This document summarizes guidelines for prescribing the antipsychotic medication clozapine. It outlines indications for clozapine including treatment-resistant schizophrenia and schizophrenia with suicidal behavior. Contraindications, pharmacology, administration procedures, monitoring requirements, adverse effects, and conclusions are described. Key points include the need for pre-treatment evaluation, slow dose titration, target dosing ranges, plasma level monitoring, potential adverse effects like neutropenia and myocarditis, and long-term maintenance dosing.

1. IGBINLADE ADEDAMOLA SEGUN
M.D. V.N KARAZIN NATIONAL UNIVERSITY
Resident, Federal Teaching Hospital Ido-Ekiti, Ekiti State, Nigeria

2.  INTRODUCTION
 INDICATIONS
 CONTRAINDICATIONS
 PHARMACOLOGY
 ADMINISTRATION
 MONITORING
 ADVERSE EFFECTS
 CONCLUSIONS

3.  Clozapine has been found to be an effective
treatment in persons with schizophrenia
resistant to treatment with other
antipsychotic drugs. In addition, clozapine is
an effective treatment for schizophrenia
accompanied by persistent suicidal or self-
injurious behavior

4.  Primary indications for clozapine in patients
with schizophrenia or schizoaffective disorder
are schizophrenia symptoms partially or fully
resistant to treatment with other
antipsychotic drugs, or accompanied by
persistent suicidal or self-injurious behavior.
Other clinical indications in schizophrenia
patients include sensitivity to extrapyramidal
side effects and patients with tardive
dyskinesia. Also used in psychotic symptoms
in parkinsons disease

5.  Neutropenia
 Benign ethnic neutropenia
 Cardiac disease
 Seizures

6.  Pharmacodynamics — Clozapine binds
loosely and transiently to dopamine D2
receptors, this may explain its reduced
potential for producing movement
abnormalities relative to tightly binding
dopamine D2 antagonists such
as haloperidol. Dopamine has a high affinity
for the D4 receptor.
 Clozapine also interacts at histamine H1,
acetylcholine muscarinic M1 and serotonin 5-
HT2A

7.  Pharmacokinetics — Clozapine is well
absorbed. First-pass metabolism reduces its
bioavailability to 60 to 70 percent of the
administered dose; food has little effect on
the bioavailability of clozapine. The
elimination half-life of clozapine averages
approximately 14 hours under steady state
conditions, but there is substantial variability
across individuals

8.  Clozapine is extensively metabolized by the
cytochrome P450 system in the liver, and
excreted in both the urine and feces. Cytochrome
P450 1A2 is primarily responsible for clozapine
metabolism; cytochromes 2C, 2D6, and 3A3/4
play less important roles. Agents that induce
cytochrome CYP1A2, such as tobacco cigarette
smoke, will increase the metabolism of
clozapine. Tobacco smokers may require twice
the dose of nonsmokers to achieve similar blood
levels. Agents that inhibit CYP1A2
(eg, theophylline, ciprofloxacin, fluvoxamine) will
decrease the metabolism of clozapine and may
produce clinical toxicity at usual doses

9.  Pretreatment assessment — Assessment prior
to treatment with clozapine should include
evaluation of the patient’s general and
cardiovascular health status
 Complete blood count that includes an
absolute neutrophil count (ANC)
 BMI, FBS/HbA1c
 ECG
 Serum PT

10.  Starting dose and titration – For patients initially
starting clozapine in nonurgent situations, we prefer a slow
titration. As an example, we suggest 25 mg once daily at
bedtime for three to four days, then 50 mg once daily at bedtime
for three to four days. Further increases of 25 mg should be
given twice weekly. An initial test dose of 12.5 mg is
recommended to confirm tolerability in patients who have never
received clozapine.
 In urgent situations (active aggression/violence or self-
injury/suicide) we double the titration rate above. For example,
we suggest 50 mg once daily for three or four days, then 100 mg
once daily for three to four days followed by increases of 50 mg
twice weekly. Sleepiness is the primary clinical ceiling side effect,
so as clozapine dose is increasing, we simultaneously taper off
other sedating agents. We monitor for seizure risk by asking
patients or their families to report myoclonic jerking movements.

11.  Initial target dose – The initial target dose for
healthy, young adults is 300 mg/day. Older
adult patients and patients with cardiac
disease may need a lower target dose and a
slower titration, particularly if they experience
sedation or orthostatic hypotension to avoid
falls or worsening cardiac function.

12.  Target plasma levels – Plasma levels can be checked
after the initial target dose is reached.
A clozapine plasma level in the range of 250 to 350
ng/mL is a reasonable target for a patient with
schizophrenia. However, patients show great
variation in both their symptomatic response and side
effects and the target plasma level should be
individualized based on these outcomes
 Once the therapeutic plasma level is reached, the
patient’s clinical response should be monitored for
two weeks before considering any further dose
increase.
 Plasma levels should be checked in the morning,
ideally 8 to 10 hours following the previous evening
dose

13.  Maintenance dosing — A maintenance dose of
300 to 600 mg/day is usually required for
efficacy. The average final daily dose in patients
with treatment-resistant psychosis is
approximately 400 mg daily. Doses higher than
900 mg/day are not recommended.
 If clozapine treatment is interrupted for more
than two days, clozapine needs to be restarted
carefully, with 12.5 mg once or twice daily. If well
tolerated, however, the previous dose can be
achieved more quickly compared with patients
who are initially started on clozapine.

