Download Clozapine Toxicity handout

3/12/12
CHILLS & THRILLS:
IATROGENIC
CLOZAPINE TOXICITY
Naren Gunja, MD FACEM
Medical Director & Toxicologist
NSW Poisons Centre, Sydney, AUSTRALIA
Clozapine
•  Atypical antipsychotic
•  Tricyclic dibenzodiazepine derivative
•  Indication: refractory schizophrenia
•  Restricted use & registry
•  Special dosing regimen
•  Dose: 200-900mg/day
Clozapine: pharmacology
1.  Dopamine – D1, D2 & D4
2.  Serotonin – 5-HT1C & 5-HT2A
3.  Adrenergic – α1 & α2
4.  Muscarinic – M1
5.  Histamine – H1
6.  ?GABAA blockade
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Dosing, Monitoring, Restricting
•  National registries (US/UK/Aust. since 1990)
•  Restricted
clozapine prescribers
CLOZARIL: Star
ting a Patient
•  Special
guide
1. Call the CLOZARIL National
Registrystarting
(CNR) to obtain
a rechallenge number and to confirm that you and your pharmacy are registered.
2. Obtain a baseline WBC with ANC from patient. If within normal limits, WBC ≥ 3500/mm3, ANC ≥ 2000/mm3, prescribe CLOZARIL tablets.
•  information to the registered pharmacy.
3. Submit WBC and ANC
4. Please be prepared to provide your DEA # to the CNR when you are registered for the first time.
Monitoring regime
•  Cessation and re-challenge protocols
For forms, patient enrollment, or medical information call the CLOZARIL National Registry:
1-800-448-5938
Recommended CLOZARIL® (clozapine) dosage titration at start of therapy1
Week 1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
*Optional
am (mg)
12.5
25
25
25
50
50
50
hs (mg)
12.5*
–
25
50
50
75
100
Total (mg)
12.5-25
25
50
75
100
125
150
Week 2
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
am (mg)
50
100
100
50
50
100
100
hs (mg)
100
100
100
200
200
200
200
Subsequent dosage increments should be made no more than once or twice weekly, in increments not to exceed 100 mg.
Total (mg)
150
200
200
250
250
300
300
www.clozaril.com
CLOZARIL: Managing the Patient
Current Monitoring Frequency
Eligibility for Monthly Monitoring
Every 2 weeks (biweekly) for 6 continuous months, following 6 continuous months of weekly
monitoring prior to May 12, 2005.
YES. Only if all WBC counts ≥ 3000/mm3 (and ANC ≥1500/mm3 if reported)
Every 2 weeks or weekly. Therapy interrupted after May 12, 2005, due to moderate leukopenia
and/or granulocytopenia*, with consecutive monitoring since restart (rechallenge) of therapy.
NO. Only after 1 year of continuous weekly monitoring and then 6 months of continuous every two
weeks monitoring from the date of restart (rechallenge) with all WBC/ANC above increased monitoring
frequency values***.
Weekly therapy for ≤6 months
NO. Patient must have 6 continuous months of weekly monitoring, followed by 6 months of continuous
monitoring every two weeks with all WBC/ANC above increased monitoring frequency values**.
Weekly therapy for ≥6 continuous months, but never monitored biweekly.
NO. Patient must have 6 continuous months of monitoring every two weeks with all WBC/ANC above
increased monitoring frequency values**.
Increased Monitoring Frequency Requirements
Patient is currently monitored monthly and experiences a WBC < 3500/mm3 and/or an ANC
< 2000/mm3.
Monitoring should be done twice weekly until WBC/ANC values are ≥3500 and ≥ 2000, respectively.
The patient can return to monthly blood work.
Patient is currently monitored every 2 weeks and experiences a WBC < 3500/mm3 and/or an ANC
< 2000/mm3.
Monitoring should be done twice weekly until WBC/ANC values are ≥3500 and ≥2000, respectively.
The patient should then be monitored every two weeks for 6 continuous months before progressing
to monthly blood work.
Clozapine toxicity
Patient is currently monitored weekly and experiences a WBC < 3500/mm3 and/or an ANC
< 2000/mm3.
Monitoring should be done twice weekly until WBC/ANC values are ≥3500 and ≥2000, respectively.
The patient should then be monitored weekly for 6 continuous months before progressing to every two
weeks, and then monthly, blood work.
**Prior to May 12, 2005 values for WBC and ANC counts requiring interruption of therapy were WBC ≤ 3000/mm and/or ANC ≤ 1500/mm3. After May 12, 2005 values for counts requiring increased monitoring frequency of therapy
are WBC ≤ 3500/ mm3 and/or ANC ≤ 2000mm3, respectively.
Following discontinuation of therapy for any reason, the patient should have WBC and ANC count monitoring once a week for a minimum of 4 weeks. If at the end of 4 weeks WBC < 3500/mm3 and/or ANC < 2000/mm3, weekly
monitoring should continue until WBC ≥3500/mm3 and ANC ≥ 2000/mm3.
