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Special Alerts
Antipsychotics: Newborn Extrapyramidal and Withdrawal Symptoms with Third Trimester Exposure
February 2011
The U.S. Food and Drug Administration (FDA) has updated the pregnancy section of the prescribing information for antipsychotics to contain detailed information about nonteratogenic effects following maternal use during pregnancy. Antipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms; EPS) and withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor. These effects vary in severity and may be self-limiting (subsiding within hours or days) or require hospitalization. In the cases reported to the FDA, concomitant use of other medications (known to precipitate withdrawal symptoms) may have contributed to the effects, although in some cases, antipsychotic medication use was the only contributing factor for the EPS and withdrawal symptoms.
Women who are taking antipsychotics should not stop them if they become pregnant (abrupt discontinuation is not recommended), but should notify their healthcare provider. Women taking antipsychotics who intend to become pregnant should discuss treatment concerns with their healthcare provider. Any adverse effects noted in newborns should be reported to the FDA's Medwatch program (1-800-332-1088 or https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm).
For additional information, please refer to http://www.fda.gov/Drugs/DrugSafety/ucm243903.htm#aihp
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(oh LAN za peen)
Generic Available (U.S.)
No
Index Terms
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Zyprexa® and Zyprexa® Zydis: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM134700.pdf
Zyprexa® Relprevv™: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM194579.pdf
REMS Components
Zyprexa®, Zyprexa® Zydis®: Medication Guide
Zyprexa® Relprevv™: Communication Plan; Elements to Assure Safe Use; Implementation System; Medication Guide
Prescribing and Access Restrictions
As a requirement of the REMS program, only prescribers, healthcare facilities, and pharmacies registered with the Zyprexa® Relprevv™ Patient Care Program are able to prescribe, distribute, or dispense Zyprexa® Relprevv™ for patients who are enrolled in and meet all conditions of the program. Zyprexa® Relprevv™ must be administered at a registered healthcare facility. Prescribers will need to be recertified every 3 years. Contact the Zyprexa® Relprevv™ Patient Care Program at 1-877-772-9390.
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Oral: Treatment of the manifestations of schizophrenia; treatment of acute or mixed mania episodes associated with bipolar I disorder (as monotherapy or in combination with lithium or valproate); maintenance treatment of bipolar disorder; in combination with fluoxetine for treatment-resistant or bipolar I depression
I.M., extended-release (Zyprexa® Relprevv™): Treatment of schizophrenia
I.M., short-acting (Zyprexa® IntraMuscular): Treatment of acute agitation associated with schizophrenia and bipolar I mania
Use: Unlabeled/Investigational
Treatment of psychosis/schizophrenia in children; chronic pain; prevention of chemotherapy-associated delayed nausea or vomiting; psychosis/agitation related to Alzheimer's dementia; acute treatment of delirium
Pregnancy Risk Factor
C
Pregnancy Considerations
No evidence of teratogenicity reported in animal studies. However, fetal toxicity and prolonged gestation have been observed. Antipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms [EPS]) and withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor; these effects may be self-limiting or require hospitalization. There are no adequate and well-controlled studies in pregnant women. Healthcare providers are encouraged to enroll women 18-45 years of age exposed to olanzapine during pregnancy in the Atypical Antipsychotics Pregnancy Registry (1-866-961-2388).
Lactation
Enters breast milk/not recommended
Breast-Feeding Considerations
At steady-state concentrations, it is estimated that a breast-fed infant may be exposed to ~2% of the maternal dose.
Contraindications
There are no contraindications listed in the manufacturer's labeling.
Canadian labeling: Hypersensitivity to olanzapine or any component of the formulation
Warnings/Precautions
Boxed warnings:
• Dementia: See “Disease-related concerns” below.
• Post-injection delirium/sedation syndrome: See “Dosage form-specific concerns” below.
Concerns related to adverse effects:
• Altered cardiac conduction: May alter cardiac conduction; life-threatening arrhythmias have occurred with therapeutic doses of antipsychotics.
• Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems (including narrow-angle glaucoma). Relative to other neuroleptics, olanzapine has a moderate potency of cholinergic blockade.
• 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, pre-existing low WBC or history of drug-induced leuko-/neutropenia) should prompt periodic blood count assessment. Discontinue therapy at first signs of blood dyscrasias or if absolute neutrophil count <1000/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.
• Esophageal dysmotility/aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; use with caution in patients at risk of pneumonia (ie, Alzheimer's disease).
• Extrapyramidal symptoms (EPS): May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is generally much lower relative to typical/conventional antipsychotics). Risk of dystonia (and probably other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients.
• Hyperglycemia: Atypical antipsychotics have been associated with development of hyperglycemia; in some cases, may be extreme and associated with ketoacidosis, hyperosmolar coma, or death. Olanzapine may have a greater association with hyperglycemia than other atypical antipsychotics. Use with caution in patients with diabetes or other disorders of glucose regulation; monitor for worsening of glucose control. Patients with risk factors for diabetes (eg, obesity or family history) should have a baseline fasting blood sugar (FBS) and periodic assessment of glucose regulation.
• Hyperlipidemia: Increases in cholesterol and triglycerides have been noted. Use with caution in patients with pre-existing abnormal lipid profile.
