Saphris

Generic Name: Asenapine Maleate
Class: Atypical Antipsychotics
VA Class: CN709
Chemical Name: (3aRS,12bRS)-5-Chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole (2Z)-2-butenedioate (1:1)
Molecular Formula: C₁₇H₁₆ClNO•C₄H₄O₄
CAS Number: 85650-56-2

Special Alerts:

[Posted 09/01/2011] ISSUE: FDA notified healthcare professionals and patients that serious allergic reactions have been reported with the use of asenapine maleate (Saphris). The Contraindications, Warnings and Precautions, Adverse Reactions, and Patient Counseling Information sections have been revised to include information about type I hypersensitivity reactions which may include anaphylaxis, angioedema, low blood pressure, rapid heart rate, swollen tongue, difficulty breathing, wheezing, or rash. In several cases, these reactions occurred after the first dose.

BACKGROUND: Asenapine maleate is used to treat symptoms of schizophrenia and bipolar disorder.

RECOMMENDATION: Healthcare professionals should be aware of the risk of hypersensitivity reactions with asenapine maleate and counsel patients who are receiving the drug about how to recognize the signs and symptoms of a serious allergic reaction. Asenapine maleate should not be used in patients with a known hypersensitivity to the drug. For more information visit the FDA website at: and .

[Posted 02/22/2011] ISSUE: FDA notified healthcare professionals that the Pregnancy section of drug labels for the entire class of antipsychotic drugs has been updated. The new drug labels now contain more and consistent information about the potential risk for abnormal muscle movements (extrapyramidal signs or EPS) and withdrawal symptoms in newborns whose mothers were treated with these drugs during the third trimester of pregnancy.

The symptoms of EPS and withdrawal in newborns may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty in feeding. In some newborns, the symptoms subside within hours or days and do not require specific treatment; other newborns may require longer hospital stays.

BACKGROUND: Antipsychotic drugs are used to treat symptoms of psychiatric disorders such as schizophrenia and bipolar disorder.

RECOMMENDATION: Healthcare professionals should be aware of the effects of antipsychotic medications on newborns when the medications are used during pregnancy. Patients should not stop taking these medications if they become pregnant without talking to their healthcare professional, as abruptly stopping antipsychotic medications can cause significant complications for treatment. For more information visit the FDA website at: and .

• Increased Mortality in Geriatric Patients with Dementia-related Psychosis


• 
  

  Geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.^{1 28 39 73 75}

  
  


• 
  

  Analyses of 17 placebo-controlled trials in geriatric patients mainly receiving atypical antipsychotic agents revealed an approximate 1.6- to 1.7-fold increase in mortality compared with that in patients receiving placebo.^{1 39 73}

  
  


• 
  

  Most fatalities appeared to result from cardiovascular-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).^{1 73}

  
  


• 
  

  Observational studies suggest that conventional or first-generation antipsychotic agents also may increase mortality in such patients.^{1 28 39}

  
  


• 
  

  Antipsychotic agents, including asenapine, are not approved for the treatment of dementia-related psychosis.^{1 39 73}

  
  

Introduction

Dibenzo-oxepino pyrrole derivative; atypical or second-generation antipsychotic agent.^{1 4 6 8 28 74 85}

Uses for Saphris

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Schizophrenia

Acute treatment of schizophrenia in adults.^{1 2 4 82 88 89}

American Psychiatric Association (APA) considers most atypical antipsychotic agents first-line drugs for management of the acute phase of schizophrenia (including first psychotic episodes).²⁸

Patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.^{28 70 71 72}

Bipolar Disorder

Acute treatment of manic or mixed episodes associated with bipolar I disorder (with or without psychotic features) in adults.^{1 3 5 74 83}

Saphris Dosage and Administration

General

• 
  

  When switching from other antipsychotic agents to asenapine, immediate discontinuance of previous agent may be acceptable for some patients with schizophrenia, but gradual discontinuance may be most appropriate for others.¹ In all cases, minimize period of overlapping antipsychotic administration.¹

  
  

Administration

Sublingual Administration

Administer tablets sublingually twice daily.¹

Do not remove sublingual tablet from blister pack until just prior to administration.¹ With dry hands, pull blister pack out of case and peel back colored tab to expose the tablet; do not push tablet through blister pack.¹ Gently remove tablet and place under the tongue, then allow to dissolve completely (usually takes about 10 seconds).^{1 6}

Do not eat or drink for 10 minutes following administration.^{1 74} Do not crush, chew, or swallow the sublingual tablets.¹ (See Food and Water under Pharmacokinetics.)

