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CARIPRAZINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Cariprazine is an atypical antipsychotic agent approved in adults for the treatment of schizophrenia and for the treatment of acute mania or mixed episodes associated with bipolar I disorder.

Specific Substances

    1) Cariprazine Hydrochloride
    2) RGH-188
    3) CAS 839712-12-8
    1.2.1) MOLECULAR FORMULA
    1) C21H33Cl3N4O (Prod Info VRAYLAR(R) oral capsules, 2015)

Available Forms Sources

    A) FORMS
    1) Cariprazine is available as 1.5 mg, 3 mg, 4.5 mg, and 6 mg capsules (Prod Info VRAYLAR(R) oral capsules, 2015).
    B) USES
    1) Cariprazine is approved in adults for the treatment of schizophrenia and for the treatment of acute mania or mixed episodes associated with bipolar I disorder (Prod Info VRAYLAR(R) oral capsules, 2015).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Cariprazine is approved in adults for the treatment of schizophrenia and for the treatment of acute mania or mixed episodes associated with bipolar I disorder.
    B) PHARMACOLOGY: Although the exact mechanism of action of cariprazine, an atypical antipsychotic, in schizophrenia and bipolar I disorder is unknown, it is a partial agonist of serotonin 5-HT-1A activity and dopamine D2 receptors, and antagonist of serotonin 5-HT-2A activity.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: For the treatment of schizophrenia, the most commonly reported adverse effects with cariprazine therapy, at an incidence rate of at least 5% and at least twice the rate for placebo, are extrapyramidal symptoms and akathisia. For the treatment of bipolar mania, the most commonly reported adverse effects with cariprazine therapy, at an incidence rate of at least 5% and at least twice the rate for placebo, are extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence and restlessness.
    2) INFREQUENT: Adverse effects that have occurred less frequently include tachycardia, hypertension, gastrointestinal effects (ie, abdominal pain, constipation, diarrhea, dry mouth, nausea, vomiting), blurred vision, toothache, fatigue, nasopharyngitis, decreased appetite, increased liver enzymes, increased creatine phosphokinase levels, arthralgia, back pain, extremity pain, headache, dizziness, agitation, insomnia, anxiety, pyrexia, and cough.
    3) RARE: Hepatitis, leukopenia and neutropenia, dysphagia, rhabdomyolysis, and ischemic stroke were rarely reported with cariprazine therapy.
    E) WITH POISONING/EXPOSURE
    1) An inadvertent overdose ingestion of 48 mg/day in one patient during premarketing clinical trials resulted in orthostasis and sedation. In general, overdose effects are anticipated to be an extension of adverse effects following therapeutic administration.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Pyrexia was reported in patients with bipolar mania who received cariprazine during clinical trials.
    0.2.20) REPRODUCTIVE
    A) Data are unavailable regarding fetal or maternal effects of cariprazine use in pregnant women; however, animal studies have indicated malformations, lower pup survival, and developmental delays following cariprazine exposure less than human exposure at the maximum recommended human dose. In general, third-trimester antipsychotic drug exposure has been associated with extrapyramidal and/or withdrawal symptoms in neonates.

Laboratory Monitoring

    A) Monitor vital signs and neurologic exam (for CNS depression, akathisia, or extrapyramidal effects).
    B) Monitor CBC with differential and liver enzymes as indicated.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Plasma cariprazine 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) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Mainstay of treatment is good supportive care, including airway management for patients with severe CNS sedation. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives.
    C) DECONTAMINATION
    1) PREHOSPITAL: Activated charcoal may be considered if the patient is awake, alert, cooperative, and able to tolerate the activated 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) There is no specific antidote available.
    F) ENHANCED ELIMINATION PROCEDURE
    1) There is no information regarding the effectiveness of hemodialysis or hemoperfusion for the removal of cariprazine from plasma. However, these procedures are unlikely to be of benefit due to the high protein binding of cariprazine.
    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 cariprazine 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) The Tmax of cariprazine was 3 to 6 hours following a single dose. Cariprazine and its major active metabolites are highly protein bound (91% to 97%) to plasma proteins. Cariprazine is extensively metabolized by CYP3A4 and, to a lesser extent, by CYP2D6. Major metabolites are desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), that are pharmacologically equipotent to cariprazine The steady-state half-life of cariprazine is 2 to 4 days.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other medications that cause CNS sedation (eg, psychotropic drugs, opioids, antiepileptics).