• Hyperprolactinemia: May increase prolactin levels; clinical significance of hyperprolactinemia in patients with breast cancer or other prolactin-dependent tumors is unknown.
• Neuroleptic malignant syndrome (NMS): Use may be associated with NMS; monitor for mental status changes, fever, muscle rigidity, and/or autonomic instability.
• Orthostatic hypotension: 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).
• Sedation: May be moderate to highly sedating, use with caution in disorders where CNS depression is a feature; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• Suicidal ideation: The possibility of a suicide attempt is inherent in psychotic illness or bipolar disorder; use with caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care.
• Temperature regulation: Impaired core body temperature regulation may occur; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.
• Weight gain: Significant weight gain (>7% of baseline weight) has been observed with antipsychotic therapy; incidence varies with product. Monitor waist circumference and BMI.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with severe cardiac disease, hemodynamic instability, prior myocardial infarction, ischemic heart disease, or hypercholesterolemia.
• Dementia: [U.S. Boxed Warning]: Elderly patients with dementia-related psychosis treated with antipsychotics are at an 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 is not approved for the treatment of dementia-related psychosis.
• Hepatic impairment: Use with caution in patients with hepatic disease or impairment; may increase transaminases (primarily ALT).
• Parkinson's disease: Use with caution in patients with Parkinson's disease.
• Renal impairment: Use with caution in patients with renal disease.
• Seizures: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold. Elderly patients may be at increased risk of seizures due to an increased prevalence of predisposing factors.
Special populations:
• Adolescents: Use in patients ≥13 years of age may result in increased weight gain and sedation, as well as greater increases in LDL cholesterol, total cholesterol, triglycerides, prolactin, and liver transaminase levels when compared to adults. Adolescent patients should be maintained on the lowest dose necessary.
• Smokers: Olanzapine levels may be lower in patients who smoke; the manufacturer does not require dosage adjustments, although dosage adjustments may be considered.
Dosage form-specific concerns:
• Intramuscular formulations: There are two Zyprexa® formulations for intramuscular injection: Zyprexa® Relprevv™ is an extended-release formulation and Zyprexa® IntraMuscular is short-acting.
Extended-release I.M. injection (Zyprexa® Relprevv™):
Post-injection delirium/sedation syndrome: [U.S. Boxed Warning]: Sedation (including coma) and delirium (including agitation, anxiety, confusion, disorientation) have been observed following use of Zyprexa® Relprevv™; events associated with an inadvertent rapid rise in serum concentrations; administer at a registered healthcare facility where patients should be continuously monitored (≥3 hours) for symptoms of olanzapine overdose; symptom development highest in first hour but may occur within or after 3 hours; risk of syndrome is cumulative with each injection; recovery expected by 72 hours. Upon determining alert status, patient should be escorted to their destination and not drive or operate heavy machinery for the remainder of the day.
Restricted distribution program: Zyprexa® Relprevv™ is only available under a restricted distribution program. Only prescribers, healthcare facilities, and pharmacies registered with the program are able to prescribe, distribute, or dispense Zyprexa® Relprevv™ for patients who are enrolled in and meet all conditions of the program.
Short-acting I.M. injection (Zyprexa® IntraMuscular): Patients should remain recumbent if drowsy/dizzy until hypotension, bradycardia, and/or hypoventilation have been ruled out. Closely monitor for orthostasis prior to any repeat dosing. Concurrent use of I.M./I.V. benzodiazepines is not recommended (fatalities have been reported, though causality not determined).
Adverse Reactions
Oral: Unless otherwise noted, adverse events are reported for placebo-controlled trials in adult patients on monotherapy:
>10%:
Central nervous system: Somnolence (dose dependent; 20% to 39%; adolescents 39% to 48%), extrapyramidal symptoms (dose dependent; ≤32%), dizziness (11% to 18%), headache (adolescents 17%), fatigue (adolescents 3% to 14%), insomnia (12%)
Endocrine & metabolic: Prolactin increased (30%; adolescents 47%)
Gastrointestinal: Weight gain (5% to 6%, has been reported as high as 40%; adolescents 29% to 31%), appetite increased (3% to 6%; adolescents 17% to 29%), xerostomia (dose dependent; 3% to 22%), constipation (9% to 11%), dyspepsia (7% to 11%)
Hepatic: ALT increased ≥3 x ULN (adolescents 12%; adults 5%)
Neuromuscular & skeletal: Weakness (dose dependent; 8% to 20%)
Miscellaneous: Accidental injury (12%)
1% to 10%:
Cardiovascular: Chest pain, hypertension, peripheral edema, postural hypotension, tachycardia
Central nervous system: Fever, personality changes, restlessness (adolescents)
Dermatologic: Bruising
Endocrine & metabolic: Breast-related events ([adolescents] discharge, enlargement, galactorrhea, gynecomastia, lactation disorder); menstrual-related events (amenorrhea, hypomenorrhea, menstruation delayed, oligomenorrhea); sexual function-related events (anorgasmia, ejaculation delayed, erectile dysfunction, changes in libido, abnormal orgasm, sexual dysfunction)
Gastrointestinal: Abdominal pain (adolescents), diarrhea (adolescents), flatulence, nausea (dose dependent), vomiting
Genitourinary: Incontinence, UTI
Hepatic: Hepatic enzymes increased
Neuromuscular & skeletal: Abnormal gait, akathisia, articulation impairment, back pain, falling, hypertonia, joint/extremity pain, muscle stiffness (adolescents), tremor (dose dependent)
