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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.
Medication Safety Issues
Sound-alike/look-alike issues:
OLANZapine may be confused with olsalazine, QUEtiapine
Zyprexa® may be confused with Celexa®, Reprexain®, Zestril®, Zyrtec®
Zyprexa® Zydis® may be confused with Zelapar™
Pronunciation
(oh LAN za peen)
U.S. Brand Names
Index Terms
Generic Available
No
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
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; acute agitation (patients with schizophrenia or bipolar mania); in combination with fluoxetine for treatment-resistant or bipolar I depression
Use: Unlabeled/Investigational
Treatment of psychosis/schizophrenia in children or adolescents; chronic pain; prevention of chemotherapy-associated delayed nausea or vomiting; psychosis/agitation related to Alzheimer's dementia
Pregnancy Risk Factor
C
Pregnancy Considerations
No evidence of teratogenicity reported in animal studies. However, fetal toxicity and prolonged gestation have been observed. 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
Hypersensitivity to olanzapine or any component of the formulation
Warnings/Precautions
Boxed warnings:
• Dementia: See “Disease-related 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:
• Pediatrics: Safety and efficacy have not been established in children.
• 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 administration: Patients should remain recumbent if drowsy/dizzy until hypotension, bradycardia, and/or hypoventilation has been ruled out. Concurrent use of I.M./I.V. benzodiazepines is not recommended (fatalities have been reported, though causality not determined).
Adverse Reactions
>10%:
Central nervous system: Somnolence (6% to 39% dose dependent), extrapyramidal symptoms (15% to 32% dose dependent), insomnia (up to 12%), dizziness (4% to 18%)
Gastrointestinal: Dyspepsia (7% to 11%), constipation (9% to 11%), weight gain (5% to 6%, has been reported as high as 40%), xerostomia (9% to 22% dose dependent)
Neuromuscular & skeletal: Weakness (2% to 20% dose dependent)
Miscellaneous: Accidental injury (12%)
1% to 10%:
Cardiovascular: Postural hypotension (1% to 5%), tachycardia (up to 3%), peripheral edema (up to 3%), chest pain (up to 3%), hyper-/hypotension (up to 2%)
Central nervous system: Personality changes (8%), speech disorder (7%), fever (up to 6%), abnormal dreams, euphoria, amnesia, delusions, emotional lability, mania, schizophrenia
Dermatologic: Bruising (up to 5%)
Endocrine & metabolic: Cholesterol increased (4%), prolactin increased
Gastrointestinal: Nausea (up to 9% dose dependent), appetite increased (3% to 6%), vomiting (up to 4%), flatulence, salivation increased, thirst
Genitourinary: Incontinence (up to 2%), UTI (up to 2%), vaginitis
Hepatic: ALT increased (2%)
Local: Injection site pain (I.M. administration)
Neuromuscular & skeletal: Tremor (1% to 7% dose dependent), abnormal gait (6%), back pain (up to 5%), joint/extremity pain (up to 5%), akathisia (3% to 5% dose dependent), hypertonia (up to 3%), articulation impairment (up to 2%), falling (particularly in older patients), joint stiffness, paresthesia, twitching
Ocular: Amblyopia (up to 3%), conjunctivitis
Respiratory: Rhinitis (up to 7%), cough (up to 6%), pharyngitis (up to 4%), dyspnea
Miscellaneous: Dental pain, diaphoresis, flu-like syndrome
<1%, postmarketing, and/or case reports (limited to important or life-threatening): Acidosis, akinesia, albuminuria, anaphylactoid reaction, anemia, angioedema, apnea, arteritis, asthma, ataxia, atelectasis, atrial fibrillation, AV block, cerebrovascular accident, coma, confusion, congestive heart failure, deafness, diabetes mellitus, diabetic acidosis, diabetic coma, dyskinesia, dysphagia, dystonia, dysuria, encephalopathy, facial paralysis, glaucoma, gynecomastia, heart arrest, heart block, heart failure, hematuria, hemoptysis, hemorrhage (eye, rectal, subarachnoid, vaginal), hepatitis, hyper-/hypoglycemia, hyper-/hypokalemia, hyperlipemia, hyper-/hyponatremia, hyperuricemia, hyper-/hypoventilation, hypoesthesia, hypokinesia, hypoproteinemia, hypoxia, jaundice, ileus, ketosis, leukocytosis (eosinophilia), leukopenia, liver damage (cholestatic or mixed), liver fatty deposit, lung edema, lymphadenopathy, menstrual irregularities, migraine, myasthenia, myopathy, neuralgia, neuroleptic malignant syndrome, neuropathy, neutropenia, osteoporosis, pancreatitis, paralysis, priapism, pulmonary embolus, rhabdomyolysis, seizure, stridor, stroke, sudden death, suicide attempt, syncope, tardive dyskinesia, thrombocythemia, thrombocytopenia, tongue edema, transient ischemic attack, venous thrombotic events, vomiting, withdrawal syndrome
Metabolism/Transport Effects
Substrate of CYP1A2 (major), 2D6 (minor); Inhibits CYP1A2 (weak), 2C9 (weak), 2C19 (weak), 2D6 (weak), 3A4 (weak)
Drug Interactions
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: 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
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Olopatadine, Ophthalmic. 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
Fluvoxamine: May decrease the metabolism of OLANZapine. 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
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
Tetrabenazine: May enhance the adverse/toxic effect of Antipsychotics. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may increase CNS depression).
