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BREXPIPRAZOLE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Brexipiprazole is an atypical antipsychotic agent used in the treatment of schizophrenia and as adjunctive therapy for the treatment of major depressive disorder.

Specific Substances

    1) OPC-34712
    2) CAS 913611-97-9
    1.2.1) MOLECULAR FORMULA
    1) C25H27N3O2S (Prod Info REXULTI(R) oral tablets, 2015)

Available Forms Sources

    A) FORMS
    1) Brexpiprazole is available as 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg tablets (Prod Info REXULTI(R) oral tablets, 2015).
    B) USES
    1) Brexpiprazole is an antipsychotic agent used in the treatment of schizophrenia and as adjunctive therapy for the treatment of major depressive disorder (Prod Info REXULTI(R) oral tablets, 2015).

Overview

Laboratory Monitoring

    A) Monitor vital signs and neurologic exam (for CNS depression, akathisia, or extrapyramidal effects).
    B) Plasma brexpiprazole concentrations are not readily available or clinically useful in the management of overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) For management of mild to moderate toxicity, good supportive care is all that is needed.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Mainstay of treatment is good supportive care, including airway management for patients with severe CNS sedation.
    C) DECONTAMINATION
    1) PREHOSPITAL: Activated charcoal may be considered if the patient is awake, alert, cooperative, and able to tolerate the charcoal orally without difficulty, and the ingestion is recent (within the last hour).
    2) HOSPITAL: Activated charcoal could be considered if the patient is awake, alert, and cooperative, and the ingestion is relatively recent (within the last hour).
    D) AIRWAY MANAGEMENT
    1) Most patients do not require advanced airway management and there is no indication for early intubation, but patients who have enough CNS depression and have trouble maintaining their airway require intubation.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION PROCEDURE
    1) There is no information regarding the effectiveness of hemodialysis or hemoperfusion for the removal of brexpiprazole from plasma. However, these procedures are unlikely to be of benefit due to the high protein binding and large volume of distribution of brexpiprazole.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) When managing a suspected brexpiprazole overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose may be similar to reported side effects of the medication.
    I) PHARMACOKINETICS
    1) Bioavailability was 95% following a single oral dose. Greater than 99% protein binding; volume of distribution was 1.56 +/- 0.42 L/kg following IV administration. Brexpiprazole is mainly a substrate of CYP3A4 and CYP2D6, with DM-3411 as its major metabolite (inactive). Terminal elimination half-life of brexpiprazole was 91 hours following multiple once daily administration.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other medications that cause CNS sedation (eg, psychotropic drugs, opioids, antiepileptics).

