Version July 2025
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.
Dosage guidance:
Safety: Antipsychotics are not indicated for use in catatonia and may worsen psychosis and increase risk for neuroleptic malignant syndrome in patients with catatonia (Ref).
Dosage form information: The transdermal patch that administers 3.8 mg per 24 hours provides similar drug exposure as the sublingual product at a dose of 5 mg twice daily, and the transdermal patch that administers 7.6 mg per 24 hours provides similar drug exposure as the sublingual product at a dose of 10 mg twice daily.
Clinical considerations: Consult a psychiatry specialist for all management decisions; select antipsychotic carefully based on patient preference, clinical characteristics, history, comorbidities, and adverse effect profile (Ref).
Agitation/aggression (severe, acute) associated with psychiatric disorders (eg, bipolar disorder, schizophrenia), substance intoxication, or other organic causes (alternative agent) (off-label use):
Note: Antipsychotics are appropriate when psychosis is suspected to be the primary cause of agitation/aggression. Other agents are used preferentially in some intoxications (eg, stimulants) or alcohol withdrawal. Depending on presentation, may combine with a benzodiazepine (Ref).
Sublingual: 10 mg as a single dose (Ref).
Bipolar disorder:
Acute mania or episodes with mixed features:
Monotherapy: Sublingual: Initial: 5 to 10 mg twice daily; maximum dose: 10 mg twice daily.
Adjunctive therapy (with lithium or valproate): Sublingual: Initial: 5 mg twice daily; may increase to 10 mg twice daily based on response and tolerability; maximum dose: 10 mg twice daily.
Maintenance: Monotherapy: Sublingual: Continue with acute episode dose; decrease to 5 mg twice daily based on response and tolerability; maximum dose: 10 mg twice daily.
Schizophrenia:
Sublingual: Initial: 10 mg/day in 2 divided doses, or if this is a first episode of psychosis, consider initiating at a reduced dose (eg, 5 mg/day in divided doses) because these patients will be more sensitive to adverse effects. After 1 week, may increase daily dose to 20 mg/day in 2 divided doses if needed based on response and tolerability; although manufacturer suggests waiting 1 week before increasing dose, some experts increase after ≥3 days if needed. Monitor for akathisia and sedation during titration. Usual dose range: 10 to 20 mg/day; maximum dose: 20 mg/day (Ref).
Transdermal patch: Initial: Apply 3.8 mg per 24 hours patch once daily. May adjust dose to another dosage strength (up to 7.6 mg per 24 hours) in weekly intervals if needed based on response and tolerability (Ref).
Discontinuation of therapy: In the treatment of chronic psychiatric disease switching therapy rather than discontinuation is generally advised if side effects are intolerable or treatment is not effective. If patient insists on stopping treatment, gradual dose reduction (ie, over several weeks to months) is advised to detect a re-emergence of symptoms and to avoid withdrawal reactions (eg, agitation, alternating feelings of warmth and chill, anxiety, diaphoresis, dyskinesias, GI symptoms, insomnia, irritability, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor, vertigo) unless discontinuation is due to significant adverse effects. Monitor closely to allow for detection of prodromal symptoms of disease recurrence (Ref).
Switching antipsychotics: An optimal universal strategy for switching antipsychotic drugs has not been established. Strategies include: Cross-titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic) and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). In patients with schizophrenia at high risk of relapse, the current medication may be maintained at full dose as the new medication is increased (eg, overlap); once the new medication is at therapeutic dose, the first medication is gradually decreased and discontinued over 1 to 2 weeks (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
No dosage adjustment necessary.
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.
Note: Avoid for behavioral problems associated with dementia or delirium unless alternative nonpharmacologic therapies have failed and patient may harm self or others. If used, consider deprescribing attempts to assess continued need and/or lowest effective dose. Of note, use in certain indications may be appropriate (eg, schizophrenia, bipolar disorder) (Ref). Consult a psychiatry specialist for all management decisions (Ref).
All indications: Refer to adult dosing. Dosages in the lower range of recommended adult dosing are generally sufficient with late-onset schizophrenia and psychosis. Titrate dosage slowly and monitor carefully (Ref).
(For additional information see "Asenapine: Pediatric drug information")
Bipolar disorder: Acute mania or episodes with mixed features ; monotherapy: Children ≥10 years and Adolescents ≤17 years: Sublingual: Initial: 2.5 mg twice daily; may titrate after 3 days to 5 mg twice daily, then after an additional 3 days to 10 mg twice daily based on tolerability; recommended daily dose range: 5 to 20 mg/day in 2 divided doses; maximum dose: 10 mg twice daily (20 mg/day).
