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Olanzapine


Pronunciation

 (oh LAN za peen)


U.S. Brand Names

 Zyprexa®; Zyprexa® Zydis®


Synonyms

 LY170053; Zyprexa Zydis


Generic Available

 No


Canadian Brand Names

 Zyprexa®; Zyprexa® Zydis®


Use

 Treatment of the manifestations of schizophrenia; treatment of acute mania episodes associated with bipolar disorder (as monotherapy or in combination with lithium or valproate); maintenance treatment of bipolar disorder; acute agitation (patients with schizophrenia or bipolar mania)


Use - Unlabeled/Investigational

 Treatment of psychotic symptoms; chronic pain


Pregnancy Risk Factor

 C


Lactation

 Enters breast milk/not recommended


Contraindications

 Hypersensitivity to olanzapine or any component of the formulation


Warnings/Precautions

 Moderate to highly sedating, use with caution in disorders where CNS depression is a feature. Use with caution in Parkinson's disease; in patients with hemodynamic instability; bone marrow suppression; predisposition to seizures; subcortical brain damage; severe cardiac, hepatic, renal, or respiratory disease. Esophageal dysmotility and aspiration have been associated with antipsychotic use; use with caution in patients at risk of pneumonia (ie, Alzheimer's disease). Caution in breast cancer or other prolactin-dependent tumors (may elevate prolactin levels). May alter temperature regulation or mask toxicity of other drugs due to antiemetic effects. Life-threatening arrhythmias have occurred with therapeutic doses of some neuroleptics. An increased incidence of cerebrovascular adverse events (including fatalities) has been reported in elderly patients with dementia-related psychosis. Significant weight gain may occur.

May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); therefore, they should be used with caution in patients with decreased gastrointestinal motility, urinary retention, BPH, xerostomia, or visual problems. Conditions which also may be exacerbated by cholinergic blockade include narrow-angle glaucoma (screening is recommended) and worsening of myasthenia gravis. Relative to other neuroleptics, olanzapine has a moderate potency of cholinergic blockade.

May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is very low relative to other neuroleptics). May be associated with neuroleptic malignant syndrome (NMS). May cause hyperglycemia; in some cases may be extreme and associated with ketoacidosis, hyperosmolar coma, or death. Use with caution in patients with diabetes or other disorders of glucose regulation; monitor for worsening of glucose control.


Adverse Reactions

>10%:

Central nervous system: Headache, somnolence, insomnia, agitation, nervousness, hostility, dizziness

Gastrointestinal: Dyspepsia, constipation, weight gain (clinically and long term)

Neuromuscular & skeletal: Weakness

1% to 10%:

Cardiovascular: Postural hypotension, tachycardia, peripheral edema, chest pain, hyper-/hypotension

Central nervous system: Dystonic reactions, parkinsonian events, amnesia, euphoria, stuttering, akathisia, anxiety, personality changes, fever, abnormal dreams, speech disorder

Dermatologic: Rash, bruising

Endocrine & metabolic: Prolactin increased, amenorrhea

Gastrointestinal: Xerostomia, abdominal pain, appetite increased, vomiting, salivation increased

Genitourinary: Premenstrual syndrome, incontinence

Hematologic: Leukopenia

Neuromuscular & skeletal: Arthralgia, neck rigidity, twitching, hypertonia, tremor, back pain, abnormal gait, akathisia, falling (particularly in older patients)

Ocular: Amblyopia

Respiratory: Rhinitis, cough, pharyngitis, dyspnea

Miscellaneous: Diaphoresis

<1% (Limited to important or life-threatening): Agranulocytosis, diabetes mellitus, hyperglycemia, neuroleptic malignant syndrome, neutropenia, photosensitivity reaction, seizure, tardive dyskinesia

Postmarketing and/or case reports: Anaphylactoid reactions, angioedema, diabetic coma, pancreatitis, priapism, pruritus, urticaria

Additional significant effects reported with I.M. administration: Articulation impairment, AV block, injection site pain, syncope


Overdosage/Toxicology

 Signs and symptoms of overdose include CNS depression (ranging from drowsiness to coma), extrapyramidal movements, fasciculations, hypotension (possible, though not described), miosis, respiratory depression, rhinitis (10%), slurred speech, tachycardia, trismus. Treatment is symptom-directed and supportive.


Drug Interactions

 Substrate (minor) of CYP1A2, 2D6; Inhibits CYP1A2 (weak), 2C8/9 (weak), 2C19 (weak), 2D6 (weak), 3A4 (weak)

Activated charcoal: Decreases the Cmax and AUC of olanzapine by 60%

Antihypertensives: Increased risk of hypotension and orthostatic hypotension with antihypertensives

Carbamazepine: Decreases olanzapine levels

Clomipramine: When used in combination, clomipramine and olanzapine have been reported to be associated with the development of seizures; limited documentation (case report)

CNS depressants: Sedative effects and may be additive with CNS depressants; includes ethanol, barbiturates, narcotic analgesics, and other sedative agents; monitor for increased effect

Fluvoxamine: Increases olanzapine levels; consider using a lower dose of olanzapine in patients receiving concomitant treatment with fluvoxamine.