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Brexpiprazole is an antipsychotic agent used in the treatment of schizophrenia and as adjunctive therapy for the treatment of major depressive disorder.
    B) PHARMACOLOGY: Although the exact mechanism of action of brexpiprazole, an atypical antipsychotic, in major depressive disorder and schizophrenia is unknown, it has partial agonist activity at serotonin 5-HT-1A and dopamine D2 receptors, and antagonist activity at serotonin 5-HT-2A receptors.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: For the treatment of major depressive disorder, the most commonly reported adverse effects with brexpiprazole therapy, at an incidence rate of at least 5% and at least twice the rate for placebo, are increased weight, akathisia, and somnolence. For the treatment of schizophrenia, the most commonly reported adverse effect with brexpiprazole therapy, at an incidence rate of at least 4% and at least twice the rate for placebo, is increased weight.
    2) INFREQUENT: Adverse effects that have occurred less frequently include hyperglycemia, hyperhidrosis, constipation, fatigue, nausea, dry mouth, salivary hypersecretion, abdominal pain, flatulence, diarrhea, dyspepsia, nasopharyngitis, blurred vision, urinary tract infection, increased prolactin levels, myalgia, headache, tremor, insomnia, abnormal dreams, dizziness, anxiety, and restlessness.
    E) WITH POISONING/EXPOSURE
    1) At the time of this review, there is no brexpiprazole overdose information reported. Overdose effects are anticipated to be an extension of adverse effects following therapeutic administration.
    0.2.20) REPRODUCTIVE
    A) There are no adequate or well-controlled studies of brexpiprazole use in pregnant women, although extrapyramidal and/or withdrawal symptoms have been reported in neonates exposed to other antipsychotic agents during the third trimester of pregnancy.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established.
    B) THERAPEUTIC DOSE: ADULTS: For treatment of major depressive disorder as adjunctive therapy, 0.5 mg to 1 mg orally once daily initially, may be titrated, at weekly intervals depending on tolerability and patient response, up to a target dose of 2 mg orally once daily. MAX dose is 3 mg orally once daily. For treatment of schizophrenia, 1 mg orally once daily days 1 to 4, titrating to 2 mg orally once daily days 5 through 7, then 4 mg on day 8. Recommended target dose is 2 to 4 mg orally once daily; MAX daily dose is 4 mg. PEDIATRIC: Safety and efficacy have not been established in pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: Brexpiprazole is an antipsychotic agent used in the treatment of schizophrenia and as adjunctive therapy for the treatment of major depressive disorder.
    B) PHARMACOLOGY: Although the exact mechanism of action of brexpiprazole, an atypical antipsychotic, in major depressive disorder and schizophrenia is unknown, it has partial agonist activity at serotonin 5-HT-1A and dopamine D2 receptors, and antagonist activity at serotonin 5-HT-2A receptors.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: For the treatment of major depressive disorder, the most commonly reported adverse effects with brexpiprazole therapy, at an incidence rate of at least 5% and at least twice the rate for placebo, are increased weight, akathisia, and somnolence. For the treatment of schizophrenia, the most commonly reported adverse effect with brexpiprazole therapy, at an incidence rate of at least 4% and at least twice the rate for placebo, is increased weight.
    2) INFREQUENT: Adverse effects that have occurred less frequently include hyperglycemia, hyperhidrosis, constipation, fatigue, nausea, dry mouth, salivary hypersecretion, abdominal pain, flatulence, diarrhea, dyspepsia, nasopharyngitis, blurred vision, urinary tract infection, increased prolactin levels, myalgia, headache, tremor, insomnia, abnormal dreams, dizziness, anxiety, and restlessness.
    E) WITH POISONING/EXPOSURE
    1) At the time of this review, there is no brexpiprazole overdose information reported. Overdose effects are anticipated to be an extension of adverse effects following therapeutic administration.

Heent

    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) NASOPHARYNGITIS: According to pooled data from two 6-week, placebo-controlled, fixed-dose trials of patients diagnosed with major depressive disorder, nasopharyngitis was reported in 4% of 643 patients receiving brexpiprazole at doses of 1 to 3 mg daily compared to 2% of 411 patients receiving placebo (Prod Info REXULTI(R) oral tablets, 2015)

