Source: FDA, National Drug Code (US) Revision Year: 2026
SIMTRIYO is contraindicated in patients:
In a short-term (6-week) clinical study, higher rates of suicidal ideation and behaviors were reported in SIMTRIYO-treated pediatric patients aged 6 to 12 years of age with ADHD than in placebo-treated pediatric patients [see Adverse Reactions (6.1)].
All pediatric patients 6 years of age and older treated with SIMTRIYO should be monitored closely for suicidal ideation and behavior, clinical worsening, or unusual changes in behavior, especially during the initial months of SIMTRIYO therapy.
Families and caregivers of pediatric patients 6 years of age and older treated with SIMTRIYO should be advised of the need to monitor patients for the emergence of suicidal ideation and behavior, and to report such symptoms immediately to a healthcare provider.
Consider changing the therapeutic regimen, including stopping SIMTRIYO, in patients who experience emergent suicidal ideation or behavior or symptoms that might be precursors to emerging suicidal ideation and behavior, especially if these symptoms are severe or abrupt in onset, or were not part of the patient's presenting symptoms.
SIMTRIYO has a potential for abuse and misuse. The use of CNS stimulants, including SIMTRIYO, exposes individuals to the risks of abuse, which can lead to the development of a substance use disorder, including addiction [see Drug Abuse and Dependence (9.1, 9.2)]. Misuse and abuse of CNS stimulants, including SIMTRIYO, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher dosage or unapproved methods of administration, such as snorting or injection.
Before prescribing SIMTRIYO, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of SIMTRIYO, and proper disposal of any unused drug. Advise patients to store SIMTRIYO in a safe place, preferably locked, and instruct patients to not give SIMTRIYO to anyone else. Throughout SIMTRIYO treatment, reassess each patient's risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.
Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage.
Prior to treating patients with SIMTRIYO, assess for the presence of cardiac disease (e.g., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam). Avoid SIMTRIYO use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.
CNS stimulants, including SIMTRIYO, can cause an increase in heart rate and blood pressure [see Adverse Reactions (6.1)]. Concomitant use of SIMTRIYO with other CNS stimulants increases the risk of cardiovascular adverse reactions, including increased blood pressure and heart rate [see Drug Interactions (7)].
Assess heart rate and blood pressure prior to initiating treatment with SIMTRIYO, following increases in dosage, and periodically while on therapy.
CNS stimulants, including SIMTRIYO, may exacerbate behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder.
CNS stimulants, including SIMTRIYO, may induce a manic or mixed episode in patients with bipolar disorder. Prior to initiating SIMTRIYO treatment, screen patients for risk factors for developing a manic episode (e.g., history of depressive symptoms or a family history of suicide, bipolar disorder, or depression).
CNS stimulants, including SIMTRIYO, at the recommended dosage, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania [see Adverse Reactions (6.1)]. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients, compared with 0% of placebo-treated patients. If such symptoms occur, consider discontinuing SIMTRIYO.
Serious hypersensitivity reactions, including angioedema and anaphylaxis, requiring emergency treatment, have been reported during clinical trials with SIMTRIYO [see Adverse Reactions (6.1)]. If a clinically significant hypersensitivity reaction occurs, immediately initiate appropriate therapy and discontinue SIMTRIYO. SIMTRIYO is contraindicated in patients with known hypersensitivity to centanafadine or any of the excipients of SIMTRIYO.
SIMTRIYO is not approved for use and is not recommended in pediatric patients less than 6 years of age or weighing less than 20 kg [see Use in Specific Populations (8.4)]. CNS stimulants, including SIMTRIYO, have been associated with weight loss. Long-term treatment with SIMTRIYO is associated with slowing of linear growth in pediatric patients, particularly those 6 to 12 years of age [see Adverse Reactions (6.1)].
Closely monitor weight, body mass index, and linear growth in SIMTRIYO-treated pediatric patients. Consider treatment interruption in pediatric patients who are not growing or gaining height or weight as expected.
CNS stimulants, including SIMTRIYO, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud's phenomenon. Signs and symptoms of these cases of peripheral vasculopathy were usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud's phenomenon, were observed in post-marketing reports and at the therapeutic dosages of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after CNS stimulant dosage reduction or discontinuation.
During SIMTRIYO treatment, carefully assess for digital changes. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for SIMTRIYO-treated patients who develop signs or symptoms of peripheral vasculopathy.
Concomitant use of SIMTRIYO with other serotonergic drugs may cause serotonin syndrome, a potentially life-threatening condition with changes including altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor [see Drug Interactions (7)].
