Asenapine

Pronunciation: a-SEN-a-peen
Class: Dibenzapine derivative/antipsychotic agent

Trade Names

Saphris
- Tablets, sublingual 5 mg
- Tablets, sublingual 10 mg

Pharmacology

Unknown. May control psychotic symptoms through antagonism of selected dopamine and serotonin receptors in the CNS.

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Pharmacokinetics

Absorption

Rapidly absorbed. Absolute bioavailability is 35%, mean C max is approximately 4 ng/mL, and T max is 0.5 to 1.5 h. Steady-state concentrations are reached within 3 days of twice-daily dosing. Food or water may decrease asenapine exposure.

Distribution

Rapidly distributed throughout the body. Vd is approximately 20 to 25 L/kg; 95% bound to plasma proteins.

Metabolism

Metabolized in the liver by direct glucuronidation by UGT1A4 and by oxidative metabolism by CYP-450 isoenzymes (predominantly CYP1A2).

Elimination

Elimination is 50% in urine and 40% in feces. The mean terminal half-life is approximately 24 h. Plasma Cl after IV administration is 52 L/h.

Special Populations

Renal Function Impairment

Pharmacokinetics are similar in patients with varying degrees of renal impairment compared with healthy patients. The effect of dialysis on the pharmacokinetics of asenapine has not been studied.

Hepatic Function Impairment

Severe hepatic impairment exposure was 7 times higher than in healthy patients; mild or moderate hepatic impairment exposure was 12% higher than in healthy patients.

Elderly

Cl decreased, increasing exposure by 30% to 40%.

Gender

No significant pharmacokinetic difference was found.

Race

No effect of race on asenapine concentrations was observed. Pharmacokinetic exposure was similar among white and Japanese patients.

Smoking

Smoking had no effect on the pharmacokinetics of asenapine.

Indications and Usage

Acute treatment of manic or mixed episodes associated with bipolar I disorder as monotherapy or adjunct therapy with lithium or valproate; treatment of schizophrenia.

Contraindications

Hypersensitivity to any component of the product.

Dosage and Administration

Bipolar Mania Adjunctive Therapy
Adults

PO 5 mg twice daily initially in combination with lithium or valproate. Increase to 10 mg twice daily depending on the clinical response and tolerability.

Bipolar Mania Monotherapy
Adults

PO 10 mg twice daily initially. Dosage may be decreased to 5 mg twice daily if there are adverse effects.

Schizophrenia
Adults

PO 5 mg twice daily. Increase up to 10 mg twice daily after 1 wk based on tolerability.

General Advice

  • For sublingual use only. Place tablet under the tongue and allow it to dissolve completely. Advise patient not to crush, chew, or swallow tablets.
  • Do not eat or drink for 10 min after administration.
  • Use dry hands when handling the tablets.
  • Periodically assess patient's need for continued treatment.
  • It is generally recommended that responding bipolar patients continue therapy beyond the acute response.

Storage/Stability

Store between 59° and 86°F. Do not remove the tablet from packaging until ready to administer.

Drug Interactions

Alcohol, CNS agents

Coadministration may enhance CNS depression. Avoid concurrent use with alcohol.

Antiarrhythmics, class IA (eg, procainamide, quinidine) and class III (eg, amiodarone, sotalol); antibiotics (eg, gatifloxacin, moxifloxacin); antipsychotics (eg, chlorpromazine, thioridazine, ziprasidone)

Additive effects on QT interval prolongation may increase the risk of life-threatening arrhythmias, including torsades de pointes. Avoid this combination.

Antihypertensive agents (eg, propranolol)

Because of alpha-1 adrenergic antagonism by asenapine, the effect of certain antihypertensive agents may be enhanced. Monitor BP and adjust the dose of the antihypertensive agent as needed.

Carbamazepine, cimetidine

Asenapine plasma concentrations may be decreased; however, no adjustment in the asenapine dose is needed.

Dextromethorphan

Plasma concentrations of dextromethorphan may be decreased. Use with caution.

Fluvoxamine, imipramine

Asenapine plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Use with caution.

Paroxetine

Asenapine plasma concentrations may be decreased, while paroxetine plasma concentrations may be increased. Use with caution.

Valproate

Asenapine plasma concentrations may be increased slightly; however, no adjustment in the asenapine dose is needed.

Adverse Reactions

CNS

Somnolence (24%); insomnia (16%); extrapyramidal symptoms, headache (12%); akathisia, dizziness (11%); anxiety, fatigue (4%); depression, irritability (2%); dystonia.

Cardiovascular

Hypertension (3%).

GI

Constipation, oral hypoesthesia, vomiting (7%); dyspepsia, increased appetite, salivary hypersecretion (4%); dry mouth, dysgeusia, stomach discomfort, toothache (3%).

Hypersensitivity

Serious hypersensitivity reactions including swollen tongue and pharyngeal edema (postmarketing).

Lab Tests

Elevated triglycerides (15%); elevated creatinine kinase (11%); elevated total cholesterol (9%); elevated fasting glucose (7%); elevated prolactin levels, elevated transaminases (3%).

Metabolic

Weight increase (5%).

Musculoskeletal

Arthralgia (3%); pain in extremity (2%).