Discontinuation of therapy: Similar to adult experience, the American Academy of Child and Adolescent Psychiatry (AACAP) guidelines recommend gradually tapering antipsychotics to avoid withdrawal symptoms (eg, insomnia, headache, GI symptoms) and minimize the risk of relapse unless discontinuation is due to significant adverse effects (Ref). In adults, decreasing the dose very gradually over weeks to months (eg, reducing the dose by 10% per month) with close monitoring is suggested to allow for detection of prodromal symptoms of disease recurrence (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Children ≥10 years and Adolescents:
Mild to severe impairment: No dosage adjustment necessary; asenapine exposure was similar to subjects with normal renal function; the effect of metabolite exposure with renal impairment has not been studied.
Dialysis: Has not been studied.
Children ≥10 years and Adolescents:
Mild to moderate hepatic impairment: No dosage adjustment necessary.
Severe hepatic impairment: Use is contraindicated.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Actual frequency may be dependent upon dose and/or indication.
>10%:
Central nervous system: Drowsiness (children and adolescents: 46% to 53%; adults: 3% to 26%;), insomnia (adults: 15% to 16%; children and adolescents: 4%), akathisia (adults: 4% to 15%; children and adolescents: 1% to 2%), fatigue (4% to 14%), extrapyramidal reaction (adults: 8% to 13%; children and adolescents: 1% to 2%), headache (8% to 11%)
Endocrine & metabolic: Weight gain (adults: 1% to 22%; children and adolescents: 2% to 12%), increased serum triglycerides (adults: 3% to 18%; children and adolescents: 2% to 4%), increased serum glucose (adults: 3% to 16%; children and adolescents: 2%), decreased HDL cholesterol (6% to 15%), increased serum cholesterol (adults: 2% to 14%)
Gastrointestinal: Oral hypoesthesia (5% to 30%)
Local: Application site reaction (transdermal: 14% to 15%)
Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen (adults: 11%)
1% to 10%:
Cardiovascular: Hypertension (adults: 2% to 3%), tachycardia (1% to 3%), orthostatic hypotension (2%), syncope (≤1%)
Central nervous system: Dizziness (5% to 10%), bipolar mood disorder (exacerbation; adults: ≤8%), mania (adults: ≤8%), agitation (adults: 3% to 4%), suicidal ideation (children and adolescents: 3% to 4%), anxiety (adults: 3%), dystonia (1% to 3%), outbursts of anger (children and adolescents: 2%), drug-induced Parkinson's disease (children and adolescents: 1% to 2%), irritability (1% to 2%), disruption of body temperature regulation (≤1%)
Dermatologic: Skin rash (children and adolescents: 2%)
Endocrine & metabolic: Increased serum prolactin (2% to 3%), dehydration (children and adolescents: 2%), increased LDL cholesterol (1%)
Gastrointestinal: Increased appetite (2% to 10%), abdominal pain (children and adolescents: 9%; adults: 2% to 3%), dysgeusia (3% to 9%), constipation (adults: 3% to 7%), vomiting (3% to 7%), nausea (4% to 6%), sialorrhea (adults: ≤4%), diarrhea (3%), dyspepsia (adults: 3%), stomach discomfort (adults: 2% to 3%), toothache (adults: 2% to 3%), xerostomia (adults: 2% to 3%), hyperinsulinism (children and adolescents: 1% to 3%), glossalgia (children and adolescents: 2%)
Genitourinary: Dysmenorrhea (≤2%), galactorrhea not associated with childbirth (≤2%)
Hepatic: Increased serum transaminases (adults: 2% to 3%), increased serum alanine aminotransferase (1% to 3%), increased liver enzymes (2%), increased serum aspartate aminotransferase (children and adolescents: 2%)
Local: Application site erythema (transdermal: 9% to 10%), application-site pruritus (transdermal: 4% to 5%)
Neuromuscular & skeletal: Arthralgia (adults: 2%), muscle strain (children and adolescents: 2%), myalgia (1% to 2%), asthenia (<2%)
Respiratory: Nasopharyngitis (adults: 3% to 5%), oropharyngeal pain (children and adolescents: 3%), upper respiratory tract infection (3%), dyspnea (children and adolescents: 2%), nasal congestion (children and adolescents: 2%)
Miscellaneous: Fever (≤1%)
Frequency not defined:
Cardiovascular: Prolonged QT interval on ECG
Central nervous system: Altered mental status, falling, neuroleptic malignant syndrome, tardive dyskinesia
Gastrointestinal: Oral paresthesia, swollen tongue
<1%, postmarketing, and/or case reports: Accommodation disturbance, anaphylaxis, anemia, angioedema, application site irritation, blurred vision, bundle branch block (temporary), choking sensation, diabetes mellitus, diplopia, dysarthria, dyslipidemia, dysphagia, exfoliation of skin (sublingual: oral mucosal), gastroesophageal reflux disease, hyperpigmentation, hypersensitivity reaction, hyponatremia, hypotension, leukopenia, neutropenia, oral inflammation (sublingual), oral mucosal ulcer (sublingual), oropharyngeal blister (sublingual), seizure, skin photosensitivity, thrombocytopenia, urinary incontinence, wheezing
Severe hepatic impairment (Child-Pugh class C); hypersensitivity to asenapine or any component of the formulation (eg, anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing, rash)
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. Compared to other antipsychotics, the risk of dyslipidemia with asenapine is minimal to low (Solmi 2017).