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as asenapine maleate; dosage expressed in terms of asenapine.^{1 4 81}

Adults

Schizophrenia

Sublingual

For acute treatment, recommended initial and target dosage is 5 mg twice daily.¹ A higher dosage (10 mg twice daily) did not provide additional therapeutic benefit in clinical trials, but was clearly associated with increased adverse effects.^{1 82} Safety of dosages >10 mg twice daily not evaluated.¹

Optimum duration of therapy not known, but maintenance therapy with antipsychotics is well established.^{1 28} In responsive patients, continue drug therapy beyond the acute response and as long as clinically necessary and tolerated; periodically reassess need for continued therapy.^{1 28}

In patients with remitted first or multiple episodes, APA recommends either indefinite maintenance therapy or gradual discontinuance of the antipsychotic with close follow-up and a plan to reinstitute treatment upon symptom recurrence.²⁸ Consider antipsychotic therapy discontinuance only after ≥1 year of symptom remission or optimal response while receiving the drug.²⁸ Indefinite maintenance treatment recommended if patient has experienced multiple previous psychotic episodes or 2 episodes within 5 years.²⁸

Bipolar Disorder

Manic and Mixed Episodes

Sublingual

Initially, 10 mg twice daily.^{1 3 83} May decrease dosage to 5 mg twice daily if adverse effects occur.¹ Safety of dosages >10 mg twice daily not evaluated.¹

Optimum duration of therapy not known.¹ In responsive patients, continue drug therapy beyond the acute response; periodically reassess long-term risks and benefits.¹

Prescribing Limits

Adults

Schizophrenia

Sublingual

Safety of dosages >10 mg twice daily not evaluated.¹

Bipolar Disorder

Manic and Mixed Episodes

Sublingual

Safety of dosages >10 mg twice daily not evaluated.¹

Special Populations

Hepatic Impairment

Severe hepatic impairment (Child-Pugh class C): Use not recommended.^{1 7}

Mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment: Dosage adjustment not necessary.^{1 7} (See Absorption: Special Populations, under Pharmacokinetics.)

Renal Impairment

Routine dosage adjustment not required.^{1 7} (See Absorption: Special Populations, under Pharmacokinetics, and also see Elimination: Special Populations, under Pharmacokinetics.)

Geriatric Patients

Routine dosage adjustment not required.¹ (See Geriatric Use under Cautions, and Absorption: Special Populations, under Pharmacokinetics, and Elimination: Special Populations, under Pharmacokinetics.)

Gender or Race

Dosage adjustment not routinely required based on gender or race.¹

Cautions for Saphris

Contraindications

• 
  

  No known contraindications.¹

  
  

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Increased risk of death with use of either conventional (first-generation) or atypical (second-generation) antipsychotics in geriatric patients with dementia-related psychosis.^{1 28 39 73 75}

Antipsychotic agents, including asenapine, are not approved for the treatment of dementia-related psychosis.^{1 39 73} (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning; and Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions; and Dysphagia under Cautions.)

Other Warnings and Precautions

Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis

Increased incidence of adverse cerebrovascular events (cerebrovascular accidents and TIAs), including fatalities, observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies.^{1 28} Asenapine is not approved for the treatment of dementia-related psychosis.¹ (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability, reported with antipsychotic agents, including asenapine.¹

Immediately discontinue therapy and initiate supportive and symptomatic therapy if NMS occurs.¹ Careful monitoring recommended if therapy is reinstituted following recovery; the risk that NMS can recur must be considered.¹

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary dyskinetic movements, reported with use of antipsychotic agents, including asenapine.^{1 84}

Reserve long-term antipsychotic treatment for patients with chronic illness known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.¹ In patients requiring chronic treatment, use smallest dosage and shortest duration of treatment producing a satisfactory clinical response; periodically reassess need for continued therapy.¹

APA recommends assessing patients receiving atypical antipsychotic agents for abnormal involuntary movements every 12 months; for patients at increased risk for tardive dyskinesia, assess every 6 months.²⁸ Consider discontinuance of asenapine if signs and symptoms of tardive dyskinesia appear.¹ However, some patients may require treatment despite the presence of the syndrome.¹

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, reported in patients receiving atypical antipsychotic agents.^{1 11 12 14 15 16 17 18 20 21 22 23 25 40 41 42 46 65} In clinical trials, the incidence of any adverse reaction related to glucose metabolism was <1% in both the asenapine and placebo treatment groups.¹