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) AKATHISIA
    1) WITH THERAPEUTIC USE
    a) According to pooled data from two 6-week, placebo-controlled, fixed-dose trials of patients diagnosed with major depressive disorder, akathisia was one of the most common adverse effects with brexpiprazole therapy, reported in 9% of 643 patients receiving brexpiprazole at doses of 1 to 3 mg daily compared to 2% of 411 patients receiving placebo (Prod Info REXULTI(R) oral tablets, 2015).
    b) According to pooled data from two 6-week, placebo-controlled, fixed-dose trials of patients diagnosed with schizophrenia, akathisia was reported in 6% of 852 patients receiving brexpiprazole at doses up to 4 mg daily compared to 5% of 368 patients receiving placebo (Prod Info REXULTI(R) oral tablets, 2015).
    B) EXTRAPYRAMIDAL SIGN
    1) WITH THERAPEUTIC USE
    a) During placebo-controlled clinical trials of patients diagnosed with major depressive disorder, extrapyramidal symptom-related adverse reactions, excluding akathisia, were reported in 6% of patients receiving brexpiprazole compared to 3% of patients receiving placebo (Prod Info REXULTI(R) oral tablets, 2015).
    b) According to placebo-controlled clinical trials of patients diagnosed with schizophrenia, extrapyramidal symptom-related adverse reactions, excluding akathisia, were reported in 5% of patients receiving brexpiprazole at doses compared to 4% of patients receiving placebo (Prod Info REXULTI(R) oral tablets, 2015).
    C) DROWSY
    1) WITH THERAPEUTIC USE
    a) According to pooled data from two 6-week, placebo-controlled, fixed-dose trials of patients diagnosed with major depressive disorder, somnolence was reported in 5% of 643 patients receiving brexpiprazole at doses of 1 to 3 mg daily compared to 0.5% of 411 patients receiving placebo (Prod Info REXULTI(R) oral tablets, 2015).
    b) According to pooled data from two 6-week, placebo-controlled, fixed-dose trials of patients diagnosed with schizophrenia, sedation was reported in 2% of 852 patients receiving brexpiprazole at doses up to 4 mg daily compared to 1% of 368 patients receiving placebo (Prod Info REXULTI(R) oral tablets, 2015).
    D) TREMOR
    1) WITH THERAPEUTIC USE
    a) According to pooled data from two 6-week, placebo-controlled, fixed-dose trials of patients diagnosed with major depressive disorder, tremor was reported in 4% of 643 patients receiving brexpiprazole at doses of 1 to 3 mg daily compared to 2% of 411 patients receiving placebo (Prod Info REXULTI(R) oral tablets, 2015).
    b) According to pooled data from two 6-week, placebo-controlled, fixed-dose trials of patients diagnosed with schizophrenia, tremor was reported in 3% of 852 patients receiving brexpiprazole at doses up to 4 mg daily compared to 1% of 368 patients receiving placebo (Prod Info REXULTI(R) oral tablets, 2015).
    E) FATIGUE
    1) WITH THERAPEUTIC USE
    a) According to pooled data from two 6-week, placebo-controlled, fixed-dose trials of patients diagnosed with major depressive disorder fatigue was reported in 3% of 643 patients receiving brexpiprazole at doses of 1 to 3 mg daily compared to 2% of 411 patients receiving placebo (Prod Info REXULTI(R) oral tablets, 2015).
    F) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) According to pooled data from two 6-week, placebo-controlled, fixed-dose trials of patients diagnosed with major depressive disorder, dizziness was reported in 3% of 643 patients receiving brexpiprazole at doses of 1 to 3 mg daily compared to 1% of 411 patients receiving placebo (Prod Info REXULTI(R) oral tablets, 2015).
    G) ANXIETY
    1) WITH THERAPEUTIC USE
    a) According to pooled data from two 6-week, placebo-controlled, fixed-dose trials of patients diagnosed with major depressive disorder anxiety and restlessness were reported in 3% of 643 patients receiving brexpiprazole at doses of 1 to 3 mg daily compared to 1% and 0%, respectively, of 411 patients receiving placebo (Prod Info REXULTI(R) oral tablets, 2015).
    H) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) During short-term placebo-controlled trials of patients with major depressive disorder and schizophrenia, insomnia was reported in at least 1% of patients receiving brexpiprazole therapy (Prod Info REXULTI(R) oral tablets, 2015).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) INCREASED APPETITE
    1) WITH THERAPEUTIC USE
    a) According to pooled data from two 6-week, placebo-controlled, fixed-dose trials of patients diagnosed with major depressive disorder, increased appetite was reported in 3% of 643 patients receiving brexpiprazole at doses of 1 to 3 mg daily compared to 2% of 411 patients receiving placebo (Prod Info REXULTI(R) oral tablets, 2015).
    B) NAUSEA
    1) WITH THERAPEUTIC USE
    a) During short-term placebo-controlled trials of patients with major depressive disorder and schizophrenia, nausea was reported in at least 1% of patients receiving brexpiprazole therapy (Prod Info REXULTI(R) oral tablets, 2015).