The concomitant use of SIMTRIYO is contraindicated in patients taking or within 14 days of stopping a MAOI, including linezolid or intravenous methylene blue [see Contraindications (4)]. If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking SIMTRIYO, discontinue SIMTRIYO before initiating treatment with the MAOI.
If concomitant use of SIMTRIYO with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. Discontinue SIMTRIYO and/or concomitant serotonergic drug immediately if the above symptoms occur and initiate supportive symptomatic treatment.
CNS stimulants have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette's syndrome has also been reported.
Before initiating SIMTRIYO, assess the family history for tics or Tourette's syndrome and clinically evaluate patients for tics or Tourette's syndrome. Regularly monitor SIMTRIYO-treated patients for the emergence or worsening of tics or Tourette's syndrome and discontinue SIMTRIYO if clinically appropriate.
The SIMTRIYO 210 mg capsule contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity [see Contraindications (4)].
The following adverse reactions are discussed in more detail in other sections of the labeling:
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 SIMTRIYO 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 SIMTRIYO 280 mg (or weight-based equivalent) once daily [see Clinical Studies (14)].
Table 2 presents adverse reactions reported in 2% or more of SIMTRIYO-treated pediatric patients aged 6 to 12 years and more frequently than placebo-treated patients in Study 1.
Table 2. Adverse Reactions in ≥2% of Pediatric Patients 6 to 12 Years of Age Treated with SIMTRIYO and Greater than Placebo in 6-Week Placebo-Controlled ADHD Study (Study 1):
| Placebo (N=153) | SIMTRIYO 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) [see Dosage and Administration (2.2)]
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 3 presents adverse reactions reported in 2% or more of SIMTRIYO-treated pediatric patients aged 13 to 17 years and more frequently than placebo-treated patients in Study 2.
Table 3. Adverse Reactions in ≥2% of Pediatric Patients 13 to 17 Years of Age Treated with SIMTRIYO and Greater than Placebo in 6-Week Placebo-Controlled ADHD Study (Study 2):
| Placebo (N=147) | SIMTRIYO 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 [see Clinical Studies (14)].
Table 4 lists adverse reactions reported in ≥2% of adult patients treated with another formulation of centanafadine and more frequently than placebo-treated patients.
Table 4. 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 SIMTRIYO 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 SIMTRIYO-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 SIMTRIYO-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 SIMTRIYO-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 SIMTRIYO 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 SIMTRIYO-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 SIMTRIYO 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 SIMTRIYO-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 SIMTRIYO 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 SIMTRIYO compared with 3% of patients who received placebo. Irritability and insomnia were the most common psychiatric adverse reactions in this age group (see Table 3). Irritability occurred in 3% of patients receiving 280 mg SIMTRIYO compared with 1% of patients receiving placebo. Insomnia occurred in 3% of patients receiving 280 mg SIMTRIYO 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 4). 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 SIMTRIYO-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 SIMTRIYO 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 SIMTRIYO-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 SIMTRIYO-treated patients compared to 3.2% of placebo-treated patients at Week 6.
In the SIMTRIYO 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 SIMTRIYO- 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 SIMTRIYO 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 SIMTRIYO-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 SIMTRIYO-treated patients compared to none in placebo-treated patients at Week 6. In the SIMTRIYO 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.
Table 5 presents clinically significant drug interactions with SIMTRIYO.
Table 5. Clinically Significant Drug Interactions with SIMTRIYO:
| Monoamine Oxidase Inhibitors (MAOIs) | |
| Prevention or Management | Concomitant use of SIMTRIYO with MAOIs or within 14 days after discontinuing an MAOI is contraindicated [see Dosage and Administration (2.4) and Contraindications (4)]. |
| Mechanism and Clinical Effect(s) | Concomitant use of SIMTRIYO with MAOIs increases the risk of hypertensive crisis (potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure) and serotonin syndrome [see Warnings and Precautions (5.9)]. |
| Alcohol | |
| Prevention or Management | Avoid consumption of alcohol at the same time as, and for at least two hours after, administration of SIMTRIYO. |
| Mechanism and Clinical Effect(s) | Consumption of alcohol at the same time as, and for at least two hours after, administration of SIMTRIYO may result in a more rapid release of centanafadine. A more rapid release of centanafadine may increase exposure- related adverse reactions and may also reduce efficacy during the late hours of the dosing interval due to lower centanafadine exposures [see Clinical Pharmacology (12.3)]. |
| CYP1A2 Substrates | |
| Prevention or Management | When SIMTRIYO is used concomitantly with CYP1A2 substrates, monitor for adverse reactions and consider dosage reduction of the concomitantly used CYP1A2 substrate. |
| Mechanism and Clinical Effect(s) | Centanafadine is a moderate inhibitor of CYP1A2. Concomitant use with centanafadine increases exposure of CYP1A2 substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions associated with these substrates. |
| CNS Stimulants | |
| Prevention or Management | Monitor for cardiovascular adverse reactions (e.g., increased blood pressure, increased heart rate) if SIMTRIYO is used with other CNS stimulants. If cardiovascular adverse reactions occur, consider reducing the dosage of the concomitant CNS stimulant or discontinuation of SIMTRIYO and/or the concomitant CNS stimulant. |
| Mechanism and Clinical Effect(s) | Concomitant use of SIMTRIYO with other CNS stimulants exerts additive pharmacological effects such as increase in blood pressure and heart rate [see Warnings and Precautions (5.4)]. |
| Serotonergic Drugs | |
| Prevention or Management | Monitor for symptoms of serotonin syndrome when SIMTRIYO is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, discontinue SIMTRIYO and/or concomitant serotonergic drug immediately and initiate supportive symptomatic treatment. |
| Mechanism and Clinical Effect | Concomitant use of SIMTRIYO with other serotonergic drugs may cause serotonin syndrome [see Warnings and Precautions (5.9)]. |
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including SIMTRIYO, during pregnancy. Pregnant women exposed to SIMTRIYO and healthcare providers are encouraged to contact the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visiting https://womensmentalhealth.org/research/pregnancyregistry/adhd-medications/.
