clozapine (Clozaril)
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Introduction
Tradename: Clozaril.
Indications
- severe schizophrenia with failure of standard antipsychotic therapy
- extrapyramidal symptoms associated with treatment of schizophrenia
- psychosis in a patient with Parkinsonism
- improves negative symptoms of schizophrenia
- reduces mortality in patients with schizophrenia[10]
- bipolar disorder, mania[13]
- refractory psychosis & agitation in the elderly[14]
Contraindications
- WBC < 3500/mm3
- history of myeloproliferative disorder or bone marrow suppression
- history of clozapine-induced granulocytopenia
- uncontrolled epilepsy
- paralytic ileus
- central nervous system depression
Caution:
- no NOT stop medication abrubtly
- taper of 1-2 weeks if possible
- use with caution in patients with seizure disorder
- use with caution in patients with cardiovascular disease
Dosage
- begin 25 mg QD or BID
- increase by 25-50 mg QD
- maintenance dose 300-450 mg/day
- maximum dose 900 mg/day; higher doses have been used
- psychosis (hallucinations) associated with Parkinson's disease
- begin 12.5 mg QD, increase slowly[8]
- generally < 50 mg/day needed to control hallucinations[8]
Tabs: 25 & 100 mg.
Pharmacokinetics
- rapidly & completely absorbed following oral administration
- absorption not affected by food
- extensive 1st pass metabolism
- 95% bound to plasma proteins
- peak serum levels in 1-4 hours
- elimination 1/2life is 8-12 hours (initial phase), 20 hours (terminal phase)
- drug is excreted in the urine & feces
- crosses placenta
- appears in breast milk
elimination via liver
elimination via kidney
1/2life = 8-12 hours initial
1/2life = 20 hours terminal
protein binding = 95 %
Monitor
(see Notes below)
- WBC* weekly for 1st 6 months
- WBC* every other week after 6 months
- WBC* monthly after one year[9]
- baseline EEG recommended prior to therapy
* WBC should include absolute neutrophil count[9]
Adverse effects
- common (> 10%)
- less common (1-10%)
- uncommon (< 1%)
- agranulocytosis, eosinophilia, granulocytopenia (neutropenia)#, leukopenia, thrombocytopenia
- difficult urination, rigidity, tremor, impotence, insomnia, seizures
- other
- ECG changes (1-10%)
- neuroleptic malignant syndrome (< 1%)
- tardive dyskinesia (< 1%)
- least likely among antipsychotics to cause extrapyramidal symptoms[16]
- pulmonary embolism
- hyperglycemia[6]; increased risk of diabetes[7]
- hepatitis
- anticholinergic effects
- sedation
- myocarditis/cardiomyopathy[5]
- dyslipidemia: increased cholesterol & triglycerides[6]
- long-term use associated with increase risk of hematologic malignancies (RR=2.7)[19]
- black box warning[14]
- increased risk of hyperglycemia
- increased risk of cerebrovascular events
- 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 adverse effects of antipsychotic agents
- drug adverse effects of psychotropic agents
- drug adverse effects of dopaminergic receptor antagonists
- drug adverse effects of antihypertensive agents
Drug interactions
- myelosuppressive agents increase the risk & severity of agranulocytosis
- severe hypotension &/or loss of consciousness may occur with concurrent administration of benzodiazepines
- phenytoin decreases plasma clozapine concentrations
- clozapine may interact with other agents that cause seizures or lower seizure threshold, i.e. demerol
- clozapine may displace other protein-bound drugs, such as warfarin
- clozapine directly antogonizes anti-Parkinson agents
- may reverse vasopressor effect of epinephrine
- increased effect of CNS depressants, guanabenz, anticholinergic agents
- increased toxicity with cimetidine, MAO inhibitors, neuroleptic agents, tricyclic antidepressants (TCA)
- any drug which inhibits cyt P450 1A2 or cyt P450 2D6 can increase clozapine levels
- any drug which induces cyt P450 1A2 orcyt P450 2D6 can diminish clozapine levels
- drug interaction(s) of antipsychotics & dopamine receptor agonists
- drug interaction(s) of antipsycotics with benzodiazepines
- drug interaction(s) of NSAIDs & antihypertensives
Laboratory
Mechanism of action
- weak dopamine D2 receptor antagonist
- central 5HT-2 & peripheral 5HT-2 receptor antagonist
- strong alpha-1 & alpha-2 adrenergic receptor antagonist
- strong H1 receptor antagonist
- strong muscarinic receptor antagonist
- 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]
- patients currently treated with clozapine will be automatically transferred to the Clozapine REMS Program
More general terms
- dibenzazepine; iminostilbene
- antipsychotic agent
- dopaminergic receptor antagonist
- serotonin antagonist
Additional terms
- 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
References
- ↑ The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
- ↑ Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 1146-47
- ↑ Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
- ↑ Kaiser Permanente Northern California Regional Drug Formulary, 1998
- ↑ 5.0 5.1 Journal Watch 21(14):113-114, 2001 Coulter et al, BMJ 322:1207, 2001
- ↑ 6.0 6.1 6.2 6.3 Prescriber's Letter 9(3):13 2002
- ↑ 7.0 7.1 Prescriber's Letter 10(11):62 2003
- ↑ 8.0 8.1 8.2 Bronstein J, In: Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 29-Oct 2, 2004
- ↑ 9.0 9.1 9.2 http://www.fda.gov/medwatch/safety/2006/safety06.htm#Clozaril
- ↑ 10.0 10.1 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/19595447 <Internet> http://dx.doi.org/10.1016/S0140-6736(09)60742-X
- ↑ Closaril registry http://www.clozarilregistry.com Contact: (800) 448-5938
- ↑ Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=260704&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 13.0 13.1 Deprecated Reference
- ↑ 14.0 14.1 14.2 Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
- ↑ 15.0 15.1 15.2 15.3 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
- ↑ 16.0 16.1 Medical Knowledge Self Assessment Program (MKSAP) 17, 18. American College of Physicians, Philadelphia 2015, 2018.
- ↑ 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 - ↑ 18.0 18.1 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
- ↑ 19.0 19.1 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: https://www.ncbi.nlm.nih.gov/pubmed/35334224