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. An inadvertent overdose ingestion of 48 mg/day in one patient during premarketing clinical trials resulted in orthostasis and sedation.
    B) THERAPEUTIC DOSE: ADULT: The starting dose is 1.5 mg orally once daily. On day 2, the dose can be increased to 3 mg and may be increased in 1.5 or 3 mg increments, depending on patient response and tolerability, up to a MAX dose of 6 mg once daily. PEDIATRIC: Safety and efficacy in pediatric patients have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Cariprazine is approved in adults for the treatment of schizophrenia and for the treatment of acute mania or mixed episodes associated with bipolar I disorder.
    B) PHARMACOLOGY: Although the exact mechanism of action of cariprazine, an atypical antipsychotic, in schizophrenia and bipolar I disorder is unknown, it is a partial agonist of serotonin 5-HT-1A activity and dopamine D2 receptors, and antagonist of serotonin 5-HT-2A activity.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: For the treatment of schizophrenia, the most commonly reported adverse effects with cariprazine therapy, at an incidence rate of at least 5% and at least twice the rate for placebo, are extrapyramidal symptoms and akathisia. For the treatment of bipolar mania, the most commonly reported adverse effects with cariprazine therapy, at an incidence rate of at least 5% and at least twice the rate for placebo, are extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence and restlessness.
    2) INFREQUENT: Adverse effects that have occurred less frequently include tachycardia, hypertension, gastrointestinal effects (ie, abdominal pain, constipation, diarrhea, dry mouth, nausea, vomiting), blurred vision, toothache, fatigue, nasopharyngitis, decreased appetite, increased liver enzymes, increased creatine phosphokinase levels, arthralgia, back pain, extremity pain, headache, dizziness, agitation, insomnia, anxiety, pyrexia, and cough.
    3) RARE: Hepatitis, leukopenia and neutropenia, dysphagia, rhabdomyolysis, and ischemic stroke were rarely reported with cariprazine therapy.
    E) WITH POISONING/EXPOSURE
    1) An inadvertent overdose ingestion of 48 mg/day in one patient during premarketing clinical trials resulted in orthostasis and sedation. In general, overdose effects are anticipated to be an extension of adverse effects following therapeutic administration.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Pyrexia was reported in patients with bipolar mania who received cariprazine during clinical trials.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) PYREXIA: According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, pyrexia was reported in 1% and 4% of patients receiving cariprazine at doses of 3 to 6 mg/day (n=263) and 9 to 12 mg/day (n=360), respectively, compared to 2% of patients receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) BLURRED VISION: According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, blurred vision was reported in 4% of patients receiving cariprazine at doses of 3 to 6 mg/day (n=263) and 9 to 12 mg/day (n=360) compared to 1% of patients receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) NASOPHARYNGITIS: According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, nasopharyngitis was reported in 1% and 2% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203), respectively, compared to 1% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) Dysphagia has been reported with cariprazine use (Prod Info VRAYLAR(R) oral capsules, 2015).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, tachycardia was reported in 2% and 3% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203), respectively, compared to 1% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    b) According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, tachycardia was reported in 2% and 1% of patients receiving cariprazine at doses of 3 to 6 mg/day (n=263) and 9 to 12 mg/day (n=360), respectively, compared to 1% of patients receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).
    B) HYPERTENSIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, hypertension was reported in 3% and 6% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203), respectively, compared to 1% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    b) According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, hypertension was reported in 5% and 4% of patients receiving cariprazine at doses of 3 to 6 mg/day (n=263) and 9 to 12 mg/day (n=360), respectively, compared to 1% of patients receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).
    C) ORTHOSTATIC HYPOTENSION
    1) WITH POISONING/EXPOSURE
    a) During premarketing clinical trials, a patient experienced orthostasis and sedation following an inadvertent cariprazine overdose ingestion of 48 mg/day. The patient completely recovered the same day (Prod Info VRAYLAR(R) oral capsules, 2015).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) COUGH
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, cough was reported in 2% and 4% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203), respectively, compared to 2% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) EXTRAPYRAMIDAL DISEASE
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, extrapyramidal symptoms (ie, bradykinesia, cogwheel rigidity, drooling, dyskinesia, dystonia, hypokinesia, masked facies, muscle rigidity, muscle tightness, musculoskeletal stiffness, oculogyric crisis, oromandibular dystonia, parkinsonism, salivary hypersecretion, tardive dyskinesia, torticollis, tremor, and trismus) were reported in 19% and 20% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203), respectively, compared to 8% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    b) According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, extrapyramidal symptoms (ie, bradykinesia, drooling, dyskinesia, dystonia, hypokinesia, muscle rigidity, muscle tightness, musculoskeletal stiffness, oromandibular dystonia, parkinsonism, salivary hypersecretion, and tremor) were reported in 26% and 29% of patients receiving cariprazine at doses of 3 to 6 mg/day (n=263) and 9 to 12 mg/day (n=360), respectively, compared to 12% of patients receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).
    B) AKATHISIA