    C) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) According to pooled data from two 6-week, placebo-controlled, fixed-dose trials of patients diagnosed with major depressive disorder, constipation was reported in 2% of 643 patients receiving brexpiprazole at doses of 1 to 3 mg daily compared to 1% of 411 patients receiving placebo (Prod Info REXULTI(R) oral tablets, 2015).
    D) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) According to pooled data from two 6-week, placebo-controlled, fixed-dose trials of patients diagnosed with schizophrenia, dyspepsia was reported in 3% of 852 patients receiving brexpiprazole at doses up to 4 mg daily compared to 2% of 368 patients receiving placebo (Prod Info REXULTI(R) oral tablets, 2015).
    E) EXCESSIVE SALIVATION
    1) WITH THERAPEUTIC USE
    a) During short-term placebo-controlled trials of patients with major depressive disorder and schizophrenia, salivary hypersecretion was reported in at least 1% of patients receiving brexpiprazole therapy (Prod Info REXULTI(R) oral tablets, 2015).
    F) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) According to pooled data from two 6-week, placebo-controlled, fixed-dose trials of patients diagnosed with schizophrenia, diarrhea was reported in 3% of 852 patients receiving brexpiprazole at doses up to 4 mg daily compared to 2% of 368 patients receiving placebo (Prod Info REXULTI(R) oral tablets, 2015).
    G) APTYALISM
    1) WITH THERAPEUTIC USE
    a) During short-term placebo-controlled trials of patients with major depressive disorder and schizophrenia, dry mouth was reported in at least 1% of patients receiving brexpiprazole therapy (Prod Info REXULTI(R) oral tablets, 2015).
    H) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) During short-term placebo-controlled trials of patients with major depressive disorder and schizophrenia, abdominal pain was reported in at least 1% of patients receiving brexpiprazole therapy (Prod Info REXULTI(R) oral tablets, 2015).
    I) FLATULENCE/WIND
    1) WITH THERAPEUTIC USE
    a) During short-term placebo-controlled trials of patients with major depressive disorder and schizophrenia, flatulence was reported in at least 1% of patients receiving brexpiprazole therapy (Prod Info REXULTI(R) oral tablets, 2015).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URINARY TRACT INFECTIOUS DISEASE
    1) WITH THERAPEUTIC USE
    a) During short-term placebo-controlled trials of patients with major depressive disorder and schizophrenia, urinary tract infection was reported in at least 1% of patients receiving brexpiprazole therapy (Prod Info REXULTI(R) oral tablets, 2015).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) HYPERHIDROSIS
    1) WITH THERAPEUTIC USE
    a) During short-term placebo-controlled trials of patients with major depressive disorder and schizophrenia, hyperhidrosis was reported in at least 1% of patients receiving brexpiprazole therapy (Prod Info REXULTI(R) oral tablets, 2015).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) During short-term placebo-controlled trials of patients with major depressive disorder and schizophrenia, myalgia was reported in at least 1% of patients receiving brexpiprazole therapy (Prod Info REXULTI(R) oral tablets, 2015).
    B) INCREASED CREATINE KINASE LEVEL
    1) WITH THERAPEUTIC USE
    a) According to pooled data from two 6-week, placebo-controlled, fixed-dose trials of patients diagnosed with schizophrenia, increased blood creatine phosphokinase levels were reported in 2% of 852 patients receiving brexpiprazole at doses up to 4 mg daily compared to 1% of 368 patients receiving placebo (Prod Info REXULTI(R) oral tablets, 2015).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) During long-term, open-label clinical studies of patients with depression, 9% of patients with either normal (less than 100 mg/dL) or borderline (100 mg/dL to less than 126 mg/dL) fasting glucose experienced a shift to high (126 mg/dL or greater) fasting glucose while taking brexpiprazole adjunctively with antidepressant therapy (Prod Info REXULTI(R) oral tablets, 2015).
    b) During long-term, open-label clinical studies of patients with schizophrenia, 10% of patients with either normal (less than 100 mg/dL) or borderline (100 mg/dL to less than 126 mg/dL) fasting glucose experienced a shift to high (126 mg/dL or greater) fasting glucose while taking brexpiprazole (Prod Info REXULTI(R) oral tablets, 2015).
    B) INCREASED PROLACTIN LEVEL
    1) WITH THERAPEUTIC USE
    a) During short-term placebo-controlled trials of patients with major depressive disorder and schizophrenia, increased blood prolactin levels were reported in at least 1% of patients receiving brexpiprazole therapy (Prod Info REXULTI(R) oral tablets, 2015).
    C) DECREASED CORTISOL LEVEL
    1) WITH THERAPEUTIC USE
    a) According to pooled data from two 6-week, placebo-controlled, fixed-dose trials of patients diagnosed with major depressive disorder, decreased blood cortisol levels were reported in 2% of 643 patients receiving brexpiprazole at doses of 1 to 3 mg daily compared to 1% of 411 patients receiving placebo (Prod Info REXULTI(R) oral tablets, 2015).