14.  Routine neutrophil monitoring is performed
at the following intervals:
 ●Weekly during the first six months
of clozapine administration
 ●Every other week for the second six months
 ●Every four weeks after one year, for the
duration of treatment

15.  If neutropenia develops during treatment, clozapine would
either need to be monitored more frequently, stopped
temporarily, or discontinued, based on the severity of
neutropenia [1]:
 ●Mild neutropenia (ANC: 1000 to 1499/microL) – Continue
treatment but increase monitoring frequency to three
times per week.
 ●Moderate neutropenia (ANC: 500 to 999/microL) –
Interrupt clozapine treatment, increase monitoring to daily
until ANC is 1000/microL at which point clozapine can be
reinstituted.
 ●Severe neutropenia/agranulocytosis (ANC: <500/microL)
– Discontinue clozapine. Rechallenge should only occur if
the benefits outweigh the risks, in consultation with
hematology.

16.  Monitoring ANC is required for prescribing and
dispensing clozapine. However, the coronavirus
2019 (COVID-19) public health emergency has
necessitated social isolation and staying at home,
which poses problems for patients treated with
this medication
 On March 22, 2020, the FDA offered guidance
regarding the COVID-19 public health emergency
and access to medications
 Patients and clinicians need to decide whether
the risks of infection outweigh the benefits of
obtaining blood work according to the
monitoring schedule

17.  One factor that determines whether it is
acceptable to waive ANC testing is duration
of clozapine treatment. As an example, it is
reasonable to temporarily forego testing in
patients who have received the drug for at least
one year and have never had an ANC
<2000/microL (or <1500/microL if there is a
history of benign ethnic neutropenia). The
rationale is that the risk of severe neutropenia
after 12 months of clozapine treatment is very
low.
 a 60- or 90-day supply may be prudent if
patients remain at high risk due to the pandemic

18.  Neutropenia/agranulocytosis — Clozapine-
induced agranulocytosis was estimated to
occur at a rate of approximately 0.8 percent
in a study of 12,760 patients receiving the
medication; leukopenia occurred in almost 3
percent of cases

19.  Myocarditis/cardiomyopathy — Studies have
estimated the risk of clozapine-induced
myocarditis to be 1 in 500
 Early myocarditis is more common than later
development of cardiomyopathy;
cardiomyopathy may be accompanied by
mitral regurgitation

20.  Pulmonary embolism — Clozapine has been
associated with an increased risk of venous
thromboembolic events including pulmonary
embolism leading to death
 Risk factors for thromboembolic disease in the
general population include:
 ●Genetic factors
 ●Recent immobilization
 ●Recent surgery
 ●Pregnancy or the postpartum state
 ●Obesity
 Clinicians starting patients on clozapine should
advise recipients to remain physically active.

21.  Weight gain
 Insulin resistance and diabetes mellitus
 Seizures - Clozapine is associated with a
dose-dependent seizure risk at a rate higher
than that seen with most other antipsychotic
drugs Higher doses of clozapine were
associated with a greater rate of seizures:
 ●600 mg/day or more – 4.4 percent
 ●300 to 600 mg/day – 2.7 percent
 ●300 mg/day or less – 1.0 percent

22.  Excessive salivation= anticholinergic
 Urinary incontinence — Treatment
with clozapine appears to be associated with
an increased incidence of urinary
incontinence. The potent anti-alpha-
adrenergic effects of clozapine, which relax
the bladder-neck sphincter, are hypothesized
 Constipation

23.  Sedation
 Teratogenic and neonatal risks
 Movement disorders — Compared with other
antipsychotics, clozapine has a reduced risk
of causing tardive dyskinesia or
extrapyramidal movement disorders
including akathisia.
 Dizziness

24.  Primary indications for clozapine include
schizophrenia or schizoaffective disorder
partially or fully resistant to treatment with
other antipsychotic drugs, or
schizophrenia/schizoaffective accompanied
by persistent suicidal or self-injurious
behavior

25.  Assessment of patients prior to starting clozapine include
baseline evaluation of
 •General and cardiovascular health status
 •Complete blood count with an ANC ≥1500/microL
(see 'Neutropenia' above)
 •Drug levels for anticonvulsant drugs, need to be in therapeutic
range
 •Weight, height, body mass index, and waist circumference
 •Fasting blood sugar or HbA1c
 •Fasting lipids (non-HDL cholesterol if non-fasting)
 •Vital signs
 •ECG
 •Absence or presence of abnormal motor movements on
Abnormal Involuntary Movement Scale test
 •Pregnancy test in women of childbearing age

26.  A maintenance dose of 300 to 600 mg/day is
usually required for efficacy. Doses higher
than 900 mg/day are not recommended. In
the older adult and medically ill population,
the titration may need to be slower, and
maintenance doses are typically in the 100 to
150 mg/day range

27.  Guidelines for prescribing clozapine in
schizophreniahttps://www.uptodate.com/con
tents/guidelines-for-prescribing-clozapine-
in-schizophrenia Authors:Oliver
Freudenreich, MDJoseph McEvoy, MDSection
Editor:Stephen Marder, MDDeputy
Editor:Michael Friedman, MD
 Center for Developmental Disabilities
Evaluation and Research . Youtube