• Esophageal dysmotility/aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; risk increases with age. Use with caution in patients at risk for aspiration pneumonia (eg, Alzheimer disease), particularly in patients >75 years (Herzig 2017; Maddalena 2004).
• Extrapyramidal symptoms: May cause extrapyramidal symptoms (EPS), including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is generally much lower relative to typical/conventional antipsychotics; frequencies reported are similar to placebo). 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 [Keepers 2020]; Soares-Weiser 2007). Consider therapy discontinuation with signs/symptoms of tardive dyskinesia.
• Falls: May increase the risk for falls due to somnolence, orthostatic hypotension, and motor or sensory instability.
• 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, family history) should have a baseline fasting blood sugar and periodic assessment of glucose regulation. Compared to other antipsychotics, the risk of hyperglycemia with asenapine is minimal to low (Solmi 2017).
• Hypersensitivity: Anaphylaxis and hypersensitivity reactions (eg, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing, 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: Use may be associated with neuroleptic malignant syndrome (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 (myocardial infarction [MI], heart failure [HF], 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; Kwok 2005; Martinez 2002).
• Weight gain: Significant weight gain has been observed with antipsychotic therapy; incidence varies with product. Compared to other antipsychotics, the risk of weight gain with asenapine is low (Solmi 2017). Monitor waist circumference and BMI.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with cardiac disease, cerebrovascular disease, hemodynamic instability, prior MI, 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. Most deaths appeared to be either cardiovascular (eg, HF, sudden death) or infectious (eg, pneumonia) in nature. Use with caution in patients with Lewy body dementia or Parkinson disease dementia due to greater risk of adverse effects, increased sensitivity to extrapyramidal effects, and association with irreversible cognitive decompensation or death (APA [Reus 2016]). 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.
• 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.
Special populations:
• Older adult: 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.
• Pediatric: Pediatric patients may be more sensitive to dystonia with initial dosing and when the recommended dosing escalation schedule is not followed.
Dosage form specific issues:
• Transdermal patch: To properly dispose of transdermal patch, fold it over on itself and dispose of in trash. Avoid exposure of application site and surrounding area to direct external heat sources (eg, electric blankets, hair dryers, heated water beds, heating pads). Asenapine release from the patch increases with prolonged application of heat. Application-site reactions, including erythema, hyperpigmentation, and pruritus, have been observed with use; increased skin irritation may occur if patch is left in place for >24 hours or if same application site is used repeatedly.
Other warnings/precautions:
• Discontinuation of therapy: When discontinuing antipsychotic therapy, gradually taper antipsychotics to avoid withdrawal symptoms and rebound symptoms (APA [Keepers 2020]; WFSBP [Hasan 2012]). Withdrawal symptoms may include agitation, alternate feelings of warmth and cold, anxiety, diaphoresis, dyskinesia, insomnia, irritability, GI symptoms, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor, and vertigo (Lambert 2007; Moncrieff 2020). The risk of withdrawal symptoms is highest following abrupt discontinuation of highly anticholinergic or dopaminergic antipsychotics (Cerovecki 2013). Patients with chronic symptoms, repeated relapses, and clear diagnostic features of schizophrenia are at risk for poor outcomes if medications are discontinued (APA [Keepers 2020]).
Use with caution in children and adolescents; elevated prolactin levels have been observed; long-term effects on growth or sexual maturation have not been evaluated. Similar to adult experience, the American Academy of Child and Adolescent Psychiatry (AACAP) guidelines recommend gradually tapering antipsychotics to avoid withdrawal symptoms and minimize the risk of relapse (AACAP [McClellan 2007]).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Patch 24 Hour, Transdermal:
Secuado: 3.8 mg/24 hr (1 ea, 30 ea); 5.7 mg/24 hr (1 ea, 30 ea); 7.6 mg/24 hr (1 ea, 30 ea)
Tablet Sublingual, Sublingual:
Saphris: 2.5 mg, 5 mg, 10 mg [black cherry flavor]
Generic: 2.5 mg, 5 mg, 10 mg
May be product dependent
Patch, 24-hour (Secuado Transdermal)
3.8 mg/24 hrs (per each): $58.45
5.7 mg/24 hrs (per each): $58.45
7.6 mg/24 hrs (per each): $58.45
Sublingual (Asenapine Maleate Sublingual)
2.5 mg (per each): $21.60 - $21.61
5 mg (per each): $21.61 - $22.52
10 mg (per each): $21.61 - $22.52
Sublingual (Saphris Sublingual)
2.5 mg (per each): $25.22
5 mg (per each): $24.01
10 mg (per each): $25.22
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet Sublingual, Sublingual:
Saphris: 5 mg, 10 mg
Sublingual: 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.
