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Clozapine Medication Study Guide

NURS 6630: Psychopharmalogical Approaches to Treat Psychopathology

Dr.
July 16, 2023

 Description

 Clozapine represents a distinctive

therapeutic option within the class of
atypical antipsychotics, characterized by a
unique pharmacological profile that
diverges from the common patterns seen in
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 Brand/Generic Names

 Clozaril
 Denzapine
 Zaponex.

 Appropriate FDA Indication Uses

The U.S. Food and Drug Administration (FDA) has granted clozapine approval for two distinct uses:
 Schizophrenia that Is Resistant to Treatment: This medicine is recommended for the treatment of
schizophrenia that Is Resistant to Treatment. When other antipsychotic drugs haven't worked,
this one is used. Clozapine is often only taken into account when the patient has tried at least two
different antipsychotic medications and they have not worked as well as expected (Medscape,
2023).  Non-Fda Uses
 Reduction of Recurrent suicide conduct in Schizophrenia or Schizoaffective Disorder: Clozapine
is also recommended for those with schizophrenia or schizoaffective disorder who are thought to
be at chronic risk for engaging in suicidal behavior again. This decision has been made in light of
previous suicidal behavior or persistent
 Treatment-Resistant Bipolar suicidal
Disorder:ideation.
(Gammon et al., 2021) show that clozapine
may be beneficial in managing symptoms in individuals with bipolar disorder who do not
respond to other treatments.
 Parkinson's Disease Psychosis: (Pham Nguyen et al., 2021) suggests that clozapine may
be beneficial for individuals with Parkinson's disease who also experience psychosis, as
it seems to be less likely to exacerbate Parkinson's symptoms compared to other
antipsychotics (Friedman, 2018).
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Drug Classification
 Clozapine belongs to the unique group of medicines known as atypical antipsychotics. This
classification of medication offers the ability to transform the chemical balance in the brain, tackling
debilitating symptoms associated with complex mental health conditions (Correll et al., 2022).
 Clozapine, an atypical antipsychotic, has proven typical in its potent efficacy against treatment-
resistant schizophrenia, bringing relief in the enigma of psychosis where other medications have
failed. Yet, the narrative of its use is entangled in a web of complexities, laced with the ever-present
threat of agranulocytosis, making its prescription a thoughtful and measured decision.

 Mechanism of Action
Clozapine operates by blocking the serotonin 5-HT2A/5-HT2C receptors as well as the
dopamine D1-4 receptors, with the D4 receptor having the highest affinity. Clozapine, as
a serotonin and D4 dopamine antagonist, can exhibit antipsychotic benefits without
causing many of the extrapyramidal motor adverse effects seen with D2 dopamine
receptor antagonists. (2023, DrugBank)
 Pharmacokinetics of clozapine
Clozapine is practically entirely absorbed, has an oral bioavailability of 27 to 47%, and is
95% bound to plasma proteins due to its widely diverse first pass metabolism (Albitar et
al., 2020). The maximum concentration is obtained approximately 2.5 hours after oral
administration. Clozapine is transformed into the major plasma metabolite N-
desmethylclozapine (norclozapine) by cytochrome P (CYP) 1A2 and, to a lesser extent,
CYP3A4 via extensive metabolism and demethylation.
 Pharmacodynamics of Clozapine
Clozapine, a psychotropic medication from the benzisoxazole derivatives family, is the
drug of choice for treating treatment-resistant schizophrenia. Despite the fact that it is
thought to exert its pharmacological effect by antagonistically binding to the serotonin
type 2A (5-HT2A) and dopamine type 2 (D2) receptors, (Jendryka et al., 2019) has
proven that clozapine can function on a variety of receptor types. Clozapine
hypersensitivity events, such as agranulocytosis and myocarditis, should be discussed
with patients (DrugBank, 2023). Clozapine-induced agranulocytosis, defined as a drop in
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absolute neutrophil or white blood cell count, puts the patient at an increased risk of
infection.
 Appropriate Dosing

 Clozapine has been shown to be safe and effective in persons with treatment-resistant schizophrenia. For
the first time, use 12.5 mg orally once per day or every 12 hours. Depending on the patient's tolerance,
the dosage is raised by 25 mg to 50 mg after the initial dose (Jiwanmall et al., 2023). The target dose of
300-450 mg per day is to be attained by the end of the second week. The dosage can be increased to 600-
900 mg per day, although this higher amount increases the chance of negative effects. In addition to
approaching the geriatric population with considerable caution, safety and efficacy for the pediatric
population have not been established.