Closely monitor patients with an established diagnosis of diabetes mellitus for worsening of glucose control, and perform fasting blood glucose testing at baseline and periodically in patients with risk factors for diabetes (e.g., obesity, family history of diabetes).^{1 11 12 14 15 16 17 18 19 20 21 22 23} If manifestations of hyperglycemia occur in any asenapine-treated patient, perform fasting blood glucose testing.^{1 11 12 14 15 16 17 18 19 20 21 22 23}

In some cases, patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the suspect drug; in other cases, hyperglycemia resolved with discontinuance of the antipsychotic.^{1 11 12 14 15 16 17 18 19 20 21 22 23 46}

Weight Gain

Weight gain reported in schizophrenia and bipolar mania studies; some asenapine-treated patients gained ≥7% of their baseline body weight.¹ (See Hyperglycemia and Diabetes Mellitus under Cautions.)

Hemodynamic Effects

Risk of orthostatic hypotension and syncope, particularly early in treatment, because of asenapine’s α₁-adrenergic blocking activity.¹

Hypotension, bradycardia, and sinus pauses reported in clinical pharmacology studies in healthy individuals; risk may be greater in nonpsychiatric patients compared with psychiatric patients, who may be more adapted to certain effects of psychotropic drugs.¹

Use with caution in patients with known cardiovascular disease (e.g., history of MI or ischemic heart disease, heart failure, conduction abnormalities), cerebrovascular disease, or conditions that would predispose patients to develop hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy) and/or in geriatric patients.¹ Also use with caution in patients receiving other drugs that can cause hypotension, bradycardia, respiratory depression, or CNS depression (see Hypotensive Agents and Drugs causing Bradycardia under Interactions).¹ Consider monitoring orthostatic vital signs and reducing asenapine dosage if hypotension develops.¹ (See Advice to Patients.)

Hematologic Effects

Leukopenia and neutropenia temporally related to antipsychotic agents, including asenapine, reported during clinical trial and/or postmarketing experience.^{1 78} Agranulocytosis (including fatal cases) also reported with other antipsychotic agents.¹

Possible risk factors for leukopenia and neutropenia include preexisting low WBC count and a history of drug-induced leukopenia or neutropenia.^{1 78} Monitor CBC frequently during the first few months of therapy in patients with such risk factors.¹ Discontinue asenapine at the first sign of a decline in WBC count in the absence of other causative factors.¹

Carefully monitor patients with clinically significant neutropenia for fever or other signs and symptoms of infection and treat promptly if they occur.¹ In patients with severe neutropenia (ANC <1000/mm³), discontinue asenapine and monitor WBC until recovery occurs.¹

Prolongation of QT Interval

Relatively small increases (2–5 msec with asenapine compared with placebo) in corrected QT (QT_c) interval observed in patients with schizophrenia in a controlled and dedicated QT study; these increases were slightly lower than those observed in patients receiving quetiapine.^{1 6 10} During clinical trials, post-baseline QT-interval prolongations >500 msec reported at similar rates for asenapine and placebo; torsades de pointes or adverse effects associated with delayed ventricular repolarization not reported.¹

Avoid use in patients concurrently receiving other drugs known to prolong the QT_c interval, in patients with a history of cardiac arrhythmias, and in other circumstances that may increase risk of torsades de pointes and/or sudden death (e.g., bradycardia, hypokalemia or hypomagnesemia, presence of congenital QT interval prolongation).¹ (See Drugs that Prolong QT Interval under Interactions.)

Hyperprolactinemia

May cause elevated serum prolactin concentrations, which may persist during chronic administration and cause clinical disturbances (e.g., galactorrhea, amenorrhea, gynecomastia, impotence); chronic hyperprolactinemia associated with hypogonadism may lead to decreased bone density.¹

If contemplating asenapine therapy in a patient with previously detected breast cancer, consider that approximately one-third of human breast cancers are prolactin-dependent in vitro.¹

Seizures

Seizures reported in 0.3% of asenapine-treated patients in schizophrenia and bipolar mania clinical trials.¹ Use with caution in patients with a history of seizures or conditions that may lower seizure threshold (e.g., dementia of the Alzheimer’s type); conditions that lower seizure threshold may be more prevalent in patients ≥65 years of age.¹

Cognitive and Motor Impairment

Somnolence, usually transient and with the highest incidence during the first week of therapy, reported in 13–24% of asenapine-treated patients in clinical trials.¹ (See Specific Drugs under Interactions and also see Advice to Patients.)

