Rexulti

Brexpiprazole.

REXULTI tablets are for oral administration and are available in 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg and 4 mg strengths.
Brexpiprazole, an atypical antipsychotic, is available as REXULTI (brexpiprazole) tablets. Brexpiprazole is 7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one. The empirical formula is C₂₅H₂₇N₃O₂S and its molecular weight is 433.57.
Excipients/Inactive Ingredients: Lactose monohydrate, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium stearate, hypromellose, and talc.
Colorants: Titanium dioxide, iron oxide and ferrosferric oxide.

Pharmacology: Mechanism of Action: The mechanism of action of brexpiprazole in the treatment of schizophrenia is unknown. However, the efficacy of brexpiprazole may be mediated through a combination of partial agonist activity at serotonin 5-HT_1A and dopamine D₂ receptors, and antagonist activity at serotonin 5-HT_2A receptors.
Pharmacodynamics: Brexpiprazole has affinity (expressed as K_i) for multiple monoaminergic receptors including serotonin 5-HT_1A (0.12 nM), 5-HT_2A (0.47 nM), 5-HT_2B (1.9 nM), 5-HT₇ (3.7 nM), dopamine D₂ (0.30 nM), D₃ (1.1 nM), and noradrenergic α_1A (3.8 nM), α_1B (0.17 nM), α_1D (2.6 nM), and α_2C (0.59 nM) receptors. Brexpiprazole acts as a partial agonist at the 5-HT_1A, D₂, and D₃ receptors and as an antagonist at 5-HT_2A, 5-HT_2B, 5-HT₇, α_1A, α_1B, α_1D, and α_2C receptors. Brexpiprazole also exhibits affinity for histamine H₁ receptor (19 nM) and for muscarinic M₁ receptor (67% inhibition at 10 μM).
Clinical Studies: The efficacy of REXULTI in the treatment of adults with schizophrenia was demonstrated in two 6-week, randomized, double-blind, placebo-controlled, fixed-dose clinical trials in patients who met DSM-IV-TR criteria for schizophrenia.
In both studies, Study 231 (hereafter "Study 1") and Study 230 (hereafter "Study 2"), patients were randomized to REXULTI 2 or 4 mg once per day or placebo. Patients in the REXULTI groups initiated treatment at 1 mg once daily on Days 1 to 4. The REXULTI dosage was increased to 2 mg on Days 5 to 7. The dosage was then either maintained at 2 mg once daily or increased to 4 mg once daily, depending on treatment assignment, for the 5 remaining weeks.
The primary efficacy endpoint of both trials was the change from baseline to Week 6 in the Positive and Negative Syndrome Scale (PANSS) total score. The PANSS is a 30-item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); the total PANSS scores range from 30 (best) to 210 (worst).
In Study 1, REXULTI at both 2 mg/day and 4 mg/day was superior to placebo on the PANSS total score. In Study 2, REXULTI 4 mg/day was superior to placebo on the PANSS total score (Table 1). Figure 1 shows the time course of response based on the primary efficacy measure (change from baseline in PANSS total score) in Study 1.
Examination of population subgroups based on age, gender and race did not suggest differential responsiveness. (See Table 1 and Figure 1.)


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The safety and efficacy of REXULTI as maintenance treatment in adults with schizophrenia aged 18 to 65 years were demonstrated in the maintenance phase of a randomized withdrawal trial (Study 331-10-232, hereafter "Study3"). Patients were stabilized for at least 12 weeks on 1 to 4 mg/day of REXULTI (N=202). They were then randomized in the double-blind treatment phase to either continue REXULTI at their achieved stable dose (N=97), or to switch to placebo (N=105).
The primary endpoint in Study 3 was time from randomization to impending relapse during the double-blind phase, defined as: 1) CGI-Improvement score of ≥ 5 (minimally worse) and an increase to a score > 4 on PANSS conceptual disorganization, hallucinatory behavior, suspiciousness, or unusual thought content items, with either a ≥ 2 increase on a specific item or ≥ 4 point increase on the combined four PANSS items, 2) hospitalization due to worsening of psychotic symptoms, 3) current suicidal behavior, or 4) violent/aggressive behavior.
A pre-specified interim analysis demonstrated a statistically significantly longer time to relapse in patients randomized to the REXULTI group compare to placebo-treated patients. The trial was subsequently terminated early because maintenance of efficacy had been demonstrated. The Kaplan-Meier curves of the cumulative proportion of patients with relapse during the double-blind treatment phase for REXULTI and placebo groups are shown in Figure 2. The key secondary endpoint, the proportion of subjects who met the criteria for impending relapse, was statistically significantly lower in REXULTI-treated patients compared with placebo group. (See Figure 2.)