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, akathisia was reported in 13% and 14% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203), respectively, compared to 4% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    b) According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, akathisia was reported in 20% and 21% of patients receiving cariprazine at doses of 3 to 6 mg/day (n=263) and 9 to 12 mg/day (n=360), respectively, compared to 5% of patients receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, headache was reported in 11% and 18% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203), respectively, compared to 13% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    b) According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, headache was reported in 14% and 13% of patients receiving cariprazine at doses of 3 to 6 mg/day (n=263) and 9 to 12 mg/day (n=360), respectively, compared to 13% of patients receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).
    D) DROWSY
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, somnolence was reported in 8% and 10% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203), respectively, compared to 5% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    b) According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, somnolence was reported in 7% and 8% of patients receiving cariprazine at doses of 3 to 6 mg/day (n=263) and 9 to 12 mg/day (n=360), respectively, compared to 4% of patients receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).
    2) WITH POISONING/EXPOSURE
    a) During premarketing clinical trials, a patient experienced orthostasis and sedation following an inadvertent cariprazine overdose ingestion of 48 mg/day. The patient completely recovered the same day (Prod Info VRAYLAR(R) oral capsules, 2015).
    E) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, dizziness was reported in 5% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203) compared to 2% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    b) According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, dizziness was reported in 7% and 6% of patients receiving cariprazine at doses of 3 to 6 mg/day (n=263) and 9 to 12 mg/day (n=360), respectively, compared to 4% of patients receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).
    F) FATIGUE
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, fatigue, including asthenia, was reported in 3% and 2% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203), respectively, compared to 1% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    b) According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, fatigue, including asthenia, was reported in 4% and 5% of patients receiving cariprazine at doses of 3 to 6 mg/day (n=263) and 9 to 12 mg/day (n=360), respectively, compared to 2% of patients receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).
    G) RESTLESSNESS
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, restlessness was reported in 6% and 5% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203), respectively, compared to 3% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    b) According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, restlessness was reported in 7% of patients receiving cariprazine at doses of 3 to 6 mg/day (n=263) and 9 to 12 mg/day (n=360) compared to 2% of patients receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).
    H) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, insomnia was reported in 13% and 11% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203), respectively, compared to 11% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    b) According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, insomnia was reported in 9% and 8% of patients receiving cariprazine at doses of 3 to 6 mg/day (n=263) and 9 to 12 mg/day (n=360), respectively, compared to 7% of patients receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).
    I) FEELING AGITATED
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, agitation and anxiety were reported in 5% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and in 3% of patients receiving cariprazine at doses of 9 to 12 mg/day (n=203) compared to 4% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    J) ISCHEMIC STROKE
    1) WITH THERAPEUTIC USE
    a) Ischemic stroke was rarely reported during clinical trials in patients receiving cariprazine at doses of at least 1.5 mg orally once daily (Prod Info VRAYLAR(R) oral capsules, 2015).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, nausea and vomiting were reported in 7% and 5% of patients, respectively, receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and in 8% and 5% of patients, respectively, receiving cariprazine at doses of 9 to 12 mg/day (n=203) compared to 5% and 3% of patients, respectively, receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    b) According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, nausea and vomiting were reported in 13% and 10% of patients, respectively, receiving cariprazine at doses of 3 to 6 mg/day (n=263) and in 11% and 8% of patients, respectively, receiving cariprazine at doses of 9 to 12 mg/day (n=360) compared to 7% and 4% of patients, respectively, receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).
    B) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, constipation was reported in 7% and 10% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203), respectively, compared to 5% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    b) According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, constipation was reported in 6% and 11% of patients receiving cariprazine at doses of 3 to 6 mg/day (n=263) and 9 to 12 mg/day (n=360), respectively, compared to 5% of patients receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).
    C) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, dyspepsia was reported in 5% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203) compared to 4% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    b) According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, dyspepsia was reported in 7% and 9% of patients receiving cariprazine at doses of 3 to 6 mg/day (n=263) and 9 to 12 mg/day (n=360), respectively, compared to 4% of patients receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).
    D) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, abdominal pain was reported in 4% and 7% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203), respectively, compared to 5% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    b) According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, abdominal pain was reported in 6% and 8% of patients receiving cariprazine at doses of 3 to 6 mg/day (n=263) and 9 to 12 mg/day (n=360), respectively, compared to 5% of patients receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).
