olanzapine (Zyprexa, Zyprexa Relprevv, Zyprexa Zydis)
Dosing and uses of Zyprexa, Zyprexa Relprevv (olanzapine)
Adult dosage forms and strengths
tablet
- 2.5mg
- 5mg
- 7.5mg
- 10mg
- 15mg
- 20mg
tablet, orally disintegrating
- 5mg
- 10mg
- 15mg
- 20mg
IM injection, short-acting
- 10mg
IM injection, extended-release suspension
- 210mg/vial
- 300mg/vial
- 405mg/vial
Schizophrenia
PO
- 5-10 mg/day initially; if necessary, may be titrated upward in increments of 5 mg/day at intervals >1 week
- Maintenance: 10-20 mg/day; not to exceed 20 mg/day
IM, extended-release
- Recommended dosing based on oral dosing
- Oral dosage 10 mg/day: 210 mg IM every 2 weeks or 405 mg IM every 4 weeks for 1st 8 weeks, then 150 mg every 2 weeks or 300 mg every 4 weeks
- Oral dosage 15 mg/day: 300 mg IM every 2 weeks for 1st 8 weeks, then 210 mg every 2 weeks or 405 mg every 4 weeks
- Oral dosage 20 mg/day: 300 mg IM every 2 weeks for 1st 8 weeks, then 300 mg every 2 weeks
Bipolar Mania
Used as monotherapy or in combination with lithium or valproate
Monotherapy: 10-15 mg/day PO initially
Adjunct to lithium or valproate: 10 mg/day PO initially
Maintenance: 5-20 mg/day PO; not to exceed 20 mg/day
Depression in bipolar disorder
- Use in combination with fluoxetine
- 5 mg in evening; adjusted to range of 5-12.5 mg/day; may be increased up to 20 mg/day in resistant depression
Dosing considerations
- Dosage adjustments, if necessary, should be made at intervals >24 hr
Schizophrenia or Bipolar-Related Agitation
10 mg IM (short-acting); consider 5-7.5 mg for geriatric patients or if circumstances warrant; subsequent IM doses up to 10 mg may be administered 2 hours after 1st dose and 4 hours after 2nd dose; not to exceed 30 mg/day
Dosing Modifications
Renal impairment: Dose adjustment not necessary
Hepatic impairment: Dose adjustment may be necessary; use caution
Administration
IM administration
- Short-acting and extended-release IM preparations are not interchangeable
- Short-acting: Dissolve in 2.1 mL SWI to yield 5 mg/mL solution; inject deep and slow within 1 hour of reconstitution
- Extended-release: Reconstitute with supplied diluent (210-mg vial in 1.3 mL; 300-mg vial in 1.8 mL; 405-mg vial in 2.3 mL); inject deep in gluteal muscle
- Do not use lorazepam injection for reconstitution, and do not mix with haloperidol or diazepam in syringe
Pediatric dosage forms and strengths
tablet
- 2.5mg
- 5mg
- 7.5mg
- 10mg
- 15mg
- 20mg
tablet, orally disintegrating
- 5mg
- 10mg
- 15mg
- 20mg
Bipolar I Disorder (Manic or Mixed Episodes)
<13 years: Safety and efficacy not established
13-17 years: 2.5-5 mg/day PO initially; target dosage, 10 mg/day; adjust by increments/decrements of 2.5-5 mg; dosage range, 2.5-20 mg/day
Schizophrenia
<13 years: Safety and efficacy not established
13-17 years: 2.5-5 mg/day PO initially; target dosage, 10 mg/day; adjust by increments/decrements of 2.5-5 mg; dosage range, 2.5-20 mg/day
Stuttering (Off-label)
≤12 years: 1.25 mg PO at bedtime for 4 weeks, then 2.5 mg at bedtime
>12 years: 2.5 mg PO at bedtime for 4 weeks, then 5 mg at bedtime
Geriatric dosage forms and strengths
Not approved for dementia-related psychosis, because of increased risk of cardiovascular or infection-related mortality (see Black box warnings)
Consider lower starting dosage
Schizophrenia
2.5-5 mg/day PO initially
IM (extended-release): 150 mg every 4 weeks in patients who are debilitated or predisposed to hypotensive episodes; not studied in patients with renal or hepatic impairment; requires deep IM administration (muscle mass in elderly may be sufficient)
Schizophrenia or Bipolar-Related Agitation
IM (short-acting): 5 mg; consider 2.5 mg if patient is predisposed to hypotensive reactions
Zyprexa, Zyprexa Relprevv (olanzapine) adverse (side) effects
>10%
Orthostatic hypotension (≥20%)
Weight gain, dose dependent (5-40%)
Hypertriglyceridemia (≤39%)
Hypercholesterolemia (≤39%)
Somnolence, dose dependent (6-39%)
Extrapyramidal symptoms (EPS), dose dependent (15-32%)
Xerostomia (9-22%)
Weakness (2-20%)
Dizziness (4-18%)
Accidental injury (12%)
Insomnia (12%)
Elevated alanine aminotransferase (ALT) level (5-12%)
Constipation (9-11%)
Dyspepsia (7-11%)
Hyperprolactinemia (30%)
Hyperglycemia (12.8%)
1-10%
Hypotension (2%)
Postural hypotension (1%)
Tremor (1%)
Asthenia (2%)
Akathisia reactions (2%)
Parkinsonism reactions (4%)
<1%
Syncope
Sudden cardiac death
Hyperglycemia
Diabetic coma with ketoacidosis
Diabetic ketoacidosis
Acute hemorrhagic pancreatitis
Venous thromboembolism
Immune hypersensitivity reaction
Cerebrovascular disease
Seizure, status epilepticus
Suicidal intent
Pulmonary embolism
Death
Neuroleptic malignant syndrome (NMS)
Tardive dyskinesia
Warnings
Black box warnings
Not approved for dementia-related psychosis; elderly patients with dementia-related psychosis who are treated with antipsychotic drugs are at increased risk of death, as shown in short-term controlled trials; in these trials, deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature
Patients are at risk for severe sedation (including coma) or delirium after each injection and must be observed for at least 3 hours in registered facility with ready access to emergency response services