Reproductive

    3.20.1) SUMMARY
    A) There are no adequate or well-controlled studies of brexpiprazole use in pregnant women, although extrapyramidal and/or withdrawal symptoms have been reported in neonates exposed to other antipsychotic agents during the third trimester of pregnancy.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) During animal studies, administration of brexpiprazole at doses up to 146 times the maximum recommended human doses (MRHD) during organogenesis did not result in teratogenicity or adverse developmental effects; however, doses 730 times the MRHD resulted in increased incidences of fetal visceral and skeletal variations and retarded ossification (Prod Info REXULTI(R) oral tablets, 2015).
    3.20.3) EFFECTS IN PREGNANCY
    A) RISK SUMMARY
    1) There are no adequate and well-controlled studies of brexpiprazole use in pregnant women. Maternal use of antipsychotic drugs during the third trimester of pregnancy has been associated with an increased risk of neonatal extrapyramidal and/or withdrawal symptoms (eg, agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) following delivery. Severity of these adverse effects have ranged from cases that are self-limiting to cases that required prolonged periods of hospitalization and ICU care (Prod Info REXULTI(R) oral tablets, 2015).
    B) PREGNANCY REGISTRY
    1) Inform women of the potential hazard to the fetus with prenatal brexpiprazole exposure. The National Pregnancy Registry for Atypical Antipsychotics has been established, and prescribers can enroll patients exposed to brexpiprazole during pregnancy by calling 1-866-961-2388 or by visiting http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ (Prod Info REXULTI(R) oral tablets, 2015).
    C) ANIMAL STUDIES
    1) During animal studies, a decrease in live-born offspring and early postnatal deaths were reported with doses up to 73 times the MRHD. Low birth weight and decreased body weight gain were also reported with doses 73 times the MRHD (Prod Info REXULTI(R) oral tablets, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown whether brexpiprazole is excreted in breast milk, the effects of brexpiprazole on milk production, or the effects in the nursing infant. Exercise caution when administering brexpiprazole to a lactating woman and weigh the benefits of breastfeeding with the risk to the infant (Prod Info REXULTI(R) oral tablets, 2015).
    B) ANIMAL STUDIES
    1) Brexpiprazole is excreted in the milk of lactating animals (Prod Info REXULTI(R) oral tablets, 2015)
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Administration of brexpiprazole up to 73 times the maximum recommended human dose (MRHD) resulted in estrus cycle irregularities and decreased fertility in female animals. Prolonged duration of pairing and increased preimplantation loss were also reported. No adverse effects on fertility were noted in male animals given brexpiprazole at doses up to 240 times the MRHD (Prod Info REXULTI(R) oral tablets, 2015).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) An increased incidence of mammary gland adenocarcinomas were reported in female mice who were administered brexpiprazole orally at doses up to 6.1 times the maximum recommended human dose (MRHD) for 2 years. The incidence of adenosquamous carcinomas was also increased in female mice at doses 2.4 and 6.1 times the MRHD (Prod Info REXULTI(R) oral tablets, 2015).
    B) LACK OF EFFECT
    1) There was no increased incidence of tumors in male mice administered brexpiprazole orally at doses up to 6.1 times the maximum recommended human dose (MRHD) for 2 years. There was also no evidence of carcinogenicity in male or female rats administered brexpiprazole at doses up to 73 times the MRHD (Prod Info REXULTI(R) oral tablets, 2015).