    E) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, diarrhea was reported in 4% and 5% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203), respectively, compared to 3% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    b) According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, diarrhea was reported in 5% and 6% of patients receiving cariprazine at doses of 3 to 6 mg/day (n=263) and 9 to 12 mg/day (n=360), respectively, compared to 5% of patients receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).
    F) APTYALISM
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, dry mouth was reported in 2% and 3% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203), respectively, compared to 2% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    b) According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, dry mouth was reported in 3% and 2% of patients receiving cariprazine at doses of 3 to 6 mg/day (n=263) and 9 to 12 mg/day (n=360), respectively, compared to 2% of patients receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).
    G) WEIGHT INCREASED
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, increased weight was reported in 2% and 3% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203), respectively, compared to 1% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    b) According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, increased weight was reported in 2% and 3% of patients receiving cariprazine at doses of 3 to 6 mg/day (n=263) and 9 to 12 mg/day (n=360), respectively, compared to 2% of patients receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).
    H) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, decreased appetite was reported in 3% and 2% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203), respectively, compared to 2% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    b) According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, decreased appetite was reported in 3% and 4% of patients receiving cariprazine at doses of 3 to 6 mg/day (n=263) and 9 to 12 mg/day (n=360), respectively, compared to 3% of patients receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).
    I) TOOTHACHE
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, toothache was reported in 3% and 6% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203), respectively, compared to 4% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    b) According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, toothache was reported in 4% and 3% of patients receiving cariprazine at doses of 3 to 6 mg/day (n=263) and 9 to 12 mg/day (n=360), respectively, compared to 2% of patients receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, increased liver enzymes were reported in 1% and 2% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203), respectively, compared to less than 1% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    b) According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, increased liver enzymes were reported in 1% and 3% of patients receiving cariprazine at doses of 3 to 6 mg/day (n=263) and 9 to 12 mg/day (n=360), respectively, compared to less than 1% of patients receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).
    B) INFLAMMATORY DISEASE OF LIVER
    1) WITH THERAPEUTIC USE
    a) Hepatitis was rarely reported during clinical trials in patients receiving cariprazine at doses of at least 1.5 mg orally once daily (Prod Info VRAYLAR(R) oral capsules, 2015).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia and neutropenia have been reported with atypical antipsychotic agent therapy, including therapy with cariprazine (Prod Info VRAYLAR(R) oral capsules, 2015).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, rash was reported in 1% and 2% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203), respectively, compared to 1% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, arthralgia was reported in 1% and 2% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203), respectively, compared to 1% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    B) BACKACHE
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, back pain was reported in 3% and 1% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203), respectively, compared to 2% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    b) According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, back pain was reported in 1% and 3% of patients receiving cariprazine at doses of 3 to 6 mg/day (n=263) and 9 to 12 mg/day (n=360), respectively, compared to 1% of patients receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).
    C) PAIN IN LIMB
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, pain in extremity was reported in 2% and 4% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203), respectively, compared to 3% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    b) According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, pain in extremity was reported in 4% and 2% of patients receiving cariprazine at doses of 3 to 6 mg/day (n=263) and 9 to 12 mg/day (n=360), respectively, compared to 2% of patients receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).
    D) INCREASED CREATINE KINASE LEVEL
    1) WITH THERAPEUTIC USE
    a) According to pooled data from four 6-week, placebo-controlled trials of patients diagnosed with schizophrenia, increased creatine phosphokinase concentrations were reported in 2% and 3% of patients receiving cariprazine at doses of 4.5 to 6 mg/day (n=575) and 9 to 12 mg/day (n=203), respectively, compared to 1% of patients receiving placebo (n=584) (Prod Info VRAYLAR(R) oral capsules, 2015).
    b) According to pooled data from three 3-week, placebo-controlled trials of patients diagnosed with bipolar mania, increased creatine phosphokinase concentrations were reported in 2% and 3% of patients receiving cariprazine at doses of 3 to 6 mg/day (n=263) and 9 to 12 mg/day (n=360), respectively, compared to 2% of patients receiving placebo (n=442) (Prod Info VRAYLAR(R) oral capsules, 2015).
    E) RHABDOMYOLYSIS
    1) WITH THERAPEUTIC USE
    a) Rhabdomyolysis was rarely reported during clinical trials in patients receiving cariprazine at doses of at least 1.5 mg orally once daily (Prod Info VRAYLAR(R) oral capsules, 2015).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) During short-term (6-week and 3-week) placebo-controlled trials, the incidence of hyperglycemia was similar in patients treated with cariprazine as compared to patients receiving placebo; however, during long-term open label schizophrenia and bipolar disorder studies, the incidence of patients with normal hemoglobin A1c baseline values who developed elevated levels (6.5% or greater) was 4% (Prod Info VRAYLAR(R) oral capsules, 2015).