Transdermal: Do not open pouch until ready to apply a patch. Apply 1 patch daily to clean, dry, intact skin of the upper arm, upper back, abdomen, or hip and leave on for only 24 hours. Wear only 1 patch at a time and do not use the same application site 2 times in a row. Do not cut patches. If application-site reaction (irritation, burning) occurs, remove patch and apply a new patch at a new application site. May shower while wearing patch but avoid swimming, bathing. Avoid placing external heat sources (eg, heating pad, hair dryer, electric blanket, heated water bed) on the patch. Discard by folding the used patch so that the adhesive side sticks to itself. See manufacturer's labeling for further administration instructions.
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.
Bipolar disorder (sublingual tablet only): Treatment of acute mania or episodes with mixed features associated with bipolar I disorder (as monotherapy in adult and pediatric patients ≥10 years of age or adjunctive treatment with lithium or valproate in adults) and maintenance treatment in adults (as monotherapy).
Schizophrenia (transdermal patch, sublingual tablet): Treatment of adults with schizophrenia.
Agitation/aggression (severe, acute) associated with psychiatric disorders (eg, bipolar disorder, schizophrenia), substance intoxication, or other organic causes
Beers Criteria: Antipsychotics are identified in the Beers Criteria as potentially inappropriate medications to be avoided in patients 65 years and older due to an increased risk of stroke and a greater rate of cognitive decline and mortality in patients with dementia. Evidence also suggests there may be an increased risk of mortality with use independent of dementia. Avoid antipsychotics for behavioral problems associated with dementia or delirium unless alternative nonpharmacologic therapies have failed and patient may harm self or others. In addition, antipsychotics should be used with caution in older adults due to their potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium closely with initiation or dosage adjustments in older adults. Use may be appropriate for labeled indications, including schizophrenia, bipolar disorder, Parkinson disease psychosis, adjunctive therapy in major depressive disorder, or for short-term use as an antiemetic (Beers Criteria [AGS 2023]).
Substrate of CYP1A2 (Major with inhibitors), CYP1A2 (Minor with inducers), CYP2D6 (Minor), CYP3A4 (Minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2D6 (Weak);
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Acrivastine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Agents With Seizure Threshold Lowering Potential: May increase adverse/toxic effects of Asenapine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Alcohol (Ethyl): CNS Depressants may increase CNS depressant effects of Alcohol (Ethyl). Risk C: Monitor
Alizapride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Amifampridine: Agents With Seizure Threshold Lowering Potential may increase neuroexcitatory and/or seizure-potentiating effects of Amifampridine. Risk C: Monitor
Amisulpride (Oral): Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Amisulpride (Oral). Specifically, the risk of seizures may be increased. Risk C: Monitor
Amisulpride (Oral): May increase adverse/toxic effects of Antipsychotic Agents. Specifically, the risk of neuroleptic malignant syndrome or increased QTc interval may be increased. Risk C: Monitor
Amisulpride (Oral): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Anti-Parkinson Agents (Dopamine Agonist): Antipsychotic Agents (Second Generation [Atypical]) may decrease therapeutic effects of Anti-Parkinson Agents (Dopamine Agonist). Management: Consider avoiding atypical antipsychotic use in patients with Parkinson disease. If an atypical antipsychotic is necessary, consider using clozapine, quetiapine, or ziprasidone at lower initial doses, or a non-dopamine antagonist (eg, pimavanserin). Risk D: Consider Therapy Modification
Antidiabetic Agents: Hyperglycemia-Associated Agents may decrease therapeutic effects of Antidiabetic Agents. Risk C: Monitor
ARIPiprazole Lauroxil: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of ARIPiprazole Lauroxil. Specifically, the risk of seizures may be increased. Risk C: Monitor
ARIPiprazole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of ARIPiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor
Articaine: May increase CNS depressant effects of CNS Depressants. Management: Consider reducing the dose of articaine if possible when used in patients who are also receiving CNS depressants. Monitor for excessive CNS depressant effects with any combined use. Risk D: Consider Therapy Modification
Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Benperidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Benperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor
Benperidol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Benzgalantamine-Galantamine: May increase neurotoxic (central) effects of Antipsychotic Agents. Risk C: Monitor
Blonanserin: CNS Depressants may increase CNS depressant effects of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider Therapy Modification
Blood Pressure Lowering Agents: May increase hypotensive effects of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor
Bornaprine: May increase adverse/toxic effects of Antipsychotic Agents. Specifically, tardive dyskinesia symptoms may be potentiated. Risk C: Monitor
Brexanolone: CNS Depressants may increase CNS depressant effects of Brexanolone. Risk C: Monitor
Brexpiprazole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Brexpiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor
Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromopride: May increase adverse/toxic effects of Antipsychotic Agents. Risk X: Avoid
Bromperidol: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Buclizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Buprenorphine: CNS Depressants may increase CNS depressant effects of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider Therapy Modification
BuPROPion: May increase neuroexcitatory and/or seizure-potentiating effects of Agents With Seizure Threshold Lowering Potential. Risk C: Monitor
BusPIRone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Cabergoline: May decrease therapeutic effects of Antipsychotic Agents. Risk X: Avoid
Cannabinoid-Containing Products: CNS Depressants may increase CNS depressant effects of Cannabinoid-Containing Products. Risk C: Monitor
Cariprazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Cariprazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Cetirizine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk D: Consider Therapy Modification
Chloral Hydrate/Chloral Betaine: CNS Depressants may increase CNS depressant effects of Chloral Hydrate/Chloral Betaine. Management: Consider alternatives to the use of chloral hydrate or chloral betaine and additional CNS depressants. If combined, consider a dose reduction of either agent and monitor closely for enhanced CNS depressive effects. Risk D: Consider Therapy Modification