Haloperidol: A case of severe Parkinsonism following the addition of olanzapine to haloperidol therapy has been reported

Levodopa: Antipsychotics may inhibit the antiparkinsonian effect of levodopa; avoid this combination

Metoclopramide: May increase extrapyramidal symptoms (EPS) or risk.


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).


Stability

Tablet and orally-disintegrating tablet: Store at room temperature of 20°C to 25°C (68°F to 77°F); protect from light and moisture

Injection, powder for reconstitution: Store at room temperature 20°C to 25°C (68°F to 77°F); protect from light; do not freeze. 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 thienobenzodiazepine antipsychotic which is thought to work by antagonizing dopamine and serotonin activities. It is a selective monoaminergic antagonist with high affinity binding to serotonin 5-HT2A and 5-HT2C, dopamine D1-4, muscarinic M1-5, histamine H1- and alpha1-adrenergic receptor sites. Olanzapine binds weakly to GABA-A, BZD, and beta-adrenergic receptors.


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)

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: 40% removed via first pass metabolism; urine (57%, 7% as unchanged drug); feces (30%)

Clearance: 40% increase in olanzapine clearance in smokers


Dosage

Children: Schizophrenia/bipolar disorder: Oral: Initial: 2.5 mg/day; titrate as necessary to 20 mg/day (0.12-0.29 mg/kg/day)

Adults:

Schizophrenia: Oral: Usual starting dose: 5-10 mg once daily; increase to 10 mg once daily within 5-7 days, thereafter adjust by 5-10 mg/day at 1-week intervals, up to a maximum of 20 mg/day; doses of 30-50 mg/day have been used; typical dosage range: 10-30 mg/day

Bipolar mania: Oral:

Monotherapy: Usual starting dose: 10-15 mg once daily; increase by 5 mg/day at intervals of not less than 24 hours; maintenance: 5-20 mg/day; maximum dose: 20 mg/day

Combination therapy (olanzapine in combination with lithium or valproate): Initial: 10 mg once daily; dosing range: 5-20 mg/day

Agitation (acute, associated with bipolar disorder 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)

Elderly: Schizophrenia: Oral: Usual starting dose: 2.5 mg/day, increase as clinically indicated and monitor blood pressure; typical dosage range: 2.5-10 mg/day

Dosage comment in renal impairment: Not removed by dialysis


Administration

Injection: For I.M. administration only; do not administer injection intravenously; 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.

Tablet: May be administered with or without food/meals.

Orally-disintegrating: 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.


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; 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 with or without food/meals. Zyprexa® Zydis®: 5 mg tablet contains phenylalanine 0.34 mg; 10 mg tablet contains phenylalanine 0.45 mg; 15 mg tablet contains phenylalanine 0.67 mg; 20 mg tablet contains phenylalanine 0.9 mg


Patient Education

 Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Use exactly as directed; do not increase dose or frequency. It may take 2-3 weeks to achieve desired results; do not discontinue without consulting prescriber. Avoid alcohol or caffeine and other prescription or OTC medications not approved by prescriber. For orally-disintegrating tablets, 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. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. If diabetic, 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, dizziness, or blurred vision (use caution driving or when engaging in tasks requiring alertness until response to drug is known); or constipation (increased exercise, fluids, fruit, or fiber may help). Report persistent CNS effects (eg, trembling fingers, altered gait or balance, excessive sedation, seizures, unusual movements, anxiety, abnormal thoughts, confusion, personality changes); 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.


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.


Dosage Forms

Injection, powder for reconstitution (Zyprexa® IntraMuscular): 10 mg [contains lactose 50 mg]

Tablet (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]


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.

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.

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.

Littrell K, Peabody CD, and Littrell SH, "Olanzapine: A New Atypical Antipsychotic," J Psychosoc Nurs Ment Health Serv , 1996, 34(8):41-6.

"Olanzapine for Schizophrenia," Med Lett Drugs Ther , 1997, 39(992):5-6.

Rozen TD, "New Treatments in Cluster Headache," Curr Neurol Neurosci Rep , 2002, 2(2):114-21.

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.

Tollefson GD, Beasley CM Jr, Tran PV, et al, "Olanzapine Versus Haloperidol in the Treatment of Schizophrenia and Schizoaffective and Schizophreniform Disorders: Results of an International Collaborative Trial," Am J Psychiatry , 1997, 154(4):457-65.


International Brand Names

 Dozic® (CO); Joyzol® (IN); Midax® (AR); Olexa® (IN); Zelta® (CO); Zolafren® (PL); Zyprexa® (AR, AT, AU, BE, BR, CA, CH, CL, CO, CR, DE, DK, DO, ES, FI, FR, GB, GT, HN, HR, HU, ID, IE, IL, IT, JP, LU, MX, NL, NO, NZ, PA, PL, PT, RU, SE, SI, SV, TH, TR, YU, ZA); Zyprexa® Zydis® (CA)


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