Ocular: Amblyopia
Respiratory: Cough, epistaxis (adolescents), pharyngitis, respiratory tract infection (adolescents), rhinitis, sinusitis (adolescents)
<1%, postmarketing, and/or case reports (limited to important or life-threatening): Acidosis, accommodation abnormal, agranulocytosis, akinesia, albuminuria, alopecia, anaphylactoid reaction, angioedema, apnea, arteritis, asthma, ataxia, atelectasis, atrial fibrillation, cerebrovascular accident, coma, confusion, congestive heart failure, deafness, diabetes mellitus, diabetic ketoacidosis, diabetic coma, dysarthria, dyskinesia, dysphagia, dystonia, dysuria, encephalopathy, facial paralysis, glaucoma, heart arrest, heart failure, hematuria, hemoptysis, hemorrhage (eye, rectal, subarachnoid, vaginal), hepatitis, hypercholesterolemia, hyper-/hypoglycemia, hyper-/hypokalemia, hyperlipemia, hyper-/hyponatremia, hypertriglyceridemia, hyperuricemia, hyper-/hypoventilation, hypoesthesia, hypokinesia, hypoproteinemia, hypoxia, jaundice, ileus, ketosis, leukocytosis (eosinophilia), leukopenia, liver damage (cholestatic or mixed), liver fatty deposit, lung edema, lymphadenopathy, migraine, myasthenia, myopathy, neuralgia, neuroleptic malignant syndrome, neuropathy, neutropenia, osteoporosis, pancreatitis, paralysis, priapism, pruritus, pulmonary embolus, rash, rhabdomyolysis, seizure, stridor, stroke, sudden death, suicide attempt, syncope, tardive dyskinesia, thrombocythemia, thrombocytopenia, tongue edema, transient ischemic attack, urticaria, venous thrombotic events, withdrawal syndrome
Injection: Unless otherwise noted, adverse events are reported for placebo-controlled trials in adult patients on extended-release I.M. injection (Zyprexa® Relprevv™). Also refer to adverse reactions noted with oral therapy.
>10%: Central nervous system: Headache (13 to 18%), sedation (8% to 13%)
1% to 10%:
Cardiovascular: Hypertension, hypotension (short-acting), postural hypotension (short-acting), QT prolongation
Central nervous system: Abnormal dreams, abnormal thinking, auditory hallucination, dizziness, dysarthria, extrapyramidal symptoms, fatigue, fever, pain, restlessness, somnolence
Dermatologic: Acne
Gastrointestinal: Abdominal pain, appetite increased, diarrhea, flatulence, nausea, vomiting, weight gain, xerostomia
Genitourinary: Vaginal discharge
Hepatic: Liver enzymes increased
Local: Injection site pain
Neuromuscular & skeletal: Arthralgia, back pain, muscle spasms, stiffness, tremor, weakness (short-acting)
Otic: Ear pain
Respiratory: Cough, nasal congestion, nasopharyngitis, pharyngolaryngeal pain, sneezing, upper respiratory tract infection
Miscellaneous: Toothache, tooth infection, viral infection
<1%, postmarketing, and/or case reports (limited to important or life-threatening): CPK increased, post-injection delirium/sedation syndrome, syncope (short-acting)
Metabolism/Transport Effects
Substrate of CYP1A2 (major), 2D6 (minor); Inhibits CYP1A2 (weak), 2C9 (weak), 2C19 (weak), 2D6 (weak), 3A4 (weak)
Drug Interactions
Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotics. Severe extrapyramidal symptoms have occurred in some patients. Risk C: Monitor therapy
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Amphetamines: Antipsychotics may diminish the stimulatory effect of Amphetamines. Risk C: Monitor therapy
Anticholinergics: May enhance the adverse/toxic effect of other Anticholinergics. Exceptions: Levocabastine (Nasal); Paliperidone. Risk C: Monitor therapy
Anti-Parkinson's Agents (Dopamine Agonist): Antipsychotics (Atypical) may diminish the therapeutic effect of Anti-Parkinson's Agents (Dopamine Agonist). Risk D: Consider therapy modification
Benzodiazepines: OLANZapine may enhance the adverse/toxic effect of Benzodiazepines. Management: Avoid concomitant use of parenteral benzodiazepines and IM olanzapine due to risks of additive adverse events (e.g., cardiorespiratory depression). Olanzapine prescribing information provides no specific recommendations regarding oral administration. Risk X: Avoid combination
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy
CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy
CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy
CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Risk D: Consider therapy modification
Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
FluvoxaMINE: May decrease the metabolism of OLANZapine. Risk D: Consider therapy modification
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: For patients being treated with hydroxyzine, a reduction in the dose of any other CNS depressants that are to be used in combination is recommended. With concurrent use, monitor patients closely for excessive response to the combination. Risk D: Consider therapy modification
LamoTRIgine: May enhance the sedative effect of OLANZapine. Risk C: Monitor therapy
Lithium formulations: May enhance the neurotoxic effect of Antipsychotics. Lithium formulations may decrease the serum concentration of Antipsychotics. Specifically noted with chlorpromazine. Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification
Methylphenidate: Antipsychotics may enhance the adverse/toxic effect of Methylphenidate. Methylphenidate may enhance the adverse/toxic effect of Antipsychotics. Risk C: Monitor therapy
Metoclopramide: May enhance the adverse/toxic effect of Antipsychotics. Risk X: Avoid combination
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Pramlintide: May enhance the anticholinergic effect of Anticholinergics. These effects are specific to the GI tract. Risk D: Consider therapy modification
Quinagolide: Antipsychotics may diminish the therapeutic effect of Quinagolide. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy
Tetrabenazine: May enhance the adverse/toxic effect of Antipsychotics. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: May increase CNS depression; monitor for increased effects with coadministration. Caution patients about effects.
