Rexulti Adverse Reactions

Clinical Trial Data For Schizophrenia: Summary of the safety profile: The most frequently observed adverse drug reactions (ADRs) were akathisia (5.6%) and weight gain (3.9%).
Tabulated list of adverse reactions: The incidences of the ADRs associated with brexpiprazole therapy are tabulated as follows. The table is based on adverse reactions reported in short-term placebo-controlled phase 2 and 3 clinical trials with relevant therapeutic doses (2 mg to 4 mg).
All ADRs are listed by system organ class (SOC) and frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See Table 7.)

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Description of selected adverse reactions: Extrapyramidal Symptoms (EPS): Akathisia was the most frequently reported EPS related ADR in the brexpiprazole 2 mg/day to 4 mg/day group (5.6%) compared to 4.5% in placebo, followed by tremor (2.7%) compared to 1.2% in placebo. The incidences of other EPS-related ADRs reported in short-term, controlled trials are dyskinesia (0.4%), extrapyramidal disorder (1.8%) and Parkinsonism (0.4%).
Akathisia: From fixed-dose trials there appears to be a dose-response relationship for akathisia in patients treated with brexpiprazole, with an increasing frequency with higher doses. The incidence of akathisia in the brexpiprazole 1 mg/day, 2 mg/day, and 4 mg/day groups was 3.0%, 4.6%, and 6.5%, respectively, compared with 5.2% of subjects in the placebo group.
The incidence of akathisia in the short-term, controlled trials (5.4%) was similar to the incidence in the long-term, open-label trials (5.7%).
Suicidality: In short-term, controlled trials, Treatment Emergent Adverse Events (TEAEs) related to suicidality were reported for 8 subjects (0.5%, 2 serious events, 1 leading to discontinuation) in the all brexpiprazole treatment group and 3 subjects (0.4%, none serious) in the placebo group. In long-term, open-label trials, TEAEs related to suicidality were reported for 23 subjects (1.6%). Overall in the brexpiprazole clinical development program for schizophrenia, one death due to suicide, considered not drug related by the investigator, occurred. Spontaneous cases reporting completed suicide and suicide attempt have been reported in the post-marketing setting.
QT prolongation: In the short-term controlled trials with brexpiprazole, 3 TEAEs related to QT prolongation were reported in the 2 mg to 4 mg group (0.3%), compared with 3 TEAEs (0.5%) reported for subjects on placebo. The incidence of TEAEs in long-term trials was similar to that of the short-term trials. The effects of brexpiprazole at therapeutic (4 mg) and supra-therapeutic (12 mg) doses on QT interval were evaluated in subjects with schizophrenia or schizoaffective disorder in a randomised, double-blind, placebo- and positive-controlled (moxifloxacin), parallel-arm trial. Subgroup analyses from this trial suggested that the QTc prolongation was larger in female subjects than in males (see Pharmacology: Pharmacodynamics under Actions).
Weight gain: Adults: In short-term, controlled trials, the percentage of subjects with clinically significant weight gain (increase of ≥7% from baseline in body weight) was 9.1% in the brexpiprazole 2 mg/day to 4 mg/day group, compared with 3.8% in the placebo group.
In the long-term, open-label trial, the percentage of subjects with clinically significant weight gain (increase of ≥7% in body weight) at any visit was 20.7% and 0.4% of the subjects discontinued due to weight gain. In subjects who had a weight gain ≥7% from baseline, weight increased over time, with mean weight gain up to 10.2 kg at week 52. The mean change in body weight overall for the brexpiprazole group in the long term, open label trial was 2.1 kg at week 52.
Pediatric Patients (13 to 17 years of age): In the long-term, open label study in pediatric patients with schizophrenia, 0.5% of patients discontinued due to weight increase. The mean increase in weight from the open-label study baseline to last visit was 3.8 kg. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for natural growth of children and adolescents by comparisons to age- and gender-matched population standards. A z score change <0.5 SD is considered not clinically significant. In this trial, the mean change in z-score from open-label baseline to last visit was 0.10 SD for body weight, while 20% of patients had an increase in age-and-gender-adjusted body weight z-score of at least 0.5 SD from baseline. When treating pediatric, weight gain should be monitored and assessed against that expected for normal growth.
Hyperglycaemia: In the long-term, open-label study in pediatric patients with schizophrenia, 2.7% of pediatric patients with normal baseline fasting glucose experienced a shift from normal (<100 mg/dL) to high (≥126 mg/dL) while taking REXULTI.
Dyslipidemia: In the long-term, open-label study in pediatric patients with schizophrenia, shifts in baseline fasting total cholesterol from normal to high (<170 to ≥200 mg/dL) were reported in 7% of patients taking REXULTI, and shifts in baseline HDL cholesterol from normal to low (≥40 to <40 mg/dL) were reported in 12.9% of patients taking REXULTI. Of patients with normal baseline triglycerides, 8.5% experienced shifts from normal to high (<150 to ≥200 mg/dL).
Prolactin: The incidence of blood prolactin increased was 0.9% in 2 mg to 4 mg brexpiprazole group compared to that of 0.5% in placebo in short-term, controlled trials. Higher frequencies of prolactin increased (1.5% versus 0.60%) were observed in females compared to males in short-term trials. In addition, the frequencies of prolactin elevations >1 × ULN in the 2 mg to 4 mg brexpiprazole group was 13.7% in females versus 6.4% in placebo and 11.1% in males versus 10.3% in placebo group.
Neuroleptic malignant syndrome: A potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with brexpiprazole (see Precautions).
Nausea: For nausea, the incidence in the 2 mg to 4 mg brexpiprazole group was 2.3% overall in short-term controlled trials, compared to 2.0% in placebo; for vomiting, these incidences were 1.0% in the brexpiprazole-treated group compared to 1.2% in placebo group.
In terms of gender differences, there were higher observed frequencies of nausea (4.8% versus 2.8%) and vomiting (4.6% versus 1.4%) in females compared to males among brexpiprazole-treated subjects in short-term trials, in subjects receiving placebo: the frequency for nausea was 2.8% for males versus 3.2% for females and for vomiting the frequency was 3.0% for males versus 2.6% for females (see Pharmacology: Pharmacokinetics under Actions).
Pediatric Patients (13 to 17 years of age): In an on-going, 2 year, open-label study in pediatric patients 13 to 17 years of age with schizophrenia, in which safety was assessed in 194 patients of which 140 received REXULTI for at least 6 months. Adverse reactions reported in clinical studies for this age group were generally similar to those observed in adult patients.
Clinical Trial Data For Major Depressive Disorder: The table as follows shows the incidence of adverse reactions that occurred in at least 2% of patients treated with 1-3 mg brexpiprazole+ADT treated group and observed more frequently than placebo. (See Table 8.)