Available data from the clinical development program with SIMTRIYO 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 (see Data).
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.
In an embryo-fetal study in rats, centanafadine was administered to females orally, once-daily, at dose levels of 10, 30, or 100 mg/kg during gestational development. Mean maternal body weight gain and/or absolute maternal body weights were decreased in the 30 and 100 mg/kg dose groups and correlated with reduced food consumption. Live fetal body weights were significantly reduced in the 30 and 100 mg/kg/day dose groups compared to controls. Treatment-related fetal abnormalities included a significant increase in the litter and fetal incidences of irregularly shaped cervical arches, incompletely ossified cervical arches, and short ribs in the 100 mg/kg dose group. The No Observed Adverse Effect Level (NOAEL) for both maternal toxicity and fetal development was 10 mg/kg/day, which is below the human exposure at the MRHD of 280 mg based on AUC.
The effects of centanafadine on pregnant female White New Zealand rabbits and development of the embryo and fetus was determined at doses of 3, 6, and 15 mg/kg/day. Mean maternal body weight gains were decreased in the 15 mg/kg/day dose group compared to controls. Centanafadine did not result in any effects on embryo-fetal survival, fetal body weights, or fetal external, visceral, or skeletal malformations or variations at any dose. The NOAEL for maternal toxicity was 6 mg/kg/day, which is below the human exposure at the MRHD of 280 mg based on AUC. The NOAEL for fetal development was 15 mg/kg/day, which is lower than the human exposure at the MRHD of 280 mg based on AUC.
Centanafadine was administered orally to pregnant rats during gestation and lactation at doses of 3, 10, or 30 mg/kg/day. Mean maternal body weight gain was decreased in the 30 mg/kg/day group during gestation and correlated with reduced food consumption. There was a slight increase in the incidence of early pup mortality in the 30 mg/kg/day group, which is lower than the human exposure at the MRHD based on AUC.
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 SIMTRIYO and any potential adverse effects on the breastfed child from SIMTRIYO or from the underlying maternal condition.
The safety and effectiveness of SIMTRIYO have been established for the treatment of ADHD in pediatric patients 6 years and older weighing at least 20 kg. Use of SIMTRIYO for this indication is based on evidence from two 6-week, randomized, double-blind, placebo-controlled studies in pediatric patients with ADHD and a long-term open-label study [see Clinical Studies (14)]. In short- term studies, increased rates of suicidal ideation and behaviors were reported in SIMTRIYO-treated patients 6 to 12 years of age [see Warnings and Precautions (5.1)]. Short- and long-term treatment with SIMTRIYO in pediatric patients 6 years of age and older was associated with increases in blood pressure and weight loss [see Warnings and Precautions (5.4, 5.7) and Adverse Reactions (6.1)]. Long term treatment with SIMTRIYO was associated with decreased linear growth [see Warnings and Precautions (5.7) and Adverse Reactions (6.1)].