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Note: A total of 202 subjects were randomized. Among them, one placebo subject did not take investigational medicinal product and one brexpiprazole subject did not have post-randomization efficacy evaluations. These two subjects were excluded from the efficacy analysis.
Pharmacokinetics: Absorption: After single dose administration of REXULTI tablets, the peak plasma brexpiprazole concentrations occurred within 4 hours after administration; and the absolute oral bioavailability was 95%. Brexpiprazole steady-state concentrations were attained within 10 to 12 days of dosing.
REXULTI can be administered with or without food. Administration of a 4 mg REXULTI tablet with a standard high fat meal did not significantly affect the C_max or AUC of brexpiprazole. After single and multiple once daily dose administration, brexpiprazole exposure (C_max and AUC) increased in proportion to the dose administered. In vitro studies of brexpiprazole did not indicate that brexpiprazole is a substrate of efflux transporters such as MDRI (P-gp) and BCRP.
Distribution: The volume of distribution of brexpiprazole following intravenous administration is high (1.56 ± 0.42 L/kg), indicating extravascular distribution. Brexpiprazole is highly protein bound in plasma (greater than 99%) to serum albumin and α1-acid glycoprotein, and its protein binding is not affected by renal or hepatic impairment. Based on results of in vitro studies, brexpiprazole protein binding is not affected by warfarin, diazepam, or digitoxin.
Elimination: Metabolism: Based on in vitro metabolism studies of brexpiprazole using recombinant human cytochrome P450 (CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4), the metabolism of brexpiprazole was shown to be mainly mediated by CYP3A4 and CYP2D6.
In vivo brexpiprazole is metabolized primarily by CYP3A4 and CYP2D6 enzymes. After single- and multiple-dose administrations, brexpiprazole and its major metabolite, DM-3411, were the predominant drug moieties in the systemic circulation. At steady-state, DM-3411 represented 23% to 48% of brexpiprazole exposure (AUC) in plasma. DM-3411 is considered not to contribute to the therapeutic effects of brexpiprazole.
Based on in vitro data, brexpiprazole showed little to no inhibition of CYP450 isozymes.
Excretion: Following a single oral dose of [¹⁴C]-labeled brexpiprazole, approximately 25% and 46% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged brexpiprazole was excreted in the urine and approximately 14% of the oral dose was recovered unchanged in the feces. Apparent oral clearance of a brexpiprazole oral tablet after once daily administration is 19.8 (± 11.4) mL/h/kg. After multiple once daily administration of REXULTI, the terminal elimination half-lives of brexpiprazole and its major metabolite, DM-3411, were 91 hours and 86 hours, respectively.
Studies In Specific Populations: Exposures of brexpiprazole in specific populations are summarized in Figure 3. Population PK analysis indicated exposure of brexpiprazole in patients with moderate renal impairment was higher compared to patients with normal renal function. (See Figure 3.)


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Drug Interaction Studies: Effects of other drugs on the exposures of brexpiprazole are summarized in Figure 4. Based on simulation, a 5.1-fold increase in AUC values at steady-state is expected when extensive metabolizers of CYP2D6 are administered with both strong CYP2D6 and CYP3A4 inhibitors. A 4.8-fold increase in mean AUC values at steady-state is expected in poor metabolizers of CYP2D6 administered with strong CYP3A4 inhibitors [see Drugs Having Clinically Important Interactions with REXULTI under Interactions]. (See Figure 4.)


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The effects of REXULTI on the exposures of other drugs are summarized in Figure 5. (See Figure 5.)


