Rexulti Adverse Reactions

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 clinical practice.
As with other drugs belonging to the therapeutic class of atypical antipsychotics, cases of restless legs syndrome and urinary retention have been reported for REXULTI.
Atypical antipsychotic drugs, such as REXULTI, have been associated with cases of sleep apnea, with or without concomitant weight gain. In patients who have a history of or are at risk for sleep apnea, REXULTI should be prescribed with caution.
Clinical Trial Data: Clinical Trial Data for Major Depressive Disorder: Table 6 shows the incidence of treatment-emergent adverse events (TEAEs) that occurred in at least 2% of patients treated with REXULTI and observed more frequently than with placebo. (See Table 8.)

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Agitation Associated with Alzheimer's Dementia (AAD): The safety of REXULTI was evaluated in 503 patients (51 to 90 years of age), with a probable diagnosis of AAD, who participated in two 12-week placebo-controlled, fixed-dose clinical studies in which REXULTI was administered at daily doses of 2 mg to 3 mg [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions].
Discontinuation of Treatment Due to Adverse Events: In two 12-week placebo-controlled, fixed-dose, clinical studies, a total of 5.6% (28/503) of patients treated with REXULTI and 4.8% (12/251) of patients treated with placebo discontinued due to adverse reactions.
Adverse Reactions Occurring at an Incidence of 2% or More in Patients Treated with REXULTI for AAD: 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 AAD are shown in Table 9. (See Table 9.)

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Adverse reactions that occurred <2% and the difference between REXULTI 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 REXULTI-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 REXULTI-treated patients was 8% versus 3% for placebo-treated patients.
Agitation Associated with Alzheimer's Dementia: 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 AAD, 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%).
Dystonia: Symptoms of dystonia may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
Other Adverse Reactions Observed during Clinical Trial Evaluation of REXULTI: Other adverse reactions (≥1% frequency and greater than placebo) within the short-term, placebo-controlled trials in adult patients with MDD and schizophrenia are shown as follows. The following listingdoes not include adverse reactions: 1) already listed in previous tables or elsewhere in the monograph, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have clinically significant implications, or 5) which occurred at a rate equal to or less than placebo.
Eye Disorders: Vision Blurred.
Gastrointestinal Disorders: Nausea, Dry mouth, Salivary hypersecretion, Abdominal pain, Flatulence.
Investigations: Blood prolactin increased.
Musculoskeletal and Connective Tissue Disorders: Myalgia.
Psychiatric Disorders: Abnormal dreams.
Skin and Subcutaneous Tissue Disorders: Hyperhidrosis.
Clinical Chemistry Findings: Fasting Glucose: In the long-term, placebo-controlled MDD study, 7.1% of patients in the REXULTI group and 3.4% of patients in the placebo group had shifts from normal or impaired to high in fasting glucose. The mean change from baseline for fasting glucose to last visit was 1.74 mg/dL and 0.21 mg/dL for REXULTI and placebo, respectively.
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 REXULTI, 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, placebo-controlled study mean changes from baseline and shifts in lipids are presented in the following table. (See Table 10.)

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In the long-term open-label studies, shifts in fasting cholesterol from normal to high were reported in 8.65% (total cholesterol), 3.20% (LDL cholesterol), and shifts from normal to low were reported in 13.30% (HDL cholesterol) of patients taking REXULTI. 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 longterm, 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 Schizophrenia: Table 8 shows the incidence of treatment-emergent adverse events (TEAEs) that occurred in at least 2% of patients treated with REXULTI and observed more frequently than placebo. (See Table 11.)

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Adverse reactions that occurred <2% and the difference between REXULTI and placebo ≥0.5% in the short-term; placebo-controlled schizophrenia clinical trials included abdominal pain upper, dental caries, flatulence, pain, blood pressure increased, blood triglycerides increased, pain in extremity, myalgia, sedation, cough and rash.
Extrapyramidal Symptoms: In the 6-week, placebo-controlled, fixed-dose schizophrenia studies for 2-4 mg REXULTI-treated patients, the incidence of reported EPS-related events, excluding akathisia events, was 12% versus 10% for placebo-treated patients. The incidence of akathisia events for REXULTI-treated patients was 6% versus 5% for placebo-treated patients.
Weight Gain: In the long-term, open-label schizophrenia studies, the mean change in body weight from baseline to last visit was 1.0 kg (N=1468). The proportion of patients with a ≥7% increase in body weight at any visit was 17.9% (226/1257) and with a ≥7% decrease in body weight at any visit was 8.2% (104/1257). Weight gain led to discontinuation of study medication in 0.4% (5/1265) of patients.
Clinical Chemistry Findings: Fasting Glucose: In the long-term, open-label schizophrenia studies, 7% of patients with normal baseline fasting glucose experienced a shift from normal to high while taking brexpiprazole, 17% of subjects with borderline fasting glucose experienced shifts from borderline to high. Combined, 9% of patients with normal or borderline fasting glucose experienced shifts to high fasting glucose during the long-term schizophrenia studies. The mean change from baseline for fasting glucose to last visit in the long-term, open-label trials was 2.35 [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 6% (total cholesterol), 3% (LDL cholesterol), and shifts in baseline from normal to low were reported in 20% (HDL cholesterol) of patients taking brexpiprazole. Of patients with normal baseline triglycerides, 14% experienced shifts to high, and 0.3% experienced shifts to very high triglycerides. Combined, 0.5% of patients with normal or borderline fasting triglycerides experienced shifts to very high fasting triglycerides during the long-term schizophrenia 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 0.89 [1.00] mg/dL, -0.97 [-1.00] mg/dL, 0.05 [0.00] mg/dL and -0.40 [-2.00] mg/dL, respectively.
Additional Findings Observed in Schizophrenia Clinical Trials: The adverse reactions reported in a 52-week maintenance phase of a randomized, placebo-controlled withdrawal trial in adults with schizophrenia were comparable with those reported in short-term, fixed-dose trials for schizophrenia.
Post-marketing Experience: The following adverse reaction has been reported during the post-marketing period with brexpiprazole. The frequency of the reported adverse reaction is unknown.
Nervous System disorders: Neuroleptic malignant syndrome.