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ASENAPINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Asenapine is an atypical antipsychotic agent that belongs to the dibenzo-oxepino pyrroles class.

Specific Substances

    1) CAS 65576-45-6

Available Forms Sources

    A) FORMS
    1) Asenapine is available in 5 mg and 10 mg sublingual tablets (Prod Info SAPHRIS(R) sublingual tablets, 2009).
    B) USES
    1) Asenapine is used for the treatment of acute schizophrenia and acute mania or mixed episodes associated with bipolar I disorder with or without psychotic features in adults (Prod Info SAPHRIS(R) sublingual tablets, 2009).

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: Asenapine, an antipsychotic agent, is used in the treatment of acute schizophrenia or the manic phase of bipolar disorder.
    B) EPIDEMIOLOGY: Overdose is rare.
    C) TOXICOLOGY: Similar to other atypical antipsychotic agents, in that it has a lower propensity to produce extrapyramidal effects. It does have alpha-1-adrenergic antagonist activity which may produce hypotension and other hemodynamic effects.
    D) PHARMACOLOGY: Asenapine belongs to dibenzo-oxepino pyrroles class. Although the mechanism remains unknown, it appears that asenapine exerts its effect through a combination of antagonist activity at D2 and 5-HT(2A) receptors.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: The most common events reported with therapeutic use in the treatment of schizophrenia or bipolar disorder include: akathisia, oral hypoesthesia, somnolence, dizziness, extrapyramidal symptoms (excluding akathisia) and weight gain. Other frequent adverse events: headache, insomnia, and gastrointestinal symptoms (ie, dysphagia, oral hypoesthesia, vomiting, constipation). Infrequent but potentially serious events: hypotension, QT prolongation, neutropenia/leukopenia, hyperglycemia, tardive dyskinesia, neuroleptic malignant syndrome, and cerebrovascular reactions (ie, stroke, transient ischemic attacks) in elderly patients with dementia-related psychosis.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: Limited experience. Doses up to 400 mg have resulted in agitation and confusion.
    2) SEVERE POISONING: At the time of this review, there is no information on severe toxicity with asenapine. It is anticipated that severe overdose might cause hypotension and altered mental status.
    0.2.20) REPRODUCTIVE
    A) Asenapine is classified as FDA pregnancy category C. There are no adequate and well-controlled studies of asenapine use in pregnant women. Third-trimester antipsychotic drug exposure has been associated with extrapyramidal and/or withdrawal symptoms in neonates. It is not known whether asenapine or its metabolites are excreted in human milk; however, asenapine is excreted in the milk of lactating rats.

