), the proportion of centanafadine-treated patients 13 to 17 years of age who developed new-onset hypertension was 10.7% compared to 8.9% treated with placebo. Compared to placebo, short-term (6-week) treatment with centanafadine in patients 13 to 17 years of age was associated with differences, ranging from +0.5 to +2.1 mmHg, in the mean absolute change from baseline SBP and with differences, ranging from +0.6 mmHg to +1.5 mmHg, in the mean absolute change from baseline DBP.
Patients enrolled in the long-term open-label study had mean absolute changes in baseline SBP ranging from +0.9 to +3.2 mmHg and in baseline DBP ranging from +1.7 to +3.1 mmHg through Week 88.
In Studies 3 and 4 in adults (18 to 55 years of age), increases in heart rate ≥20 beat per minute (bpm) in supine position at any visit occurred in 15% (44/292) of patients on the high dose of another formulation of centanafadine and 12% (34/294) on the low dose, versus 11% (32/290) on placebo. Increases in systolic blood pressure of ≥20 mmHg in supine position at any visit occurred in 9% (25/292) of patients treated with the high dose of another centanafadine formulation and 12% (36/294) of patients treated with the low dose, versus 7% (21/290) on placebo.
In Study 1, psychiatric adverse reactions occurring in <2% of centanafadine-treated patients receiving the weight-based dose equivalent of 280 mg daily and greater than placebo included suicide attempt and insomnia. In a long-term open-label safety study, psychiatric adverse reactions led to discontinuation of centanafadine in 2% of pediatric patients 6 to 12 years of age. Psychiatric adverse reactions leading to discontinuation included irritability, auditory hallucination, visual hallucination, major depression, altered mood, and suicidal ideation.
In Study 2, psychiatric adverse reactions occurred in 9% of patients receiving 280 mg daily of centanafadine compared with 3% of patients who received placebo. Irritability and insomnia were the most common psychiatric adverse reactions in this age group (see Table 2). Irritability occurred in 3% of patients receiving 280 mg centanafadine compared with 1% of patients receiving placebo. Insomnia occurred in 3% of patients receiving 280 mg centanafadine compared with 1% of patients receiving placebo. In a long-term open-label pediatric safety study, psychiatric adverse reactions led to discontinuation in 4% of pediatric patients 13 to 17 years of age. Psychiatric adverse reactions leading to discontinuation included suicidal ideation, depression, irritability, apathy, aggression, anxiety, defiant behavior, and feelings of worthlessness.
In Studies 3 and 4, psychiatric adverse reactions occurred in 16% of patients receiving the high dose of another centanafadine formulation, 14% of patients receiving the low dose, and 8% of patients receiving placebo. The most frequent psychiatric adverse reactions were insomnia, irritability, abnormal dreams, depressed mood, and anxiety (see Table 3). In a long-term open-label study in adults, 21% of patients experienced psychiatric adverse reactions. The most common psychiatric adverse reactions were insomnia (8%), anxiety (6%), and irritability (3%).
In two other ADHD clinical trials, and one trial in an unapproved population, two adult patients reported angioedema, and one patient reported suspected anaphylactic reaction, some of these events required urgent treatment as outpatients.
The mean baseline BMI in centanafadine-treated patients 6 to 12 years of age compared to placebo was 20.4 kg/m² and 20.0 kg/m², respectively. Short-term (6-week) treatment (Study 1) with centanafadine was associated with a mean change from baseline weight of -0.6 kg compared to +0.8 kg in placebo-treated patients at Week 6. The mean baseline weight z-score decreased by at least 0.5 in 0.8% of centanafadine-treated patients compared to none in placebo-treated patients at Week 6. The mean baseline BMI z-score decreased by at least 0.5 in 7.3% of centanafadine-treated patients compared to 3.2% of placebo-treated patients at Week 6.
In the centanafadine long-term open-label study, 2.2% of patients had a change from baseline weight leading to a decrease in weight z-score by at least 1, 2.2% had a decrease in BMI z-score by at least 1, and 15.6% had a decrease in height z-score by at least 1 at Week 88.
The mean baseline BMI in both centanafadine- and placebo-treated patients 13 to 17 years of age was 24.4 kg/m²; however, placebo-treated patients had higher mean baseline weight (69 kg vs. 67.7 kg) and height (167.7 cm vs. 166.7 cm). Short-term (6-week) treatment (Study 2) with centanafadine was associated with a mean change from baseline weight of -1.2 kg compared to +0.6 kg in placebo-treated patients at Week 6. The mean baseline weight z score decreased by at least 0.5 in 2% of centanafadine-treated patients compared to none in placebo-treated patients at Week 6. The mean baseline BMI z-score decreased by at least 0.5 in 4.9% of Centanafadine-treated patients compared to none in placebo-treated patients at Week 6. In the centanafadine long-term open-label study, 4.6% of patients had a change from baseline weight leading to a decrease in weight z-score by at least 1, 4.6% had a decrease in BMI z-score by at least 1, and 1.5% had a decrease in height z-score by at least 1 at Week 88.
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