Body Temperature Regulation

Disruption of ability to regulate core body temperature possible with antipsychotic agents, including asenapine; ≤1% of asenapine-treated patients in clinical trials experienced adverse effects suggestive of body temperature increases (e.g., pyrexia, feeling hot).¹

Use appropriate caution in patients who will be experiencing conditions that may contribute to an elevation in core body temperature (e.g., strenuous exercise, extreme heat, concomitant use of agents with anticholinergic activity, dehydration).¹

Suicide

Attendant risk with psychotic illnesses and bipolar disorder; closely supervise high-risk patients.^{1 83} Prescribe in the smallest quantity consistent with good patient management to reduce risk of overdosage.¹

Dysphagia

Esophageal dysmotility and aspiration associated with the use of antipsychotic agents.¹ Dysphagia reported in 0.1% of asenapine-treated patients in clinical trials.¹

Aspiration pneumonia is a common cause of morbidity and mortality in geriatric patients, particularly in those with advanced Alzheimer’s dementia.¹ (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Concomitant Illnesses

Not adequately evaluated in patients with a recent history of MI or unstable cardiovascular disease.¹ Risk of orthostatic hypotension; use with caution in patients with cardiovascular disease.¹ (See Hemodynamic Effects under Cautions.)

Specific Populations

Pregnancy

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Category C.¹

Lactation

Distributes into milk in rats; not known whether distributes into human milk.¹ Caution if used in nursing women.¹ Manufacturer recommends avoiding breast-feeding.¹

Pediatric Use

Safety and effectiveness not established in pediatric patients <18 years of age.^{1 81}

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.¹ Risk of poorer tolerance and orthostasis; carefully monitor.¹

Geriatric patients with dementia-related psychosis treated with either conventional or atypical antipsychotic agents are at an increased risk of death;^{1 28 39 73 75} increased incidence of adverse cerebrovascular events also observed with certain atypical antipsychotic agents.^{1 74} (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning and also see Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions.)

Hepatic Impairment

Increased exposures observed in individuals with severe hepatic impairment.¹ Use not recommended in patients with severe hepatic impairment (Child-Pugh class C).¹ (See Hepatic Impairment under Dosage and Administration and also see Absorption: Special Populations, under Pharmacokinetics.)

Renal Impairment

Exposure was similar in individuals with varying degrees of renal impairment and those with normal renal function; dosage adjustment not required.¹ (See Absorption: Special Populations, under Pharmacokinetics and also see Elimination: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Patients with schizophrenia: somnolence (including sedation and hypersomnia),^{1 2 6 82} akathisia (including hyperkinesia),^{1 6 82} oral hypoesthesia.^{1 6 82}

Patients with bipolar disorder: somnolence (including sedation and hypersomnia),^{1 3 5 6 74 83} dizziness,^{1 3 5 6 74 83} extrapyramidal symptoms other than akathisia (e.g., dystonia, blepharospasm, torticollis, dyskinesia, tardive dyskinesia, muscle rigidity, parkinsonism, gait disturbance, masked facies, tremor),^{1 3 6 83} weight gain.^{1 3 6 83}

Interactions for Saphris

Metabolized mainly by direct glucuronidation by UGT1A4 and oxidative metabolism by CYP isoenzymes, principally by CYP1A2 and, to a lesser extent, by CYP3A4 and CYP2D6.^{1 3 6 7} Weakly inhibits CYP2D6; does not appear to induce CYP1A2 or CYP3A4.¹

Risks of using asenapine in combination with other drugs not extensively evaluated.¹

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Use caution if concurrently administered with known inhibitors or substrates of CYP2D6 or inhibitors of CYP1A2.^{1 7} (See Specific Drugs under Interactions.)

Drugs that Prolong QT Interval

Potential additive effect on QT-interval prolongation; avoid concomitant use of other drugs known to prolong QT_c interval,.^{1 10 76 77 79} (See Prolongation of QT Interval under Cautions.)

Hypotensive Agents and Drugs causing Bradycardia

May enhance hypotensive effects of certain antihypertensive agents and other drugs that can cause hypotension or bradycardia.¹ Use concomitantly with caution; consider monitoring orthostatic vital signs in such patients.¹ If hypotension develops, consider reducing dosage of asenapine.¹ (See Hemodynamic Effects under Cautions and also see Advice to Patients.)

