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clozapine (Clozaril)

Tradename: Clozaril. Indications: 1) severe schizophrenia with failure of standard antipsychotic therapy - extrapyramidal symptoms associated with treatment of schizophrenia 2) psychosis in a patient with Parkinsonism 3) improves negative symptoms of schizophrenia 4) reduces mortality in patients with schizophrenia [10] 5) bipolar disorder, mania [13] 6) refractory psychosis & agitation in the elderly [14] Contraindications: 1) WBC < 3500/mm3 2) history of myeloproliferative disorder or bone marrow suppression 3) history of clozapine-induced granulocytopenia 4) uncontrolled epilepsy 5) paralytic ileus 6) central nervous system depression Caution: 1) no NOT stop medication abrubtly 2) taper of 1-2 weeks if possible 3) use with caution in patients with seizure disorder 4) use with caution in patients with cardiovascular disease Dosage: 1) begin 25 mg QD or BID 2) increase by 25-50 mg QD 3) maintenance dose 300-450 mg/day a) in divided doses BID-QID b) reach by 2nd week of therapy 4) maximum dose 900 mg/day; higher doses have been used 5) psychosis (hallucinations) associated with Parkinson's disease a) begin 12.5 mg QD, increase slowly [8] b) generally < 50 mg/day needed to control hallucinations [8] Tabs: 25 & 100 mg. Monitor: (see Notes below) 1) WBC* weekly for 1st 6 months 2) WBC* every other week after 6 months 3) WBC* monthly after one year [9] 3) baseline EEG recommended prior to therapy * WBC should include absolute neutrophil count [9] Pharmacokinetics: 1) rapidly & completely absorbed following oral administration 2) absorption not affected by food 3) extensive 1st pass metabolism - metabolized by cyt P450 1A2 & cyt P450 2D6 4) 95% bound to plasma proteins 5) peak serum levels in 1-4 hours 6) elimination 1/2life is 8-12 hours (initial phase), 20 hours (terminal phase) 7) drug is excreted in the urine & feces 8) crosses placenta 9) appears in breast milk Adverse effects: 1) common (> 10%) - tachycardia, orthostatic hypotension, fever*, constipation [18], drowsiness, headache, nausea/vomiting, unusual weight gain [6] 2) less common (1-10%) - agitation, akathisia, blurred vision, hypertension, abdominal discomfort, heartburn, dry mouth, increased sweating 3) uncommon (< 1%) - agranulocytosis, eosinophilia, granulocytopenia (neutropenia)#, leukopenia, thrombocytopenia - difficult urination, rigidity, tremor, impotence, insomnia, seizures 4) other a) ECG changes (1-10%) - ST segment depression - T-wave inversion b) neuroleptic malignant syndrome (< 1%) c) tardive dyskinesia (< 1%) - least likely among antipsychotics to cause extrapyramidal symptoms [16] d) pulmonary embolism e) hyperglycemia [6]; increased risk of diabetes [7] f) hepatitis g) anticholinergic effects h) sedation i) myocarditis/cardiomyopathy [5] j) dyslipidemia: increased cholesterol & triglycerides [6] k) long-term use associated with increase risk of hematologic malignancies (RR=2.7) [19] 5) black box warning [14] a) increased risk of hyperglycemia b) increased risk of cerebrovascular events c) increased risk of mortality in patients with dementia * benign, self-limited temperature elevations may occur in the 1st 3 weeks of therapy # mandatory participation in Clozapine REMS Program (see notes) [15] Drug interactions: 1) myelosuppressive agents increase the risk & severity of agranulocytosis 2) severe hypotension &/or loss of consciousness may occur with concurrent administration of benzodiazepines 3) phenytoin decreases plasma clozapine concentrations 4) clozapine may interact with other agents that cause seizures or lower seizure threshold, i.e. demerol 5) clozapine may displace other protein-bound drugs, such as warfarin 6) clozapine directly antogonizes anti-Parkinson agents 7) may reverse vasopressor effect of epinephrine 8) increased effect of CNS depressants, guanabenz, anticholinergic agents 9) increased toxicity with cimetidine, MAO inhibitors, neuroleptic agents, tricyclic antidepressants (TCA) 10) any drug which inhibits cyt P450 1A2 or cyt P450 2D6 can increase clozapine levels 11) any drug which induces cyt P450 1A2 orcyt P450 2D6 can diminish clozapine levels Laboratory: - clozapine in specimen - clozapine in dried blood spot - clozapine in gastric fluid - clozapine in serum/plasma - clozapine in urine Mechanism of action: 1) weak dopamine D2 receptor antagonist 2) central 5HT-2 & peripheral 5HT-2 receptor antagonist 3) strong alpha-1 & alpha-2 adrenergic receptor antagonist 4) strong H1 receptor antagonist 5) strong muscarinic receptor antagonist 6) GABA effects Notes: - prescribers must register with the Clozaril National Registry (CNR) - prescriber is responsible for registering patients - prescriber must obtain a white blood cell count (WBC) & an absolute neutrophil count (ANC) value for the patient - pharmacist must be supplied with this info (drawn within 7 days) before dispensing - pharmacies that dispense Clozaril must be registered with CNR to purchase Clozaril from a wholesaler - pharmacists must verify that patients with prescriptions for Clozaril are registered with CNR prior to dispensing - FDA has approved a new shared risk evaluation & mitigation strategy (REMS), the Clozapine REMS Program [15] - patients currently treated with clozapine will be automatically transferred to the Clozapine REMS Program - in order to prescribe & dispense clozapine, prescribers & pharmacies will be required to be certified in the Clozapine REMS Program according to a specific transition schedule starting October 12, 2015 [15]