 Administration Route
Clozapine is available in several forms for oral administration, including tablets, tablets that
dissolve quickly in the tongue, and liquids (MedlinePlus, 2023). It is usually taken once or twice
a day. Clozapine should be taken at the same time(s) every day.
 Considerations for Dosing Alterations

Laboratory testing is required:

 Before beginning treatment, obtain a CBC count with differential for baseline ANC; ANC must be
monitored often in order to maintain treatment.
 To begin treatment, ANC must be less than 1500/mm3 in the general population and less than
1000/mm3 in persons with benign ethnic neutropenia (Medscape, 2023).

 Special Populations
 Children and adolescents, for instance, are in crucial stages of neurodevelopment, thus warranting
particular consideration regarding the potential long-term impacts of antipsychotic medications.
Therefore, a comprehensive assessment of the risk-benefit ratio is essential in these younger age groups,
and close monitoring for side effects, including metabolic disturbances, is necessary.
 The elderly represents another population where Clozapine use necessitates extra caution. Age-related
changes in pharmacokinetics and pharmacodynamics, coupled with an increased likelihood of comorbid
medical conditions, may necessitate dose adjustments and frequent monitoring (Correll et al., 2022).
 In terms of pregnancy, Clozapine is classified as a Category B drug by the FDA, meaning it should be
used during pregnancy only if clearly needed, and after thorough risk-benefit analysis. It is also found in
breast milk, so caution should be exercised if the mother is nursing.
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 Half-Life

o When 100 mg twice

o In the field of o For any given drug, half-life is daily was administered
pharmacology, "half- helpful in calculating steady- to reach a steady state,
life" refers to the state concentrations and the mean elimination
amount of time it takes excretion rates. Although half-life of clozapine
for a drug's body different medications have was 12 hours (range: 4 to
concentration to reduce varied half-lives, they always 66 hours), as opposed to
by half. Understanding adhere to the same principle: 8 hours (range: 4 to 12
the drug's duration of 50% of the initial drug dose is hours) following a single
effect and how quickly eliminated from the body after 75 mg dosage
it leaves the body one half-life. (Hallare & (DrugBank, 2023).
depends on this Gerriets, 2021).
characteristic.
o .

 Side Effects/Adverse Reactions Potential

 Some patients may experience increased salivation and sedation, along with tachycardia,
which refers to a faster than normal heart rate. Hypotension or lower blood pressure,
constipation, and weight gain are other possible adverse reactions (Correll et al., 2022).
Despite these potential discomforts, the drug's effectiveness in treating resistant cases of
schizophrenia often outweighs the inconvenience of these side effects.
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 Contraindications for Use / Drug-Drug Interactions

 Patients who have experienced severe hypersensitivity responses to clozapine or any other ingredient in the
formulation should not use clozapine.
 The following Black Box warnings are provided by FDA; Neutropenia, Orthostatic tachycardia, Seizures,
Myocarditis and Alzheimer’s disease (Haidary & Padhy, 2023).
 Antifungals, oral contraceptives, fluvoxamine, ciprofloxacin, and caffeine disulfiram are just a few of the
medications that may block cytochrome CYP1A2 and cause clozapine levels to rise.
 Among the medications that can cause CYP1A2 include omeprazole, rifampicin, cigarettes, phenytoin, and
phenobarbital. The levels of the drug clozapine may also be impacted by additional medications that both
activate (carbamazepine and rifampicin) and inhibit (cimetidine and erythromycin, among others) CYP3A4.

 Overdose Considerations

 Hyper salivation, tachycardia, hypotension, sedation, delirium, coma, respiratory depression, or failure are
some of the frequent side effects linked to clozapine overdose. Few cases of cardiac arrhythmias,
aspiration pneumonia, and seizures have been reported (Haidary & Padhy, 2022). Death is documented at
doses greater than 2500 mg, but some patients have recovered despite taking 4000 mg of clozapine.

 Diagnostics and Labs Monitoring

 A complete blood count (CBC) with differential is required before initiating treatment. This step is crucial
to establish baseline levels of various blood cells, including neutrophils, given Clozapine's potential to
cause agranulocytosis, a severe decrease in white blood cells that leaves individuals vulnerable to
infections(Haidary & Padhy, 2023).
 Once treatment begins, regular CBC checks are mandatory to monitor for any significant changes in white
blood cell counts. This scrutiny must persist for 4 weeks following discontinuation of Clozapine due to the
lingering risk of agranulocytosis. Hence, the use of Clozapine demands consistent coordination between
the patient, healthcare provider, and laboratory services to ensure safe use.

 Comorbidities Considerations

 Due to the existence of concomitant medical illnesses, people using clozapine are at risk for cardiovascular
events and mortality. The risk is increased by common comorbidities including diabetes and cardiovascular
disease(MedlinePlus,
 Legal and 2023).
ethicalThe effects of COVID-19 with clozapine may combine to cause myocarditis,
considerations
pericarditis, and cardiomyopathy.
Regular blood tests are mandatory, and the results must be recorded in the REMS database
before the medication can be dispensed. In addition to these legal considerations, informed
consent is an ethical prerequisite before initiating Clozapine (Haidary & Padhy, 2022). Patients
must be made aware of the potential benefits and risks associated with its use, including the risk
of agranulocytosis, the necessity of regular blood tests, and other potential side effects. This
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transparency facilitates a therapeutic alliance, where the patient actively participates in their
treatment decisions.