Reproductive

    3.20.1) SUMMARY
    A) Data are unavailable regarding fetal or maternal effects of cariprazine use in pregnant women; however, animal studies have indicated malformations, lower pup survival, and developmental delays following cariprazine exposure less than human exposure at the maximum recommended human dose. In general, third-trimester antipsychotic drug exposure has been associated with extrapyramidal and/or withdrawal symptoms in neonates.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) During animal studies, administration of cariprazine at doses up to 3.5 times the maximum recommended human dose (MRHD) during organogenesis resulted in fetal developmental toxicity (ie, reduced body weight, decreased male anogenital distance, skeletal malformations) and fetal external malformations (ie, localized fetal thoracic edema), visceral variations, and skeletal developmental variations (Prod Info VRAYLAR(R) oral capsules, 2015).
    3.20.3) EFFECTS IN PREGNANCY
    A) NEONATAL EFFECTS
    1) Neonates that are exposed to antipsychotic drugs during the third trimester are at an increased risk for extrapyramidal or withdrawal symptoms. Symptoms may include agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorders. Recovery has been reported within hours without specific treatment; although some cases have required prolonged hospitalization (Prod Info VRAYLAR(R) oral capsules, 2015).
    B) PREGNANCY REGISTRY
    1) Advise pregnant women of the potential for fetal harm if used during pregnancy. Patients exposed to cariprazine during pregnancy may register with the National Pregnancy Registry for Atypical Antipsychotics by calling 1-866-961-2388 or by visiting http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ (Prod Info VRAYLAR(R) oral capsules, 2015).
    C) ANIMAL STUDIES
    1) During animal studies, maternal toxicity occurred at cariprazine doses up to 3.5 times the maximum recommended human dose (MRHD) and included reductions in body weight and food consumption. Decreases in postnatal survival, birth weight, and post-weaning body weight of first generation offspring were observed with cariprazine doses up to 0.4 times the MRHD (Prod Info VRAYLAR(R) oral capsules, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is unknown if cariprazine is present in human milk, its effects on milk production, or the effects of cariprazine on a nursing infant. Administer to lactating women only if the maternal benefit outweighs the infant risk (Prod Info VRAYLAR(R) oral capsules, 2015).
    B) ANIMAL STUDIES
    1) Cariprazine is present in the milk of lactating animals (Prod Info VRAYLAR(R) oral capsules, 2015).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Oral administration of cariprazine (at doses up to 16 times the maximum recommended human dose) in animals prior to mating, during mating, and up to day 7 of gestation resulted in lower fertility and conception indices in female animals. No effects on male fertility were noted (Prod Info VRAYLAR(R) oral capsules, 2015).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) During animal studies, there was no evidence of an increased incidence of tumors following cariprazine oral daily doses up to 19 times the maximum recommended human dose (Prod Info VRAYLAR(R) oral capsules, 2015).