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Adverse reactions that occurred <2% and the difference between brexpiprazole and placebo ≥0.5% in the short-term; placebo-controlled MDD adjunctive therapy clinical trials included palpitations, blepharospasm, toothache, salivary hypersecretion, urinary tract infection, blood prolactin increased, blood cortisol decreased, aspartate aminotransferase increased, muscle spasms, tension, night sweats and hypertension.
Selected Adverse Reactions: Extrapyramidal Symptoms: In the three 6-week, placebo-controlled, fixed-dose and one 6-week, placebo-controlled, flexible-dose MDD studies for brexpiprazole-treated patients, the incidence of reported EPS-related events, excluding akathisia events, was 5% versus 3% for placebo-treated patients. The incidence of akathisia events for brexpiprazole-treated patients was 8% versus 3% for placebo-treated patients.
Clinical Chemistry Findings: Weight Gain: In the long-term, open-label MDD studies, the mean change in body weight from baseline to last visit was 2.6 kg (N=2232). The proportion of patients with a ≥7% increase in body weight at last visit was 22.12% (494/2232) and with a ≥7% decrease in body weight was 3.2% (72/2232). At 52 weeks, the proportion of patients with a ≥7% increase in body weight was 28.2% (286/1013) and with a ≥7% decrease in body weight was 3.7% (37/1013). Weight gain led to discontinuation of study medication in 3.8% (84/2240) of patients.
Fasting Glucose: In the long-term, open-label MDD studies, 5.22% of patients with normal baseline fasting glucose experienced a shift from normal to high while taking brexpiprazole, 24.35% of subjects with borderline fasting glucose experienced shifts from borderline to high. Combined, 9.06% of patients with normal or borderline fasting glucose experienced shifts to high fasting glucose during the long-term MDD studies. The mean change from baseline for fasting glucose to last visit in the long-term, open label trials was 3.53 [2.00] mg/dL.
Fasting Lipids: In the long-term open-label studies, shifts in baseline fasting cholesterol from normal to high were reported in 8.65% (total cholesterol), 3.20% (LDL cholesterol), and shifts in baseline from normal to low were reported in 13.30% (HDL cholesterol) of patients taking brexpiprazole. Of patients with normal baseline triglycerides, 17.26% experienced shifts to high, and 0.22% experienced shifts to very high triglycerides. Combined, 0.61% of patients with normal or borderline fasting triglycerides experienced shifts to very high fasting triglycerides during the long-term MDD studies. The mean changes from baseline for fasting HDL cholesterol, fasting LDL cholesterol, fasting cholesterol and fasting triglycerides to last visit in the long-term, open label trials were -2.13 [-2.00] mg/dL, 1.36 [1.00] mg/dL, 0.05 [0.00] mg/dL and 11.46 [8.00] mg/dL, respectively.
Clinical Trial Data For Agitation Associated With Dementia Due to Alzheimer's Disease: Adverse reactions associated with REXULTI (incidence ≥2% and greater than placebo) during the 12-week fixed-dose clinical studies in geriatric patients for treatment of agitation associated with dementia due to Alzheimer's disease are shown in the Table as follows. (See Table 9.)