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Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Lifetime carcinogenicity studies were conducted in ICR mice and SD rats. Brexpiprazole was administered orally for two years to male and female mice at doses of 0.75, 2 and 5 mg/kg/day (0.9 to 6.1 times the oral MRHD of 4 mg/day based on mg/m² body surface area) and to male and female rats at doses of 1, 3, and 10 mg/kg and 3, 10, and 30 mg/kg/day, respectively (2.4 to 24 and 7.3 to 73 times the oral MRHD, males and females). In female mice, the incidence of mammary gland adenocarcinoma was increased at all doses and the incidence of adenosquamous carcinoma was increased at 2.4 and 6.1 times the MRHD. No increase in the incidence of tumors was observed in male mice. In the rat study, brexpiprazole was not carcinogenic in either sex at doses up to 73 times the MRHD.
Proliferative and/or neoplastic changes in the mammary and pituitary glands of rodents have been observed following chronic administration of antipsychotic drugs and are considered to be prolactin mediated. The potential for increasing serum prolactin level of brexpiprazole was shown in both mice and rats. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown.
Mutagenesis: Brexpiprazole was not mutagenic when tested in the in vitro bacterial reverse mutation assay (Ames test). Brexpiprazole was negative for clastogenic activity in the in vivo micronucleus assay in rats, and was not genotoxic in the in vivo/in vitro unscheduled DNA synthesis assay in rats. In vitro with mammalian cells brexpiprazole was clastogenic but only at doses that induced cytotoxicity. Based on a weight of evidence, brexpiprazole is not considered to present a genotoxic risk to humans.
Impairment of Fertility: Female rats were treated with oral doses of 0.3, 3 or 30 mg/kg/day (0.7, 7.3, and 73 times the oral MRHD on a mg/m² basis) prior to mating with untreated males and continuing through conception and implantation. Estrus cycle irregularities and decreased fertility were observed at 3 and 30 mg/kg/day. Prolonged duration of pairing and increased preimplantation losses were observed at 30 mg/kg/day.
Male rats were treated with oral doses of 3, 10, or 100 mg/kg/day (7.3, 24 and 240 times the oral MRHD on a mg/m² basis) for 63 days prior to mating with untreated females and throughout the 14 days of mating. No differences were observed in the duration of mating or fertility indices in males at any dose of brexpiprazole.

REXULTI is indicated for: Treatment of exacerbation and maintenance of schizophrenia for adults [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions].

Treatment of Schizophrenia: The recommended starting dosage for REXULTI is 1 mg once daily on Days 1 to 4, taken orally with or without food [see Pharmacology: Pharmacokinetics under Actions].
The recommended target REXULTI dosage is 2 mg to 4 mg once daily. Titrate to 2 mg once daily on Day 5 through Day 7, then to 4 mg on Day 8 based on the patient's clinical response and tolerability. The maximum recommended daily dosage is 4 mg.
Switching from other antipsychotics to brexpiprazole: When switching from other antipsychotics to brexpiprazole gradual cross-titration should be considered, with gradual discontinuation of the previous treatment while brexpiprazole treatment is initiated.
Switching to other antipsychotics from brexpiprazole: When switching to other antipsychotics from brexpiprazole, no gradual cross-titration is needed, the new antipsychotics should be initiated in its lowest dose while brexpiprazole is discontinued. It should be considered that plasma concentration of brexpiprazole will decline gradually and will be completely washed out in 1 to 2 weeks.
Dosage Adjustments for Hepatic Impairment: For patients with moderate to severe hepatic impairment (Child-Pugh score ≥ 7), the maximum recommended dosage is 3 mg once daily for patients with schizophrenia [see Hepatic Impairment under Precautions, Pharmacology: Pharmacokinetics under Actions].
Dosage Adjustments for Renal Impairment: For patients with moderate, severe or end-stage renal impairment the maximum recommended dosage is 3 mg once daily for patients with schizophrenia [see Renal Impairment under Precautions, Pharmacology: Pharmacokinetics under Actions].
Dosage Modifications for CYP2D6 Poor Metabolizers and for Concomitant Use with CYP Inhibitors or Inducers: Dosage adjustments are recommended in patients who are known cytochrome P450 (CYP) 2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers (see Table 2). If the coadministered drug is discontinued, adjust the REXULTI dosage to its original level. If the coadministered CYP3A4 inducer is discontinued, reduce the REXULTI dosage to the original level over 1 to 2 weeks [see Drugs Having Clinically Important Interactions with REXULTI under Interactions, Pharmacology: Pharmacokinetics under Actions]. (See Table 2.)


