Asenapine

Indications

• Schizophrenia in adults, for acute treatment and for maintenance, using the sublingual tablet or the Secuado transdermal patch.
• Acute manic or mixed episodes of bipolar I disorder in adults as monotherapy or as adjunct to lithium or valproate.
• Acute manic or mixed episodes of bipolar I disorder in pediatric patients ages 10-17 as monotherapy, with a slower titration schedule.
• Secuado is a once-daily transdermal system approved only for schizophrenia in adults, useful when sublingual dosing is not tolerated.
• Off-label use includes patients who cannot swallow tablets reliably or where covert nonadherence to oral therapy is suspected.

Mechanism of action

• High-affinity antagonist across dopamine D2, D3, and D4 receptors and multiple serotonin receptors, giving an unusually broad profile.
• Very potent 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 antagonism may contribute to effects on mood, negative symptoms, and cognition.
• Alpha-1 and alpha-2 adrenergic blockade produces orthostatic hypotension and dizziness, especially during the first week.
• Histamine H1 affinity is high and drives sedation and appetite, while muscarinic affinity is negligible so anticholinergic effects are minimal.
• Local anesthetic action on the oral mucosa explains the oral hypoesthesia and altered taste that patients report immediately after dosing.

Pharmacokinetics

• Sublingual bioavailability is about 35 percent, but falls below 2 percent if the tablet is swallowed, so route counts as part of the dose.
• Patients must not eat or drink for 10 minutes after dosing, since water within that window markedly reduces absorption.
• Cleared by direct UGT1A4 glucuronidation and by CYP1A2 oxidation, with asenapine itself a moderate CYP2D6 inhibitor.
• Terminal half-life is about 24 hours but twice-daily dosing is required because of the mucosal absorption profile.
• Exposure rises about sevenfold in severe hepatic impairment, which makes Child-Pugh class C an outright contraindication.

Dosing

• Schizophrenia in adults: 5 mg sublingually twice daily, which may be increased to 10 mg twice daily after one week if needed.
• Bipolar mania monotherapy in adults: start 10 mg sublingually twice daily and reduce to 5 mg twice daily if tolerability is a problem.
• As adjunct to lithium or valproate, start at 5 mg twice daily and increase to 10 mg twice daily based on response and tolerability.
• Pediatric bipolar mania ages 10-17: start 2.5 mg twice daily, increase to 5 mg twice daily after 3 days, then to 10 mg twice daily after 3 more.
• Secuado transdermal is 3.8 mg per 24 hours, increased to 5.7 or 7.6 mg per 24 hours after at least one week, applied to intact skin.
• Contraindicated in severe hepatic impairment; no adjustment is required for renal impairment, and taper gradually when stopping.

Adverse effects

• Oral hypoesthesia, tongue numbness, and altered taste occur in about 5-25 percent and are the most common reason patients stop the drug.
• Somnolence, dizziness, and akathisia are common and dose related, with akathisia more frequent at 10 mg twice daily than at 5 mg.
• Weight gain is intermediate, generally less than olanzapine or quetiapine but more than lurasidone or ziprasidone.
• Extrapyramidal symptoms and modest prolactin elevation occur, and oral ulceration or blistering has been reported at the application site.
• Serious hypersensitivity including anaphylaxis, angioedema, and hypotension is specifically labeled and can occur after the first dose.

Monitoring

• Weight, BMI, blood pressure, fasting glucose or A1c, and lipids at baseline, at 12 weeks, and annually thereafter.
• Inspect the oral mucosa at follow-up visits for ulceration, blistering, or persistent numbness that would justify switching to the patch.
• Assess orthostatic vital signs during the first week, particularly in older adults and in patients on antihypertensives.
• AIMS examination at baseline and every 6-12 months, with specific attention to akathisia at each visit in the first month.
• Check liver function before starting, since severe hepatic impairment contraindicates the drug entirely.

Interactions

• Asenapine is a moderate CYP2D6 inhibitor and can roughly double paroxetine exposure, so reduce the paroxetine dose when combining.
• Fluvoxamine inhibits CYP1A2 and raises asenapine levels; smoking induces CYP1A2 but has limited clinical effect on this drug.
• Additive orthostatic hypotension with antihypertensives and additive sedation with opioids, benzodiazepines, and alcohol.
• Modest QT prolongation is additive with Class IA and III antiarrhythmics, methadone, and macrolide antibiotics.
• Contraindicated in severe hepatic impairment and in patients with known hypersensitivity to asenapine or its excipients.

Special populations

• Third-trimester exposure carries the class risk of neonatal extrapyramidal and withdrawal signs; human pregnancy data remain limited.
• Lactation data are sparse, so monitor breastfed infants for sedation and consider better-characterized agents where possible.
• Approved from age 10 for bipolar mania, where the stepwise titration exists specifically to limit sedation and dystonia.
• In older adults expect more orthostasis and sedation, and note that clearance is roughly 30 percent lower than in younger adults.
• No renal adjustment is needed, but Child-Pugh class C hepatic impairment is a contraindication rather than a dose reduction.

Clinical pearls

• Sublingual only: swallowed tablets deliver under 2 percent of the dose and simply do not work.
• No food or drink for 10 minutes after dosing, which is the instruction patients most often forget.
• Consider the Secuado patch when oral numbness rather than efficacy is the reason for failure.