Herb/Nutraceutical: Avoid dong quai, St John's wort (may also cause photosensitization). Avoid kava kava, gotu kola, valerian, St John's wort (may increase CNS depression).
Storage
Injection, extended-release: Store at 20° to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Injection, short-acting: Store at 20° to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F); do not freeze. Protect from light.
Tablet and orally-disintegrating tablet: Store at 20° to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light and moisture.
Reconstitution
Injection, extended-release: Dilute as directed to final concentration of 150 mg/mL. Shake vigorously to mix; will form yellow, opaque suspension. Following reconstitution, suspension may be stored at room temperature and used within 24 hours. Shake vigorously to resuspend prior to administration. Use immediately once suspension is in syringe. Suspension may be irritating to skin; wear gloves during reconstitution.
Injection, short-acting: Reconstitute 10 mg vial with 2.1 mL SWFI. Resulting solution is ~5 mg/mL. Use immediately (within 1 hour) following reconstitution. Discard any unused portion.
Compatibility
Compatibility in syringe: Incompatible: Diazepam, haloperidol.
Mechanism of Action
Olanzapine is a second generation thienobenzodiazepine antipsychotic which 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. Although the precise mechanism of action in schizophrenia and bipolar disorder is not known, the efficacy of olanzapine is thought to be mediated through combined antagonism of dopamine and serotonin type 2 receptor sites.
Pharmacodynamics/Kinetics
Absorption:
Oral: Well absorbed; not affected by food; tablets and orally-disintegrating tablets are bioequivalent
Short-acting injection: Rapidly absorbed
Distribution: Vd: Extensive, 1000 L
Protein binding, plasma: 93% bound to albumin and alpha1-glycoprotein
Metabolism: Highly metabolized via direct glucuronidation and cytochrome P450 mediated oxidation (CYP1A2, CYP2D6); 40% removed via first pass metabolism
Half-life elimination: 21-54 hours; ~1.5 times greater in elderly; Extended-release injection: ~30 days
Time to peak, plasma: Maximum plasma concentrations after I.M. administration are 5 times higher than maximum plasma concentrations produced by an oral dose.
Extended-release injection: ~7 days
Short-acting injection: 15-45 minutes
Oral: ~6 hours
Excretion: Urine (57%, 7% as unchanged drug); feces (30%)
Clearance: 40% increase in olanzapine clearance in smokers; 30% decrease in females
Dosage
Adolescents ≥13 years: Schizophrenia/bipolar disorder: Oral: Initial: 2.5-5 mg once daily; adjust by 2.5-5 mg/day to target dose of 10 mg/day; dosing range: 2.5-20 mg/day
Adults:
Agitation (acute, associated with bipolar I mania or schizophrenia): Short-acting I.M. injection: Initial dose: 10 mg (a lower dose of 5-7.5 mg may be considered when clinical factors warrant); additional doses (up to 10 mg) may be considered, however, 2-4 hours should be allowed between doses to evaluate response (maximum total daily dose: 30 mg, per manufacturer's recommendation)
Bipolar I acute mixed or manic episodes: Oral:
Monotherapy: Initial: 10-15 mg once daily; increase by 5 mg/day at intervals of not less than 24 hours. Maintenance: 5-20 mg/day; recommended maximum dose: 20 mg/day.
Combination therapy (with lithium or valproate): Initial: 10 mg once daily; dosing range: 5-20 mg/day; recommended maximum dose: 20 mg/day.
Depression:
Depression associated with bipolar disorder (in combination with fluoxetine): Oral: Initial: 5 mg in the evening; adjust as tolerated to usual range of 5-12.5 mg/day. See "Note."
Treatment-resistant depression (in combination with fluoxetine): Oral: Initial: 5 mg in the evening; adjust as tolerated to range of 5-20 mg/day. See "Note."
Note: When using individual components of fluoxetine with olanzapine rather than fixed dose combination product (Symbyax®), approximate dosage correspondence is as follows:
Olanzapine 2.5 mg + fluoxetine 20 mg = Symbyax® 3/25
Olanzapine 5 mg + fluoxetine 20 mg = Symbyax® 6/25
Olanzapine 12.5 mg + fluoxetine 20 mg = Symbyax® 12/25
Olanzapine 5 mg + fluoxetine 50 mg = Symbyax® 6/50
Olanzapine 12.5 mg + fluoxetine 50 mg = Symbyax® 12/50
Schizophrenia:
Oral: Initial: 5-10 mg once daily (increase to 10 mg once daily within 5-7 days); thereafter, adjust by 5 mg/day at 1-week intervals, up to a recommended maximum of 20 mg/day. Maintenance: 10-20 mg once daily. Doses of 30-50 mg/day have been used; however, doses >10 mg/day have not demonstrated better efficacy, and safety and efficacy of doses >20 mg/day have not been evaluated.
