Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Olanzapine/samidorphan is not approved for the treatment of patients with dementia-related psychosis.
Note: In patients who use opioids, delay initiation of olanzapine and samidorphan for a minimum of 7 days after last use of short-acting opioids and 14 days after last use of long-acting opioids. In patients who have a higher risk of hypotensive reactions, are at risk of slower olanzapine metabolism, or may be more pharmacodynamically sensitive to olanzapine, initial doses of olanzapine 5 mg/samidorphan 10 mg are recommended.
Bipolar I disorder , acute mania and acute episodes with mixed features:
Monotherapy: Initial: Oral: Olanzapine 10 mg/samidorphan 10 mg or olanzapine 15 mg/samidorphan 10 mg once daily; may adjust dose based on response and tolerability in decrements/increments of 5 mg (based on the olanzapine component) at ≥24 hours intervals to olanzapine 5 to 20 mg/samidorphan 10 mg once daily; maximum dose: olanzapine 20 mg/samidorphan 10 mg.
Adjunctive therapy to lithium or valproate : Initial: Oral: Olanzapine 10 mg/samidorphan 10 mg once daily; may adjust dose based on response and tolerability in increments of 5 mg (based on the olanzapine component) at weekly intervals up to olanzapine 20 mg/samidorphan 10 mg once daily; maximum dose: olanzapine 20 mg/samidorphan 10 mg once daily.
Schizophrenia : Initial: Oral: Olanzapine 5 mg/samidorphan 10 mg or olanzapine 10 mg/samidorphan 10 mg once daily; may adjust dose based on response and tolerability in increments of 5 mg (based on the olanzapine component) at weekly intervals up to olanzapine 10 to 20 mg/samidorphan 10 mg once daily; maximum dose: olanzapine 20 mg/samidorphan 10 mg once daily.
Mild to moderate impairment (eGFR 30 to 89 mL/minute/1.73 m2): No dosage adjustment necessary.
Severe impairment (eGFR 15to 29 mL/minute/1.73 m2): There are no dosage adjustments necessary; however, use caution (increased exposure in patients with severe renal impairment).
End-stage renal disease (eGFR <15 mL/minute/1.73 m2): Use not recommended (has not been studied).
No dosage adjustment necessary; however, use caution (increased exposure in patients with moderate hepatic impairment).
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).
Consider a lower dosage of the olanzapine component; clearance may be decreased and/or side effects may be greater.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Also see olanzapine monograph.
>10%: Endocrine & metabolic: Increased serum glucose (normal to high [<100 mg/dL to ≥126 mg/dL]: 4%), increased serum prolactin (males: 33%; females: 41%), increased serum triglycerides (14%), weight gain (19%)
1% to 10%:
Gastrointestinal: Hyperinsulinism (3%), xerostomia (7%)
Hematologic & oncologic: Decreased neutrophils (2%)
Nervous system: Dizziness (2%), drowsiness (9%), headache (6%), sedated state (2%)
Frequency not defined: Hepatic: Abnormal liver function tests
Concomitant use with opioids; patients undergoing acute opioid withdrawal.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• Accidental opioid overdose: Patients with a history of chronic opioid use prior to olanzapine/samidorphan therapy may respond to lower opioid doses than previously used if therapy is interrupted or discontinued; may increase the risk of opioid overdose if resumed at previously tolerated dose. Warn patients that any attempt to overcome opioid blockade during olanzapine/samidorphan therapy is dangerous and could potentially lead to life-threatening opioid intoxication (eg, respiratory arrest, circulatory collapse). If opioid therapy is required as part of anesthesia or analgesia, discontinue olanzapine/samidorphan and monitor closely.
• Anticholinergic effects: Olanzapine may cause anticholinergic effects (eg, constipation, xerostomia, blurred vision, urinary retention, tachycardia); use with caution in patients with decreased GI motility, urinary retention, or benign prostatic hyperplasia. Relative to other neuroleptics, olanzapine has a moderate potency of cholinergic blockade (Richelson 1999).
