Olanzapine (Zyprexa)

Emergency & Prehospital

• Acute agitation with schizophrenia or bipolar I mania: the FDA label for the IM product, adults only
• Undifferentiated severe agitation in the ED: ACEP's 2024 clinical policy lists an atypical antipsychotic as a Level B option, alone or with midazolam. Off-label. ACEP names no agent for the out-of-hospital setting or for patients over 65
• Cooperative agitated patient: the oral tablet or orally disintegrating tablet (ODT) when the patient will take medication by mouth. Off-label for acute agitation

ED / ICU / Transport

• Agitation with alcohol intoxication: the most common setting in large ED olanzapine studies. Watch oxygenation closely. Off-label
• Moderate or severe agitation in children and adolescents: one option in the 2019 AAEP pediatric consensus and NASEMSO v3.0. Off-label
• Chemotherapy-induced nausea and vomiting (CINV) prophylaxis: added to an NK₁ antagonist, a 5-HT₃ antagonist and dexamethasone for high-emetic-risk chemotherapy, per ASCO. Off-label

Other Uses

• Schizophrenia: oral treatment and maintenance, adults and adolescents 13–17 years
• Bipolar I disorder, manic or mixed episodes: oral monotherapy or adjunct to lithium or valproate; maintenance
• Bipolar I depression and treatment-resistant depression: only in combination with fluoxetine (Symbyax or the two components)
• Long-acting injection (olanzapine pamoate): schizophrenia only, through a restricted patient care program; never for acute agitation

Doses vary by protocol; follow local protocols and medical direction.

Available Forms

• IM injection (Zyprexa IntraMuscular and generics): 10 mg powder in a single-dose vial; reconstituted with 2.1 mL Sterile Water for Injection it gives about 5 mg/mL. This is the form EDs and some EMS agencies keep on hand.
• Tablets: 2.5, 5, 7.5, 10, 15 and 20 mg (not scored)
• Orally disintegrating tablets (Zyprexa Zydis and generics): 5, 10, 15 and 20 mg; bioequivalent to the tablets
• Long-acting injectable suspension (Zyprexa Relprevv, olanzapine pamoate): schizophrenia only; not interchangeable with the short-acting IM product
• Combination products: olanzapine/fluoxetine (Symbyax); olanzapine/samidorphan (Lybalvi, which contains an opioid antagonist)

Adult Dosing

Pediatric Dosing

Preparation & Administration

• Reconstitution: dissolve the 10 mg vial in 2.1 mL Sterile Water for Injection (about 5 mg/mL; clear yellow). Use Sterile Water only; lorazepam injection as the diluent delays reconstitution.
• Volumes at 5 mg/mL: 10 mg = withdraw the whole vial; 7.5 mg = 1.5 mL; 5 mg = 1 mL; 2.5 mg = 0.5 mL.
• Timing: give immediately, within 1 hour of reconstitution; discard the rest.
• Route: IM only. Inject slowly, deep into the muscle mass. The label says do not give IV or subcut.
• Syringe mixing: never in the same syringe as diazepam (precipitates) or haloperidol (the low pH degrades olanzapine).
• ODT: peel back the foil (do not push the tablet through) and place on the tongue with dry hands; it dissolves in saliva, with or without water. Contains aspartame (phenylalanine).
• After injection: keep a drowsy or dizzy patient recumbent until postural hypotension, bradycardia and hypoventilation are excluded.

Contraindications

• None with olanzapine monotherapy (label). Avoid it after a previous allergic reaction to olanzapine. Anaphylactoid reactions and angioedema have been reported.
• With fluoxetine, lithium or valproate: those products' contraindications still apply.
• Olanzapine/samidorphan (Lybalvi): contraindicated with opioid use or acute opioid withdrawal.

Precautions

• Parenteral benzodiazepines: the label does not recommend them with IM olanzapine. The concern is excess sedation and cardiorespiratory depression. See Interactions for the ED evidence.
• Alcohol intoxication: IM olanzapine, alone or with a benzodiazepine, has been linked to falling SpO₂ in alcohol-exposed patients. Monitor oxygenation continuously.
• Cardiovascular or cerebrovascular disease, dehydration, hypovolemia, antihypertensives: the risk of orthostatic hypotension, bradycardia and syncope is higher.
• Seizure disorder or a lowered seizure threshold: seizures in 0.9% in premarketing trials.
• Urinary retention, prostatic hypertrophy, constipation or ileus: these are antimuscarinic effects. Severe reactions, including deaths, were more likely with other anticholinergic drugs.
• Diabetes or its risk factors: hyperglycemia, sometimes with ketoacidosis or hyperosmolar coma.
• Heat, exertion, dehydration: impaired core temperature regulation.
• History of low WBC or drug-induced neutropenia: leukopenia, neutropenia and agranulocytosis reported.
• Dysphagia or aspiration risk (e.g., advanced Alzheimer disease): antipsychotics are linked to esophageal dysmotility and aspiration.