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There is limited clinical trial experience regarding human overdosage with REXULTI.
Management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers.
Charcoal: Oral activated charcoal and sorbitol (50 g/240 mL), administered one hour after ingesting oral brexpiprazole, decreased brexpiprazole Cmax and area under the curve (AUC) by approximately 5% to 23% and 31% to 39% respectively; however, there is insufficient information available on the therapeutic potential of activated charcoal in treating an overdose with REXULTI.
Hemodialysis: There is no information on the effect of hemodialysis in treating an overdose with REXULTI; hemodialysis is unlikely to be useful because brexpiprazole is highly bound to plasma proteins.

REXULTI is contraindicated in patients with a known hypersensitivity to brexpiprazole or any of its components. Reactions have included rash, facial swelling, urticaria, and anaphylaxis.

Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. REXULTI is not approved for the treatment of patients with dementia-related psychosis [see Increased Mortality in Elderly Patients with Dementia-Related Psychosis under Precautions].

Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.
Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. REXULTI is not approved for the treatment of patients with dementia-related psychosis [see Warnings, Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis as follows].
Suicidal Thoughts and Behaviors: The possibility of a suicide attempt is inherent in psychotic illnesses. Close supervision and appropriate clinical management of high-risk patients should accompany drug therapy.
Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis: In placebo-controlled trials in elderly subjects with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of cerebrovascular adverse reactions (stroke and transient ischemic attacks), including fatal stroke. REXULTI is not approved for the treatment of patients with dementia-related psychosis [see Warnings, Increased Mortality in Elderly Patients with Dementia-Related Psychosis as previously mentioned].
QT Prolongation: QT prolongation can develop in patients treated with antipsychotics. In clinical trials, only a few, non-serious, QT prolongations have been reported with brexpiprazole. Caution should be exercised when brexpiprazole is prescribed in patients with known cardiovascular disease, family history of QT prolongation, electrolyte imbalance or in concomitant use with other medicinal products thought to prolong the QT interval.
Venous Thromboembolism: Cases of venous thromboembolism (VTE) have been reported with antipsychotics. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with brexpiprazole and preventive measures undertaken.
Neuroleptic Malignant Syndrome (NMS): A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including REXULTI. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
If NMS is suspected, immediately discontinue REXULTI and provide intensive symptomatic treatment and monitoring.
Tardive Dyskinesia: Tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. The risk appears to be highest among the elderly, especially elderly women, but it is not possible to predict which patients are likely to develop the syndrome. Whether antipsychotic drugs differ in their potential to cause tardive dyskinesia is unknown.
The risk of tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses. It may also occur after discontinuation of treatment.
Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of tardive dyskinesia is unknown.
Given these considerations, REXULTI should be prescribed in a manner most likely to reduce the risk of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs; and (2) for whom alternative, effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment needed to produce a satisfactory clinical response. Periodically reassess the need for continued treatment.
If signs and symptoms of tardive dyskinesia appear in a patient on REXULTI, dose reduction or drug discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment. However, some patients may require treatment with REXULTI despite the presence of the syndrome.
Metabolic Changes: Atypical antipsychotic drugs, including REXULTI, have caused metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and body weight gain. Although all of the drugs in the class to date have been shown to produce some metabolic changes, each drug has its own specific risk profile.
Hyperglycemia and Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with REXULTI [see Clinical Trials Experience under Adverse Reactions]. Assess fasting plasma glucose before or soon after initiation of antipsychotic medication and monitor periodically during long-term treatment.
In the 6-week, placebo-controlled, fixed-dose clinical trials in patients with schizophrenia, the proportions of patients with shifts in fasting glucose from normal (< 100 mg/dL) to high (≥ 126 mg/dL) or borderline (≥ 100 and < 126 mg/dL) to high were similar in patients treated with REXULTI and placebo.
In the long-term, open-label schizophrenia studies, 8% of patients with normal baseline fasting glucose experienced a shift from normal to high while taking REXULTI, 17% of subjects with borderline fasting glucose experienced shifts from borderline to high. Combined, 10% of subjects with normal or borderline fasting glucose experienced shifts to high fasting glucose during the long-term schizophrenia studies.
Patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control.
Dyslipidemia: Atypical antipsychotics cause adverse alterations in lipids. Before or soon after initiation of antipsychotic medication, obtain a fasting lipid profile at baseline and monitor periodically during treatment.
In the 6-week, placebo-controlled, fixed-dose clinical trials in patients with schizophrenia, changes in fasting total cholesterol, LDL cholesterol, and HDL cholesterol were similar in REXULTI- and placebo-treated patients. Table 3 shows the proportions of patients with changes in fasting triglycerides. (See Table 3.)