Genotoxicity

    A) Brexpiprazole was not genotoxic in the in vivo/in vitro unscheduled DNA assay in rats, nor was it mutagenic in the in vitro bacterial reverse mutation assay (Ames test). It was clastogenic with mammalian cells in vitro, but only at doses that induced cytotoxicity; however, it was not clastogenic in the in vivo micronucleus assay in rats (Prod Info REXULTI(R) oral tablets, 2015).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and neurologic exam (for CNS depression, akathisia, or extrapyramidal effects).
    B) Plasma brexpiprazole concentrations are not readily available or clinically useful in the management of overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe symptoms despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Monitor vital signs and neurologic exam (for CNS depression, akathisia, or extrapyramidal effects).
    B) Plasma brexpiprazole concentrations are not readily available or clinically useful in the management of overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) For management of mild to moderate toxicity, good supportive care is all that is needed.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Mainstay of treatment is good supportive care, including airway management for patients with severe CNS sedation.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and neurologic exam (for CNS depression, akathisia, or extrapyramidal effects).
    2) Plasma brexpiprazole concentrations are not readily available or clinically useful in the management of overdose.
    C) AIRWAY MANAGEMENT
    1) Most patients do not require advanced airway management and there is no indication for early intubation, but patients who have enough CNS depression and have trouble maintaining their airway require intubation.
    D) ANTIDOTE
    1) None

Enhanced Elimination

    A) HEMODIALYSIS
    1) There is no information regarding the effectiveness of hemodialysis or hemoperfusion for the removal of brexpiprazole from plasma. However, these procedures are unlikely to be of benefit due to the high protein binding (greater than 99%) and large volume of distribution (1.56 +/- 0.42 L/kg) of brexpiprazole (Prod Info REXULTI(R) oral tablets, 2015).

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established.
    B) THERAPEUTIC DOSE: ADULTS: For treatment of major depressive disorder as adjunctive therapy, 0.5 mg to 1 mg orally once daily initially, may be titrated, at weekly intervals depending on tolerability and patient response, up to a target dose of 2 mg orally once daily. MAX dose is 3 mg orally once daily. For treatment of schizophrenia, 1 mg orally once daily days 1 to 4, titrating to 2 mg orally once daily days 5 through 7, then 4 mg on day 8. Recommended target dose is 2 to 4 mg orally once daily; MAX daily dose is 4 mg. PEDIATRIC: Safety and efficacy have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) MAJOR DEPRESSIVE DISORDER, ADJUNCTIVE THERAPY: Initially, 0.5 mg to 1 mg orally once daily, may be titrated at weekly intervals, depending on tolerability and patient response, up to a target dose of 2 mg orally once daily. MAX dose is 3 mg orally once daily (Prod Info REXULTI(R) oral tablets, 2015)
    B) SCHIZOPHRENIA: Initially, 1 mg orally once daily days 1 to 4, titrating to 2 mg orally once daily days 5 through 7, then 4 mg on day 8. Recommended target dose is 2 to 4 mg orally once daily; MAX daily dose is 4 mg (Prod Info REXULTI(R) oral tablets, 2015).
    7.2.2) PEDIATRIC
    A) Safety and efficacy have not been established in pediatric patients (Prod Info REXULTI(R) oral tablets, 2015).

Maximum Tolerated Exposure

    A) A specific toxic dose has not been established.

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Although the exact mechanism of action of brexpiprazole, an atypical antipsychotic, in major depressive disorder and schizophrenia is unknown, it has partial agonist activity at serotonin 5-HT-1A and dopamine D2 receptors, and antagonist activity at serotonin 5-HT-2A receptors (Prod Info REXULTI(R) oral tablets, 2015).

Physicochemical

Molecular Weight

    A) 433.57 (Prod Info REXULTI(R) oral tablets, 2015)

References

General Bibliography

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    2) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    3) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
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    5) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
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    7) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    8) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    9) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    10) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    11) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    12) Product Information: REXULTI(R) oral tablets, brexpiprazole oral tablets. Otsuka America Pharmaceutical, Inc. (per manufacturer), Rockville, MD, 2015.
    13) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    14) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    15) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.