The safety and effectiveness of SIMTRIYO have not been established in pediatric patients less than 6 years of age or weighing less than 20 kg. The use of SIMTRIYO is not recommended in pediatric patients younger than 6 years of age because this pediatric subpopulation had a higher incidence of weight loss than pediatric patients 6 years of age and older. The use of SIMTRIYO is not recommended in pediatric patients weighing less than 20 kg because of a lack of data for this subpopulation and the risk of weight loss. A higher proportion of patients 4 to less than 6 years of age developed changes in mean baseline weight z-score and BMI z-score with short-term (6-week) SIMTRIYO treatment compared to pediatric patients 6 years of age and older. The mean baseline weight z-score decreased by at least 0.5 in 8.5% of SIMTRIYO-treated patients compared to none of the placebo-treated patients at Week 6. The mean baseline BMI z-score decreased by at least 0.5 in 25.5% of SIMTRIYO-treated patients compared to 4.2% of placebo-treated patients at Week 6. With short- and long-term SIMTRIYO treatment, a higher proportion of patients 4 to less than 6 years of age also developed decreases in heart rate of at least 10% leading to a measured heart rate below the first percentile for age compared to pediatric patients 6 years of age and older.
Juvenile rats were administered centanafadine at dose levels of 3, 10, and 30 mg/kg/day on post- natal day 21 through post-natal day 62. Lower body weights were observed at the 30 mg/kg/day dose and correlated with lower mean food consumption. A delay in preputial separation (which was associated with a decrease in body weight gain) and a slightly lower proportion of sperms with normal morphology were observed at 30 mg/kg/day, but there were no effects on fertility or reproductive performance. The NOAEL was 30 mg/kg/day, which is less than the human exposure at the MRHD of 280 mg based on AUC in pediatrics.
Clinical studies of SIMTRIYO did not include patients 65 years of age and older to determine if they respond differently than younger adult patients.
The pharmacokinetics of centanafadine was not studied in patients with severe hepatic impairment (Child-Pugh Class C) or in patients with mild hepatic impairment (Child-Pugh Class A). The exposure of centanafadine in patients with moderate hepatic impairment (Child-Pugh Class B) is similar to that in patients with normal hepatic function [see Clinical Pharmacology (12.3)].
SIMTRIYO is not recommended in patients with severe hepatic impairment. The recommended dosage of SIMTRIYO in patients with mild (Child-Pugh A) or moderate hepatic impairment is the same as that for patients with normal hepatic function.
SIMTRIYO contains centanafadine. (Controlled substance schedule to be determined after review by the Drug Enforcement Administration.)
SIMTRIYO has a potential for abuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions (5.1)]. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.
SIMTRIYO has a potential for misuse. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Misuse, like abuse, is often associated with higher doses and/or more frequent use of the drug, which may lead to adverse reactions similar to those seen in the context of abuse and substance use disorder.
Misuse and abuse of SIMTRIYO may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including SIMTRIYO, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.
Two human abuse potential studies were conducted with centanafadine, using individuals with a history of recreational use of stimulants as subjects:
These human data demonstrate that centanafadine has abuse potential.
Centanafadine may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).
Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.
Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation. However, in two phase 3 studies in which adults with ADHD received chronic administration of SIMTRIYO (200 and 400 mg total daily dose), abrupt discontinuation of the drug produced a very low degree of withdrawal symptoms that were indistinguishable from those produced by placebo. This suggests that even though SIMTRIYO is a CNS stimulant, it does not produce physical dependence.
WARNING: SUICIDAL IDEATION AND BEHAVIORS IN PEDIATRIC PATIENTS AGED 6 YEARS AND OLDER; and ABUSE, MISUSE AND ADDICTION
Suicidal Ideation and Behaviors in Pediatric Patients 6 Years of Age and Older
In a short-term (6-week) clinical study, higher rates of suicidal ideation and behavior were reported in SIMTRIYO-treated pediatric patients with attention deficit/hyperactivity disorder (ADHD) aged 6 to 12 years than in pediatric patients treated with placebo. All pediatric patients 6 years of age or older treated with SIMTRIYO should be monitored closely for suicidal ideation and behaviors, clinical worsening, or unusual changes in behavior, especially during the initial months of therapy. Families and caregivers should be advised of the need for close observation and communication with the healthcare provider. Consider stopping SIMTRIYO in patients who experience emergent suicidal ideation and behavior [see Warnings and Precautions (5.1)].
Abuse, Misuse, and Addiction
SIMTRIYO has a potential for abuse and misuse. Abuse of central nervous system (CNS) stimulants, including SIMTRIYO, can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including SIMTRIYO, can result in overdose and death [see Overdosage (10)], and this risk is increased with a higher dosage or unapproved methods of administration, such as snorting or injection.
Before prescribing SIMTRIYO, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of SIMTRIYO, and proper disposal of any unused drug. Throughout SIMTRIYO treatment, reassess each patient's risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [see Warnings and Precautions (5.2) and Drug Abuse and Dependence (9.1, 9.2)].
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