asenapine

General Information

Asenapine (brand Saphris sublingual tablets; Secuado transdermal system) is a second-generation (atypical) antipsychotic formulated to avoid extensive first-pass metabolism and provide rapid absorption.

This profile focuses on its use in schizophrenia and bipolar I disorder; U.S. approvals include schizophrenia in adults (sublingual 2009, transdermal 2019) and acute manic or mixed episodes in adults and pediatric patients ≥10 years, as monotherapy or adjunct to lithium/valproate.

The compare view to weigh sedation, metabolic effects, and formulation logistics against alternative SGAs when tailoring adherence strategies.

Asenapine-focused evidence summaries can be reviewed alongside mood-stabiliser planning via the bipolar disorder hub or adherence workflows through the schizophrenia hub.

Sublingual tablets can cause oral numbness and require avoiding food or drink for 10 minutes after dosing. The patch can be helpful when swallowing is unreliable or when a patient declines LAIs, but cost and skin reactions can be limiting.

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Asenapine exerts multi-receptor antagonism with high affinity for serotonergic and dopaminergic targets, stabilizing mesolimbic dopamine while modulating cortical serotonin pathways.

Strong 5-HT2A/5-HT2C antagonism coupled with D2/D3/D4 blockade underpins efficacy in psychosis and mania, while α1 and H1 antagonism explains orthostasis and sedation; minimal muscarinic activity keeps anticholinergic effects low.

• Potent antagonist at serotonin 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors.
• High-affinity antagonist at dopamine D2, D3, and D4 receptors with moderately rapid dissociation.
• Antagonist at adrenergic α1 and histamine H1 receptors.
• Negligible muscarinic receptor binding.

Metabolism and Pharmacokinetics

• Sublingual bioavailability ≈35%; swallowing reduces exposure to <2%; Tmax 0.5–1 hour (sublingual) and 12–24 hours for the transdermal system.
• Approximately 95% protein bound with large apparent distribution (~20–25 L/kg).
• Metabolized hepatically via UGT1A4 and CYP1A2 (minor CYP2D6/CYP3A4 contributions); metabolites are largely inactive.
• Terminal half-life ~24 hours after sublingual dosing; effective half-life for patch ~30 hours; smoking (CYP1A2 induction) may reduce exposure ~20%.
• Excreted ~50% in feces and ~40% in urine predominantly as metabolites.

Dosing and Administration

• Schizophrenia (adults): initiate 5 mg sublingually twice daily; increase to 10 mg twice daily based on response; patch initiation 3.8 mg/24 h once daily with titration to 5.7–7.6 mg/24 h.
• Bipolar I acute manic/mixed episodes (adults): start 10 mg sublingually twice daily on day 1, then 5–10 mg twice daily; adjunct dosing with lithium/valproate mirrors monotherapy.
• Pediatric bipolar I (≥10 years): initiate 2.5 mg twice daily; titrate by 2.5–5 mg to a maximum 10 mg twice daily.
• Therapeutic drug monitoring is not routinely recommended; serum levels have not correlated with efficacy.
• Counsel sublingual users to avoid food or drink for 10 minutes after dosing; instruct patch users to rotate application sites and secure edges to maintain adhesion.

Adverse Effects

Interactions

• Strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin) raise concentrations—monitor for sedation and EPS; dose reduction may be needed.
• CYP1A2 inducers, including cigarette smoking and carbamazepine, lower exposure—monitor efficacy and adjust dose within labeling limits.
• Potent enzyme inducers affecting UGT pathways (e.g., rifampin) can reduce levels; consider alternatives or monitor closely.
• Additive CNS depression with benzodiazepines, opioids, alcohol, or antihistamines.
• May antagonize effects of levodopa and dopamine agonists; avoid coadministration in Parkinson’s disease when possible.

Other Useful Information

• Store sublingual tablets in original blister packaging; handle with dry hands and allow to dissolve fully under the tongue.
• Oral numbness usually resolves within an hour; severe dysesthesia, swelling, or signs of hypersensitivity warrant urgent evaluation.
• Rotate patch sites daily (upper arm, abdomen, hip, back) and inspect for erythema; mild application-site reactions occur in <10%.
• Weight, fasting lipids, and glucose are typically monitored periodically despite relatively modest metabolic liability.
• Changes in smoking status can alter plasma exposure through CYP1A2 induction or cessation; dosing may need reassessment when tobacco use changes.
• Consider baseline and follow-up ECGs in patients with cardiac risk factors or concomitant QT-prolonging regimens.
• The asenapine compare view, evidence feed, and printable counseling sheets via the asenapine print page can support longitudinal adherence discussions across visits.

References

1. SAPHRIS (asenapine) prescribing information — DailyMed (2024)
2. SECUADO (asenapine transdermal system) prescribing information — DailyMed (2024)
3. A 3 Week, Randomized, Placebo Controlled Trial OF Asenapine IN THE Treatment OF Acute Mania IN Bipolar I Disorder — Bipolar Disorders (2009)
4. Asenapine review, part II: clinical efficacy, safety and tolerability — Expert Opinion on Drug Safety (2014)
5. AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology — Pharmacopsychiatry (2018)