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olanzapine (Zyprexa, Zydis, Zyprexa, Relprevv)

Tradename: Zyprexa. FDA-approved generic Oct 2011 [14] Indications: 1) psychotic disorders including schizophrenia 2) psychosis & agitation in the elderly 3) treatment of acute mania & depression in patients with bipolar disorder [4] 4) used for anorexia nervosa [6] Contraindications: (Caution) 1) cardiovascular disease 2) cerebrovascular disease 3) hypovolemia 4) dehydration 5) seizures 6) Alzheimer's disease 7) hepatic insufficiency 8) prostatic hypertrophy 9) narrow-angle glaucoma 10) history of paralytic ileus 11) history of breast cancer 12) elderly or nursing home patients 13) adolescents [13] Dosage: 1) start 5-10 mg PO QD 2) increase by 5 mg/day at intervals >= 1 week 3) average effective dose: 10-15 mg PO QD 4) max dose: 20 mg PO QD Tabs: 2.5, 5, 7.5, 10 mg. Injection (Zyprexa IM), extended release Zyprexa Relprevv Tablets: oral disintegrating tablets (Zydis) Pharmacokinetics: 1) oral doses are well absorbed (unaffected by food) 2) peak plasma concentrations are reached 6 hours after oral dose 3) eliminated extensively by 1st pass metabolism 4) 93% bound to plasma proteins 5) 1/2 life 21-54 hours 6) metabolized in the liver by: a) cyt P450 1A2 & cyt P450 2D6 b) flavoprotein monooxygenase 7) metabolites excreted in urine (57%) & feces (30%) -> 10-N-glucuronide (44%) & 4'-N-desmethyl (31%) derivatives are the major metabolites 8) 7% recovered unchanged in the urine Monitor: - serum glucose, Lipid panel, weight Adverse effects: 1) common (> 10%) - headache, somnolence, insomnia, agitation, nervousness, hostility, dizziness 2) less common (1-10%) - dystonic reactions, parkinsonism, akathisia, anxiety, personality changes, fever, dry mouth, constipation, abdominal pain, weight gain, arthralgia, amblyopia, rhinitis, cough, pharyngitis 3) uncommon (< 1%) - peripheral edema, tardive dyskinesia, neuroleptic malignant syndrome 4) other [2, 4] - sedation - headache - nausea - anticholinergic effects - orthostatic hypotension - tremor - rhinitis - weakness [4] - falls in the elderly - gait ataxia - dyslipidemia: - increased serum cholesterol non non-HDL cholesterol - increased serum triglycerides [8,12] - hyperglycemia [8] - increased risk of diabetes mellitus [9] relative to risperidone & conventional antipsychotics odds ratio 4.2 - increased risk of diabetic ketoacidosis [20] - does NOT appear to cause agranulocytosis - lower risk of extrapyramidal effects than respiridone - increased risk of stroke (2-3 fold) in patients with dementia [10] - weight gain, substantial [12]; greatest among antipsychotics [21] - olanzapine > quetiapine > risperidone > aripiprazole [12] - in adolescents 8.5 kg after 11 weeks of therapy [12] - melatonin 5 mg QD may attenuate weight gain [17] - 2 unexplained deaths following IM injection [15] - Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [18] 5) black box warning [16] - increased risk of hyperglycemia - increased risk of cerebrovascular events - increased risk of mortality in patients with dementia - see atypical antipsychotic agent for number needed to harm Drug interactions: 1) similar to clozapine 2) cyt P450 inhibitors may decrease metabolism of olanzapine - rifampin, omeprazole, carbamazepine 3) decreased effect with: - tobacco smoke, levodopa, pergolide, bromocryptine, charcoal 4) increased effect with: - cyt P450 1A2 inhibitors such as fluvoxamine 5) increased toxicity: - increased sedation with alcohol or other CNS depressants, orthostatic hypotension with antihypertensive agents 6) any drug which inhibits cyt P450 1A2 or cyt P450 2D6 can increase olanzapine levels 7) any drug which induces cyt P450 1A2 or cyt P450 2D6 can diminish olanzapine levels Mechanism of action: 1) atypical antipsychotic (see clozapine) 2) combined dopamine & serotonin receptor blockade 3) affinity for several receptors a) serotonin receptors (5-HT3 receptor antagonist [11]) b) dopamine receptors c) muscarinic receptors d) histamine-H1 receptor 4) reduces irritability, euphoria & psychosis [4]

Interactions

drug interactions drug adverse effects (more general classes) monitor with atypical antipsychotic agents

Related

clozapine (Clozaril) cytochrome p450 1A2 (cytochrome P3-450, phenacetin deethylase, cytochrome p450-4, CYP1A2) cytochrome P450 2D6 (cytochrome P450 2D, cytochrome P450 DB1, debrisoquine-4-hydroxylase, CYP2D6)

