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Asenapine

Pronunciation

(a SEN a peen)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet Sublingual, Sublingual:

Saphris: 2.5 mg [black cherry flavor]

Saphris: 5 mg

Saphris: 5 mg [black cherry flavor]

Saphris: 10 mg

Saphris: 10 mg [black cherry flavor]

Brand Names: U.S.

  • Saphris

Pharmacologic Category

  • Antimanic Agent
  • Second Generation (Atypical) Antipsychotic

Pharmacology

Asenapine is a dibenzo-oxepino pyrrole atypical antipsychotic with mixed serotonin-dopamine antagonist activity. It exhibits high affinity for 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5-7, D1-4, H1 and, alpha1- and alpha2-adrenergic receptors; moderate affinity for H2 receptors. Asenapine has no significant affinity for muscarinic receptors. The binding affinity to the D2 receptor is 19 times lower than the 5-HT2A affinity (Weber 2009). The addition of serotonin antagonism to dopamine antagonism (classic neuroleptic mechanism) is thought to improve negative symptoms of psychoses and reduce the incidence of extrapyramidal side effects as compared to typical antipsychotics.

Absorption

Rapid

Distribution

Vd: ~20-25 L/kg

Metabolism

Hepatic via CYP1A2 oxidation and UGT1A4 glucuronidation

Excretion

Urine (~50%); feces (~40%)

Time to Peak

0.5-1.5 hours

Half-Life Elimination

Terminal: ~24 hours

Protein Binding

95% (including albumin and α1-acid glycoprotein)

Special Populations: Hepatic Function Impairment

Severe hepatic impairment (Child-Pugh class C) exposure was 7 times higher than in healthy patients.

Special Populations: Elderly

Clearance is decreased, increasing exposure by 30% to 40%.

Use: Labeled Indications

Bipolar disorder: Treatment of acute manic or mixed episodes associated with bipolar I disorder (as monotherapy or adjunctive treatment with lithium or valproate)

Schizophrenia: Treatment of schizophrenia

Contraindications

Severe hepatic impairment (Child-Pugh class C); hypersensitivity to asenapine or any component of the formulation

Dosage

Sublingual: Note: Safety of doses >20 mg/day has not been evaluated:

Schizophrenia: Adults: Initial: 5 mg twice daily; may increase to 10 mg twice daily after 1 week based on tolerability; maximum dose: 10 mg twice daily. Daily doses ≥20 mg/day in clinical trials did not appear to offer any additional benefit and had an increased risk of adverse effects.

Bipolar disorder:

Children ≥10 years and Adolescents ≤17 years: Monotherapy: Initial: 2.5 mg twice daily; may increase dose after 3 days to 5 mg twice daily, then after an additional 3 days to 10 mg twice daily based on tolerability (pediatric patients appear to be more sensitive to dystonia with initial dosing when the escalation schedule is not followed); maximum dose: 10 mg twice daily.

Adults:

Monotherapy: Initial: 10 mg twice daily; decrease to 5 mg twice daily if dose not tolerated; maximum dose: 10 mg twice daily.

Combination therapy (with lithium or valproate): Initial: 5 mg twice daily; may increase to 10 mg twice daily based on tolerability; maximum dose: 10 mg twice daily.

Dosage adjustment in renal impairment: No dosage adjustment necessary.

Dosage adjustment in hepatic impairment:

Mild-to-moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe hepatic impairment (Child-Pugh class C): Use is contraindicated.

Administration

Sublingual tablets should be placed under the tongue and allowed to completely dissolve. Do not split, crush, chew, or swallow. Avoid eating or drinking for at least 10 minutes after administration.

Dietary Considerations

Avoid eating or drinking for at least 10 minutes after administration.

Storage

Store at 15°C to 30°C (59°F to 86°F).