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In the long-term, open-label schizophrenia studies, shifts in baseline fasting cholesterol from normal to high were reported in 6% (total cholesterol), 2% (LDL cholesterol), and shifts in baseline from normal to low were reported in 17% (HDL cholesterol) of patients taking REXULTI. Of patients with normal baseline triglycerides, 13% experienced shifts to high, and 0.4% experienced shifts to very high triglycerides. Combined, 0.6% of subjects with normal or borderline fasting triglycerides experienced shifts to very high fasting triglycerides during the long-term schizophrenia studies.
Weight Gain: Weight gain has been observed in patients treated with atypical antipsychotics, including REXULTI. Monitor weight at baseline and frequently thereafter.
Table 4 shows weight gain data at last visit and percentage of adult patients with ≥ 7% increase in body weight at endpoint from the 6-week, placebo-controlled, fixed-dose clinical studies in patients with schizophrenia. (See Table 4.)


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In the long-term, open-label schizophrenia studies, 0.6% of patients discontinued due to weight increase. REXULTI was associated with mean change from baseline in weight of 1.3 kg at week 26 and 2.0 kg at week 52. In the long-term, open label schizophrenia studies, 20% of patients demonstrated a ≥ 7% increase in body weight and 10% demonstrated a ≥ 7% decrease in body weight.
Pathological Gambling and Other Compulsive Behaviors: Post-marketing case reports suggest that patients can experience intensive urges, particularly for gambling, and the inability to control these urges while taking REXULTI. Other compulsive urges, reported less frequently, include: sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with REXULTI. In some cases, although not all, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Patients with a prior history of impulse-control disorders may be at increased risk and should be monitored carefully. It should be noted that impulse-control symptoms can be associated with the underlying disorder. Compulsive behaviors may result in harm to the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges.
Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia and neutropenia have been reported during treatment with antipsychotic agents. Agranulocytosis (including fatal cases) has been reported with other agents in this class.
Possible risk factors for leukopenia and neutropenia include pre-existing low white blood cell count (WBC) or absolute neutrophil count (ANC) and history of drug-induced leukopenia or neutropenia. In patients with a pre-existing low WBC or ANC or a history of drug-induced leukopenia or neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of REXULTI at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue REXULTI in patients with absolute neutrophil count < 1000/mm³ and follow their WBC until recovery.
Orthostatic Hypotension and Syncope: Atypical antipsychotics cause orthostatic hypotension and syncope. Adverse reactions related to orthostatic hypotension can include dizziness, lightheadedness and tachycardia. Generally, the risk is greatest during initial dose titration and when increasing the dose. In the short-term, placebo-controlled clinical studies of REXULTI in patients with schizophrenia, the incidence of orthostatic hypotension-related adverse reactions in REXULTI-treated patients compared to placebo patents included: dizziness (2% versus 2%), orthostatic hypotension (0.4% versus 0.2%), and syncope (0.1% versus 0%).
Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension, (e.g., elderly patients, patients w/ dehydration, hypovolemia, concomitant treatment w/ antihypertensive medication), patients with known cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. In such patients, consider using a lower starting dose and slower titration, and monitor orthostatic vital signs. REXULTI has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease. Such patients were excluded from pre-marketing clinical trials.