Chlormethiazole: May increase CNS depressant effects of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider Therapy Modification
Chlorphenesin Carbamate: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
ChlorproMAZINE: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of ChlorproMAZINE. Specifically, the risk of seizures may be increased. Risk C: Monitor
Ciprofloxacin (Systemic): May increase serum concentration of Asenapine. Risk C: Monitor
Clothiapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Clothiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor
CloZAPine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of CloZAPine. Specifically, the risk of seizures may be increased. Risk C: Monitor
CNS Depressants: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
CYP1A2 Inhibitors (Strong): May increase serum concentration of Asenapine. Risk C: Monitor
Dantrolene: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Daridorexant: May increase CNS depressant effects of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification
Deutetrabenazine: May increase adverse/toxic effects of Antipsychotic Agents. Specifically, the risk for akathisia, parkinsonism, or neuroleptic malignant syndrome may be increased. Risk C: Monitor
DexmedeTOMIDine: CNS Depressants may increase CNS depressant effects of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider Therapy Modification
Dexmethylphenidate-Methylphenidate: Antipsychotic Agents may increase adverse/toxic effects of Dexmethylphenidate-Methylphenidate. Dexmethylphenidate-Methylphenidate may increase adverse/toxic effects of Antipsychotic Agents. Specifically, the risk of extrapyramidal symptoms may be increased when these agents are combined. Risk C: Monitor
Diazoxide Choline: May increase serum concentration of CYP1A2 Substrates (High risk with Inhibitors). Risk X: Avoid
Difelikefalin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Difenoxin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dihydralazine: CNS Depressants may increase hypotensive effects of Dihydralazine. Risk C: Monitor
Dimethindene (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Donepezil: May increase neurotoxic (central) effects of Antipsychotic Agents. Risk C: Monitor
Dothiepin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Doxylamine: CNS Depressants may increase CNS depressant effects of Doxylamine. Risk C: Monitor
DroPERidol: May increase CNS depressant effects of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider Therapy Modification
Emedastine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk C: Monitor
Entacapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Esketamine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Flunarizine: CNS Depressants may increase CNS depressant effects of Flunarizine. Risk X: Avoid
Flunitrazepam: CNS Depressants may increase CNS depressant effects of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider Therapy Modification
Flupentixol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Flupentixol. Specifically, the risk of seizures may be increased. Risk C: Monitor
FluPHENAZine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of FluPHENAZine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Guanethidine: Antipsychotic Agents may decrease therapeutic effects of Guanethidine. Risk C: Monitor
Haloperidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Haloperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Avoid) may increase QTc-prolonging effects of Haloperidol. Risk C: Monitor
Huperzine A: May increase neurotoxic (central) effects of Antipsychotic Agents. Risk C: Monitor
HydrOXYzine: May increase CNS depressant effects of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider Therapy Modification
Iloperidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iloperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Iohexol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider Therapy Modification
Iomeprol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider Therapy Modification
Iopamidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider Therapy Modification
Ixabepilone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kava Kava: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ketotifen (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kratom: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Lemborexant: May increase CNS depressant effects of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider Therapy Modification
Levocetirizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Levoketoconazole: QT-prolonging Agents (Indeterminate Risk - Avoid) may increase QTc-prolonging effects of Levoketoconazole. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
Lithium: May increase neurotoxic effects of Antipsychotic Agents. Lithium may decrease serum concentration of Antipsychotic Agents. Specifically noted with chlorpromazine. Risk C: Monitor
Lofepramine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lofexidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Loxapine: CNS Depressants may increase CNS depressant effects of Loxapine. Management: Consider reducing the dose of CNS depressants administered concomitantly with loxapine due to an increased risk of respiratory depression, sedation, hypotension, and syncope. Risk D: Consider Therapy Modification
Lumateperone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Lumateperone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Lurasidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Lurasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Magnesium Sulfate: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Melitracen [INT]: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metergoline: Antipsychotic Agents may decrease therapeutic effects of Metergoline. Metergoline may decrease therapeutic effects of Antipsychotic Agents. Risk C: Monitor
Metergoline: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Methotrimeprazine: CNS Depressants may increase CNS depressant effects of Methotrimeprazine. Methotrimeprazine may increase CNS depressant effects of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider Therapy Modification
Methoxyflurane: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metoclopramide: May increase adverse/toxic effects of Antipsychotic Agents. Risk X: Avoid
MetyroSINE: May increase adverse/toxic effects of Antipsychotic Agents. Specifically, the risk for extrapyramidal symptoms and excessive sedation may be increased. Risk C: Monitor
Minocycline (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Molindone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Molindone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Moxonidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Nabilone: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Nalfurafine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid
OLANZapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of OLANZapine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Olopatadine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Opicapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Opioid Agonists: CNS Depressants may increase CNS depressant effects of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification
Opipramol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Orphenadrine: CNS Depressants may increase CNS depressant effects of Orphenadrine. Risk X: Avoid
Oxomemazine: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Oxybate Salt Products: CNS Depressants may increase CNS depressant effects of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider Therapy Modification
OxyCODONE: CNS Depressants may increase CNS depressant effects of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification
Paliperidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Paliperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Paliperidone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Paraldehyde: CNS Depressants may increase CNS depressant effects of Paraldehyde. Risk X: Avoid
PARoxetine: Asenapine may increase serum concentration of PARoxetine. Management: Decrease the paroxetine dose by half when used concomitantly with asenapine. Monitor patients receiving this combination closely for signs and symptoms of increased paroxetine toxicity. Risk D: Consider Therapy Modification
Perampanel: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Periciazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Periciazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Periciazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Perphenazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Perphenazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Pimozide: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Pimozide. Specifically, the risk of seizures may be increased. Risk C: Monitor
Pipamperone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Pipamperone. Specifically, the risk of seizures may be increased. Risk X: Avoid
Piribedil: Antipsychotic Agents may decrease therapeutic effects of Piribedil. Piribedil may decrease therapeutic effects of Antipsychotic Agents. Management: Use of piribedil with antiemetic neuroleptics is contraindicated, and use with antipsychotic neuroleptics, except for clozapine, is not recommended. Risk X: Avoid
Pizotifen: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Polyethylene Glycol-Electrolyte Solution: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Polyethylene Glycol-Electrolyte Solution. Specifically, the risk of seizure may be increased. Risk C: Monitor
Primaquine: May increase serum concentration of CYP1A2 Substrates (High risk with Inhibitors). Risk C: Monitor
Procarbazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Prochlorperazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Prochlorperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Promazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Promazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Avoid) may increase QTc-prolonging effects of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
QUEtiapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of QUEtiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Quinagolide: Antipsychotic Agents may decrease therapeutic effects of Quinagolide. Risk C: Monitor
Rilmenidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
RisperiDONE: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of RisperiDONE. Specifically, the risk of seizures may be increased. Risk C: Monitor
Rivastigmine: May increase neurotoxic (central) effects of Antipsychotic Agents. Risk C: Monitor
Ropeginterferon Alfa-2b: CNS Depressants may increase adverse/toxic effects of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider Therapy Modification
Serotonergic Agents (High Risk): May increase adverse/toxic effects of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor
Sertindole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Sertindole. Specifically, the risk of seizures may be increased. Risk C: Monitor
Sodium Phosphates: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Sodium Phosphates. Specifically, the risk of seizure or loss of consciousness may be increased in patients with significant sodium phosphate-induced fluid or electrolyte abnormalities. Risk C: Monitor
Sulpiride: Antipsychotic Agents may increase adverse/toxic effects of Sulpiride. Risk X: Avoid
Suvorexant: CNS Depressants may increase CNS depressant effects 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. Risk D: Consider Therapy Modification
Tetrabenazine: May increase adverse/toxic effects of Antipsychotic Agents. Specifically, the risk for NMS and extrapyramidal symptoms may be increased. Risk C: Monitor
Thalidomide: CNS Depressants may increase CNS depressant effects of Thalidomide. Risk X: Avoid
Thioridazine: CYP2D6 Inhibitors (Weak) may increase serum concentration of Thioridazine. Management: Consider avoiding concomitant use of thioridazine and weak CYP2D6 inhibitors. If combined, monitor closely for QTc interval prolongation and arrhythmias. Some weak CYP2D6 inhibitors list use with thioridazine as a contraindication. Risk D: Consider Therapy Modification
Thiothixene: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Thiothixene. Specifically, the risk of seizures may be increased. Risk C: Monitor
Trifluoperazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Trifluoperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Trimeprazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Triptorelin: Hyperprolactinemic Agents may decrease therapeutic effects of Triptorelin. Risk X: Avoid
Valerian: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ziprasidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Ziprasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Zolpidem: CNS Depressants may increase CNS depressant effects 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. Risk D: Consider Therapy Modification
Zuclopenthixol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Zuclopenthixol. Specifically, the risk of seizures may be increased. Risk C: Monitor
Zuranolone: May increase CNS depressant effects of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider Therapy Modification
Evaluate pregnancy status and provide preconception counseling prior to initiating treatment in patients who could become pregnant (APA [Keepers 2020]; BAP [McAllister-Williams 2017]; CANMAT [Yatham 2018]). Patients effectively treated may continue their current antipsychotic medication when planning a pregnancy unless contraindications exist (ACOG 2023; BAP [McAllister-Williams 2017]); the lowest effective dose and avoidance of polytherapy is recommended (BAP [Barnes 2020]; BAP [McAllister-Williams 2017]; CANMAT [Yatham 2018]). Management of mental health conditions in patients who could become pregnant should be based on a shared decision-making process that considers the possibility of pregnancy during treatment and the risks of discontinuing antipsychotic therapy (ACOG 2023; BAP [McAllister-Williams 2017]; CANMAT [Yatham 2018]).