• Blood dyscrasias: Leukopenia, neutropenia, and agranulocytosis (sometimes fatal) have been reported in clinical trials and postmarketing reports with antipsychotic use; presence of risk factors (eg, preexisting low WBC, history of drug-induced leukopenia/neutropenia) should prompt periodic blood count assessment. Discontinue therapy at first signs of blood dyscrasias or if absolute neutrophil count <1,000/mm3.
• Cerebrovascular effects: An increased incidence of cerebrovascular effects (eg, transient ischemic attack, stroke), including fatalities, has been reported in placebo-controlled trials of olanzapine for the unapproved use in elderly patients with dementia-related psychosis.
• CNS depression: Antipsychotics 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, driving).
• Dermatologic reactions: Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with olanzapine; may be fatal. Symptoms of DRESS include cutaneous reaction (rash or exfoliative dermatitis), fever, lymphadenopathy, eosinophilia, and systemic complications (eg, hepatitis, nephritis, pneumonitis, myocarditis, pericarditis); discontinue use if DRESS is suspected.
• 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 of age (Herzig 2017; Maddalena 2004).
• Extrapyramidal symptoms: Olanzapine 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 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: Olanzapine may increase the risk for falls due to somnolence, orthostatic hypotension, and motor or sensory instability.
• Hyperglycemia: Atypical antipsychotics (including olanzapine) have been associated with development of hyperglycemia; in some cases, may be extreme and associated with ketoacidosis, hyperosmolar coma, or death. Patients with risk factors for diabetes (eg, obesity or family history) should have a baseline fasting blood sugar and periodically during treatment.
• Hyperlipidemia: Has been reported with atypical antipsychotics; risk profile may differ between agents.
• Hyperprolactinemia: Olanzapine may cause dose-related increases in prolactin levels; clinical significance of hyperprolactinemia in patients with breast cancer or other prolactin-dependent tumors is unknown. Clinical manifestations of increased prolactin levels included menstrual-, sexual- and breast-related events.
• Opioid withdrawal: Olanzapine/samidorphan is contraindicated in patients who are receiving opioids or undergoing acute opioid withdrawal; use may precipitate symptoms of acute withdrawal in opioid-dependent patients. An opioid-free interval of at least 7 days is recommended for patients receiving short-acting opioids; consider an opioid-free interval of up to 14 days in patients receiving long-acting opioids.
• Orthostatic hypotension: Atypical antipsychotics may cause orthostatic hypotension; use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use, which may predispose to hypotension/bradycardia).
• Neuroleptic malignant syndrome: Antipsychotic use has been associated with neuroleptic malignant syndrome (NMS); discontinue use if NMS is suspected.
• Temperature regulation: Impaired core body temperature regulation may occur with atypical antipsychotics; use caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.
• Weight gain: Significant weight gain has been observed with antipsychotic therapy; incidence varies with product. Compared to olanzapine monotherapy, olanzapine/samidorphan was associated with significantly less weight gain and smaller increases in waist circumference (Correll 2020).
Disease-related concerns:
• Bariatric surgery: Presurgical assessment of the indication for use, symptoms, and goals of therapy should be documented to enable postsurgical assessment. Olanzapine is strongly associated with significant weight gain (increase of ≥7% from baseline) (Alonso-Pedrero 2019; Cai 2023; Domecq 2015; Leucht 2023; Zhang 2020). Monitor weight closely postoperatively and consider changing agent to alternative agent if weight loss goals are not being met.
• Cardiovascular disease: Use with caution in patients with severe cardiac disease, hemodynamic instability, prior myocardial infarction, ischemic heart disease, or hypercholesterolemia.
• Dementia: Elderly patients with dementia-related disorders treated with antipsychotics are at increased risk of death compared to placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Olanzapine and samidorphan is not approved for the treatment of dementia-related psychosis.
• GI motility: Use with caution in patients with decreased GI motility (eg, paralytic ileus), as anticholinergic effects may exacerbate underlying condition.
• Hepatic impairment: Use with caution in patients with hepatic disease or impairment.
• Parkinson disease: Use with caution in patients with Parkinson disease; antipsychotics may aggravate motor disturbances (APA [Reus 2016]).