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Monitor therapy

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Amisulpride: Antipsychotic Agents may enhance the adverse/toxic effect of Amisulpride. Avoid combination

Amphetamines: Antipsychotic Agents may diminish the stimulatory effect of Amphetamines. Monitor therapy

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Anti-Parkinson's Agents (Dopamine Agonist): Antipsychotic Agents (Second Generation [Atypical]) may diminish the therapeutic effect of Anti-Parkinson's Agents (Dopamine Agonist). Management: Consider using an alternative antipsychotic agent when possible in patients with Parkinson's disease. If an atypical antipsychotic is necessary, consider using clozapine or quetiapine, which may convey the lowest interaction risk. Consider therapy modification

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Monitor therapy

CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Monitor therapy

CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Consider therapy modification

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

FluvoxaMINE: May increase the serum concentration of Asenapine. Monitor therapy

Highest Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Highest Risk QTc-Prolonging Agents. Avoid combination

Hydrocodone: CNS Depressants may enhance the CNS depressant effect of Hydrocodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification

Ivabradine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Methylphenidate: Antipsychotic Agents may enhance the adverse/toxic effect of Methylphenidate. Methylphenidate may enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy

Metoclopramide: May enhance the adverse/toxic effect of Antipsychotic Agents. Avoid combination

Metyrosine: CNS Depressants may enhance the sedative effect of Metyrosine. Monitor therapy

Metyrosine: May enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy

Mifepristone: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

PARoxetine: May enhance the QTc-prolonging effect of Asenapine. Asenapine may increase the serum concentration of PARoxetine. Consider therapy modification

Peginterferon Alfa-2b: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Quinagolide: Antipsychotic Agents may diminish the therapeutic effect of Quinagolide. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Serotonin Modulators: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Sulpiride: Antipsychotic Agents may enhance the adverse/toxic effect of Sulpiride. Avoid combination

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

Teriflunomide: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Adverse Reactions

Actual frequency may be dependent upon dose and/or indication.

>10%:

Central nervous system: Drowsiness (13% to 24%), insomnia (6% to 16%), extrapyramidal reaction (6% to 12%), headache (12%), akathisia (4% to 11%; dose related), dizziness (3% to 11%)

Endocrine & metabolic: Hypertriglyceridemia (13% to 15%), weight gain (2% to 15%)

Neuromuscular and skeletal: Increased creatine phosphokinase (6% to 11%)

1% to 10%:

Cardiovascular: Peripheral edema (3%), hypertension (2% to 3%)

Central nervous system: Hypoesthesia (4% to 7%), anxiety (4%), fatigue (3% to 4%), taste disorder (3%), depression (2%), irritability (1% to 2%)

Endocrine & metabolic: Increased serum cholesterol (8% to 9%), increased serum glucose (5% to 7%), hyperprolactinemia (2% to 3%)

Gastrointestinal: Constipation (4% to 7%), vomiting (4% to 7%), increased appetite (≤4%), sialorrhea (≤4%), dyspepsia (3% to 4%), dysgeusia (3%), toothache (3%), abdominal distress (≤3%), xerostomia (1% to 3%)

Hepatic: Increased serum transaminases (<1% to 3%)

Neuromuscular & skeletal: Arthralgia (3%), limb pain (2%)

<1% (Limited to important or life-threatening): Accommodation disturbance, anaphylaxis, anemia, angioedema, application site reaction, bradycardia, bundle branch block (temporary), diabetes mellitus, dyskinesia, dysphagia, glossalgia, hyperglycemia, hypersensitivity, hyponatremia, hypotension, leukopenia, localized warm feeling, mucous membrane lesion, neuroleptic malignant syndrome, neutropenia, oral paresthesia, prolonged Q-T interval on ECG, seizure, skin rash, syncope, tachycardia, thrombocytopenia, tongue edema, wheezing

ALERT: U.S. Boxed Warning

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. Asenapine is not approved for the treatment of patients with dementia-related psychosis.

