1. CLOZAPINE
Rami James Aoun

2. CLOZAPINE
Is an atypical antipsychotic medication marketed
under several brands

3. CLOZAPINE
Historic Facts
•The first of the atypical
antipsychotics to be developed, NEW DRUG IS SAID TO HELP SEVERE
SCHIZOPHRENICS
•Clozapine was developed by Sandoz in AP
Published: May 15, 1987
1961,
Nearly one-third of the severe schizophrenics who were given a
•It was first introduced in Europe in 1971, new drug improved significantly, but the drug requires weekly blood
but was voluntarily withdrawn by tests because of a potentially fatal side effect, researchers said today.
the manufacturer in 1975 after it The severly affected victims had irreversible, structural brain damage that led
was shown to cause agranulocytosis, researchers to think no drug would ever be able to help them, said Dr.
Herbert Meltzer, one of the directors of a new study conducted at 16
that led to death in some patients. hospitals around the country.
''It's a major, major advance,'' Dr. Meltzer said at the annual
•In 1989, after studies demonstrated that meeting of the American Psychiatric Association. The findings of the
it was more effective than any study by Dr. Meltzer of Case Western Reserve University in Cleveland and
other antipsychotic for treating Dr. John Kane of Long Island Jewish Medical Center were reported for the
schizophrenia first time at the meeting.
It is estimated that 300,000 Americans have the most severe form of
schizophrenia. Many other neuroleptic or antipsychotic drugs are used to
•the FDA approved clozapine's use but treat schizophrenia, in which people become grossly out of touch with reality,
only for treatment-resistant but they are of no value in the most severe cases, Dr. Meltzer said.
schizophrenia

4. CLOZAPINE
Mechanism of Action
Strong antagonism for D4
receptor , weak antagonism It blocks alpha-
of D1, D2, D3, and D5 adrenergic, histamine
dopamine receptor subtypes, H1, and cholinergic
but receptors
Serotonin (5HT2) antagonist

5. CLOZAPINE
Mechanism of Action
•Blockage of dopaminergic neurons to the
limbic and prefrontal cortex will
decrease psychotic symptoms
•However blockage of the dopaminergic
neurons to the Basal Ganglia
(mainly striatum) will produce extra
pyramidal symptoms
•Atypical antipsychotics, of which clozapine
is a member of, differ from traditional anti-
psychotics in treating the negative
symptoms of schizophrenia in
addition to less side effects

6. CLOZAPINE
Pharmacodynamics/kinetics
•Clozapine is administered PO
•The absorption of clozapine is almost complete, but the
oral bioavailability is 50 to 60% due to first-pass
metabolism
•Peak concentration is at 2.5 hours, and food
does not appear to affect the bioavailability
•The elimination half-life is 12 hours
•The major metabolite, norclozapine (desmethyl-
clozapine), has limited pharmacological activity
•The cytochrome P450 isoenzyme 1A2 in the
liver is primarily responsible for clozapine metabolism.
Agents that induce (e.g., cigarette smoke) or inhibit (e.g.,
theophylline, ciprofloxacin, fluvoxamine) CYP1A2 may
increase or decrease, respectively, the metabolism of
clozapine
•The induction of metabolism caused by smoking means
that smokers require up to double the dose of
clozapine compared with non-smokers to achieve an
equivalent plasma concentration
•Excretion: Urine (50%) and feces (30%)

7. CLOZAPINE
Indications
•Principally in treating treatment-resistant
schizophrenia also known as refractory
schizophrenia.
• It is not used routinely for treating schizophrenia
because of its adverse effects (will be discussed
later)
•The label “refractory” is given to schizophrenia after
failure of symptoms to respond satisfactorily to at
least two different antipsychotics
•Also Clozapine is used to reduce risk of recurrent
suicidal behavior in schizophrenia or
schizoaffective disorder
• Unlabeled indications include; Schizoaffective
disorder, bipolar disorder, childhood psychosis, severe
obsessive-compulsive disorder; psychosis/agitation
related to Alzheimer’s dementia

8. CLOZAPINE
Contraindications
•Hypersensitivity to clozapine
or any component of the
formulation;
• History of agranulocytosis
or severe granulocytopenia with
clozapine;
• Uncontrolled epilepsy, severe
central nervous system depression or
comatose state
• Paralytic ileus
• Myeloproliferative disorders
or use with other agents which have
a well-known risk of agranulocytosis
or bone marrow suppression

9. CLOZAPINE
Drug Interactions
•Any drug that increases QT interval,
may cause Ventricular arrhythmias
•Metoclopromide, May enhance the
adverse/toxic effect of Antipsychotics
•Macrolide Antibiotics: May
decrease the metabolism of CloZAPine
•CYP1A2 Inhibitors (Strong): May
decrease the metabolism of CYP1A2
Substrates.(ex; theophylline, ciprofloxacin,
fluvoxamine)
•Carbamazepine: May increase the
metabolism of Clozapine
•Benzodiazepines: May enhance the
adverse/toxic effect of Clozapine.
•Anti-Parkinson's Agents
(Dopamine Agonist): Antipsychotics
(Atypical) may diminish the therapeutic
effect of Anti-Parkinson's Agents