Laboratory Monitoring

    A) Monitor vital signs including temperature.
    B) Monitor mental status and perform a neurologic exam.
    C) Obtain a baseline ECG and repeat as indicated; continuous cardiac monitoring may be necessary in symptomatic patients.
    D) Routine laboratory studies are not likely to be necessary.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Limited experience. Monitor neurologic status; protect airway and intubate as necessary. Monitor patients for hypotension. Initially treat with 0.9% NaCl at 10 to 20 mL/kg. If necessary, add dopamine or norepinephrine. Serial ECGs to evaluate for QT prolongation or dysrhythmias.
    C) DECONTAMINATION
    1) Decontamination is rarely indicated. Severe toxicity is unlikely and oral bioavailability (ie, ingestion rather than sublingual administration) is very low (2%). Consider activated charcoal after a very large ingestion if the patient is awake and able to protect their airway.
    D) AIRWAY MANAGEMENT
    1) Endotracheal intubation and mechanical ventilation may rarely be required in patients with significant CNS depression.
    E) ANTIDOTE
    1) None.
    F) HYPOTENSION
    1) Monitor blood pressure; hypotension may develop due to its alpha 1-adrenergic antagonist effect. Initially treat with 0.9% NaCl at 10 to 20 mL/kg. If necessary, add dopamine or norepinephrine.
    G) PROLONGED QT INTERVAL
    1) Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients. Clinically insignificant QT prolongation has been observed in clinical use; to date, there have been no reports of clinically significant dysrhythmias, including torsades de pointes, with asenapine.
    H) NEUTROPENIA
    1) For severe neutropenia, administer colony stimulating factor. Filgrastim 5 mcg/kg/day subQ or IV over 15 to 30 minutes OR sargramostim 250 mcg/meter(2)/day IV over 4 hours.
    I) ENHANCED ELIMINATION PROCEDURE
    1) Enhanced elimination is not anticipated to be useful following exposure to asenapine due to the high degree of protein binding and large volume of distribution.
    J) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: Mild to moderately symptomatic patients should be sent to a health care facility for evaluation and treated until symptoms resolve.
    2) ADMISSION CRITERIA: Patients who remain symptomatic despite adequate treatment should be admitted.
    3) CONSULT CRITERIA: Consult a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    K) PITFALLS
    1) When managing a suspected asenapine overdose, the possibility of multidrug involvement should be considered. Asenapine can also potentiate the effects of certain antihypertensive agents.
    L) PHARMACOKINETICS
    1) Asenapine is rapidly absorbed following sublingual administration. Bioavailability is low (2%) after ingestion. Highly bound (95%) to plasma proteins. It is rapidly distributed with a large volume of distribution (approximately 20 to 25 L/kg). Primary activity is due to the parent compound. The terminal half-life is estimated to be 24 hours, after an initial more rapid distribution phase. After a single dose, approximately 50% was recovered in urine and 40% in feces.
    M) DIFFERENTIAL DIAGNOSIS
    1) Includes overdose of other atypical antipsychotic agents.

Range Of Toxicity

    A) Limited data; no fatalities have been reported. Based on several reports of overdose, the highest estimated dose was 400 mg. Agitation and confusion were observed.
    B) THERAPEUTIC DOSE: ADULTS: Initial therapy: 5 to 10 mg sublingually twice daily; doses above 10 mg twice daily have not been evaluated. PEDIATRIC: The safety and effectiveness have not been established in the pediatric population.

