Clozapine

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Contents 1 Introduction 2 Indications 3 Contraindications 4 Dosage 5 Pharmacokinetics 6 Monitor 7 Adverse-effects 8 Drug-interactions 9 Mechanism-of-action 10 Notes 11 More General Terms 12 Additional Terms 13 Internet Database 14 References

Introduction

• Tradename: Clozaril.

Indications

• severe schizophrenia with failure of standard antipsychotic therapy
• psychosis in a patient with Parkinsonism
• improves negative symptoms of schizophrenia
• reduces mortality in patients with schizophrenia [10]

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
  

• pregnancy category = b
• safety in lactation = -

Dosage

• begin 25 mg QD or BID
• increase by 25-50 mg QD
• maintenance dose 300-450 mg/day

• in divided doses BID- QID
• reach by 2nd week of therapy

• 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

• metabolized by cyt P450 1A2 & cyt P450 2D6

• 95% bound to plasma proteins
• peak serum levels in 1-4 hours
• elimination 1/2life is 8-12 hours (inital 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%)

• tachycardia, orthostatic hypotension, fever*, constipation, drowsiness, headache, nausea/vomiting, unusual weight gain [6]

• less common (1-10%)

• agitation, akathisia, blurred vision, hypertension, abdominal discomfort, heartburn, dry mouth, increased sweating

• uncommon (< 1%)

• agranulocytosis, eosinophilia, granulocytopenia, leukopenia, thrombocytopenia difficult urination, rigidity, tremor, impotence, insomnia, seizures

• other

• ECG changes (1-10%)

• ST segment depression
• T-wave inversion

• neuroleptic malignant syndrome (< 1%)
• tardive dyskinesia (< 1%)
• pulmonary embolism
• hyperglycemia [6]; increased risk of diabetes [7]
• hepatitis
• anticholinergic effects
• sedation
• myocarditis/ cardiomyopathy [5]
• dyslipidemia: increased cholesterol & triglycerides [6]

• * benign, self-limited temperature elevations may occur in the 1st 3 weeks of therapy
  

• drug adverse effects of antipsychotic 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 antipsycotics with benzodiazepines

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

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

Internet Database

PubChem: 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. url>http://www.fda.gov/medwatch/safety/2006/safety06.htm#Clozaril</url>
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 <PubMed> PMID: [1] <Internet> [2]
11. Closaril registry [3] Contact: (800) 448-5938
12. Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Detail-Document#: [4] (subscription needed) [5]

clozapine (Clozaril)