• Seizure disorder: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcohol use disorder, or concurrent therapy with medications that may lower seizure threshold, 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.
• Urinary retention (eg, benign prostatic hyperplasia): Use with caution in patients with urinary retention, as anticholinergic effects may exacerbate underlying condition.
Special populations:
• Smokers: Olanzapine levels may be lower in patients who smoke. Smokers may require an increased daily dose (Tsuda 2014). Discontinuation of smoking should also merit a dose reduction as olanzapine levels may be higher as smoking cessations occurs.
Other warnings/precautions:
• Discontinuation of antipsychotic therapy: When discontinuing antipsychotic therapy, gradually taper antipsychotics to avoid physical withdrawal symptoms and rebound symptoms (APA [Keepers 2020]; WFSBP [Hasan 2012]). Withdrawal symptoms may include agitation, alternating feelings of warmth and cold, anxiety, diaphoresis, dyskinesia, GI symptoms, insomnia, irritability, 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]).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Lybalvi: Olanzapine 5 mg and samidorphan l-malate 10 mg, Olanzapine 20 mg and samidorphan l-malate 10 mg, Olanzapine 10 mg and samidorphan l-malate 10 mg
Lybalvi: Olanzapine 15 mg and samidorphan l-malate 10 mg [contains fd&c blue #2 (indigo carm) aluminum lake]
No
Tablets (Lybalvi Oral)
5-10 mg (per each): $65.89
10-10 mg (per each): $65.89
15-10 mg (per each): $65.89
20-10 mg (per each): $65.89
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Oral: Administer with or without food. Do not divide tablets or combine strengths.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Lybalvi: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/213378s008lbl.pdf#page=41
Bipolar I disorder: Treatment of acute mania or acute episodes with mixed features of bipolar I disorder (as monotherapy or in combination with lithium or valproate), and maintenance monotherapy treatment.
Schizophrenia: Treatment of schizophrenia in adults.
Olanzapine and samidorphan may be confused with olanzapine and fluoxetine.
Lybalvi may be confused with Livalo brand name for pitavastatin.
Beers Criteria: Antipsychotics (olanzapine) 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 of antipsychotics 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]).
Refer to individual components.
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.
Acetylcholinesterase Inhibitors: May decrease therapeutic effects of Agents with Clinically Relevant Anticholinergic Effects. Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Acetylcholinesterase Inhibitors. Risk C: Monitor
Aclidinium: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid
Acrivastine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Acrivastine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Agents with Clinically Relevant Anticholinergic Effects: May increase anticholinergic effects of OLANZapine. Risk C: Monitor
Agents With Seizure Threshold Lowering Potential: May increase adverse/toxic effects of OLANZapine. 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 CNS depressant effects of CNS Depressants. Risk C: Monitor
Amisulpride (Oral): May increase QTc-prolonging effects of QT-prolonging Agents (Moderate Risk). 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
Antihepaciviral Combination Products: May decrease serum concentration of OLANZapine. 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
Asenapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Asenapine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Azithromycin (Systemic): May increase QTc-prolonging effects of QT-prolonging Antipsychotics (Moderate 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
Benperidol: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Benperidol. Risk C: Monitor
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
Benzodiazepines: May increase adverse/toxic effects of OLANZapine. Management: Monitor closely for hypotension, respiratory or central nervous system depression, and bradycardia if olanzapine is combined with benzodiazepines. Use of parenteral benzodiazepines with IM olanzapine is not recommended. Risk C: Monitor
Benztropine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Benztropine. Risk C: Monitor
Biperiden: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Biperiden. 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
Botulinum Toxin-Containing Products: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. 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
Broccoli: May decrease serum concentration of CYP1A2 Substrates (High risk with Inducers). 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: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Buclizine. Risk C: Monitor
Buclizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
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: Agents with Clinically Relevant Anticholinergic Effects may increase tachycardic effects of Cannabinoid-Containing Products. Risk C: Monitor
Cannabinoid-Containing Products: CNS Depressants may increase CNS depressant effects of Cannabinoid-Containing Products. Risk C: Monitor
Cannabis: May decrease serum concentration of CYP1A2 Substrates (High risk with Inducers). 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
