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quetiapine (Seroquel)

Tradename: Seroquel. (quetiapine fumarate) Generic 2012 [13] Indications: - treatment of psychosis - psychosis & agitation in the elderly - may be especially useful in patients with Parkinson's disease - bipolar disorder, depression, mania [14] Contraindications: - not useful for agitation in severely demented patients [7] - drug of abuse, alias quell, baby heroin, Suzie-Q abused for sedating, anti-anxiety effects [8] - history of cardiac arrhythmias - hypokalemia - hypomagnesemia - congenital QT prolongation [12] Caution: 1) cardiovascular disease 2) cerebrovascular disease 3) hepatic insufficiency 4) seizures 5) pregnancy & lactation - risk to fetus in 3rd trimester of extrapyramidal symptoms after delivery Dosage: 1) initial dose 25 mg PO BID 2) usual effective oral dose 300-400 mg/day divided BID-TID 3) maximum dose: 750 mg QD 4) safety of doses > 800 mg/day has not been determined 5) up to 200 mg QD effective for agitation in the elderly Tabs: 25 mg, 100 mg, 200 mg. Dosage adjustment may be necessary with hepatic insufficiency. Monitor: 1) liver function tests 2) complete blood count 3) serum prolactin levels 4) ocular exam for cataracts: initially & every 6 months 5) consider serum TSH, free T4 Pharmacokinetics: 1) bioavailablity: a) 9% after oral dose b) food increases absorption 2) peak serum levels occur 1.5 hours after oral dose 3) protein binding is 83% 4) steady-state levels occur in 2 days 5) peak serum concentration of 140-365 ng/mL after midday dose of 75 mg 6) volume of distribution: 10 L/kg 7) metabolized extensively in liver via cyt P450 3A4 a) sufoxidation & hydroxylation b) 7-hydroxyquetiapine & N-dealkylated metabolites are active 8) elimination: a) < 1% of drug excreted unchanged in the urine b) metabolites excreted in the urine (70-73%) c) biliary excretion 9) elimination 1/2life is 6 hours Adverse effects: 1) most common - dizziness, postural hypotension, constipation, dry mouth, somnolence, sedation 2) less common - dyspepsia, headache 3) other - low propensity to cause extrapyramidal effects - potentially hepatotoxic - leukopenia has occurred - weight gain, in adolescents 6.1 kg after 11 weeks of therapy [[3,5,11] - dyslipidemia: - increased serum cholesterol non non-HDL cholesterol - increased serum triglycerides [8,11] - hyperglycemia [5]; increased risk of diabetes mellitus [6] - associated with cognitive decline in patients with severe Alzheimer's disease [7] - increased mortality in elderly patients with dementia-related psychosis [12] - hypothyroidism: dose-related decrease in serum T4 generally not clinically significant [12] - increased risk of out-of-hospital cardiac arrest (RR=3.64) [10] - case report of hyperosmolar hyperglycemic state in a patient with dementia [16] 4) black box warning [15] - 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) drugs that increase quetiapine levels: a) any drug that inhibits cyt P450 3A4 may increase levels of quetiapine b) cimetidine (20%), erythromycin, fluconazole, itraconazole, ketoconazole 2) drugs that decrease levels: a) any drug that induces cyt P450 3A4 may diminish levels of quetiapine b) phenytoin (moderate), thioridazine 3) lithium: increased toxicity, mechanism unknown (major effect) 4) increases levels of: - lorazepam (minor) 5) ethanol (increased toxicity) 6) interactions that increase QT prolongation [12] a) class 1A antiarrhythmics (quinidine, procainamide) b) class III antiarrhythmics (amiodarone, sotalol) c) antipsychotics (ziprasidone, chlorpromazine, thioridazine) d) antibiotics (gatifloxacin, moxifloxacin) e) other drugs associated with QT prolongation (pentamidine, methadone) Laboratory: - quetiapine in gastric fluid - quetiapine in serum/plasma - quetiapine in urine Mechanism of action: 1) high affinity for serotonin [5HT]-2 receptors 2) moderate affinity for dopamine D2 receptor 3) appreciable affinity for a) alpha-1 adrenergic receptors b) alpha-2 adrenergic receptors c) histamine H1 receptors 4) atypical antipsychotic agent structurally related to olanzapine & clozapine

Interactions

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

Related

clozapine (Clozaril) cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4) olanzapine (Zyprexa, Zydis, Zyprexa, Relprevv)

General

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

Properties

MISC-INFO: protein-binding 83% 1/2life 6 HOURS

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Micromedex
  3. Prescriber's Letter 7(8):45 200
  4. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  5. Prescriber's Letter 9(3):17 2002
  6. Prescriber's Letter 10(11):62 2003
  7. Journal Watch 25(12):96, 2005 Ballard C, Margallo-Lana M, Juszczak E, Douglas S, Swann A, Thomas A, O'Brien J, Everratt A, Sadler S, Maddison C, Lee L, Bannister C, Elvish R, Jacoby R. Quetiapine and rivastigmine and cognitive decline in Alzheimer's disease: randomised double blind placebo controlled trial. BMJ. 2005 Apr 16;330(7496):874. Epub 2005 Feb 18. PMID: 15722369 - Gauthier S Drugs for Alzheimer's disease and related dementias. BMJ. 2005 Apr 16;330(7496):857-8. No abstract available. PMID: 15831849 http://bmj.bmjjournals.com/cgi/content/full/330/7496/874
  8. Prescriber's Letter 14(10): 2007 Quetiapine (Seroquel) abuse Detail-Document#: 231008 (subscription needed) http://www.prescribersletter.com
  9. Department of Veterans Affairs, VA National Formulary
  10. Weeke P et al. Antipsychotics and associated risk of out-of-hospital cardiac arrest. Clin Pharmacol Ther 2014 Jun 24 PMID: 24960522
  11. 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
  12. Revised quetiapine labeling - FDA July 2011 http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020639s049s054lbl.pdf
  13. Prescriber's Letter 19(4): 2012 CHART: Anticipated Availability of First-Time Generics Detail-Document#: 280401 (subscription needed) http://www.prescribersletter.com
  14. Deprecated Reference
  15. Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
  16. Cheslock M, Garry RT, Stewart JT Quetiapine Leads to Hyperosmolar Hyperglycemic State in a Nonagenarian. Annals of Long-Term Care 2022. March 4. https://www.hmpgloballearningnetwork.com/site/altc/case-report/quetiapine-leads-hyperosmolar-hyperglycemic-state-nonagenarian
  17. Mann JS, Ershadi M, Khan I, Saadabadi A Quetiapine National Library of Medicine, NCBI Bookshelf: StatPearls https://www.ncbi.nlm.nih.gov/books/NBK459145/
  18. Medscape: quetiapine (Rx) https://reference.medscape.com/drug/seroquel-xr-quetiapine-342984