Clozapine (Clozaril)

Primer

Clozapine (Trade name: Clozaril) is a an antipsychotic in the atypical antipsychotic class used in the treatment of schizophrenia, especially in patients who are resistant to other antipsychotics. It is commonly referred to as a “last-line antipsychotic.” It is a low potency antipsychotic and highly anticholingeric, which gives it a very low incidence of extrapyramidal side effects. However, it carries a risk of neutropenia and agranulocytosis, which requires intensive blood work and monitoring. Other serious side effects include the risk of constipation and related GI-issues.

Pharmacokinetics

Pharmacokinetics of Clozapine

Absorption Clozapine undergoes almost complete absorption. Oral bioavailability is 27-47% due to variable first pass metabolism, and peak concentration is around 2.5 hours following oral dosing.[1]
Distribution 95% bound to plasma proteins[2]
Metabolism Norclozapine is the major metabolite of clozapine.
Elimination
Half-life

Clozapine: Cytochrome P450 Metabolism

Substrate of (Metabolized by) 1A2
Induces
Inhibits

Pharmacodynamics

Mechanism of Action

  • Clozapine has the second lowest affinity for the D2 receptor (quetiapine is first).[3] It dissociates quickly from the D2 receptor (this has been referred to the “kiss and run” hypothesis).[4][5] As a result, these two rapidly dissociating atypical antipsychotics have a very low incidence of EPS.

Toxicity

Indications

Benefits

Low EPS

Clozapine has the same incidence of extrapyramidal symptoms as placebo.[6] This makes it a particularly useful switch antipsychotic for patients who are experiencing significant EPS from other antipsychotics.

Suicide Prevention

Clozapine is only one of two psychotropics (the other is lithium) that has been clinically shown to reduce the risk of suicide.[7]

Dosing

Dosing for Clozapine

Starting 25-50 mg PO daily, can be titrated 25-50 mg per day up to 300 mg.
Once at 300 mg daily… Titration should not exceed more than 25 mg each day
Once at daily doses of 400 mg, 500 mg 600 mg, 700 mg, 800 mg, and 900 mg… Maintain at each interval for at least 2 weeks before moving on
Once past 500 mg daily… Consider increasing the dose by 25-50 mg only every 2 weeks.
Maximum 900 mg

Note that an adequate trial of clozapine is considered to be a minimum of 8 weeks, but preferably 12 weeks, reaching a minimum dose of 400 mg per day.[8]

Formulations

  • Clozapine comes in oral or liquid formulation.

Pre-Treatment Investigations

Pre-Treatment Investigations

Investigations
Physical • Height
• Weight
• Waist circumference
• Blood pressure
• Heart rate
Labwork • CBC
• Glucose fasting
• AST, ALT, ALP
• Lipid Panel
• HbA1C
• CRP
• High sensitivity troponin I
• Baseline ECG

Target Plasma Level

  • The clozapine dose (i.e. - milligrams you take) is not correlated with clinical response, rather, it is the clozapine plasma level that matters.
  • Additionally, the dose taken does not always correspond to plasma levels. Plasma levels are generally lower in younger patients, males and smokers, while being higher in Asians.
  • Other factors that can change clozapine levels include adherence, inflammation, and infection. Retrospective studies have also been used to create nomograms to help determine whether serum levels are therapeutic based on specific patient demographics such as smoking, age, sex, and metabolic activity.[9]

Recommended Clozapine Levels

ng/mL (µg/L) nmol/L (nM/L)* Notes
Lower bound <200 <600 May place patients at a higher risk of relapse
Recommended level (divided dosing)[10] ≥250 ≥765 Typical dose is ~400mg to achieve this level
Recommended level (once daily dosing)[11] ≥350 ≥1100 Typical dose is ~400mg to achieve this level
Upper bound >1000 >3000 Increased risk of seizures
Maximum/Toxic Levels[12] >2000 >6000 Risk of clozapine-related toxicity
* = nmol/L × 0.33 = ng/mL

Hematological Monitoring

Hematological monitoring is required prior to starting and also during treatment to monitor for agranulocytosis-and-neutropenia (see Table below). Orthostatic vitals should also be monitored daily during any initiation or dose titration period, since hypotension can result.