Hold / Reassess If

• Before any repeat IM dose: a clinically significant postural SBP drop (the label sets no number; e.g., ≥20 mmHg, the standard orthostatic threshold) or symptoms: no repeat
• SpO₂ <90%, rising EtCO₂ or falling respiratory rate: no further sedatives; support the airway and ventilation
• New bradycardia, sinus pauses or syncope: keep supine, stop further doses
• Fever with rigidity or altered mental status: stop all antipsychotics and evaluate for neuroleptic malignant syndrome (NMS)
• Absolute neutrophil count <1,000/mm³: discontinue (label)

Common

• Somnolence: 26% with oral olanzapine (15% placebo); 6% in the 24 hours after IM (3% placebo)
• Orthostatic hypotension and dizziness: orthostatic hypotension recorded in ≥20% in pooled adult oral data; dizziness about 11%
• Dry mouth and constipation: antimuscarinic effects (dry mouth 22% in bipolar trials)
• Weight gain and increased appetite: 22% gained ≥7% of body weight in short-term trials; more in adolescents
• Akathisia and tremor: about 5–6% with oral use; extrapyramidal effects in 0.1% after IM agitation doses in an ED cohort
• Prolactin elevation: 30% of adults, 47% of adolescents

Serious / Life-Threatening

Overdose & Toxicity Management

• Signs: agitation or aggression, dysarthria, tachycardia, extrapyramidal symptoms and reduced consciousness from sedation to coma; less often aspiration, respiratory depression, seizures, hypotension or hypertension, arrhythmias, delirium and NMS. Death has followed ingestions of possibly as little as 450 mg. One patient survived about 2 g.
• Immediate care: airway, oxygenation and ventilation; continuous ECG monitoring; consider co-ingestants; call Poison Control (1-800-222-1222).
• Decontamination: Activated charcoal cut the peak level and AUC of oral olanzapine by about 60%. Oral levels peak about 6 hr after a dose. That is why charcoal may help once the airway is protected.
• Hypotension: The label (Relprevv overdose section) advises IV fluids and/or sympathomimetics. It advises against epinephrine, dopamine or other sympathomimetics with beta-agonist activity. Beta stimulation can worsen hypotension when alpha is blocked. In practice an alpha-predominant agent such as norepinephrine or phenylephrine is used, per toxicology or medical control.
• No antidote. Dialysis does not remove olanzapine. For acute dystonia, use an anticholinergic such as diphenhydramine per protocol.

Clinically Significant Interactions

IV Compatibility

• Not an IV product: the label directs IM use only. Some ED protocols use it IV off-label, so follow institutional guidance.
• Reconstitute only with Sterile Water for Injection.
• Do not mix in a syringe with diazepam (precipitation) or haloperidol (degradation).
• Verify with an institutional compatibility resource.

• Pediatrics: Oral use is established only from 13 years, for schizophrenia and bipolar mania. With fluoxetine, it starts at 10 years, for bipolar depression. The label does not establish IM use in children. The off-label IM doses in the Pediatric Dosing table come from NASEMSO v3.0. Adolescents gain more weight and show larger lipid, prolactin and ALT rises. Doses are in the Pediatric Dosing table.
• Neonates: third-trimester exposure can cause extrapyramidal or withdrawal signs: agitation, abnormal tone, tremor, somnolence, respiratory distress and feeding problems. Tell the neonatal team.
• Pregnancy: published epidemiologic data have not established a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Untreated schizophrenia or bipolar disorder carries its own maternal risk. Don't withhold an indicated dose for dangerous agitation. A national pregnancy registry for atypical antipsychotics exists.
• Lactation: olanzapine enters breast milk. Infants have had excess sedation, irritability, poor feeding and extrapyramidal symptoms. Monitor the infant.
• Older Adults: boxed warning for increased mortality in older adults with dementia-related psychosis. The label also warns of stroke and TIA in this group, including deaths. The half-life runs about 1.5 times longer. Use 5 mg IM, or 2.5 mg if frail, and watch for falls and orthostasis. The AGS Beers Criteria (2023) advise avoiding antipsychotics for behavioral symptoms of dementia or delirium. The exception: nonpharmacologic measures have failed or are not possible, and the patient threatens substantial harm.
• Renal Impairment: no dose adjustment is needed. Only 7% is excreted unchanged. Dialysis does not remove it.
• Hepatic Impairment: no specific adjustment is established. In a small label study, Child-Pugh A–B cirrhosis had little effect on kinetics. Other data show moderate impairment cut clearance by about 45%. Use caution and a lower starting dose.
• Obesity / Dosing Weight: adult doses are fixed. They are not weight-based.
• Slow Metabolizers: clearance is about 30% lower in women and about 40% higher in smokers. When several slow-clearance factors stack up (nonsmoking, female, age ≥65), start low.
• Patients on Lybalvi (olanzapine/samidorphan): samidorphan blocks opioids. In an emergency that needs opioid analgesia, stop Lybalvi. Have opioids given by staff trained in airway management, with continuous monitoring. Overcoming the blockade with high doses risks fatal opioid toxicity.