Because of this risk, olanzapine is available only through restricted distribution program
Contraindications
Documented hypersensitivity
Cautions
Increased risk of hyperglycemia and diabetes; in some cases, hyperglycemia concomitant with use of atypical antipsychotics has been associated with ketoacidosis, hyperosmolar coma, or death
Monitor blood glucose of high-risk patients
Irreversible, involuntary, dyskinetic movements may develop with antipsychotic drugs; prevalence appears to be highest among elderly individuals, especially elderly women; discontinue if clinically appropriate
May cause anticholinergic effects including paralytic ileus, urinary retention, xerostomia, BPH, and visual problems
Neutropenia, leukopenia, and agranulocytosis reported; discontinue therapy at firs sign of blood dyscrasias or if absolute neutrophil count <1000/mm³
Cerebrovascular effects including, stroke and transient ischemic attack resulting in death reported
NMS has been reported
Increased potential for weight gain; patients should receive regular monitoring of weight
Appropriate clinical monitoring is recommended, including fasting blood lipid testing at the beginning of, and periodically during, treatment
May elevate prolactin levels
May induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, especially during initial dose-titration period, probably as consequence of alpha1-adrenergic antagonistic properties
Do not reconstitute with lorazepam injection; do not mix with diazepam or haloperidol in syringe
FDA warning regarding off-label use for dementia in elderly (see Black box warnings)
In narrow-angle glaucoma, cardiovascular disease, cerebrovascular disease, prostatic hypertrophy, hypovolemia, and dehydration, hyperglycemia may occur and in some cases may be extreme, resulting in ketoacidosis, hyperosmolar coma, or death; IM administration of >1 injection is associated with substantial orthostatic hypotension (33%); maintain patient in recumbent position and monitor blood pressure before repeating IM doses
Use caution in patients with history of seizures or with conditions that potentially lower seizure threshold
Changes from normal to high prolactin levels observed in controlled studies (incidence, 30%)
Use caution in patients at risk of pneumonia; may cause esophageal dysmotility and aspiration
Use caution with strenuous exercise, dehydration, heat exposure, and medications with anticholinergic effects; impaired core body temperature regulation may occur
Increased potential (in adolescents as compared with adults) for weight gain and hyperlipidemia; clinicians prescribing to adolescents should consider potential long-term risks, which in many cases may lead them to prescription of other drugs first in this population
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) reported with olanzapine exposure; DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis; DRESS is sometimes fatal; discontinue olanzapine if DRESS suspected
Possibility of suicide attempt is inherent in schizophrenia and in bipolar I disorder, and close supervision of high-risk patients should accompany drug therapy; when using in combination with fluoxetine, also refer to Boxed Warning and Precautions sections of package insert for Symbyax
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) reported; management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available; there is no general agreement about specific pharmacological treatment regimens for NMS; if patient requires antipsychotic drug treatment after recovery from NMS, potential reintroduction of drug therapy should be carefully considered; patient should be carefully monitored, since recurrences of NMS reported
Has potential to impair judgment, thinking, and motor skills; use caution when operating machinery
Olanzapine indicated as integral part of comprehensive treatment program for pediatric patients with schizophrenia and bipolar disorder, which may include other measures (eg, psychological, educational, social) as welL
IM, extended-release
- Because of risk of postinjection delirium/sedation syndrome, availability is restricted and requires registration (call 877-772-9390)
Pregnancy and lactation
Pregnancy category: C
Neonates exposed to antipsychotic drugs during 3rd trimester of pregnancy are at risk for EPS or withdrawal symptoms after delivery; these complications vary in severity, with some being self-limited and others requiring ICU support and prolonged hospitalization
Lactation: Drug enters breast milk; not recommended
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Zyprexa, Zyprexa Relprevv (olanzapine)
Mechanism of action
May act through combination of dopamine and serotonin type 2 receptor site antagonism
Absorption
Peak plasma time: 6 hr (PO); 15-45 min (short-acting IM); 7 days (extended-release IM)
Distribution
Protein bound: 93%
Vd: 1000 L
Metabolism
Extensively metabolized through direct glucuronidation and CYP450 oxidation
Metabolites: Inactive
Elimination
Half-life: 21-54 hr (immediate release); 30 days (extended release)
Excretion: Urine (57%), feces (30%)