Falls: Antipsychotics, including REXULTI, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.
Seizures: Like other antipsychotic drugs, REXULTI may cause seizures. This risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in older patients.
Body Temperature Dysregulation: Atypical antipsychotics may disrupt the body's ability to reduce core body temperature. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use REXULTI with caution in patients who may experience these conditions.
Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Antipsychotic drugs, including REXULTI, should be used cautiously in patients at risk for aspiration.
Potential for Cognitive and Motor Impairment: REXULTI, like other antipsychotics, has minor to moderate influence on ability to drive and use machines, impair judgement, or thinking due to potential nervous system effects, such as sedation and dizziness that are common adverse drug reactions. In 6-week, placebo-controlled clinical trials in patients with schizophrenia, somnolence (including sedation and hypersomnia) was reported in 5% of REXULTI-treated patients compared to 3% of placebo-treated patients.
Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that REXULTI therapy does not affect them adversely.
Lactose: REXULTI film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
CYP2D6 Poor Metabolizers: Dosage adjustment is recommended in known CYP2D6 poor metabolizers, because these patients have higher brexpiprazole concentrations than normal metabolizers of CYP2D6. Approximately 8% of Caucasians and 3-8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM) [see Dosage Modifications for CYP2D6 Poor Metabolizers and for Concomitant use with CYP Inhibitors or Inducers under Dosage & Administration, Pharmacology: Pharmacokinetics under Actions].
Hepatic Impairment: Reduce the maximum recommended dosage in patients with moderate to severe hepatic impairment (Child-Pugh score ≥ 7). Patients with moderate to severe hepatic impairment (Child-Pugh score ≥ 7) generally had higher exposure to brexpiprazole than patients with normal hepatic function [see Pharmacology: Pharmacokinetics under Actions]. Greater exposure may increase the risk of REXULTI-associated adverse reactions [see Dosage Adjustments for Hepatic Impairment under Dosage & Administration].
Renal Impairment: Reduce the maximum recommended dosage in patients with moderate, severe, or end-stage renal impairment (CLcr < 60 mL/minute). Patients with impaired renal function (CLcr < 60 mL/minute) had higher exposure to brexpiprazole than patients with normal renal function [see Pharmacology: Pharmacokinetics under Actions]. Greater exposure may increase the risk of REXULTI-associated adverse reactions [see Dosage Adjustments for Renal Impairment under Dosage & Administration].
Other Specific Populations: No dosage adjustment for REXULTI is required on the basis of a patient's sex, race, or smoking status [see Pharmacology: Pharmacokinetics under Actions].
Drug Abuse and Dependence: Controlled Substance: REXULTI is not a controlled substance.
Abuse: Animals given access to REXULTI did not self-administer the drug, suggesting that REXULTI does not have rewarding properties.
Dependence: Humans and animals that received chronic REXULTI administration did not demonstrate any withdrawal signs upon drug discontinuation. This suggests that REXULTI does not produce physical dependence.
Use in Children: Safety and effectiveness in pediatric patients have not been established.
Use in Elderly: Clinical studies of the efficacy of REXULTI did not include any patients aged 65 or older to determine whether they respond differently from younger patients. The safety and efficacy of brexpiprazole in the treatment of schizophrenia in patients aged 65 years and older have not been established. It is not possible to advise on a minimum effective/safe dose in this population.
Antipsychotic drugs increase the risk of death in elderly patients with dementia-related psychosis. REXULTI is not approved for the treatment of patients with dementia-related psychosis [see Warnings, Increased Mortality in Elderly Patients with Dementia-Related Psychosis ].