Extended-release I.M. injection: Note: Establish tolerance to oral olanzapine prior to changing to extended-release I.M. injection. Maximum dose: 300 mg/2 weeks or 405 mg/4 weeks
Patients established on oral olanzapine 10 mg/day: Initial dose: 210 mg every 2 weeks for 4 doses or 405 mg every 4 weeks for 2 doses; Maintenance dose: 150 mg every 2 weeks or 300 mg every 4 weeks
Patients established on oral olanzapine 15 mg/day: Initial dose: 300 mg every 2 weeks for 4 doses; Maintenance dose: 210 mg every 2 weeks or 405 mg every 4 weeks
Patients established on oral olanzapine 20 mg/day: Initial and maintenance dose: 300 mg every 2 weeks
Delirium (unlabeled use): Oral: 5 mg daily for up to 5 days (NICE, 2010)
Prevention of chemotherapy-associated delayed nausea or vomiting (unlabeled use; in combination with a corticosteroid and serotonin [5HT3] antagonist): Oral: 10 mg once daily for 3-5 days, beginning on day 1 of chemotherapy or 5 mg once daily for 2 days before chemotherapy, followed by 10 mg once daily (beginning on the day of chemotherapy) for 3-8 days
Elderly:
Short-acting I.M., Oral: Consider lower starting dose of 2.5-5 mg/day for elderly or debilitated patients; may increase as clinically indicated and tolerated with close monitoring of orthostatic blood pressure
Extended release I.M.: Consider lower starting dose of 150 mg every 4 weeks for elderly or debilitated patients; increase dose with caution as clinically indicated.
Delirium (unlabeled use): Patients >60 years: 2.5 mg daily for up to 5 days (NICE, 2010)
Psychosis/agitation related to Alzheimer's dementia (unlabeled use): Oral: Initial: 2.5-5 mg/day (Sultzer, 2008)
Dosage adjustment in renal impairment: No adjustment required. Not removed by dialysis.
Dosage adjustment in hepatic impairment: Dosage adjustment may be necessary; however, there are no specific recommendations. Monitor closely.
Administration: Oral
Tablet: May be administered without regard to meals.
Orally-disintegrating tablet: Remove from foil blister by peeling back (do not push tablet through the foil). Place tablet in mouth immediately upon removal. Tablet dissolves rapidly in saliva and may be swallowed with or without liquid. May be administered with or without food/meals.
Administration: I.M.
Short-acting I.M. injection: For I.M. administration only; do not administer injection intravenously or subcutaneously; inject slowly, deep into muscle. If dizziness and/or drowsiness are noted, patient should remain recumbent until examination indicates postural hypotension and/or bradycardia are not a problem.
Extended-release I.M. injection: For I.M. gluteal injection only; do not administer I.V. or subcutaneously. After needle insertion into muscle, aspirate to verify that no blood appears. Do not massage injection site. Use diluent, syringes, and needles provided in convenience kit; obtain a new kit if aspiration of blood occurs.
Monitoring Parameters
Vital signs; fasting lipid profile and fasting blood glucose/Hgb A1c (prior to treatment, at 3 months, then annually); periodic assessment of hepatic transaminases (in patients with hepatic disease); BMI, waist circumference; orthostatic blood pressure; mental status, abnormal involuntary movement scale (AIMS), extrapyramidal symptoms (EPS). Weight should be assessed prior to treatment, at 4 weeks, 8 weeks, 12 weeks, and then at quarterly intervals. Consider titrating to a different antipsychotic agent for a weight gain ≥5% of the initial weight.
Extended-release I.M. injection: Sedation/delirium for 3 hours after each dose
Dietary Considerations
Tablets may be taken without regard to meals. Some products may contain phenylalanine.
Patient Education
It may take 2-3 weeks to achieve desired results. Avoid alcohol. Maintain adequate hydration. If you have diabetes, you may experience increased blood sugars; monitor closely. If you have glaucoma, periodic ophthalmic exams are recommended. You may experience excess drowsiness, restlessness, weakness, dizziness, or blurred vision; postural hypotension; constipation; heartburn; dry mouth; or weight gain. Report persistent CNS effects (eg, trembling fingers, altered gait or balance, excessive sedation, seizures, unusual movements, anxiety, abnormal thoughts, confusion, personality changes); suicide ideation; unresolved constipation or GI effects; vision changes; respiratory difficulty; unusual cough; or worsening of condition.
Orally-disintegrating tablet: Remove from foil blister by peeling back; do not push tablet through the foil. Place tablet in mouth immediately upon removal. Tablet dissolves rapidly in saliva and may be swallowed with or without liquid.