Interactions

drug interactions drug adverse effects (more general classes)

Related

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) neutropenia seizure; epileptic seizure

General

antipsychotic agent dibenzazepine; iminostilbene dopaminergic receptor antagonist serotonin antagonist

Properties

MISC-INFO: elimination route LIVER KIDNEY 1/2life 8-12 HOURS 20 HOURS protein-binding 95% pregnancy-category B safety in lactation -

Database Correlations

PUBCHEM cid=2818

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 1146-47
  3. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  4. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  5. Journal Watch 21(14):113-114, 2001 Coulter et al, BMJ 322:1207, 2001
  6. Prescriber's Letter 9(3):13 2002
  7. Prescriber's Letter 10(11):62 2003
  8. Bronstein J, In: Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 29-Oct 2, 2004
  9. http://www.fda.gov/medwatch/safety/2006/safety06.htm#Clozaril
  10. Tiihonen J et al. 11-year follow-up of mortality in patients with schizophrenia: A population-based cohort study (FIN11 study). Lancet 2009 Jul 11 PMID: 19595447 http://dx.doi.org/10.1016/S0140-6736(09)60742-X
  11. Closaril registry http://www.clozarilregistry.com Contact: (800) 448-5938
  12. Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Detail-Document#: 260704 (subscription needed) http://www.prescribersletter.com
  13. Deprecated Reference
  14. Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
  15. FDA Safety Alert. Sept 15, 2015 Clozapine: Drug Safety Communication - FDA Modifies Monitoring for Neutropenia; Approves New Shared REMS Program. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm462229.htm
  16. Medical Knowledge Self Assessment Program (MKSAP) 17, 18. American College of Physicians, Philadelphia 2015, 2018.
  17. FDA Drug Safety and Availability. Jan 16, 2019 The Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program Modification will go live on February 28, 2019. https://www.fda.gov/drugs/drugsafety/ucm467560.htm - Information on Clozapine. https://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm497790.htm - Cloxapine REMS program https://www.clozapinerems.com/CpmgClozapineUI/home.u
  18. fDA MedWatch. Safety Alert. Jan 28, 2020 Clozaril, Fazaclo ODT, Versacloz (clozapine): Drug Safety Communication - FDA Strengthens Warning That Untreated Constipation Can Lead to Serious Bowel Problems. https://www.fda.gov/safety/medical-product-safety-information/clozaril-fazaclo-odt-versacloz-clozapine-drug-safety-communication-fda-strengthens-warning-untreated
  19. Osorio L Clozapine and Cancer Risk: New Data. Medscape. May 12, 2022 https://www.medscape.com/viewarticle/973902 - Tiihonen J, et al. Long-term treatment with clozapine and other antipsychotic drugs and the risk of haematological malignancies in people with schizophrenia: a nationwide case-control and cohort study in Finland. Lancet Psychiatry. 2022 May;9(5):353-362 PMID: 35334224