Pregnancy: Risk Summary: Adequate and well-controlled studies have not been conducted with REXULTI in pregnant women to inform drug-associated risks. However, neonates whose mothers are exposed to antipsychotic drugs, like REXULTI, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms. In animal reproduction studies, no teratogenicity was observed with oral administration of brexpiprazole to pregnant rats and rabbits during organogenesis at doses up to 73 and 146 times, respectively, of maximum recommended human dose (MRHD) of 4 mg/day on a mg/m² basis. However, when pregnant rats were administered brexpiprazole during the period of organogenesis through lactation, the number of perinatal deaths of pups was increased at 73 times the MRHD [see Data as follows]. The background risk of major birth defects and miscarriage for the indicated population(s) is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Use of REXULTI in pregnancy or in women of childbearing potential requires the benefits of treatment be weighed against the possible risks to mother and child.
Clinical Considerations: Fetal/Neonatal Adverse Reactions: Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates whose mothers were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately.
Data: Animal Data: Pregnant rats were treated with oral doses of 3, 10, and 30 mg/kg/day (7.3, 24, and 73 times the MRHD on a mg/m² basis) of brexpiprazole during the period of organogenesis. Brexpiprazole was not teratogenic and did not cause adverse developmental effects at doses up to 73 times the MRHD.
Pregnant rabbits were treated with oral doses of 10, 30, and 150 mg/kg/day (49, 146, and 730 times the MRHD) of brexpiprazole during the period of organogenesis. Brexpiprazole was not teratogenic and did not cause adverse developmental effects at doses up to 146 times the MRHD. Findings of decreased body weight, retarded ossification, and increased incidences of visceral and skeletal variations were observed in fetuses at 730 times the MRHD, a dose that induced maternal toxicity.
In a study in which pregnant rats were administered oral doses of 3, 10, and 30 mg/kg/day (7.3, 24, and 73 times the MRHD) during the period of organogenesis and through lactation, the number of live-born pups was decreased and early postnatal deaths increased at a dose 73 times the MRHD. Impaired nursing by dams, and low birth weight and decreased body weight gain in pups were observed at 73 times, but not at 24 times, the MRHD.
Lactation: Risk Summary: Lactation studies have not been conducted to assess the presence of brexpiprazole in human milk, the effects of brexpiprazole on the breastfed infant, or the effects of brexpiprazole on milk production. Brexpiprazole is present in rat milk. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for REXULTI and any potential adverse effects on the breastfed infant from REXULTI or from the underlying maternal condition.

The following adverse reactions are discussed in more detail in other sections of the monograph: Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings, Increased Mortality in Elderly Patients with Dementia-Related Psychosis under Precautions].
Suicidal Thoughts and Behaviors [see Suicidal Thoughts and Behaviors under Precautions].
Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis [see Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis under Precautions].
QT prolongation [see QT Prolongation under Precautions].
Venous thromboembolism [see Venous Thromboembolism under Precautions].
Neuroleptic Malignant Syndrome (NMS) [see Neuroleptic Malignant Syndrome (NMS) under Precautions].
Tardive Dyskinesia [see Tardive Dyskinesia under Precautions].
Metabolic Changes [see Metabolic Changes under Precautions].
Pathological Gambling and Other Compulsive Behaviors [see Pathological Gambling and Other Compulsive Behaviors under Precautions].
Leukopenia, Neutropenia, and Agranulocytosis [see Leukopenia, Neutropenia, and Agranulocytosis under Precautions].
Orthostatic Hypotension and Syncope [see Orthostatic Hypotension and Syncope under Precautions].
Falls [see Falls under Precautions].
Seizures [see Seizures under Precautions].
Body Temperature Dysregulation [see Body Temperature Dysregulation under Precautions].
Dysphagia [see Dysphagia under Precautions].
Potential for Cognitive and Motor Impairment [see Potential for Cognitive and Motor Impairment under Precautions].
Clinical Trials Experience: 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.
The safety of REXULTI was evaluated in 852 patients (18 to 65 years of age) diagnosed with schizophrenia who participated in two 6-week, placebo-controlled, fixed-dose clinical trials in which REXULTI was administered at daily doses of 1 mg, 2 mg and 4 mg [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions].
Common Adverse Reactions: Adverse reactions associated with REXULTI (incidence of 2% or greater and REXULTI incidence greater than placebo) during short-term (up to 6 weeks) trials in patients with schizophrenia are shown in Table 5. (See Table 5.)


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Extrapyramidal Symptoms: The incidence of reported EPS-related adverse reactions, excluding akathisia, was 5% for REXULTI-treated patients versus 4% for placebo-treated patients. The incidence of akathisia events for REXULTI-treated patients was 6% versus 5% for placebo-treated patients.
In the 6-week, placebo-controlled, fixed-dose schizophrenia studies, data was objectively collected on the Simpson Angus Rating Scale (SAS) for extrapyramidal symptoms (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 BARS (2% versus 1%) and the SAS (7% versus 5%).
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 the Premarketing Evaluation of REXULTI: Other adverse reactions (≥ 1% frequency and greater than placebo) within the short-term, placebo-controlled trials are shown as follows. The following listing does not include adverse reactions: 1) already listed in previous tables or elsewhere in the labeling, 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.
Infections and Infestations: Urinary Tract Infection.
Investigations: Blood Prolactin Increased.
Musculoskeletal and Connective Tissue Disorders: Myalgia.
Psychiatric Disorders: Abnormal Dreams, Insomnia.
Skin and Subcutaneous Tissue Disorders: Hyperhidrosis.
Postmarketing Experience: The following adverse reaction has been identified during post-approval use of REXULTI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Nervous System disorders: Neuroleptic Malignant Syndrome.