Geriatric Considerations
Elderly patients have an increased risk of adverse response to side effects or adverse reactions to antipsychotics. A higher incidence of falls has been reported in elderly patients, particularly in debilitated patients. Olanzapine half-life that was 1.5 times that of younger (<65 years of age) adults; therefore, lower initial doses are recommended. Olanzapine is not indicated in dementia-related psychosis.
Studies with patients ≥65 years of age with schizophrenia showed no difference in tolerability compared to younger adults. Studies in the elderly with dementia-related psychosis suggested a different tolerability compared to younger patients with schizophrenia. In light of significant risks and adverse effects in the elderly population (compared with limited data demonstrating efficacy in the treatment of dementia-related psychosis, aggression, and agitation), an extensive risk:benefit analysis should be performed prior to use. Therefore, use with caution and at lower recommended doses.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Child/Adolescent Considerations
Five hospitalized children 6-11 years of age with varying diagnoses were treated with a mean daily dose of 7.5 mg/day (2.5-10 mg/day) or 0.22 mg/kg/day (0.12-0.29 mg/kg/day) for a mean of 32 days (Krishnamoorthy, 1998). Seven adolescents 12-17 years of age with DSM-IV bipolar disorder, manic episode were treated with a mean dose of 11 mg/day or 0.146 ± 0.086 mg/kg/day (Soutullo, 1999).
Krishnamoorthy J and King BH, “Open-Label Olanzapine Treatment in Five Preadolescent Children,” J Child Adolesc Psychopharmacol, 1998, 8(2):107-13.
Soutullo CA, Sorter MT, Foster KD, et al, “Olanzapine in the Treatment of Adolescent Acute Mania: A Report of Seven Cases,” J Affect Disord, 1999, 53(3):279-83.
Schizophrenia: Olanzapine has shown modest efficacy in pediatric schizophrenia, although treatment effects appear inferior to clozapine. However, the more favorable safety profile (compared to clozapine) may justify its continued use in this patient population.
In an open-label, single-arm pilot study, 8 children/adolescents (mean age: 15.3 years) diagnosed with childhood-onset schizophrenia (DSM-III-R) that was refractory to two prior typical neuroleptic regimens were evaluated for efficacy on olanzapine therapy for 8 weeks (Kumra, 1998). Rating instruments included the CGI, SANS, SAPS, and BPRS scales. In a separate study, a cohort of 15 children who received clozapine for 6 weeks was used as a comparative control group. Overall, olanzapine was well tolerated and did not cause any hematologic, EEG, or epileptogenic adverse effects, whereas 4 patients on clozapine required prophylactic anticonvulsant treatment. Body weight increases did not differ significantly between groups. Olanzapine dosing was initiated at 2.5 mg every other day (<40 kg) or every day (>40 kg), and titrated every 5-9 days by 2.5-5 mg up to a maximum of 20 mg/day. By the 6th week of treatment, the mean daily olanzapine dose was 17.5 mg (range: 12.5-20 mg) or 0.27 mg/kg. After 8 weeks of treatment, improvements relative to baseline were noted in each of the rating scales, ranging from 6% to 33%. However, the magnitude of response as measured by these scales was approximately threefold lower than the improvements seen with clozapine (using the same instruments) at the 6-week mark. Further, none of the olanzapine treated patients were rated as responders (based on standard criteria) at 6 weeks of therapy, and only 3 (38%) were responsive or partially responsive at 8 weeks. In comparison, 8 (53%) of clozapine-receiving patients were considered responders at the 6-week time point.
A double-blind, randomized, 8 week trial of olanzapine compared to clozapine was conducted in children/adolescents aged 7-16 years who met DSM-IV criteria for treatment-refractory schizophrenia (Shaw, 2006). The primary outcome measures were the CGI-S and SANS/SAPS scales. Patients randomized to olanzapine (n=13) were 12.8 years of age on average and received an average daily dose of 18.1 mg (20 mg/day maximum). Clozapine patients (n=12) were 11.7 years of age and received a mean daily dose of 387 mg (900 mg/day maximum). Side effects were reported more frequently in the clozapine arm (55 events) compared to the olanzapine arm (28 events, p<0.001), including significantly more cardiovascular events noted. Body weight increases and incidence of neutropenia did not differ significantly between groups. Relative to baseline antipsychotic-free scores, patients receiving clozapine showed improvements in the assessment scales of 23% to 48%, compared to 15% to 29% for olanzapine treated patients. Based on differential treatment effects, this equated to a 2.5-fold greater treatment effect in the clozapine arm.
A double-blind, randomized, placebo-controlled 6-week trial was conducted to assess the efficacy and tolerability of olanzapine in adolescents (aged 13-17 years) with schizophrenia (n=107) (Kryzhanovskaya, 2009). The primary efficacy outcome measure was the Brief Psychiatric Rating Scale for Children (BPRS-C). Adolescents randomized to olanzapine (n=72) received an initial dose of 2.5 or 5 mg/day which could be increased to a maximum dose of 20 mg/day. With a mean dose of 11.1 mg/day, olanzapine was found to be more effective than placebo for the treatment of schizophrenia. Olanzapine-treated patients had significantly greater improvements in BPRS-C scores compared to the placebo group. Significantly more olanzapine-treated adolescents completed the 6-week study compared to the placebo-treated adolescents (49/72 vs 15/35): 13.9% of the olanzapine-treated group compared to 51.4% of the placebo-treated group discontinued treatment due to lack of efficacy while 6.9% of the olanzapine-treated group compared to 0% of the placebo-treated group discontinued treatment due to an adverse event (all were related to elevated liver enzyme activity).