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, powder for reconstitution: Store at room temperature 15°C to 30°C (59°F to 86°F); do not freeze. Protect from light.
Tablet and orally-disintegrating tablet: Store at room temperature of 15°C to 30°C (59°F to 86°F). Protect from light and moisture.
Reconstitution
Injection, powder for reconstitution: 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.
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:
I.M.: Rapidly absorbed
Oral: Well absorbed; not affected by food; tablets and orally-disintegrating tablets are bioequivalent
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
Bioavailability: >57%
Half-life elimination: 21-54 hours; ~1.5 times greater in elderly
Time to peak, plasma: Maximum plasma concentrations after I.M. administration are 5 times higher than maximum plasma concentrations produced by an oral dose.
I.M.: 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
Children: Schizophrenia/bipolar disorder (unlabeled use): Oral: Initial: 2.5 mg/day; titrate as necessary to 20 mg/day (0.12-0.29 mg/kg/day)
Adults:
Agitation (acute, associated with bipolar I mania or schizophrenia): I.M.: Initial dose: 5-10 mg (a lower dose of 2.5 mg may be considered when clinical factors warrant); additional doses (2.5-10 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 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."
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.
Treatment-resistant depression (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."
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
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: Oral, I.M.: 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
Psychosis/agitation related to Alzheimer's dementia (unlabeled use): Initial: 1.25-5 mg/day; if necessary, gradually increase as tolerated not to exceed 10 mg/day
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.
Injection: For I.M. administration only; 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. Concurrent use of I.M./I.V. benzodiazepines is not recommended (fatalities have been reported, though causality not determined).
Administration: I.V.
Do not administer injection intravenously.
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, personal/family history of obesity, 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.
Dietary Considerations
Tablets may be taken without regard to meals. Some products may contain phenylalanine.
Patient Education
Do not take any new medication during therapy unless approved by prescriber. Use exactly as directed; do not increase dose or frequency. Do not stop taking medication abruptly without consulting prescriber. It may take 2-3 weeks to achieve desired results. Avoid alcohol or caffeine and other prescription or OTC medications not approved by prescriber. Maintain adequate hydration unless instructed to restrict fluid intake. If you have diabetes, you may experience increased blood sugars. Monitor blood sugars closely. If you have glaucoma, periodic ophthalmic exams are recommended. You may experience excess drowsiness, restlessness, weakness, dizziness, or blurred vision (use caution driving or when engaging in tasks requiring alertness until response to drug is known); postural hypotension (use caution when rising from lying or sitting position or climbing stairs); constipation (increased exercise, fluids, fruit, or fiber may help); 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); suicidal ideation; unresolved constipation or GI effects; vision changes; respiratory difficulty; unusual cough or flu-like symptoms; or worsening of condition. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.
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.
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
Assess potential for interactions with other prescriptions, OTC medications, or herbal products patient may be taking. Initiate at lower doses. Taper dosage slowly when discontinuing. Instruct patients with diabetes to monitor blood glucose levels closely (may cause hyperglycemia). Monitor therapeutic effectiveness, and adverse reactions at beginning of therapy and periodically with long-term use. 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. Teach patient appropriate administration, interventions to reduce side effects, and adverse symptoms to report.
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]
Tablet, oral:
Zyprexa®: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg
Tablet, orally disintegrating:
Zyprexa® Zydis®:
5 mg [contains phenylalanine 0.34 mg/tablet]
10 mg [contains phenylalanine 0.45 mg/tablet]
15 mg [contains phenylalanine 0.67 mg/tablet]
20 mg [contains phenylalanine 0.9 mg/tablet]
Pricing: U.S. (www.drugstore.com)
Tablet, orally-disintegrating (ZyPREXA Zydis)
5 mg (30): $335.72
10 mg (30): $484.76
Tablets (ZyPREXA)
2.5 mg (30): $245.00
5 mg (30): $295.70
7.5 mg (30): $358.23
10 mg (30): $439.64
15 mg (30): $639.31
20 mg (30): $841.93
References
American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity, “Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes,” Diabetes Care, 2004, 27(2):596-601.
Baldwin DS and Montgomery SA, “First Clinical Experience With Olanzapine (LY 170053): Results of an Open-Label Safety and Dose-Ranging Study in Patients With Schizophrenia,” Int Clin Psychopharmacol, 1995, 10(4):239-44.
Carrillo JA, Herraiz AG, Ramos SI, et al, “Role of the Smoking-Induced Cytochrome P450 (CYP)1A2 and Polymorphic CYP2D6 in Steady-State Concentration of Olanzapine,” J Clin Psychopharmacol, 23(2):119-27.
Davis JM, Chen N, and Glick ID, “A Meta-analysis of the Efficacy of Second-Generation Antipsychotics,” Arch Gen Psychiatry, 2003, 60(6):553-64.
Dixon L, Perkins D, and Calmes C, Guideline Watch (September 2009): Practice Guideline for the Treatment of Schizophrenia, Arlington, Va: American Psychiatric Association, 2009. Available at http://www.psychiatryonline.com/content.aspx?aid=501001.
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.
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Content last modified January 2010
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