Clinical Effects

Summary Of Exposure

    A) USES: Asenapine, an antipsychotic agent, is used in the treatment of acute schizophrenia or the manic phase of bipolar disorder.
    B) EPIDEMIOLOGY: Overdose is rare.
    C) TOXICOLOGY: Similar to other atypical antipsychotic agents, in that it has a lower propensity to produce extrapyramidal effects. It does have alpha-1-adrenergic antagonist activity which may produce hypotension and other hemodynamic effects.
    D) PHARMACOLOGY: Asenapine belongs to dibenzo-oxepino pyrroles class. Although the mechanism remains unknown, it appears that asenapine exerts its effect through a combination of antagonist activity at D2 and 5-HT(2A) receptors.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: The most common events reported with therapeutic use in the treatment of schizophrenia or bipolar disorder include: akathisia, oral hypoesthesia, somnolence, dizziness, extrapyramidal symptoms (excluding akathisia) and weight gain. Other frequent adverse events: headache, insomnia, and gastrointestinal symptoms (ie, dysphagia, oral hypoesthesia, vomiting, constipation). Infrequent but potentially serious events: hypotension, QT prolongation, neutropenia/leukopenia, hyperglycemia, tardive dyskinesia, neuroleptic malignant syndrome, and cerebrovascular reactions (ie, stroke, transient ischemic attacks) in elderly patients with dementia-related psychosis.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: Limited experience. Doses up to 400 mg have resulted in agitation and confusion.
    2) SEVERE POISONING: At the time of this review, there is no information on severe toxicity with asenapine. It is anticipated that severe overdose might cause hypotension and altered mental status.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Orthostatic hypotension and syncope have been reported infrequently with therapeutic use of asenapine (Prod Info SAPHRIS(R) sublingual tablets, 2009). However, these events were not found to be clinically significant (Potkin et al, 2007).
    B) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) In a study of 151 patients with stable schizophrenia who received ECG monitoring and evaluation at doses of 5 mg, 10 mg, 15 mg, and 20 mg twice daily and placebo, asenapine was associated with increases in QTc interval ranging from 2 to 5 msec compared with placebo. No patient experienced a QTc increase greater than or equal to 60 msec from baseline. No patient experienced a QTc of greater than 500 msec (Prod Info SAPHRIS(R) sublingual tablets, 2009). These events were not found to be clinically significant (Potkin et al, 2007).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) WITH THERAPEUTIC USE
    a) Somnolence was one of the most frequently reported adverse events with asenapine therapy (Potkin et al, 2007).
    b) In clinical trials in patients with bipolar mania, somnolence was reported in 24% of patients who received asenapine 5 mg or 10 mg twice daily (n=379) compared with 6% of patients who received placebo (n=203) (Prod Info SAPHRIS(R) sublingual tablets, 2009).
    B) AKATHISIA
    1) WITH THERAPEUTIC USE
    a) In clinical trials in patients with bipolar mania, akathisia was reported in 4% of patients who received asenapine 5 mg or 10 mg twice daily (n=379) compared with 2% of patients who received placebo (n=203) (Prod Info SAPHRIS(R) sublingual tablets, 2009).
    C) EXTRAPYRAMIDAL DISEASE
    1) WITH THERAPEUTIC USE
    a) In clinical trials in patients with bipolar mania, extrapyramidal symptoms (excluding akathisia) were reported in 7% of patients who received asenapine 5 mg or 10 mg twice daily (n=379) compared with 2% of patients who received placebo (n=203) (Prod Info SAPHRIS(R) sublingual tablets, 2009).
    D) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) Insomnia was one of the most frequently reported adverse events with asenapine therapy (Potkin et al, 2007).
    b) In clinical trials in patients with schizophrenia, insomnia was reported in 15% of patients (n=572) receiving 5 mg or 10 mg of asenapine twice daily compared with 13% of patients who received placebo (n=378) (Prod Info SAPHRIS(R) sublingual tablets, 2009).
    E) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In clinical trials in patients with bipolar mania, dizziness was reported in 11% of patients who received asenapine 5 mg or 10 mg twice daily (n=379) compared with 3% of patients in the placebo group (n=203) (Prod Info SAPHRIS(R) sublingual tablets, 2009).
    F) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In clinical trials in patients with bipolar mania, reports of headache were similar in patients who received asenapine 5 mg or 10 mg twice daily (n=379) compared with patients who received placebo (n=203) (12% vs 11%)(Prod Info SAPHRIS(R) sublingual tablets, 2009).
    G) NEUROLEPTIC MALIGNANT SYNDROME
    1) WITH THERAPEUTIC USE
    a) Neuroleptic malignant syndrome (eg, hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability) has been reported in some patients treated with atypical antipsychotics, including asenapine (Prod Info SAPHRIS(R) sublingual tablets, 2009).
    H) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures were rarely reported in clinical trials with asenapine (Prod Info SAPHRIS(R) sublingual tablets, 2009).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) In a clinical trial in patients with bipolar mania, constipation and vomiting occurred in 5% of patients receiving asenapine, which was similar to the placebo group. Dry mouth, stomach discomfort and salivary hypersecretion have been reported infrequently in patients treated with asenapine (Prod Info SAPHRIS(R) sublingual tablets, 2009).
    B) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) In clinical trials in patients with bipolar mania, dyspepsia was reported in 4% of patients who received asenapine 5 mg or 10 mg twice daily (n=379) compared with 2% of patients who received placebo (n=203). Oral hypoesthesia was reported in 5% of patients treated with 5 or 10 mg twice daily of asenapine (Prod Info SAPHRIS(R) sublingual tablets, 2009).
    C) INCREASED APPETITE
    1) WITH THERAPEUTIC USE
    a) In clinical trials in patients with bipolar mania, an increase in appetite was reported in 4% of patients who received asenapine 5 mg or 10 mg twice daily (n=379) compared with 1% of patients who received placebo (n=203) (Prod Info SAPHRIS(R) sublingual tablets, 2009).
    D) WEIGHT GAIN FINDING
    1) WITH THERAPEUTIC USE
    a) In clinical trials in patients with bipolar mania, an increase in weight was reported in 5% of patients who received asenapine 5 mg or 10 mg twice daily (n=379) compared with less than 1% of patients who received placebo (n=203) (Prod Info SAPHRIS(R) sublingual tablets, 2009).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Transient elevations in serum transaminases have been reported with therapy, but were not clinically significant (Prod Info SAPHRIS(R) sublingual tablets, 2009).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Based on clinical trials and postmarketing experience, leukopenia has been temporally related to antipsychotic agents, including asenapine (Prod Info SAPHRIS(R) sublingual tablets, 2009).
    B) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) Based on clinical trials and postmarketing experience, neutropenia has been temporally related to antipsychotic agents, including asenapine. In patients with an absolute neutrophil count of less than 1000/mm(3), therapy should be discontinued and serial WBCs should be monitored until recovery occurs (Prod Info SAPHRIS(R) sublingual tablets, 2009).
    C) AGRANULOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) Agranulocytosis, including fatal outcomes, has been associated with antipsychotic agents in this class (Prod Info SAPHRIS(R) sublingual tablets, 2009). At the time of this review, it has not been reported with asenapine.