Kryzhanovskaya L, Schulz SC, McDougle C, et al, “Olanzapine Versus Placebo in Adolescents With Schizophrenia: A 6-Week, Randomized, Double-Blind, Placebo-Controlled Trial,” J Am Acad Child Adolesc Psychiatry, 2009, 48(1):60-70.
Kumra S, Jacobsen LK, Lenane M, et al, “Childhood-Onset Schizophrenia: An Open-Label Study of Olanzapine in Adolescents,” J Am Acad Child Adolesc Psychiatry, 1998, 37(4):377-85.
Shaw P, Sporn A, Gogtay N, et al, “Childhood-Onset Schizophrenia: A Double-Blind, Randomized Clozapine-Olanzapine Comparison,” Arch Gen Psychiatry, 2006, 63(7):721-30.
Mental Health: Comment
Olanzapine is an antipsychotic agent of a class often referred to as atypical. It should be noted that the definition of the term “atypical” is not universally agreed upon. Some prefer to describe antipsychotics based on their pharmacological properties. A common feature of all definitions used to describe “atypical” antipsychotics is the lack of significant acute or subacute EPS, at dosages generally associated with antipsychotic actions. Other experts have included definitions of atypicality that include a) failure to increase serum prolactin levels; b) superior efficacy for positive, negative, and cognitive symptoms; and c) lack of evidence of tardive dyskinesia or dystonia following chronic administration. Olanzapine meets most of these criteria, but is associated with dose-dependent EPS. Fortunately, if doses are kept within the approved dosage range (5-20 mg/day), EPS is low.
Tardive dyskinesia (TD) secondary to typical antipsychotics has an estimated incidence of 3% to 5% per year for the first 5 years of treatment. The incidence of TD associated with the atypical antipsychotics is estimated to be 0.5% to 1%. It is not clear if this estimate represents a risk associated with mental illness or to what extent drug therapy can be implicated. Atypical antipsychotics appear less likely to cause tardive dyskinesia than typical antipsychotics (fluphenazine, haloperidol).
Coadministration of two or more antipsychotics does not generally improve clinical response and may increase the potential for adverse effects.
In 2008, the FDA issued a warning regarding increased mortality risk with typical and atypical antipsychotic drugs when used in elderly patients with dementia-related psychosis.
Nursing: Physical Assessment/Monitoring
Initiate at lower doses. Taper dosage slowly when discontinuing. Instruct patients with diabetes to monitor blood glucose levels closely; may cause hyperglycemia. Assess for extrapyramidal symptoms, suicide ideation, sedation, and CNS changes prior to treatment and periodically throughout. Monitor weight prior to initiating therapy and at least monthly. Consider titrating to a different antipsychotic agent for a weight gain ≥5% of initial weight. If Zyprexa® Relprevv™ is administered, monitor closely for at least 3 hours for symptoms of oversedation and/or delirium.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution:
ZyPREXA® IntraMuscular: 10 mg [contains lactose 50 mg]
Injection, powder for suspension, extended release [kit]:
ZyPREXA® Relprevv™: 210 mg, 300 mg, 405 mg [contains polysorbate 80 (in diluent); supplied with diluent]
Tablet, oral:
ZyPREXA®: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg
Tablet, orally disintegrating, oral:
ZyPREXA® Zydis®: 5 mg [contains phenylalanine 0.34 mg/tablet]
ZyPREXA® Zydis®: 10 mg [contains phenylalanine 0.45 mg/tablet]
ZyPREXA® Zydis®: 15 mg [contains phenylalanine 0.67 mg/tablet]
ZyPREXA® Zydis®: 20 mg [contains phenylalanine 0.9 mg/tablet]
Pricing: U.S. (www.drugstore.com)
Tablet, orally-disintegrating (ZyPREXA Zydis)
5 mg (30): $399.99
10 mg (30): $598.99
Tablets (ZyPREXA)
2.5 mg (30): $301.99
5 mg (30): $365.97
7.5 mg (30): $409.99
10 mg (30): $529.01
15 mg (30): $769.99
20 mg (30): $1089.99
References
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Duggal HS, Gates C, and Pathak PC, “Olanzapine-Induced Neutropenia: Mechanism and Treatment,” J Clin Psychopharmacol, 2004, 24(2):234-5.
Farwell WR, Stump TE, Wang J, et al, “Weight Gain and New Onset Diabetes Associated With Olanzapine and Risperidone,” J Gen Intern Med, 2004, 19(12):1200-5.
Gill SS, Bronskill SE, Normand SL, et al, “Antipsychotic Drug Use and Mortality in Older Adults With Dementia,” Ann Intern Med, 2007, 146(11):775-86.
Goldberg RJ, “Managing Psychosis-Related Behavioral Problems in the Elderly,” Consult Pharm, 1997, 12(Suppl C):4-10.
Gorski ED and Willis KC, “Report of Three Cases Studied With Olanzapine for Chronic Pain,” J Pain, 2003, 4:166-8.