General

atypical antipsychotic agent; second generation antipsychotic dopaminergic receptor antagonist serotonin antagonist

Properties

MISC-INFO: elimination route LIVER 1/2life 21-54 HOURS protein-binding 93% pregnancy-category C safety in lactation -

Database Correlations

PUBCHEM cid=4585

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998 Department of Veterans Affairs, VA National Formulary - restricted to monotherapy for the treatment of acute agitation associated with schizophrenia or bipolar I mania.
  3. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  4. Prescriber's Letter 7(7):41 2000
  5. PDR 2000
  6. Prescriber's Letter 8(9):52 2001
  7. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  8. Prescriber's Letter 9(3):17 2002
  9. Journal Watch 22(19):149-50, 2002 Koro CE et al, BMJ 325:243, 2002 http://bmj.com/cgi/content/full/325/7358/243
  10. Safety Data on Zyprexa (Olanzapine) and Symbyax (Olanzapine and Fluoxetine): Elderly Patients with Dementia-Related Psychosis Prescriber's Letter 11(4):20 2004 Detail-Document#: 200406 (subscription needed) http://www.prescribersletter.com
  11. Prescriber's Letter 11(6):34 2004 Olanzapine for Nausea Detail-Document#: 200609 (subscription needed) http://www.prescribersletter.com
  12. Correll CU et al Cardiometabolic Risk of Second-Generation Antipsychotic Medications During First-Time Use in Children and Adolescents JAMA. 2009;302(16):1765-1773 PMID: 19861668 http://jama.ama-assn.org/cgi/content/short/302/16/1765 - Varley CK & McClellan J Implications of Marked Weight Gain Associated With Atypical Antipsychotic Medications in Children and Adolescents JAMA. 2009;302(16):1811-1812 PMID: 19861677 http://jama.ama-assn.org/cgi/content/short/302/16/1811
  13. FDA MedWatch Zyprexa (olanzapine): Use in Adolescents http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm198402.htm
  14. FDA NEWS RELEASE: Oct. 24, 2011 FDA approves first generic olanzapine to treat schizophrenia, bipolar disorder http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm277022.htm
  15. FDA MedWatch. June 18, 2013 Zyprexa Relprevv (Olanzapine Pamoate): Drug Safety Communication - FDA Investigating Two Deaths Following Injection. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm357601.htm - FDA Medwatch. March 23, 2015 Zyprexa Relprevv (olanzapine pamoate): Drug Safety Communication - FDA Review of Study Sheds Light on Two Deaths Associated with the Injectable Schizophrenia Drug. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm439472.htm - FDA Safety Alert: March 23, 2015 FDA Drug Safety Communication: FDA review of study sheds light on two deaths associated with the injectable schizophrenia drug Zyprexa Relprevv (olanzapine pamoate). http://www.fda.gov/Drugs/DrugSafety/ucm439147.htm
  16. Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
  17. Romo-Nava F et al. Melatonin attenuates antipsychotic metabolic effects: An eight-week randomized, double-blind, parallel-group, placebo- controlled trial. Bipolar Disord 2014 Mar 17 PMID: 24636483 http://onlinelibrary.wiley.com/doi/10.1111/bdi.12196/abstract
  18. FDA Safety Alert. May 10, 2016 Olanzapine: Drug Safety Communication - FDA Warns About Rare But Serious Skin Reactions. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm500123.htm
  19. Medical Knowledge Self Assessment Program (MKSAP) 19. American College of Physicians, Philadelphia 2021
  20. NEJM Knowledge+ Endocrinology
  21. Sabe M, Pallis K, Solmi M et al Comparative Effects of 11 Antipsychotics on Weight Gain and Metabolic Function in Patients With Acute Schizophrenia: A Dose-Response Meta-Analysis. J Clin Psychiatry. 2023 Feb 8;84(2):22r14490. PMID: 36752753
  22. Sandhya L et al. Randomized double-blind placebo-controlled study of olanzapine for chemotherapy- related anorexia in patients with locally advanced or metastatic gastric, hepatopancreaticobiliary, and lung cancer. J Clin Oncol 2023 May 10; 41:2617 PMID: 36977285 Clinical Trial. https://ascopubs.org/doi/10.1200/JCO.22.01997 - Roeland EJ, Bohlke K, Baracos VE et al Cancer Cachexia: ASCO Guideline Rapid Recommendation Update. J Clin Oncol. 2023 Sep 1;41(25):4178-4179. PMID: 37467399

Component-of

fluoxetine/olanzapine (Symbyax) olanzapine/samidorphan