Ceritinib: May increase QTc-prolonging effects of QT-prolonging Antipsychotics (Moderate 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
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
Chlorprothixene: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Chlorprothixene. Risk C: Monitor
Cimetropium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Cimetropium. Risk X: Avoid
Clarithromycin: QT-prolonging Antipsychotics (Moderate Risk) may increase QTc-prolonging effects of Clarithromycin. 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
ClomiPRAMINE: QT-prolonging Antipsychotics (Moderate Risk) may increase QTc-prolonging effects of ClomiPRAMINE. QT-prolonging Antipsychotics (Moderate Risk) may increase serotonergic effects of ClomiPRAMINE. This could result in serotonin syndrome. Management: Monitor for QTc interval prolongation, ventricular arrhythmias, and serotonin syndrome/serotonin toxicity (SS/ST) or NMS when these agents are combined. Patients with additional risk factors for QTc prolongation or SS/ST may be at even higher risk. 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 Clinically Relevant Anticholinergic Effects may increase constipating effects of CloZAPine. Management: Consider alternatives to this combination whenever possible. If combined, monitor closely for signs and symptoms of gastrointestinal hypomotility and consider prophylactic laxative treatment. Risk D: Consider Therapy Modification
CNS Depressants: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Cyclizine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
CYP1A2 Inducers (Moderate): May decrease serum concentration of OLANZapine. Risk C: Monitor
CYP1A2 Inducers (Weak): May decrease serum concentration of OLANZapine. Risk C: Monitor
CYP1A2 Inhibitors (Moderate): May increase serum concentration of OLANZapine. Risk C: Monitor
CYP1A2 Inhibitors (Strong): May increase serum concentration of OLANZapine. Risk C: Monitor
CYP3A4 Inducers (Moderate): May decrease serum concentration of Samidorphan. Risk C: Monitor
CYP3A4 Inducers (Strong): May decrease serum concentration of Samidorphan. Risk X: Avoid
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
Darifenacin: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Darifenacin. Risk C: Monitor
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
Dicyclomine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Dicyclomine. Risk C: Monitor
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 (Systemic): Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Dimethindene (Systemic). Risk C: Monitor
Dimethindene (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Domperidone: QT-prolonging Agents (Moderate Risk) may increase QTc-prolonging effects of Domperidone. Risk X: Avoid
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
DroNABinol: Agents with Clinically Relevant Anticholinergic Effects may increase tachycardic effects of DroNABinol. Risk X: Avoid
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
Eluxadoline: Agents with Clinically Relevant Anticholinergic Effects may increase constipating effects of Eluxadoline. Risk X: Avoid
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
Fesoterodine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Fesoterodine. Risk C: Monitor
Fexinidazole: May increase QTc-prolonging effects of OLANZapine. Fexinidazole may increase serum concentration of OLANZapine. Management: Monitor for increased olanzapine toxicities, including 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
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
Fluorouracil Products: QT-prolonging Antipsychotics (Moderate Risk) may increase QTc-prolonging effects of Fluorouracil Products. Management: Monitor for QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
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
Flupentixol: QT-prolonging Antipsychotics (Moderate Risk) may increase QTc-prolonging effects of Flupentixol. 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
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
FluPHENAZine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Gastrointestinal Agents (Prokinetic): Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Gastrointestinal Agents (Prokinetic). Risk C: Monitor
Gepotidacin: May decrease anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Glucagon: Agents with Clinically Relevant Anticholinergic Effects may increase adverse/toxic effects of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Risk C: Monitor
Glycopyrrolate (Oral Inhalation): Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Glycopyrrolate (Oral Inhalation). Risk X: Avoid
Glycopyrrolate (Systemic): Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Glycopyrrolate (Systemic). Risk C: Monitor
Glycopyrronium (Topical): May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid
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 Antipsychotics (Moderate Risk) may increase QTc-prolonging effects of Haloperidol. Management: Monitor for QTc interval prolongation, ventricular arrhythmias, and serotonin syndrome/serotonin toxicity (SS/ST) or NMS when these agents are combined. Patients with additional risk factors for QTc prolongation or SS/ST may be at even higher risk. 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