• Scope: paramedic, flight and critical-care transport, ED and inpatient RN under protocol or order; varies by state and agency protocol.
• Storage & Stability: Store at 20–25 °C (68–77 °F). Excursions to 15–30 °C (59–86 °F) are acceptable. Protect the vial from light and do not freeze it. Once reconstituted, keep it at room temperature and use it within 1 hour.
• Carried Concentration: one 10 mg vial gives about 5 mg/mL after 2.1 mL Sterile Water. Say the dose in both mg and mL at the cross-check: 5 mg = 1 mL.
• Agitation Calls: verbal de-escalation first; avoid prone restraint (NASEMSO v3.0, p. 63); check glucose; continuous SpO₂, EtCO₂ and ECG once sedated.
• Benzodiazepine Coordination: find out whether a parenteral benzodiazepine was already given and when; follow the agency rule on combining or spacing them.
• Long-Acting Injection Patients: sedation or delirium after a Zyprexa Relprevv injection is post-injection delirium/sedation syndrome. Treat it as olanzapine overdose with supportive care. Onset is most likely in the first hour, and most cases start within 3 hours. Every reported patient had largely recovered by 72 hours.
• Handoff Essentials: drug, dose, route and time of each dose; other sedatives and alcohol; sedation score before and after; orthostatic BP; airway events; glucose; whether the patient takes Lybalvi or Relprevv.

Mechanism of Action

• Dopamine D₂ and serotonin 5-HT₂A antagonism → psychosis and agitation ease, with less extrapyramidal effect than first-generation drugs.
• Histamine H₁ blockade → sedation, appetite and weight gain.
• Alpha-1 adrenergic blockade → orthostatic hypotension.
• Muscarinic blockade (moderate affinity) → dry mouth, constipation, urinary retention, delirium risk.
• Low affinity for GABA-A and benzodiazepine receptors → no benzodiazepine-like action. Sedation adds up when it is given with benzodiazepines.

Pharmacokinetics

• Half-life: 21–54 hr (mean 30 hr), similar after IM and oral doses. In older adults it runs about 1.5 times longer. Steady state takes about 1 week.
• Metabolism: direct glucuronidation and CYP1A2 oxidation do most of the work. CYP2D6 and flavin monooxygenase play a minor role. About 40% is lost to first-pass metabolism.
• Active metabolites: none at clinical concentrations.
• Elimination: 57% urine and 30% feces, mostly as metabolites; 7% unchanged.
• Distribution: volume of distribution about 1,000 L; 93% protein bound.

Generic Name

Olanzapine (long-acting injection: olanzapine pamoate)

Brand Names

Zyprexa (tablets), Zyprexa Zydis (ODT), Zyprexa IntraMuscular, Zyprexa Relprevv (long-acting); combinations Symbyax (with fluoxetine) and Lybalvi (with samidorphan); generics

Pharmacologic Class

Thienobenzodiazepine; second-generation (atypical) antipsychotic

Therapeutic Class

Antipsychotic; agent for acute agitation; adjunct antiemetic (off-label)

Controlled Substance

Not controlled

ISMP High-Alert

No

Look-Alike / Sound-Alike

OLANZapine / QUEtiapine; ZyPREXA / ZyrTEC, CeleXA, Zestril; Symbyax / Cymbalta (ISMP). Also short-acting IM olanzapine vs long-acting Zyprexa Relprevv