 Pertinent Patient Education Considerations

 Patients must understand the critical importance of regular lab monitoring. It should be emphasized
that these tests, particularly complete blood counts, are not optional but required to ensure their
safety while taking this medication. They should be aware that the frequency of these tests may
decrease over time, but will remain a regular part of their care (Albitar et al., 2020).
 Secondly, patients should be educated about the signs of agranulocytosis, which include fever, sore
throat, and other flu-like symptoms. They should be instructed to seek immediate medical attention
if they experience these symptoms, as they might indicate a severe reduction in white blood cells, a
potentially life-threatening condition (MedlinePlus, 2023).
 Finally, patients should be informed about the potential side effects of Clozapine, such as
salivation, sedation, tachycardia, hypotension, constipation, and weight gain. It's crucial to stress
that if side effects become bothersome, or if they experience symptoms of an overdose, such as
delirium, stupor, or seizures, they should contact their healthcare provider immediately.

References
Albitar, O., Harun, S. N., Zainal, H., Ibrahim, B., & Sheikh Ghadzi, S. M. (2020). Population
Pharmacokinetics of Clozapine: A Systematic Review. BioMed Research International,
1–11. https://doi.org/10.1155/2020/9872936
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Correll, C. U., Agid, O., Crespo-Facorro, B., de Bartolomeis, A., Fagiolini, A., Seppälä, N., &
Howes, O. D. (2022). A Guideline and Checklist for Initiating and Managing Clozapine
Treatment in Patients with Treatment-Resistant Schizophrenia. CNS Drugs, 36(7), 659–
679. https://doi.org/10.1007/s40263-022-00932-2

DrugBank. (2023, June 13). Clozapine. Go.drugbank.com.

https://go.drugbank.com/drugs/DB00363

Gammon, D., Cheng, C., Volkovinskaia, A., Baker, G. B., & Dursun, S. M. (2021). Clozapine:
Why Is It So Uniquely Effective in the Treatment of a Range of Neuropsychiatric
Disorders? Biomolecules, 11(7), 1030. https://doi.org/10.3390/biom11071030

Haidary, H. A., & Padhy, R. K. (2022). Clozapine. PubMed; StatPearls Publishing.

https://www.ncbi.nlm.nih.gov/books/NBK535399/#:~:text=The%20common%20adverse
%20events%20associated

Haidary, H. A., & Padhy, R. K. (2023). Clozapine. PubMed; StatPearls Publishing.

https://www.ncbi.nlm.nih.gov/books/NBK535399/#:~:text=Clozapine%20is
%20contraindicated%20in%20patients

Hallare, J., & Gerriets, V. (2021). Half Life. PubMed; StatPearls Publishing.
https://www.ncbi.nlm.nih.gov/books/NBK554498/#:~:text=Understanding%20the
%20concept%20of%20half

Jendryka, M., Palchaudhuri, M., Ursu, D., van der Veen, B., Liss, B., Kätzel, D., Nissen, W., &
Pekcec, A. (2019). Pharmacokinetic and pharmacodynamic actions of clozapine-N-oxide,
clozapine, and compound 21 in DREADD-based chemo genetics in mice. Scientific
Reports, 9(1). https://doi.org/10.1038/s41598-019-41088-2

Jiwanmall, S., Kar, N., Akua Obuobie, Tanay Maiti, Lester, D., Mclaughlin, K., & Hanson, T.
(2023). Ethnic Differences in Dose and Levels of Clozapine: Exploring Need for Any
Specific Monitoring Needs. 9(S1), S136–S136. https://doi.org/10.1192/bjo.2023.375

MedlinePlus. (2023). Clozapine: MedlinePlus Drug Information. Medlineplus.gov.

https://medlineplus.gov/druginfo/meds/a691001.html#:~:text=Clozapine%20comes
%20as%20a%20tablet
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Medscape. (2023). Clozaril, Versacloz (clozapine) dosing, indications, interactions, adverse

effects, and more. Reference.medscape.com.
https://reference.medscape.com/drug/clozaril-versacloz-clozapine-342972

Pham Nguyen, T. P., Abraham, D. S., Thibault, D., Weintraub, D., & Willis, A. W. (2021). Low
continuation of antipsychotic therapy in Parkinson disease – intolerance, ineffectiveness,
or inertia? BMC Neurology, 21(1). https://doi.org/10.1186/s12883-021-02265-x