Imipramine: May increase QTc-prolonging effects of QT-prolonging Antipsychotics (Moderate Risk). QT-prolonging Antipsychotics (Moderate Risk) may increase serotonergic effects of Imipramine. This could result in serotonin syndrome. Management: Monitor for QTc interval prolongation, ventricular arrhythmias, and serotonin syndrome/serotonin toxicity (SS/ST) or NMS when these agents are combined. Patients with additional risk factors for QTc prolongation or SS/ST may be at even higher risk. 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
Ipratropium (Nasal): May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Ipratropium (Oral Inhalation): May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid
Itopride: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Itopride. Risk C: Monitor
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 (Moderate Risk) may increase QTc-prolonging effects of Levoketoconazole. Risk X: Avoid
Levosulpiride: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Levosulpiride. Risk X: Avoid
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
Lonafarnib: May increase QTc-prolonging effects of QT-prolonging Antipsychotics (Moderate 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
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
Maprotiline: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Maprotiline. Risk C: Monitor
Melitracen [INT]: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Melperone: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. 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
Methscopolamine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Methscopolamine. Risk C: Monitor
Methylnaltrexone: May increase adverse/toxic effects of Opioid Antagonists. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid
Metoclopramide: May increase adverse/toxic effects of Antipsychotic Agents. Risk X: Avoid
MetyroSINE: CNS Depressants may increase sedative effects of MetyroSINE. Risk C: Monitor
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
Mirabegron: Agents with Clinically Relevant Anticholinergic Effects may increase adverse/toxic effects of Mirabegron. 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
Naldemedine: Opioid Antagonists may increase adverse/toxic effects of Naldemedine. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid
Nalfurafine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Naloxegol: Opioid Antagonists may increase adverse/toxic effects of Naloxegol. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid
Nirmatrelvir and Ritonavir: May decrease serum concentration of OLANZapine. Risk C: Monitor
Nitroglycerin: Agents with Clinically Relevant Anticholinergic Effects may decrease absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Risk C: Monitor
Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid
Olopatadine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Ondansetron: May increase QTc-prolonging effects of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation, ventricular arrhythmias, including torsades de pointes, when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
Opicapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Opioid Agonists: Samidorphan may decrease therapeutic effects of Opioid Agonists. Risk X: Avoid
Opipramol: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
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
Oxatomide: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. 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
OxyBUTYnin: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of OxyBUTYnin. Risk C: Monitor
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
Pentamidine (Systemic): May increase QTc-prolonging effects of QT-prolonging Antipsychotics (Moderate 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
Perampanel: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Perazine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. 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 Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Perphenazine. 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: May increase QTc-prolonging effects of QT-prolonging Agents (Moderate Risk). Risk X: Avoid
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
Piperaquine: QT-prolonging Agents (Moderate Risk) may increase QTc-prolonging effects of Piperaquine. 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
Potassium Chloride: Agents with Clinically Relevant Anticholinergic Effects may increase ulcerogenic effects of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Risk X: Avoid
Potassium Citrate: Agents with Clinically Relevant Anticholinergic Effects may increase ulcerogenic effects of Potassium Citrate. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium citrate. Risk X: Avoid
Pramlintide: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. These effects are specific to the GI tract. Risk X: Avoid
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
Promethazine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Promethazine. Risk C: Monitor
Propantheline: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Propantheline. Risk C: Monitor
Propiverine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Propofol: QT-prolonging Antipsychotics (Moderate Risk) may increase QTc-prolonging effects of Propofol. 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
QT-prolonging Agents (Highest Risk): May increase QTc-prolonging effects of OLANZapine. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider Therapy Modification