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Extrapyramidal Symptoms: The incidence of reported EPS-related adverse reactions, excluding akathisia, was 3% for REXULTI treated patients versus 2% for placebo-treated patients. The incidence of akathisia events for REXULTI-treated patients was 1% versus 0% for placebo-treated patients.
In the 12-week placebo-controlled, fixed-dose studies in agitation associated with dementia due to Alzheimer's disease, data was objectively collected on the Simpson-Angus Rating Scale (SAS) for EPS, the Barnes Akathisia Rating Scale (BARS) for akathisia and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesia. The mean change from baseline at last visit for REXULTI-treated patients for the SAS, BARS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in REXULTI-treated patients versus placebo for the SAS (6% versus 2%).
Clinical Chemistry Findings: Weight gain: In the 12-week placebo-controlled, fixed-dose clinical studies in patients (51 to 90 years of age) with agitation associated with dementia due to Alzheimer's disease, the proportion of the patients with a ≥7% increase in body weight (kg) at any visit were 2% in REXULTI compared to 0% in placebo group. In patients who were previously treated with REXULTI for 12 weeks and who continued into a 12-week, active-treatment extension study, there was no mean change in weight (kg) from baseline to last visit in association with REXULTI. In this extension study, 4% of patients demonstrated ≥7% increase in body weight, and 5% demonstrated a ≥7% decrease in body weight from baseline to last visit.
Fasting Glucose: In the 12-week placebo-controlled, fixed-dose studies in patients (51 to 90 years of age) with agitation associated with dementia due to Alzheimer's disease, the proportions of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) or impaired (≥100 and <126 mg/dL) to high were similar in patients treated with REXULTI (14%) and patients treated with placebo (16%).
Of the patients who were previously treated with REXULTI for 12-weeks and continued into a 12-week, active-treatment extension study, 15% of patients with normal baseline fasting glucose experienced a shift from normal (<100 mg/dL) to high (≥126 mg/dL) fasting glucose while taking REXULTI; 30% of patients with impaired fasting glucose experienced shifts from impaired fasting glucose (≥100 and <126 mg/dL) to high fasting glucose. Combined, 20% of patients with normal or impaired fasting glucose experienced shifts to high fasting glucose.
Fasting Lipids: In the 12-week placebo-controlled, fixed-dose clinical studies in patients (55 to 90 years of age) with agitation associated with dementia due to Alzheimer's disease, changes in total cholesterol, LDL cholesterol, and HDL cholesterol were similar in REXULTI- and placebo-treated patients. The Table as follows shows the proportions of patients with changes in fasting triglycerides in REXULTI- and placebo-treated patients. (See Table 10.)

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Of the patients who were previously treated with REXULTI for 12 weeks and continued into a 12-week, active-treatment extension study, 9% of patients taking REXULTI showed shifts in baseline fasting total cholesterol from normal (<200 mg/dL) to high (≥240 mg/dL), and 16% of patients taking REXULTI showed shifts in baseline HDL cholesterol from normal to low (≥40 to <40 mg/dL). Of the patients with normal baseline triglycerides, 18% experienced shifts from normal (<150 mg/dL) to high (200 to <500 mg/dL).