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•  Agranulocytosis 1-2%
Clozaril (clozapine) use is associated with a substantial risk of seizure, affected 1% to 2% of patients at low doses (below 300 mg/day), 3% to 4% at moderate doses (300 mg/day to
600 mg/day), and 5% at high doses (600 mg/day to 900 mg/day). Clozaril is contraindicated in patients with paralytic ileus. In clinical trials, Clozaril was associated with a 1% to 2%
incidence of agranulocytosis, a potentially fatal blood disorder, which, if caught early, can be reversed. Mandatory monitoring of WBC counts and ANC's and drug dispensing as per
the requirements specified in the package insert, provide an efficient means of determining developing agranulocytosis. Analysis of post-marketing safety databases suggests that
Clozaril is associated with an increased risk of fatal myocarditis, especially during, but not limited to, the first month of therapy. Orthostatic hypotension may occur in some patients,
especially during the initial phases of treatment, and can, in rare cases (approximate incidence of 1/3000), be accompanied by collapse and/or cardiac arrest. Analysis of clinical
studies reveal that elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Patients with an
established diagnosis of diabetes mellitus who are started on CLOZARIL should be monitored regularly for worsening glucose control (e.g., polydipsia, polyuria, polyphagia, and weakness).
•  CNS: sedation, delirium, seizures
•  Autonomic:
•  Anti-muscarinic toxicity
•  Sialorrhea
•  Neuromuscular: akathisia, myoclonus, NMS
•  Clozapine fever
•  Cardiovascular toxicity
•  Sudden death
Focus: Clozapine
1.  Fever
2.  Cardiac:
•  Orthostatic hypotension & tachycardia
•  Myocarditis
•  Cardiomyopathy
•  Pericarditis
•  ?QT prolongation?
3.  Sudden Death
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Clozapine fever
•  Common in initial 4 weeks (0.5%-50%)
•  Systematic retrospective study (HKG): 14% *
•  Risk factors
•  Rate of titration
•  Physical illness
•  Valproate therapy
•  Differential Diagnosis
•  Infection/sepsis
•  NMS
•  Pathophysiology
•  Cytokines (TNF-α, IL-6, GCSF)
* Chung. Can J Psych 2008
Clozapine cardiac disease
•  First attention late 1990s
•  Kilian, Celermajer et al, Lancet 1999:
•  15 cases of myocarditis
•  8 cases of cardiomyopathy
•  amongst 8000 patients & reported to ADRAC
•  What’s so special about CLOZAPINE?
Kilian et al. Myocarditis and cardiomyopathy associated with clozapine. Lancet 1999
Epidemiology
Myocarditis – Absolute risk comparison
Australia (ADRAC) ^
0.188% (1999)
UK #
0.080% (1993)
US FDA *
0.015% (2001)
^ Kilian. Lancet 1999.
# UK Committee on Safety of Medicines. Curr Prob Pharmacovigilance 1993
* La Grenade. NEJM 2001.
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In Australia
Disease
Incidence
Myocarditis
0.7 - 1.2%
Cardiomyopathy
0.1%
•  Haas. Drug Saf 2007.
•  Kilian. Lancet 1999.
Pathophysiology
•  IgE-mediated hypersensitivity reaction
•  Eosinophilia
•  Endomyocardial eosinophilic
inclusions
•  Others
•  Inflammatory cytokines
•  Low selenium
Layland. Med J Aust 2009
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Clozapine-induced myocarditis
Ronaldson et al. Aust NZ J Psych, 2011
Investigations
• 
CRP: non-specific but earliest marker
• 
Troponin I/T: Low sensitivity but high specificity
• 
NT-proBNP
•  Raised in cardiac failure but also acute myocarditis
•  2 small series show significant increase and resolution with
treatment of clozapine-induced myocarditis
• 
Eosinophilia: variably reliable
• 
CK not useful
Investigations
•  ECG: 66% non-specific ECG abnormalities
•  Echocardiogram
•  Non-specific findings e.g. segmental/global wall motion
abnormalities, increased sphericity/LV vol.
•  cMRI: Growing body of data in acute myocarditis
•  Endomyocardial biopsy
•  Risky, low sensitivity, conflict with interpretation
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Management
•  Withhold/cease clozapine
•  Supportive treatment based on morbidity
•  Ongoing monitoring:
•  BP @ 6w, 18w, q6M
•  ECG @ 6M, q1Y
•  ECHO @ 6M, PRN
•  Troponin & CRP: pre, 1-4w, 6w, 18w, 6M, q6M
•  CK-MB & NT-proBNP when myocarditis suspected
•  Corticosteroids
•  Re-challenge regimes
Sudden death
•  Sudden death rate ~4x higher for clozapine
#
•  Potentially due to:
•  Cardiac arrhythmias: ?QT prolongation
•  Underlying cardiac disease
•  Clozapine-induced cardiac complications
•  Pulmonary embolus
•  Agranulocytosis/sepsis
•  Significant QT prolongation rare *
# Modai. J Clin Psychopharm 2000
* Warner. ADR Tox Reviews 2002
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