Warnings/Precautions

Concerns related to adverse reactions:

• Blood dyscrasias: Leukopenia, neutropenia, and agranulocytosis (sometimes fatal) have been reported with antipsychotic use; presence of risk factors (eg, preexisting low WBC or history of drug-induced leuko/neutropenia) should have a complete blood count performed frequently during the first few months of therapy. Discontinue therapy at first signs of blood dyscrasias or if absolute neutrophil count <1,000/mm3.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

• Dyslipidemia: Has been reported with atypical antipsychotics; risk profile may differ between agents. In clinical trials, the incidence of hypertriglyceridemia observed with asenapine was greater than that observed with placebo, while total cholesterol elevations were similar.

• Esophageal dysmotility/aspiration: Antipsychotic use has been associated with esophageal dysmotility, dysphagia, and aspiration; use with caution in patients at risk of aspiration pneumonia (eg, Alzheimer disease) (Maddalena 2004).

• Extrapyramidal symptoms (EPS): May cause EPS, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is generally much lower relative to typical/conventional antipsychotics). Risk of dystonia (and probably other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients. Factors associated with greater vulnerability to tardive dyskinesia include older in age, female gender combined with postmenopausal status, Parkinson disease, pseudoparkinsonism symptoms, affective disorders (particularly major depressive disorder), concurrent medical diseases such as diabetes, previous brain damage, alcoholism, poor treatment response, and use of high doses of antipsychotics (APA [Lehman 2004]; Soares-Weiser 2007).

• Hyperglycemia: Atypical antipsychotics have been associated with development of hyperglycemia; in some cases, may be extreme and associated with ketoacidosis, hyperosmolar coma, or death. All patients should be monitored for symptoms of hyperglycemia (eg, polydipsia, polyuria, polyphagia, weakness). Use with caution in patients with diabetes or other disorders of glucose regulation; monitor for worsening of glucose control. Patients with risk factors for diabetes (eg, obesity or family history) should have a baseline fasting blood sugar (FBS) and periodic assessment of glucose regulation.

• Hypersensitivity: Anaphylaxis and hypersensitivity reactions (eg, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing, and rash) have been reported; some cases have occurred after a single dose.

• Hyperprolactinemia: May increase prolactin levels; clinical significance of hyperprolactinemia in patients with breast cancer or other prolactin-dependent tumors is unknown.

• Neuroleptic malignant syndrome (NMS): Use may be associated with NMS; monitor for mental status changes, fever, muscle rigidity, and/or autonomic instability. NMS can recur. Following recovery from NMS, reintroduction of drug therapy should be carefully considered; if an antipsychotic agent is resumed, monitor closely for NMS.

• Orthostatic hypotension: May cause orthostatic hypotension and syncope; use with caution in patients at risk of this effect (eg, concurrent medication use which may predispose to hypotension/bradycardia or presence of dehydration or hypovolemia) or in those who would not tolerate transient hypotensive episodes. Use caution with history of cerebrovascular or cardiovascular disease (MI, heart failure, conduction abnormalities, or ischemic disease).

• QT prolongation: May result in QTc prolongation. Risk may be increased by conditions or concomitant medications which cause bradycardia, hypokalemia, and/or hypomagnesemia. Avoid use in combination with QTc-prolonging drugs and in patients with congenital long QT syndrome or patients with history of cardiac arrhythmia.

• Suicidal ideation: The possibility of a suicide attempt is inherent in psychotic illness or bipolar disorder; use with caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care.

• Temperature regulation: Antipsychotic use has been associated with impaired core body temperature regulation; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects (Kerwin 2004; Kowk 2005; Martinez 2002).

• Weight gain: Significant weight gain has been observed with antipsychotic therapy; incidence varies with product. Monitor waist circumference and BMI.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiac disease, cerebrovascular disease, hemodynamic instability, prior myocardial infarction, or ischemic heart disease.

• Dementia: [US Boxed Warning]: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Risk of death in drug-treated patients was 1.6 to 1.7 times greater than placebo-treated patients in analyses of placebo-controlled trials. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Asenapine is not approved for the treatment of dementia-related psychosis.

• Hepatic impairment: Use is contraindicated in patients with severe hepatic impairment (Child-Pugh class C); increased drug concentrations may occur.