10. CLOZAPINE
Dosing
Schizophrenia:
•Initial: 12.5 mg once or twice daily;
•Increased, as tolerated, in increments of 25-50 mg/day to a target dose of 300-450 mg/day after 2 weeks;
•May require doses as high as 600-900 mg/day (maximum dose: 900 mg/day).
•In some efficacy studies, total daily dosage was administered in 3 divided doses.
Suicidal behavior in schizophrenia or schizoaffective disorder:
•Initial: 12.5 mg once or twice daily;
•increased, as tolerated, in increments of 25-50 mg/day to a target dose of 300-450 mg/day after 2 weeks;
•mean dose is ~300 mg/day (range: 12.5-900 mg); treatment duration 2 years then reassess need.
•If no longer a suicide risk, may resume prior antipsychotic therapy after gradually tapering off clozapine over 1-2 weeks.
Termination of therapy:
•If dosing is interrupted for ≥48 hours, therapy must be reinitiated at 12.5-25 mg/day; may be increased
more rapidly than with initial titration, unless cardiopulmonary arrest occurred during initial titration.
•In the event of planned termination of clozapine, gradual reduction in dose over a 1- to 2-week period
is recommended. If conditions warrant abrupt discontinuation (leukopenia), monitor patient for psychosis and
cholinergic rebound (headache, nausea, vomiting, diarrhea).

11. CLOZAPINE
Pricing

12. CLOZAPINE
Pricing
25 mg (100tabs): $242.17

13. CLOZAPINE
FDA Blackbox Warning
1. Agranulocytosis, this is a potentially fatal side
effect.
Clozapine is available only through a distribution system that
ensures monitoring of WBC count and ANC prior to
delivery of the next supply of medication.
2. Seizures have been associated with the use of Clozapine,
with a greater likelihood at higher doses. Caution should be
used in patients with a history of seizures or predisposing
factors.
3. Myocarditis Analyses of post-marketing safety databases
suggested an increased risk of fatal myocarditis, especially
during the first month of therapy.
4. Cardiovascular and Respiratory Effects;
Orthostatic hypotension, with or without syncope,
more likely to occur during initial titration in association
with rapid dose escalation. Respiratory arrest and
cardiac arrest during initial treament has occurred in
patients who were being administered
benzodiazipines or other psychotropic drugs,
5. Increased Mortality in Elderly Patients With
Dementia Elderly patients with dementia-related psychosis
treated with atypical antipsychotic drugs are at an increased
risk of death compared to placebo. Although the causes of
death were varied, most of the deaths appeared to be either
cardiovascular or infectious

14. CLOZAPINE
Agranulocytosis
•Therapy should not be initiated in patients with
WBC <3500 cells/mm3 or ANC <2000
cells/mm3 or history of myeloproliferative
disorder.
•Without monitoring, agranulocytosis occurs in
about 1% of patients who take clozapine
during the first few months of treatment
•Initial episodes of moderate leukopenia or
granulopoietic suppression confer up to a 12-
fold increased risk for subsequent episodes
of agranulocytosis.
•Use with caution in patients receiving other
marrow suppressive agents.
•Eosinophilia has been reported to occur in
1% of patients on clozapine. Interrupt therapy for
eosinophil count >4000/mm3. May resume
therapy when eosinophil count <3000/mm3.
•Patient must fail at least two trials of
other primary medications for the
treatment of schizophrenia before initiating
therapy with clozapine.

15. CLOZAPINE
Agranulocytosis
•Patients taking clozapine are required to have a
blood cell count every week, for the first 6
months of therapy
• Then every other week for the second
6 months after initiation of therapy.
•After twelve months, blood cell counts
need be performed every 4 weeks.
•The manufacturers of both the brand and
generic clozapine are required by the FDA
to track white blood cells counts for
patients receiving clozapine, and pharmacies
are required to obtain a copy of the CBC
prior to dispensing the medication to the patient.
•WBC ≥ 3500/mm3 and ANC ≥ 2000/
mm3
•If the number of white blood-cells drops notably
then referral to a hematologist is
undertaken.

16. CLOZAPINE
Dosage Relation to Side Effects
• Agranulocytosis is not
dose dependant.
•Seizures on the other
hand is dose dependant

17. CLOZAPINE
Other Side Effects
•The risks of extrapyramidal
symptoms are much more less
when compared to the typical
antipsychotics;
• Weight gain and DM.
• Anticholinergic effects:
extreme constipation, dry mouth
(Xerostomia), blurred vision, urinary
retention
• Night-time drooling, or wet pillow
syndrome(Sialorrhea
• Muscle stiffness
• Sedation, Drowziness
• Tachycardia, Tremors
• Hyperglycemia
• Many male patients have experienced
cessation of ejaculation during
orgasm as a side effect of clozapine