https://www.youtube.com/watch?v=c8vh4AvskwA

1. CLOZAPINE
SERIOUS ADVERSE EFFECTS
By
Dr Mohammud Ibraheem

2. Clozapine (CZP)
Clozapine (CZP), a dibenzodiazepine atypical
antipsychotic drug, was introduced for
treatment of schizophrenia in Europe in 1971,
rapidly gaining popularity due to its efficacy
and virtual absence of extrapyramidal side
effects.
Its propensity to cause neutropenia and
agranulocytosis leading to its withdrawal. It
was reintroduced in 1989 in Europe and in
1990 in the USA

3. 1.Agranulocytosis
2.Thromboembolism
3.Cardiomyopathy and
myocarditis

4. The National Institute for Clinical
Excellence 2014 guidelines state that
CZP is the drug of choice for
treatment-resistant psychosis,
defined as failure to respond to at
least two other trials of antipsychotic
drugs .
Treatment resistance affects
approximately one third of patients

5. Agranulocytosis
Agranulocytosis, defined as neutrophil count of
less than 0.5 × 109/L (500/μL).
The incidence of agranulocytosis is 0.38% (1 in 250
patients). Risk of fatal agranulocytosis is less than 1 in
8000 patients treated.
CLIA typically occurs within the first 18 weeks of
treatment, with few cases occurring beyond 6 months.
After 1 year of treatment, residual risk is estimated at
0.39/1000 patient/years
Mortality due to CLIA estimates from 2.7 to 3.1%

6. Risk factors
1. Females
2. Age
3. Caucasians individuals is 2.4 fold higher
than non Caucasians.
Prevention
The patient must have full blood counts weekly
in the first 18 weeks of treatment, then
fortnightly until week 52, and then monthly for
the duration of treatment

7. All UK monitoring services classify
the WBC and absolute neutrophil
counts (ANC) into three zones

8. Clinical picture
1) Fever
2) Mouth ulcers
3) Sore throat
4) Some patients remain entirely
asymptomatic despite very low
neutrophil counts.

9. Management
I. Stop CZP
II. Careful clinical and microbiological
monitoring should be instituted
III. Transfer to a hematology unit with
isolation facility and clean-air system
IV. Starting GCSF, e.g. Filgrastim 300 μg or
Lenograstim 263 μg SC daily
V. If the patient becomes febrile, or
develops signs of sepsis or a focal
infection, antibiotics should be instituted

10. Re-challenge with clozapine
Re-challenge with CZP is an option for
patients with resistant schizophrenia.
re-challenge should be conducted with
a management plan agreed in close
collaboration with a haematologist.
lithium and GCSF have a role in
supporting re-challenge.

11. Thromboembolism
It occur in the first 3 months of treatment but can occur
at any time.
The risk of fatal pulmonary embolism is 1 in 4500;
about 20 times the risk in the population as a whole.
Thromboembolism is related to:
1) Clozapine’s effects on antiphospholipid antibodies
and platelet aggregation
2) Sedation lead to a reduction in movement and
consequent venous stasis
3) Obesity
4) Hyperprolactinaemia

12. Prevention
1. Encouraging exercise
2. Ensuring good hydration
Other antipsychotics associated with thromboembolism
I. Olanzapine
II. Risperidone
III. Haloperidole
IV. Prochlorperazine
No risk of thromboembolism with
A. Quetiapine
B. Aripiprazole
C. Chlorpromazine

13. Myocarditis and cardiomyopathy
Myocarditis is hypersensitivity response to
clozapine, resulting in inflammation of the
myocardium.
Myocarditis is potentially fatal, and is mostly
occur in the first 6–8 weeks of starting
treatment (median 3 weeks), but cab occur at
any time
Incidence: 1% or less. Risk of fatal myocarditis
or cardiomyopathy is 1 in 1000 patients
Patients should be monitored for signs of
myocarditis, especially in the first few months of
treatment.

14. Symptoms of myocarditis include
1) Hypotension
2) Tachycardia
3) Fever, flu‐like symptoms
4) Fatigue
5) Dyspnoea (with increased respiratory rate)
6) Chest pain
Many of these symptoms occur in patients on clozapine
not developing myocarditis and, conversely, their
absence does not rule out myocarditis.
Myocarditis can occur in the absence of clear cardiac
symptoms, although tachycardia and fever are usually
present.

15. Factors that may increase the risk of
developing myocarditis include
A. Rapid dose increases
B. Concurrent use of sodium valproate
C. Older age (31% increased risk for each
additional decade)
D. Other psychotropic drugs, including
lithium, risperidone, haloperidol,
chlorpromazine and fluphenazine

16. Cardiomyopathy develop following
myocarditis. Factors increase the risk
include
1) Persistent tachycardia
2) Obesity
3) Diabetes
4) Previous personal or familial cardiac
events
Cardiomyopathy may occur later in
treatment than myocarditis (median 9
months)

17. Cardiomyopathy should be suspected in any patient
showing signs of HF.
Presentation of cardiomyopathy is:
1) Asymptomatic in the early stages
2) Palpitations
3) Chest pain
4) Syncope
5) Sweating
6) Decreased exercise capacity or breathing difficulties

18. Younger patients have an increased
risk of sudden death, because of
clozapine‐induced ECG changes.
ECG changes (ST depression),
enlarged heart on
radiography/echocardiography and
eosinophilia.
.

19. Monitoring for myocarditis

20. Thank you