QT-prolonging Antidepressants (Moderate Risk): QT-prolonging Antipsychotics (Moderate Risk) may increase QTc-prolonging effects of QT-prolonging Antidepressants (Moderate Risk). QT-prolonging Antipsychotics (Moderate Risk) may increase serotonergic effects of QT-prolonging Antidepressants (Moderate Risk). This could result in serotonin syndrome. Management: Monitor for QTc interval prolongation, ventricular arrhythmias, and serotonin syndrome/serotonin toxicity (SS/ST) or NMS when these agents are combined. Patients with additional risk factors for QTc prolongation or SS/ST may be at even higher risk. Risk C: Monitor
QT-prolonging Antipsychotics (Moderate Risk): May increase QTc-prolonging effects of OLANZapine. 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
QT-prolonging Class IC Antiarrhythmics (Moderate Risk): May increase QTc-prolonging effects of QT-prolonging Antipsychotics (Moderate 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
QT-Prolonging Inhalational Anesthetics (Moderate Risk): May increase QTc-prolonging effects of QT-prolonging Antipsychotics (Moderate 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
QT-prolonging Kinase Inhibitors (Moderate Risk): OLANZapine may increase QTc-prolonging effects of QT-prolonging Kinase Inhibitors (Moderate 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
QT-prolonging Miscellaneous Agents (Moderate Risk): May increase QTc-prolonging effects of QT-prolonging Antipsychotics (Moderate 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
QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): May increase QTc-prolonging effects of QT-prolonging Antipsychotics (Moderate 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
QT-prolonging Quinolone Antibiotics (Moderate Risk): May increase QTc-prolonging effects of QT-prolonging Antipsychotics (Moderate 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
Quinagolide: Antipsychotic Agents may decrease therapeutic effects of Quinagolide. Risk C: Monitor
Ramosetron: Agents with Clinically Relevant Anticholinergic Effects may increase constipating effects of Ramosetron. Risk C: Monitor
Revefenacin: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Revefenacin. Risk X: Avoid
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
Ritonavir: May decrease serum concentration of OLANZapine. Risk C: Monitor
Rivastigmine: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Rivastigmine. Rivastigmine may decrease therapeutic effects of Agents with Clinically Relevant Anticholinergic Effects. Management: Use of rivastigmine with an anticholinergic agent is not recommended unless clinically necessary. If the combination is necessary, monitor for reduced anticholinergic effects. Risk D: Consider Therapy Modification
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
Saquinavir: QT-prolonging Antipsychotics (Moderate Risk) may increase QTc-prolonging effects of Saquinavir. 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
Scopolamine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Scopolamine. Risk C: Monitor
Secretin: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Secretin. Management: Avoid concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of secretin. 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: May increase QTc-prolonging effects of QT-prolonging Agents (Moderate Risk). Risk X: Avoid
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
Sofpironium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Sofpironium. Risk X: Avoid
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
Thiazide and Thiazide-Like Diuretics: Agents with Clinically Relevant Anticholinergic Effects may increase serum concentration of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor
Thioridazine: QT-prolonging Agents (Moderate Risk) may increase QTc-prolonging effects of Thioridazine. Risk X: Avoid
Thiothixene: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Thiothixene. Risk C: Monitor
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
Tiapride: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Tiapride. Risk C: Monitor
Tiotropium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Tiotropium. Risk X: Avoid
Tobacco (Smoked): May decrease therapeutic effects of OLANZapine. Tobacco (Smoked) may decrease serum concentration of OLANZapine. Risk C: Monitor
Tolterodine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Tolterodine. Risk C: Monitor
Topiramate: Agents with Clinically Relevant Anticholinergic Effects may increase adverse/toxic effects of Topiramate. 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
Trimethobenzamide: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Trimethobenzamide. Risk C: Monitor
Trospium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Trospium. Risk C: Monitor
Umeclidinium: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid
Valerian: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Valproic Acid and Derivatives: May decrease serum concentration of OLANZapine. Risk C: Monitor
Voriconazole: May increase QTc-prolonging effects of QT-prolonging Antipsychotics (Moderate 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
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 Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Zuclopenthixol. Risk C: Monitor
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
Olanzapine may cause hyperprolactinemia, which may decrease reproductive function. Refer to the olanzapine monograph for additional information.