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCULOSKELETAL FINDING
    1) WITH THERAPEUTIC USE
    a) In clinical trials in patients with bipolar mania, arthralgia (3%) and pain (2%) were reported infrequently in patients who received asenapine 5 mg or 10 mg twice daily (n=379) (Prod Info SAPHRIS(R) sublingual tablets, 2009).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Hyperglycemia, in some cases severe, has been reported in patients treated with atypical antipsychotics; however, it was observed in less than 1% of patients treated with asenapine during clinical trials (Prod Info SAPHRIS(R) sublingual tablets, 2009).

Reproductive

    3.20.1) SUMMARY
    A) Asenapine is classified as FDA pregnancy category C. There are no adequate and well-controlled studies of asenapine use in pregnant women. Third-trimester antipsychotic drug exposure has been associated with extrapyramidal and/or withdrawal symptoms in neonates. It is not known whether asenapine or its metabolites are excreted in human milk; however, asenapine is excreted in the milk of lactating rats.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RATS, RABBITS: In animal studies, there was no evidence of teratogenicity in rats and rabbits with exposures up to 0.7 times the maximum recommended human dose (MRHD). In the rabbit study, the AUC at the highest dose tested was 2 times that in humans receiving the MRHD (Prod Info SAPHRIS(R) oral sublingual tablets, 2015).
    3.20.3) EFFECTS IN PREGNANCY
    A) RISK SUMMARY
    1) There are no adequate and well-controlled studies of asenapine use during pregnancy; however, third-trimester antipsychotic drug exposure has been associated with extrapyramidal and withdrawal symptoms in neonates. Patients should be advised of the potential fetal harm when using this drug during pregnancy. If a fetus is exposed to asenapine during the third trimester of pregnancy, monitor the neonate for extrapyramidal and/or withdrawal symptoms, and manage symptoms appropriately (Prod Info SAPHRIS(R) oral sublingual tablets, 2015).
    B) EXTRAPYRAMIDAL AND/OR WITHDRAWAL SYMPTOMS
    1) 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 SAPHRIS(R) oral sublingual tablets, 2015).
    C) ANIMAL STUDIES
    1) RATS: Increases in post-implantation loss and early pup deaths were seen with exposures between 0.15 to 0.7 times the maximum recommended human dose (MRHD) from gestation day 6 through postpartum day 21. Pup deaths and reduced weights occurred with exposures 0.4 and 0.7 times the MRHD (Prod Info SAPHRIS(R) oral sublingual tablets, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown whether asenapine is excreted in human milk. The health benefits of breastfeeding and the mother's clinical need for this drug should be measured along with the potential adverse fetal effects from the drug or the underlying maternal condition (Prod Info SAPHRIS(R) oral sublingual tablets, 2015).
    B) ANIMAL STUDIES
    1) RATS: Asenapine is excreted in the milk of rats (Prod Info SAPHRIS(R) oral sublingual tablets, 2015).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs including temperature.
    B) Monitor mental status and perform a neurologic exam.
    C) Obtain a baseline ECG and repeat as indicated; continuous cardiac monitoring may be necessary in symptomatic patients.
    D) Routine laboratory studies are not likely to be necessary.
    4.1.2) SERUM/BLOOD
    A) Routine laboratory studies are not likely to be necessary.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Obtain a baseline ECG; repeat as indicated following a significant exposure. A clinically insignificant increase in QTc interval has been reported with therapeutic use, but dysrhythmias (ie, Torsade de Pointes) were not observed during clinical trials (Prod Info SAPHRIS(R) sublingual tablets, 2009).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients who remain symptomatic despite adequate treatment should be admitted.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Mild to moderately symptomatic patients should be sent to a health care facility for evaluation and treatment as necessary.