Antipsychotic agents may be associated with sexual dysfunction. Some second generation (atypical) antipsychotics may cause hyperprolactinemia, resulting in menstrual disorders or impaired spermatogenesis. Consider changing to a medication that is prolactin-sparing in patients with clinical symptoms. Contraception should be provided if pregnancy is not desired, as unintended pregnancies may occur when changing to a prolactin-sparing medication (APA [Keepers 2020]; BAP [McAllister-Williams 2017]).
Outcome data following exposure to second generation (atypical) antipsychotics (SGAs) as a class do not show a significant increased risk of major congenital malformations (BAP [Barnes 2020]); however, specific outcomes vary due to differences in study design and data are not specific for asenapine (BAP [McAllister-Williams 2017]; Ellfolk 2021; Huybrechts 2016; Terrana 2015; Viguera 2021; Wang 2021). Additional studies are needed for individual agents and specific outcomes (BAP [Barnes 2020]). Data related to the long-term effects of in utero antipsychotic exposure on infant neurodevelopment and behavior are limited (BAP [McAllister-Williams 2017]; Straub 2022; Swetlik 2024).
Antipsychotic use during the third trimester of pregnancy increases the risk for extrapyramidal symptoms and/or withdrawal symptoms in newborns following delivery (Viguera 2023). Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor. These effects may require prolonged hospitalization or resolve within hours or days without specific treatment. Tapering the dose late in pregnancy to reduce the risk of symptoms is not recommended (APA [Keepers 2020]).
Atypical antipsychotics are associated with metabolic changes and the risk varies by specific agent. Available studies that evaluated the risk of developing gestational diabetes mellitus (GDM) during antipsychotic therapy have conflicting results, possibly due to differences in study design (ACOG 2023; Uguz 2019). Pregnant patients with diabetes mellitus or GDM may continue antipsychotic treatment (ACOG 2023). Consider the metabolic risks of the specific antipsychotic if treatment is initiated for the first-time during pregnancy (Heinonen 2022). Screening for GDM should continue as part of standard prenatal care; early screening is not needed due to psychiatric medication exposure (ACOG 2023; BAP [McAllister-Williams 2017]).
Untreated and undertreated mental health conditions are associated with adverse pregnancy outcomes (ACOG 2023). Adverse obstetric and neonatal outcomes are associated with schizophrenia; however, comparisons between treated and untreated pregnancies are limited (BAP [McAllister-Williams 2017]). Untreated bipolar disorder is associated with fetal growth restriction, preterm birth, and adverse neurodevelopment, and may increase the risk of postpartum psychosis, worsening mood, and postpartum hospitalization. Discontinuing effective medications during pregnancy increases the risk of symptom relapse (ACOG 2023). Patients effectively treated for schizophrenia or bipolar disorder pre-pregnancy may use the same medication during pregnancy unless contraindications exist (ACOG 2023; APA [Keepers 2020]). SGAs are better tolerated and have fewer extrapyramidal adverse effects than first-generation (typical) antipsychotics (ACOG 2023).
Management of mental health conditions should be made as part of a shared decision-making process (ACOG 2023; BAP [McAllister-Williams 2017]). Treatment should not be withheld or discontinued based only on pregnancy status. When medications are used, the lowest effective dose of a single agent is recommended. Optimize dosing prior to changing a medication or adding additional agents whenever possible. Close monitoring for symptom improvement with a validated screening tool during pregnancy is recommended. Manage side effects as needed (ACOG 2023).
Data collection to monitor pregnancy and infant outcomes following exposure to psychiatric medications is ongoing. Encourage pregnant patients 45 years and younger with a history of psychiatric illness to enroll in the National Pregnancy Registry for Psychiatric Mediations (1-866-961-2388 or https://womensmentalhealth.org/research/pregnancyregistry/).