Genotoxicity

    A) Cariprazine was not mutagenic in the in vitro bacterial reverse mutation assay; however, mutation frequency was increased in the in vitro mouse lymphoma assay with metabolic activation. Clastogenicity of cariprazine was not reported with the in vitro human lymphocyte chromosomal aberration assay or with the in vivo mouse bone marrow micronucleus assay (Prod Info VRAYLAR(R) oral capsules, 2015).
    B) Cariprazine's major metabolite, DDCAR, was not mutagenic in the in vitro bacterial reverse mutation assay; however, it induced structural chromosomal aberrations in the in vitro human lymphocyte chromosomal aberration assay (Prod Info VRAYLAR(R) oral capsules, 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) Monitor CBC with differential and liver enzymes as indicated.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Plasma cariprazine 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) Monitor CBC with differential and liver enzymes as indicated.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Plasma cariprazine 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) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Mainstay of treatment is good supportive care, including airway management for patients with severe CNS sedation. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and neurologic exam (for CNS depression, akathisia, or extrapyramidal effects).
    2) Monitor CBC with differential and liver enzymes as indicated.
    3) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    4) Plasma cariprazine concentrations are not readily available or clinically useful in the management of overdose.
    C) HYPERTENSIVE EPISODE
    1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
    2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
    3) SODIUM NITROPRUSSIDE/INDICATIONS
    a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.
    4) SODIUM NITROPRUSSIDE/DOSE
    a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).
    5) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION
    a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    6) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
    a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    7) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS
    a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    8) NITROGLYCERIN/INDICATIONS
    a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).
    9) NITROGLYCERIN/ADULT DOSE
    a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).
    10) NITROGLYCERIN/PEDIATRIC DOSE
    a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).
    11) PHENTOLAMINE/INDICATIONS
    a) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).
    12) PHENTOLAMINE/ADULT DOSE
    a) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
    b) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).
    13) PHENTOLAMINE/PEDIATRIC DOSE
    a) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).
    14) PHENTOLAMINE/ADVERSE EFFECTS
    a) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).
    15) CAUTION
    a) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).
    16) LABETALOL
    a) INTRAVENOUS INDICATIONS
    1) Consider if severe hypertension is unresponsive to short acting titratable agents such as sodium nitroprusside. Although labetalol has mixed alpha and beta adrenergic effects (Pearce & Wallin, 1994), it should be used cautiously if sympathomimetic agents are involved in the poisoning, as worsening hypertension may develop from alpha adrenergic effects.
    b) ADULT DOSE
    1) INTRAVENOUS BOLUS: Initial dose of 20 mg by slow IV injection over 2 minutes. Repeat with 40 to 80 mg at 10 minute intervals. Maximum total dose: 300 mg. Maximum effects on blood pressure usually occur within 5 minutes (Prod Info Trandate(R) IV injection, 2010).
    2) INTRAVENOUS INFUSION: Administer infusion after initial bolus, until desired blood pressure is reached. Administer IV at 2 mg/min of diluted labetalol solution (1 mg/mL or 2 mg/3 mL concentrations); adjust as indicated and continue until adequate response is achieved; usual effective IV dose range is 50 to 200 mg total dose; maximum dose: 300 mg. Prepare 1 mg/mL concentration by adding 200 mg labetalol (40 mL) to 160 mL of a compatible solution and administered at a rate of 2 mL/min (2 mg/min); also can be mixed as an approximate 2 mg/3 mL concentration by adding 200 mg labetalol (40 mL) to 250 mL of solution and administered at a rate of 3 mL/min (2 mg/min) (Prod Info Trandate(R) IV injection, 2010). Use of an infusion pump is recommended (Prod Info Trandate(R) IV injection, 2010).
    c) PEDIATRIC DOSE
    1) INTRAVENOUS: LOADING DOSE: 0.2 to 1 mg/kg, may repeat every 5 to 10 minutes (Hari & Sinha, 2011; Flynn & Tullus, 2009; Temple & Nahata, 2000; Fivush et al, 1997; Fivush et al, 1997; Bunchman et al, 1992). Maximum dose: 40 mg/dose (Hari & Sinha, 2011; Flynn & Tullus, 2009). CONTINUOUS INFUSION: 0.25 to 3 mg/kg/hour IV (Hari & Sinha, 2011; Flynn & Tullus, 2009; Temple & Nahata, 2000; Fivush et al, 1997; Miller, 1994; Deal et al, 1992; Bunchman et al, 1992).
    d) ADVERSE REACTIONS
    1) Common adverse events include postural hypotension, dizziness; fatigue; nausea; vomiting, sweating, and flushing (Pearce & Wallin, 1994).
    e) PRECAUTIONS
    1) Contraindicated in patients with bronchial asthma, congestive heart failure, greater than first degree heart block, cardiogenic shock, or severe bradycardia or other conditions associated with prolonged or severe hypotension. In patients with pheochromocytoma, labetalol should be used with caution because it has produced a paradoxical hypertensive response in some patients with this tumor (Prod Info Trandate(R) IV injection, 2010).
    2) Use caution in hepatic disease or intermittent claudication; effects of halothane may be enhanced by labetalol (Prod Info Trandate(R) IV injection, 2010). Labetalol should be stopped if there is laboratory evidence of liver injury or jaundice (Prod Info Trandate(R) IV injection, 2010).
    f) MONITORING PARAMETER
    1) Monitor blood pressure frequently during initial dosing and infusion (Prod Info Trandate(R) IV injection, 2010).