Olanzapine crosses the placenta in variable concentrations (Schoretsanitis 2020).
Extrapyramidal and/or withdrawal symptoms may occur in newborns exposed to olanzapine during pregnancy; refer to the olanzapine monograph for additional information.
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 Atypical Antipsychotics (1-866-961-2388 or https://womensmentalhealth.org/research/pregnancyregistry/atypicalantipsychotic/).
Olanzapine and samidorphan are present in breast milk.
Data related to the presence of olanzapine/samidorphan in breast milk are available from a single dose study. Breast milk was sampled in 12 lactating patients following an oral dose of olanzapine 5 mg/samidorphan 10 mg. Mean concentrations in breast milk were olanzapine 0.002 mg and samidorphan 0.006 mg. According to the manufacturer, the estimated infant dose via breast milk is ~0.0005 mg/kg for olanzapine and 0.001 mg/kg for samidorphan, providing a relative infant dose (RID) of <1% compared to the weight adjusted maternal dose for olanzapine (0.07 mg/kg) and samidorphan (0.15 mg/kg).
In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000); however, some sources note breastfeeding should only be considered if the RID is <5% for psychotropic agents (Anderson 2021).
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. Infants exposed to olanzapine/samidorphan via breast milk should be monitored for symptoms, such as excess sedation, extrapyramidal symptoms, irritability, and poor feeding. Refer to the olanzapine monograph for additional information.
Frequency of Antipsychotic Monitoring for Olanzapine and Samidorphana,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 risk.c |
|
Fall risk |
Every visit |
|
Fasting plasma glucose/A1C |
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 risk.d |
|
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 to 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 >5 years of age, female sex, White or African ethnicity, presence of a mood disorder, intellectual disability, CNS injury, or past or current EPS. |
Olanzapine is a second generation thienobenzodiazepine antipsychotic that displays potent antagonism of serotonin 5-HT2A and 5-HT2C, dopamine D1-4, histamine H1, and alpha1-adrenergic receptors. Olanzapine shows moderate antagonism of 5-HT3 and muscarinic M1-5 receptors, and weak binding to GABA-A, BZD, and beta-adrenergic receptors. Samidorphan is an antagonist at the mu-opioid receptors with partial agonist activity at kappa- and delta-opioid receptors. The exact mechanism of action of olanzapine in schizophrenia and bipolar disorder is not known; the efficacy is thought to be mediated through combined antagonism of dopamine and serotonin type 2 receptor sites. Samidorphan may mitigate olanzapine associated weight gain (Correll 2020).
Absorption: Samidorphan: Well-absorbed; not affected by food (Kumar 2019).
Protein binding: Olanzapine: 93%; samidorphan: 23% to 33%.
Metabolism:
Olanzapine: UGT1A4, CYP1A2, CYP2D6 (minor); inactive metabolites: 10-N-glucuronide and 4′-N-desmethyl-olanzapine.
Samidorphan: CYP3A4 (primary), CYP3A5, CYP2C19, CYP2C8; inactive metabolites: N-dealkylated and cis-N-oxide metabolites.
Bioavailability: Samidorphan: 69%.
Half-life elimination: Olanzapine: 35 to 52 hours; samidorphan: 7 to 11 hours.
Time to peak: Olanzapine: 4.5 to 7 hours; samidorphan: 1 to 2 hours.
Excretion:
Olanzapine: Urine (57% unchanged + metabolites, 7% unchanged); feces (30% unchanged + metabolites).
Samidorphan: Urine (67% unchanged + metabolites, 18% unchanged); feces (16% unchanged + metabolites).
Altered kidney function: Increased exposure in patients with severe renal impairment.
Hepatic function impairment: Increased exposure in patients with moderate hepatic impairment.
Older adult: Olanzapine: The half-life increases 1.5 times.
Sex: Olanzapine: Clearance is ~30% lower in female patients.
Race/ethnicity: Olanzapine: Clearance is greater in Black patients than in non-Black patients.
Cigarette smoking: Olanzapine: Clearance is ~40% higher in smokers.