Monitoring

    A) Monitor vital signs including temperature.
    B) Monitor mental status and perform a neurologic exam.
    C) Obtain a baseline ECG and repeat as indicated; continuous cardiac monitoring may be necessary in symptomatic patients.
    D) Routine laboratory studies are not likely to be necessary.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital decontamination is not indicated. Severe toxicity is unlikely and oral bioavailability (ie, ingestion rather than sublingual administration) is very low.

Range Of Toxicity

Summary

    A) Limited data; no fatalities have been reported. Based on several reports of overdose, the highest estimated dose was 400 mg. Agitation and confusion were observed.
    B) THERAPEUTIC DOSE: ADULTS: Initial therapy: 5 to 10 mg sublingually twice daily; doses above 10 mg twice daily have not been evaluated. PEDIATRIC: The safety and effectiveness have not been established in the pediatric population.

Therapeutic Dose

    7.2.1) ADULT
    A) SCHIZOPHRENIA
    1) 5 to 10 mg sublingually twice a day; MAX: 10 mg twice daily (Prod Info SAPHRIS(R) oral sublingual tablets, 2015)
    B) BIPOLAR DISORDER
    1) 5 to 10 mg sublingually twice daily; MAX 10 mg twice daily (Prod Info SAPHRIS(R) oral sublingual tablets, 2015)
    7.2.2) PEDIATRIC
    A) UNDER 10 YEARS
    1) The safety and efficacy have not been established (Prod Info SAPHRIS(R) oral sublingual tablets, 2015).
    B) 10 TO 17 YEARS
    1) Initial, 2.5 sublingually twice daily; may be increased to up to 10 mg twice daily; MAX: 10 mg twice daily (Prod Info SAPHRIS(R) oral sublingual tablets, 2015)

Minimum Lethal Exposure

    A) At the time of this review, a minimum lethal dose has not been established. No fatalities have been reported (Prod Info SAPHRIS(R) sublingual tablets, 2009).

Maximum Tolerated Exposure

    A) Based on several reports of overdose, the highest estimated dose was 400 mg. Agitation and confusion were observed (Prod Info SAPHRIS(R) sublingual tablets, 2009).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The mechanism of action is unknown, but the manufacturer suggests that the efficacy of asenapine in the treatment of schizophrenia is mediated through a combination of antagonist activity at D(2) and 5-HT(2A) receptors (Prod Info SAPHRIS(R) sublingual tablets, 2009).

References

General Bibliography

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    7) Khan IA & Gowda RM: Novel therapeutics for treatment of long-QT syndrome and torsade de pointes. Int J Cardiol 2004; 95(1):1-6.
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    9) Link MS, Berkow LC, Kudenchuk PJ, et al: Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S444-S464.
    10) Neumar RW , Otto CW , Link MS , et al: Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S729-S767.
    11) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
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