Enhanced Elimination

    A) HEMODIALYSIS
    1) There is no information regarding the effectiveness of hemodialysis or hemoperfusion for the removal of cariprazine from plasma. However, these procedures are unlikely to be of benefit due to the high protein binding (91% to 97%) of cariprazine (Prod Info VRAYLAR(R) oral capsules, 2015).

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. An inadvertent overdose ingestion of 48 mg/day in one patient during premarketing clinical trials resulted in orthostasis and sedation.
    B) THERAPEUTIC DOSE: ADULT: The starting dose is 1.5 mg orally once daily. On day 2, the dose can be increased to 3 mg and may be increased in 1.5 or 3 mg increments, depending on patient response and tolerability, up to a MAX dose of 6 mg once daily. PEDIATRIC: Safety and efficacy in pediatric patients have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) SCHIZOPHRENIA: Starting dose is 1.5 mg orally once daily. On day 2, the dose can be increased to 3 mg, and may be increased in 1.5 or 3 mg increments, depending on patient response and tolerability, up to a MAX dose of 6 mg once daily (Prod Info VRAYLAR(R) oral capsules, 2015).
    B) BIPOLAR I ASSOCIATED MANIA OR MIXED EPISODES: Starting dose is 1.5 mg orally once daily on Day 1 and increased to 3 mg on Day 2. The dose can be increased in increments of 1.5 mg or 3 mg, depending on patient response and tolerability, up to a MAX dose of 6 mg once daily (Prod Info VRAYLAR(R) oral capsules, 2015).
    7.2.2) PEDIATRIC
    A) Safety and efficacy in pediatric patients have not been established (Prod Info VRAYLAR(R) oral capsules, 2015).

Maximum Tolerated Exposure

    A) During premarketing clinical trials, a patient experienced orthostasis and sedation following an inadvertent cariprazine overdose ingestion of 48 mg/day. The patient completely recovered the same day (Prod Info VRAYLAR(R) oral capsules, 2015).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Although the exact mechanism of action of cariprazine, an atypical antipsychotic, in schizophrenia and bipolar I disorder is unknown, it is a partial agonist of serotonin 5-HT-1A activity and dopamine D2 receptors, and antagonist of serotonin 5-HT-2A activity (Prod Info VRAYLAR(R) oral capsules, 2015).

Physicochemical

Physical Characteristics

    A) White to off-white powder (Prod Info VRAYLAR(R) oral capsules, 2015).

Molecular Weight

    A) 463.9 g/mol (Prod Info VRAYLAR(R) oral capsules, 2015)

References

General Bibliography

    1) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    2) American Heart Association: 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2005; 112(24 Suppl):IV 1-203. Available from URL: http://circ.ahajournals.org/content/vol112/24_suppl/. As accessed 12/14/2005.
    3) Bunchman TE, Lynch RE, & Wood EG: Intravenously administered labetalol for treatment of hypertension in children. J Pediatr 1992; 120(1):140-144.
    4) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    5) 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.
    6) Deal JE , Barratt TM , & Dillon MJ : Management of hypertensive emergencies. Arch Dis Child 1992; 67(9):1089-1092.
    7) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    8) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    9) Fivush B , Neu A , & Furth S : Acute hypertensive crises in children: emergencies and urgencies. Curr Opin Pediatr 1997; 9(3):233-236.
    10) Flynn JT & Tullus K: Severe hypertension in children and adolescents: pathophysiology and treatment. Pediatr Nephrol 2009; 24(6):1101-1112.
    11) Friedman WF & George BL : Treatment of congestive heart failure by altering loading conditions of the heart. J Pediatr 1985; 106(5):697-706.
    12) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    13) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    14) 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.
    15) Hari P & Sinha A: Hypertensive emergencies in children. Indian J Pediatr 2011; 78(5):569-575.
    16) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
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