Asenapine Maleate

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

Schizophrenia

Acute and maintenance treatment of schizophrenia in adults.1 2 4 82 84 88 89 93

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 as monotherapy or adjunctive therapy with lithium or valproate of manic or mixed episodes associated with bipolar I disorder (with or without psychotic features) in adults.1 3 5 74 94

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

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

Adults

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

For maintenance treatment, recommended initial dosage is 5 mg twice daily for 1 week.1 May increase to recommended target dosage of 10 mg twice daily after 1 week based on tolerability.1

Optimum duration of therapy not known.1 28 If used for an extended time, 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

Monotherapy: Initially, 10 mg twice daily.1 3 83 May decrease dosage to 5 mg twice daily if adverse effects occur or based on individual tolerability.1 Safety of dosages >10 mg twice daily not evaluated.1

Adjunctive therapy with lithium or valproate: Initially, 5 mg twice daily.1 May increase dosage to 10 mg twice daily based on clinical response and tolerability.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

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

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 95

Mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment: Dosage adjustment not necessary.1 7 95 (See Absorption: Special Populations, under Pharmacokinetics.)

Renal Impairment

Routine dosage adjustment not required.1 7 95 (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, Absorption: Special Populations, under Pharmacokinetics, and also see Elimination: Special Populations, under Pharmacokinetics.)

Gender or Race

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

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 drugs that are both substrates and inhibitors of CYP2D6 or that are 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 QTc 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

• 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 serious allergic reactions.1 96 Importance of informing patients of signs and symptoms of such reactions (e.g., difficulty breathing; swelling of the face, tongue, or throat; lightheadedness; itching) and to immediately seek emergency medical attention if they develop.1 96

• Importance of informing patients that application site reactions (e.g., oral ulcers, blisters, peeling/sloughing, inflammation), primarily in the sublingual area, have been reported.1 Instruct patients to monitor for such reactions during therapy.1

• 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.1

• 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

• Importance of patients being aware of the symptoms of hyperglycemia and diabetes mellitus (e.g., increased thirst, increased urination, increased appetite, weakness).1 Importance of informing patients with diabetes, those with risk factors for diabetes, and those who develop hyperglycemia symptoms during treatment that they should have their blood glucose monitored at the beginning of and periodically during asenapine treatment.1

• Risk of weight gain.1 Importance of patients being aware of need to monitor their weight during therapy.1

• Risk of orthostatic hypotension and syncope (fainting), especially when initiating or reinitiating treatment or increasing the 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

• Risk of leukopenia/neutropenia.1 Importance of advising patients with a preexisting low WBC count or history of drug-induced leukopenia/neutropenia that their CBC count should be monitored during asenapine therapy.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, oral paresthesia, and/or dysgeusia (abnormal or altered taste) may occur and that these effects are not serious and are typically transient (i.e., resolving within 1 hour) following sublingual administration.1 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 92 Importance of clinicians informing patients about the benefits and risks of taking antipsychotics during pregnancy (see Pregnancy under Cautions).1 92 Importance of advising patients not to stop taking asenapine if they become pregnant without consulting their clinician; abruptly discontinuing antipsychotic agents may cause complications.92 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.)