Drugs Having Clinically Important Interactions with REXULTI: See Table 6.


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Drugs Having No Clinically Important Interactions with REXULTI: Based on pharmacokinetic studies, no dosage adjustment of REXULTI is required when administered concomitantly with CYP2B6 inhibitors (e.g., ticlopidine) or gastric pH modifiers (e.g., omeprazole). Additionally, no dosage adjustment for substrates of CYP2D6 (e.g., dextromethorphan), CYP3A4 (e.g., lovastatin), CYP2B6 (e.g., bupropion), BCRP (e.g., rosuvastatin), or P-gp (e.g., fexofenadine) is required when administered concomitantly with REXULTI.

Store below 30°C.

Suicidal Thoughts and Behaviors: Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down and instruct them to report such symptoms to the healthcare provider [see Warnings, Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults under Precautions].
Dosage and Administration: Advise patients that REXULTI can be taken with or without food. Advise patients regarding importance of following dosage escalation instructions and adjustment [see Treatment of Schizophrenia, Dosage Adjustments for Hepatic Impairment, Dosage Adjustments for Renal Impairment, Dosage Modifications for CYP2D6 Poor Metabolizers and for Concomitant Use with CYP Inhibitors or Inducers under Dosage & Administration].
Neuroleptic Malignant Syndrome (NMS): Counsel patients about a potentially fatal adverse reaction -Neuroleptic Malignant Syndrome (NMS) that has been reported in association with administration of antipsychotic drugs. Advise patients to contact a health care provider or report to the emergency room if they experience signs or symptoms of NMS [see Neuroleptic Malignant Syndrome (NMS) under Precautions].
Tardive Dyskinesia: Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur [see Tardive Dyskinesia under Precautions].
Metabolic Changes: Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Metabolic Changes under Precautions].
Pathological Gambling and Other Compulsive Behaviors: Advise patients and their caregivers of the possibility that they may experience compulsive urges to shop, intense urges to gamble, compulsive sexual urges, binge eating and/or other compulsive urges and the inability to control these urges while taking REXULTI. In some cases, but not all, the urges were reported to have stopped when the dose was reduced or stopped [see Pathological Gambling and Other Compulsive Behaviors under Precautions].
Leukopenia, Neutropenia and Agranulocytosis: Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia that they should have their CBC monitored while taking REXULTI [see Leukopenia, Neutropenia and Agranulocytosis under Precautions].
Orthostatic Hypotension and Syncope: Educate patients about the risk of orthostatic hypotension and syncope especially early in treatment, and also at times of re-initiating treatment or increases in dosage [see Orthostatic Hypotension and Syncope under Precautions].
Heat Exposure and Dehydration: Counsel patients regarding appropriate care in avoiding overheating and dehydration [see Body Temperature Dysregulation under Precautions].
Interference with Cognitive and Motor Performance: Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that REXULTI therapy does not adversely affect their ability to engage in such activities [see Potential for Cognitive and Motor Impairment under Precautions].
Concomitant Medications: Advise patients to inform their health care providers of any changes to their current prescription or over-the-counter medications because there is a potential for clinically significant interactions [see Drugs Having Clinically Important Interactions with REXULTI under Interactions].
Pregnancy: Advise patients that third trimester use of REXULTI may cause extrapyramidal and/or withdrawal symptoms in a neonate and to notify their healthcare provider with a known or suspected pregnancy. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to REXULTI during pregnancy [see Pregnancy under Use in Pregnancy & Lactation].

Antipsychotics

N05AX16 - brexpiprazole ; Belongs to the class of other antipsychotics.

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