• Parkinson disease: Use with caution in patients with Parkinson disease; patients may have increased risk of extrapyramidal side effects, including tardive dyskinesia (APA [Lehman 2004]; Soares-Weiser 2007).

• Seizures: Use with caution in patients at risk of seizures or conditions that potentially lower the seizure threshold (eg, Alzheimer dementia). Elderly patients may be at increased risk of seizures due to an increased prevalence of predisposing factors.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Pharmacokinetic studies showed a decrease in clearance in older adults (65 to 85 years of age) with psychosis compared to younger adults; increased risk of adverse effects and orthostasis may occur.

Monitoring Parameters

Mental status; vital signs (as clinically indicated); blood pressure and pulse (baseline; repeat 3 months after antipsychotic initiation, then yearly); weight, height, BMI, waist circumference (baseline; repeat at 4, 8, and 12 weeks after initiating or changing therapy, then quarterly; consider switching to a different antipsychotic for a weight gain more than 5% of initial weight [ADA 2004]); CBC (as clinically indicated; monitor frequently during the first few months of therapy in patients with preexisting low WBC or history of drug-induced leukopenia/neutropenia); electrolytes and liver function (annually and as clinically indicated); personal and family history of obesity, diabetes, dyslipidemia, hypertension, or cardiovascular disease (baseline; repeat annually); fasting plasma glucose level/HbA1c (baseline; repeat 3 months after starting antipsychotic, then yearly); fasting lipid panel (baseline; repeat 3 months after initiation of antipsychotic; if low-density lipoprotein level is normal, repeat at 2- to 5-year intervals or more frequently if clinical indicated [ADA 2004]); prolactin level (baseline [NICE 2014]); changes in menstruation, libido, development of galactorrhea, and erectile and ejaculatory function (yearly); abnormal involuntary movements or parkinsonian signs (baseline; repeat weekly until dose stabilized for at least 2 weeks after introduction and for 2 weeks after any significant dose increase); tardive dyskinesia (every 12 months; high-risk patients every 6 months); ocular examination (yearly in patients older than 40 years; every 2 years in younger patients) (ADA 2004; Lehman 2004; Marder 2004; NICE 2014).

Pregnancy Considerations

Antipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms [EPS]) and/or withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor; these effects may be self-limiting or require hospitalization; monitoring of the neonate is recommended. Asenapine may cause hyperprolactinemia, which may decrease reproductive function in both males and females.

The ACOG recommends that therapy during pregnancy be individualized; treatment with psychiatric medications during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary healthcare provider, and pediatrician. Safety data related to atypical antipsychotics during pregnancy is limited and routine use is not recommended. However, if a woman is inadvertently exposed to an atypical antipsychotic while pregnant, continuing therapy may be preferable to switching to a typical antipsychotic that the fetus has not yet been exposed to; consider risk:benefit (ACOG 2008).

Healthcare providers are encouraged to enroll women 18-45 years of age exposed to asenapine during pregnancy in the Atypical Antipsychotics Pregnancy Registry (866-961-2388 or http://www.womensmentalhealth.org/pregnancyregistry).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, headache, agitation, vomiting, numbness or tingling of mouth, weight gain, insomnia, or constipation. Have patient report immediately to prescriber signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of depression (suicidal ideation, anxiety, emotional instability, illogical thinking), arrhythmia, bradycardia, tachycardia, shortness of breath, severe dizziness, passing out, abnormal movements, twitching, change in balance, dysphagia, difficulty speaking, menstrual irregularities, enlarged breasts, nipple discharge, sexual dysfunction, mouth pain or sores, seizures, signs of neuroleptic malignant syndrome (fever, muscle cramps or stiffness, dizziness, very bad headache, confusion, change in thinking, fast heartbeat, abnormal heartbeat, or sweating a lot), or signs of tardive dyskinesia (unable to control body movements; tongue, face, mouth, or jaw sticking out; mouth puckering; and puffing cheeks) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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