Specific Drugs

Drug	Interaction	Comments
Alcohol	Possible additive CNS effects1	Avoid concomitant use1
Antiarrhythmics (class Ia and III; e.g., amiodarone, procainamide, quinidine, sotalol)	Increased risk of QT-interval prolongation1	Avoid concomitant use1
Anticholinergic agents	Possible disruption of body temperature regulation1	Use with caution1
Antipsychotic agents that prolong QT interval (e.g., chlorpromazine, haloperidol, olanzapine, paliperidone, pimozide, quetiapine, thioridazine, ziprasidone)	Increased risk of QT-interval prolongation1 76 77	Avoid concomitant use1
Carbamazepine	Carbamazepine decreased peak plasma asenapine concentrations and AUCs by 16%1 7	Asenapine dosage adjustment not required1
Cimetidine	Cimetidine decreased peak plasma concentrations of asenapine by 13% and slightly increased (by 1%) asenapine AUCs1 7	Asenapine dosage adjustment not required1
CNS agents	Possible additive CNS and respiratory depressant effects1	Use concomitantly with caution1
Fluvoxamine	Fluvoxamine increased peak plasma asenapine concentrations and AUCs by 13 and 29%, respectively; therapeutic fluvoxamine dosage may cause a greater increase in plasma asenapine concentrations1 7	Use concomitantly with caution1
Gatifloxacin	Increased risk of QT-interval prolongation1	Avoid concomitant use1
Hypotensive agents	Additive hypotensive effects1	Use concomitantly with caution;1 consider monitoring orthostatic vital signs and reducing asenapine dosage if hypotension develops1
Imipramine	Imipramine increased peak plasma asenapine concentrations and AUCs by 17 and 10%, respectively1 Asenapine did not affect plasma concentrations of imipramine’s metabolite, desipramine1 7	Asenapine dosage adjustment not required1
Moxifloxacin	Increased risk of QT-interval prolongation1	Avoid concomitant use1
Paroxetine	Concurrent administration of a single dose of paroxetine and multiple asenapine doses results in an almost twofold increase in paroxetine exposure1 7 Concomitant administration of paroxetine (20 mg once daily for 9 days) and a single 5-mg dose of asenapine decreased peak plasma asenapine concentrations and AUCs by 13 and 9%, respectively1 7	Use concomitantly with caution; asenapine dosage adjustment not required1
Smoking	Pharmacokinetic interaction unlikely1
Tetrabenazine	Increased risk of QT-interval prolongation79	Avoid concomitant use1 79
Valproic acid	Valproate increased peak plasma asenapine concentrations by 2% and decreased asenapine AUCs by 1% 1	Asenapine dosage adjustment not required1

Saphris Pharmacokinetics

Absorption

Bioavailability

Administered sublingually because of the low bioavailability (<2%) and extensive first-pass metabolism observed following oral administration of tablets.^{1 4 6 74}

Rapidly absorbed in the sublingual, supralingual, and buccal mucosa following sublingual administration; peak plasma concentrations occur within 0.5–1.5 hours.^{1 3 6 10 74}

Absolute bioavailability of sublingual tablets (5 mg) is 35%.^{1 3 74}

Steady-state plasma concentrations reached within 3 days with twice-daily administration.¹

Food and Water

Food ingestion immediately before or 4 hours after sublingual administration of a single 5-mg dose decreased exposure by 20 or 10%, respectively, probably due to increased hepatic blood flow.¹

Water intake 2 and 5 minutes following sublingual administration of asenapine 10 mg decreased exposure by 19 and 10%, respectively; effects of water intake 10 or 30 minutes after administration were equivalent.¹ (See Administration under Dosage and Administration.)

Special Populations

In individuals with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, exposure was 12% higher compared with those with normal hepatic function.¹ In individuals with severe hepatic impairment (Child-Pugh class C), exposures were an average of 7 times higher compared with individuals with normal hepatic function.¹

In individuals with varying degrees of renal impairment, exposure was similar to individuals with normal renal function.¹

In geriatric patients with psychosis, plasma concentrations were an average of 30–40% higher compared with younger individuals; highest exposure in geriatric patients was up to twofold higher.¹

Distribution

Extent

Rapidly distributed; large volume of distribution indicates extensive extravascular distribution.^{1 74}

Distributes into milk in rats; not known whether asenapine and/or its metabolites distribute into milk in humans.¹

Plasma Protein Binding

95% to plasma proteins (including albumin and α₁-acid glycoprotein).^{1 74}

Elimination

Metabolism

Metabolized mainly through direct glucuronidation by UGT1A4 and oxidative metabolism, primarily by CYP1A2 and, to a lesser extent, by CYP3A4 and CYP2D6.^{1 3 6 7}