Khojainova N, Santiago-Palma J, Kornick C, et al, “Olanzapine in the Management of Cancer Pain,” J Pain Symptom Manage, 2002, 23(4):346-50.
Kiser RS, Cohen HM, Freedenfeld RN, et al, “Olanzapine for the Treatment of Fibromyalgia Symptoms,” J Pain Symptom Manage, 2001, 22(2):704-8.
Krishnamoorthy J and King BH, “Open-Label Olanzapine Treatment in Five Preadolescent Children,” J Child Adolesc Psychopharmacol, 1998, 8(2):107-13.
Kroon LA, “Drug Interactions With Smoking,” Am J Health Syst Pharm, 2007, 64(18):1917-21.
Kryzhanovskaya L, Schulz SC, McDougle C, et al, “Olanzapine Versus Placebo in Adolescents With Schizophrenia: A 6-Week, Randomized, Double-Blind, Placebo-Controlled Trial,” J Am Acad Child Adolesc Psychiatry, 2009, 48(1):60-70.
Kumra S, Jacobsen LK, Lenane M et al, “Childhood-Onset Schizophrenia: An Open-Label Study of Olanzapine in Adolescents,” J Am Acad Child Adolesc Psychiatry, 1998, 37(4):377-85.
Lauriello J, Lambert T, Andersen S, et al, “An 8-Week, Double-Blind, Randomized, Placebo-Controlled Study of Olanzapine Long-Acting Injection in Acutely Ill Patients With Schizphrenia,” J Clin Psychiatry, 2008, 69(5):790-9.
National Institute for Health and Clinical Excellence (NICE), National Clinical Guideline Centre, “Delirium: Diagnosis, Prevention and Management,” National Clinical Practice Guideline Number 103, 2010. Available at http://www.nice.org.uk/CG103
National Institute for Health and Clinical Excellence (NICE), National Collaborating Centre for Mental Health , “Schizophrenia. Core Interventions in the Treatment and Management of Schizophrenia in Primary and Secondary Care (Updated),” National Clinical Practice Guideline Number 82, 2009:1-399. Available at www.nice.org.uk/cg082
Navari RM, Einhorn LH, Loehrer PJ, et al, “A Phase II Trial of Olanzapine, Dexamethasone, and Palonosetron for the Prevention of Chemotherapy-Induced Nausea and Vomiting: A Hoosier Oncology Group Study,” Support Care Cancer, 2007, 15(11):1285-91.
Navari RM, Einhorn LH, Passik SD, et al, “A Phase II Trial of Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting: A Hoosier Oncology Group Study,” Support Care Cancer, 2005, 13(7):529-34.
Passick SD, Navari RM, Jung SH, et al, “A Phase I Trial of Olanzapine (Zyprexa) for the Prevention of Delayed Emesis in Cancer Patients: A Hoosier Oncology Group Study,” Cancer Invest, 2004, 22(3):383-8.
Rabins PV, Blacker D, Rovner BW, et al, “Practice Guidelines for the Treatment of Patients With Alzheimer's Disease and Other Dementias,” October, 2007. Available at http://www.psych.org/psych_pract/treatg/pg/prac_guide.cfm
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Schneeweiss S, Setoguchi S, Brookhart A, et al, “Risk of Death Associated With the Use of Conventional Versus Atypical Antipsychotic Drugs Among Elderly Patients,” CMAJ, 2007, 176(5): 627-32.
Schneider LS, Tariot PN, Dagerman KS, et al, “Effectiveness of Atypical Antipsychotic Drugs in Patients With Alzheimer's Disease,” N Engl J Med, 2006, 355(15):1525-38.
Shaw P, Sporn A, Gogtay N et al, “Childhood-Onset Schizophrenia: A Double-Blind, Randomized Clozapine-Olanzapine Comparison,” Arch Gen Psychiatry, 2006, 63(7):721-30.
Sorsaburu S, Hornbuckle K, Blake D, et al, “The First 21 Months of Safety Experience With Postmarketing Use of Olanzapine's Intramuscular Formulation,” College of Psychiatric and Neurologic Pharmacists, April, 2006, Baltimore, MD.
Soutullo CA, Sorter MT, Foster KD, et al, “Olanzapine in the Treatment of Adolescent Acute Mania: A Report of Seven Cases,” J Affect Disord, 1999, 53(3):279-83.
Sultzer DL, Davis SM, Tariot PN, et al, “Clinical Symptom Responses to Atypical Antipsychotic Medications in Alzheimer's Disease: Phase 1 Outcomes from the CATIE-AD Effectiveness Trial,” Am J Psychiatry, 2008, 165(7):844-54.
Suppes T, Dennehy EB, Hirschfeld RMA, et al, “The Texas Implementation of Medication Algorithms: Update to the Algorithms for the Treatment of Bipolar I Disorder,” J Clin Psychiatry, 2005, 66(7):870-86.
Thangadurai P, Jyothi KS, Gopalakrishman R, et al, “Reversible Neutropenia With Olanzapine Following Clozapine-Induced Neutropenia,” Am J Psychiatry, 2006, 163(7):1298.
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International Brand Names
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Last full review/revision May 2011
Content last modified May 2011
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