It is not known if asenapine is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Drowsiness, irritability, motor abnormalities, poor feeding, sedation, and slowed development have been reported in infants exposed to antipsychotics via breast milk. Monitor breastfed infants, especially those who are premature or of low birth weight, or when other sedative drugs are also prescribed (BAP [Barnes 2020]; BAP [McAllister-Williams 2017]).
|
Frequency of Antipsychotic Monitoring for Asenapinea,b | ||
|---|---|---|
|
Monitoring parameter |
Frequency of monitoring |
Comments |
|
Adherence |
Every visit |
|
|
Blood chemistries (electrolytes, renal function, liver function, TSH) |
Annually |
|
|
CBC |
As clinically indicated |
Check frequently during the first few months of therapy in patients with preexisting low WBC or history of drug-induced leukopenia/neutropenia |
|
Extrapyramidal symptoms |
Every visit; 4 weeks after initiation and dose change; annually. Use a formalized rating scale at least annually or every 6 months if high riskc |
|
|
Fall risk |
Every visit |
|
|
Fasting plasma glucose/HbA1c |
4 months after initiation; annually |
Check more frequently than annually if abnormal. Follow diabetes guidelines. |
|
Lipid panel |
4 months after initiation; annually |
Check more frequently than annually if abnormal. Follow lipid guidelines. |
|
Mental status and alertness |
Every visit |
|
|
Metabolic syndrome history |
Annually |
Evaluate for personal and family history of obesity, diabetes, dyslipidemia, hypertension, or cardiovascular disease |
|
Prolactin |
Ask about symptoms at every visit until dose is stable. Check prolactin level if symptoms are reported. |
Hyperprolactinemia symptoms: Changes in menstruation, libido, gynecomastia, development of galactorrhea, and erectile and ejaculatory function |
|
Tardive dyskinesia |
Every visit; annually. Use a formalized rating scale at least annually or every 6 months if high riskd |
|
|
Vital signs (BP, orthostatics, temperature, pulse, signs of infection) |
Every visit (at least weekly during first 3 to 4 weeks of treatment); 4 weeks after dose change. |
|
|
Weight/Height/BMI |
8 and 12 weeks after initiation and dose change; quarterly |
Consider monitoring waist circumference at baseline and annually, especially in patients with or at risk for metabolic syndrome. Consider changing antipsychotic if BMI increases by ≥1 unit. Some experts recommend checking weight and height at every visit. |
|
a For all monitoring parameters, it is appropriate for check at baseline and when clinically relevant (based on symptoms or suspected ADRs) in addition to the timeline. b ADA 2004; APA [Keepers 2020]; de Hert 2011; Gugger 2011; manufacturer’s labeling. c Risk factors for extrapyramidal symptoms (EPS) include prior history of EPS, high doses of antipsychotics, young age (children and adolescents at higher risk than adults), and dopaminergic affinity of individual antipsychotic. d Risk factors for tardive dyskinesia include age >55 years; females; White or African ethnicity; presence of a mood disorder, intellectual disability, or CNS injury; and past or current EPS. | ||
Timing of serum samples: Draw trough just before next dose (Hiemke 2018).
Therapeutic reference range: 1 to 5 ng/mL (SI: 3.5 to 17.5 nmol/L) (Hiemke 2018). Note: Dosing should be based on therapeutic response as opposed to serum concentrations; however, therapeutic drug monitoring can be used to confirm adherence (APA [Keepers 2020]).
Laboratory alert level: 10 ng/mL (SI: 35 nmol/L) (Hiemke 2018).
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 (Huttunen 1995).
Onset of effect: Sublingual:
Agitation: Initial effects within 15 minutes (Pratts 2014).
Bipolar disorder, acute mania: Initial effects may be observed within days of treatment with continued improvements over 1 to 2 weeks (Goikolea 2013; Tohen 2000; Welten 2016).
Schizophrenia: Initial effects may be observed within 1 to 2 weeks of treatment with continued improvements through 4 to 6 weeks (Agid 2003; Levine 2010).
Absorption: Sublingual: Rapid; Transdermal: External heat source (eg, heating pad) applied to patch increases rate and extent of absorption.
Distribution: Vd: ~20 to 25 L/kg.
Protein binding: 95% (including albumin and α1-acid glycoprotein).
Metabolism: Hepatic via CYP1A2 oxidation and UGT1A4 glucuronidation.
Bioavailability: Sublingual: 35%; decreased if swallowed (<2%); decreased if administered with food or liquid.
Half-life elimination: Sublingual: Terminal: ~24 hours; Transdermal: ~30 hours.
Time to peak, plasma: Sublingual: 0.5 to 1.5 hours; Transdermal: 12 to 24 hours.
Excretion: Urine (~50%); feces (~40%).
Hepatic function impairment: Severe hepatic impairment (Child-Pugh class C) exposure was 7 times higher than in healthy patients.
Older adult: Clearance is decreased, increasing exposure by 30% to 40%.