Metabolites (primarily asenapine N-glucuronide, also N-desmethylasenapine and N-desmethylasenapine N-carbamoyl glucuronide) are largely inactive.^{1 3 7}

Elimination Route

Following administration of a single radiolabeled dose, about 90% of the dose was recovered; approximately 50% recovered in urine and 40% in feces.¹

Half-life

Terminal phase half-life (t_½β) averages about 24 hours.^{1 74}

Special Populations

Smoking does not affect clearance.¹

Effect of renal function on elimination of metabolites and effect of hemodialysis on pharmacokinetics not evaluated.¹

Decreased clearance observed with increasing age, suggesting a 30% higher exposure in geriatric patients compared with younger adult patients.¹

Stability

Storage

Sublingual

Tablets

15–30°C.¹

Actions

• 
  

  Exact mechanism of asenapine and other antipsychotic agents in schizophrenia and bipolar disorder unknown; efficacy in schizophrenia may be mediated through a combination of antagonist activity at central dopamine type 2 (D₂) and serotonin type 2 (5-hydroxytryptamine [5-HT_2A]) receptors.^{1 2 6 7 8 89}

  
  


• 
  

  Exhibits high affinity for serotonin 5-HT_1A, 5-HT_1B, 5-HT_2A, 5-HT_2B, 5-HT_2C, 5-HT₅, 5-HT₆, and 5-HT₇ receptors; dopamine D₁, D₂, D₃, and D₄ receptors; α₁- and α₂-adrenergic receptors; and histamine H₁ receptors (moderate affinity for H₂ receptors).^{1 2 3 6 7 8 9 74 85} Asenapine acts as an antagonist at these receptors in vitro.^{1 85}

  
  


• 
  

  Possesses no appreciable affinity for muscarinic cholinergic receptors^{1 2 3 6 7 8 9 74 85} or β-adrenergic receptors.⁷

  
  

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  Importance of advising patients and caregivers that elderly patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.^{1 28 39 73} Patients and caregivers also should be informed that asenapine is not approved for treating elderly patients with dementia-related psychosis.^{1 73}

  
  


• 
  

  Risk of somnolence (i.e., sleepiness, drowsiness).¹ Importance of advising patients to exercise caution when performing activities requiring mental alertness (e.g., driving, operating hazardous machinery) until they gain experience with the drug’s effects.

  
  


• 
  

  Importance of avoiding alcohol during asenapine therapy.¹

  
  


• 
  

  Importance of informing patients and caregivers about the risk of NMS, which can cause high fever, stiff muscles, sweating, fast or irregular heart beat, change in BP, and confusion.¹

  
  


• 
  

  Risk of orthostatic hypotension and syncope (fainting), especially early in treatment and at times of reinitiation of therapy or increases in dosage.¹ Importance of informing patients about interventions that may help (e.g., sitting on the edge of the bed for several minutes before standing in the morning, slowly rising from a seated position).¹

  
  


• 
  

  Importance of informing patients in whom chronic asenapine use is contemplated of risk of tardive dyskinesia.^{1 67} Importance of advising patients to report any muscle movements that cannot be stopped to a healthcare professional.⁶⁷

  
  


• 
  

  Importance of informing patients that oral hypoesthesia (numbing of the tongue) and/or dysgeusia (abnormal or altered taste) may occur and that these effects are not serious and are typically transient following sublingual administration.^{74 81 88}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular disease, diabetes mellitus, seizures).¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ Importance of advising patients not to breast-feed during asenapine therapy.¹

  
  


• 
  

  Importance of avoiding overheating or dehydration.¹

  
  


• 
  

  Importance of correctly taking sublingual tablets.¹ Do not remove sublingual tablet from the blister pack until just before administration.¹ With dry hands, pull blister pack out of case, peel back the colored tab on the pack, and gently remove the tablet.¹ Place the sublingual tablet under the tongue and allow to dissolve completely.¹ Importance of sliding the blister pack back into the case until it clicks after use.¹ Importance of not eating or drinking for 10 minutes following administration.^{1 74} (See Food and Water under Pharmacokinetics.)

  
  


• 
  

  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Asenapine Maleate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Sublingual	Tablets	5 mg (of asenapine)	Saphris	Merck
		10 mg (of asenapine)	Saphris	Merck

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Saphris 10MG Sublingual Tablets (ORGANON): 10/$114.00 or 60/$665.99

Saphris 5MG Sublingual Tablets (ORGANON): 60/$676.02 or 180/$1,885.96