Precautions

Warnings

Increased mortality in elderly patients with dementia-related psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Over the course of a 10-wk controlled trial, the rate of death in drug-treated patients was approximately 4.5% compared with 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either CV (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Asenapine is not approved for the treatment of patients with dementia-related psychosis.


Monitor

Monitor patients with diabetes regularly for worsening of glucose control. Have patients with risk factors of diabetes who are starting therapy undergo fasting blood glucose testing at the beginning or treatment and periodically thereafter. Monitor all patients for symptoms of hyperglycemia. In patients receiving treatment for an extended time, periodically reevaluate the long-term usefulness of continued therapy. Regularly monitor patient's weight and orthostatic vital signs. Carefully monitor patients with neutropenia for fever or other symptoms of infection. Frequently monitor CBC in patients with a preexisting low WBC or a history of drug-induced leukopenia/neutropenia during the first few months of therapy. Monitor elderly patients carefully.


Pregnancy

Category C . Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk of extrapyramidal and/or withdrawal symptoms following delivery.

Lactation

Undetermined. Women receiving asenapine should not breast-feed.

Children

Safety and efficacy not established.

Elderly

Multiple risk factors that might increase the pharmacodynamic response to asenapine, causing poorer tolerance or orthostasis, would be present in elderly patients.

Hypersensitivity

Hypersensitivity reactions (eg, anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing, rash) have been observed, sometimes occurring after the first dose.

Hepatic Function

Not recommended in patients with severe hepatic impairment.

Special Risk Patients

Clinical experience is limited in patients with concomitant illnesses. Use with caution in cardiac patients (eg, recent history of MI or unstable heart disease).

Body temperature regulation

Antipsychotics disrupt the ability to reduce core body temperature. Use with caution in patients who will experience conditions that may contribute to an elevation in core body temperature (eg, concomitant anticholinergic therapy, exposure to extreme heat, strenuous exercise, subject to dehydration).

Dysphagia

Esophageal dysmotility and aspiration may occur. Do not use asenapine in patients at risk of aspiration pneumonia.

Hazardous tasks

Caution patients about operating potentially hazardous machinery or motor vehicles until they know whether the drug impairs their ability.

Hematologic effects

Leukopenia and neutropenia have been reported.

Hyperglycemia

Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma, or death, may occur.

Hyperprolactinemia

Asenapine may elevate prolactin levels; however, there is no evidence of increased breast tumor risk.

NMS

NMS has occurred and is potentially fatal.

Orthostatic hypotension/syncope

May occur. Most common during early treatment. Use with caution in patients with known CV disease (history of MI or ischemic heart disease, heart failure, conduction abnormalities), cerebrovascular disease, and conditions that predispose to hypotension (eg, dehydration, hypovolemia, treatment with antihypertensive agents).

QT prolongation

May occur. Avoid use in patients with a history of cardiac arrhythmias and in other circumstances that may increase the risk of torsades de pointes and/or sudden death.

Seizures

May occur. Use with caution in patients with a history of seizures or with conditions that lower the seizure threshold (eg, Alzheimer dementia).

Somnolence

May occur and is usually transient, most commonly occurring during the first week of treatment.

Suicide

Possible suicide attempts are inherent to schizophrenia and bipolar disorder. Closely supervise high-risk patients.

Tardive dyskinesia

Syndrome of potentially irreversible, involuntary dyskinetic movements may develop. Prevalence is highest in elderly patients, especially women.

Weight gain

There is a potential for weight gain. In a 52-wk trial, approximately 14.7% of patients receiving asenapine gained at least 7% of their baseline weight.

Overdosage

Symptoms

Agitation, confusion.

Patient Information

  • Instruct patients that sublingual tablets should be placed under the tongue and allowed to dissolve completely. Do not crush, chew, or swallow the tablets.
  • Advise patients not to eat or drink for 10 min after a dose is taken.
  • Advise patients and caregivers that elderly patients with dementia-related psychosis are at an increased risk of death and that asenapine is not approved for elderly patients with dementia-related psychosis.
  • Instruct patients with diabetes to monitor blood glucose more frequently when drug is started or dose is changed, and to inform health care provider of significant changes in readings.
  • Advise patients to notify health care provider of the following: change in personality or mood, excessive drowsiness, involuntary body or facial movements, rapid pulse, swelling in the feet or ankles, weight gain.
  • Advise patients to avoid strenuous activity in high temperature or humidity.
  • Instruct patients to avoid alcoholic beverages while taking asenapine.
  • Advise patients to inform their health care provider if they become pregnant or intend to become pregnant during treatment.
  • Advise patients with preexisting low WBC or a history of drug-induced leukopenia/neutropenia that they should have their CBC monitored while taking this medicine.
  • Inform patients of the risk of orthostatic hypotension. Symptoms may include feeling dizzy or light-headed upon standing, especially early in treatment, and also at times of reinitiating treatment or increases in dose.
  • Advise patients that drug may impair judgment, thinking, or motor skills, or cause drowsiness, and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.
  • Advise women not to breast-feed while taking asenapine.
  • Inform patients that they may experience weight gain and to monitor their weight regularly.

Copyright © 2009 Wolters Kluwer Health.

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