Hematological Monitoring

Adapted from: Canadian AA-CLOZAPINE Product Monograph, AA Pharma, December 2, 2016
Treatment Status Bloodwork Action
Baseline • WBC ≥3.5 x 109/L
• ANC ≥2.0 x 109/L 		Begin clozapine treatment
Green • WBC ≥3.5 x 109/L
• ANC ≥2.0 x 109/L 		• Continue treatment
• Monitor patient:
– Weekly for the first 26 weeks
– q2 weeks for the next 26 weeks
– q4 weeks thereafter
Flashing Yellow Any of the following:
• A single (or sum of) fall in WBC of 3.0 x 109/L over the last 4 weeks, reaching a value <4.0 x 109/L
• A single (or sum of) fall in ANC of 1.5 x 109/L over the last 4 weeks, reaching a value <2.5 x 109/Lo 		• Patient should be evaluated immediately
• Check WBC count and ANC twice weekly
• Continue treatment
Yellow Any of the following:
• WBC 2.0-3.5 x 109/L
• ANC 1.5-2.0 x 109/L 		• Patient should be evaluated immediately
• Check WBC count and ANC twice weekly
• Continue treatment
Red Any of the following:
• WBC <2.0 x 109/L
• ANC <1.5 x 109/L 		• Immediately stop treatment and confirm results within 24 hours
• Patient must be closely monitored
• Attention must be paid to any flu-like complaints or other symptoms which might suggest infection
• Clozapine must NOT be resumed if results are confirmed and the patient should be assigned a non-rechallengeable status
Critical Any of the following:
• WBC <1.0 x 109/L
• ANC <0.5 x 109/L 		• Place the patient in protective isolation with close observation
• Physician must watch for signs of infection
The change from a weekly to a once-every-two-weeks, or from a once-every-two-weeks to a once-every-four-weeks schedule should be based upon the hematological profile of the patient as well as the clinical judgment of the treating physician, and if deemed appropriate, a consulting hematologist, and on the patient’s willingness to pursue a given frequency of blood monitoring. The clinical evaluation should take into consideration possible factors that would place the patient in a higher risk group.

Benign Ethnic Neutropenia (BEN)

Among certain ethnic groups, a significant proportion of people have a low baseline neutrophil count, or benign ethnic neutropenia. This is “the occurrence of neutropenia, defined by normative data in white populations, in individuals of other ethnic groups who are otherwise healthy and who do not have repeated or severe infections.” About 25% to 50% of Africans and some ethnic groups in the Middle East, including Yemenite Jews and Jordanians, have BEN. BEN has only been reported in ethnic groups that have tanned or dark skin. It is important to be aware of this so that individuals from certain ethnic groups do not have to stop clozapine unnecessarily.

Morning Pseudoneutropenia

Some patients have a very pronounced diurnal variation in their number of circulating neutrophils.[13][14] Thus, morning blood work may reveal a critical WBC count that falls below the normal range. In this case, it is wise to repeat a neutrophil count in the afternoon, before deciding to change clozapine treatment.[15]

Missed Doses

  • Doses missed for more than 48 hours (i.e. - 2 days) must be re-titrated!
    • Stopping clozapine for 48 to 72 hours is considered a full treatment break, and thus must be retitrated
    • Risks of continuing at the original dose include increased risk of seizures, orthostatic hypotension, and excessive sedation.
  • If more than > 3 days are missed, increased frequency of WBC monitoring and CBC differential will be required as well

Tapering or Discontinuation

Don't Forget to Continue Bloodwork Monitoring!

When discontinuing clozapine, a weekly white blood cell and absolute neutrophil count still needs ordered in the 4 weeks post-discontinuation![16]
  • The abrupt withdrawal of clozapine has been associated with cholinergic rebound symptoms and rapid onset of psychosis.[17]
  • Discontinuation-induced supersensitivity of dopamine receptors may lead to worsening and the appearance of new and more complex symptoms, and there have been case reports of suicide.[18][19]
  • Therefore, clozapine should always be gradually and slowly tapered over time.

Contraindications

Absolute

  • Clozapine is contraindicated in patients with a previous hypersensitivity to clozapine
  • Myeloproliferative disorders[20]
  • Uncontrolled epilepsy
  • Paralytic ileus

Relative

  • A history of clozapine-induced severe neutropenia or agranulocytosis is a relative contraindication for restarting clozapine.
  • A history of clozapine-induced myocarditis
  • Controlled seizures or epilepsy

Drug-Drug Interactions

  • Fluvoxamine increases clozapine levels by inhibiting CYP 1A2 metabolism
    • Clinically, sometimes fluvoxamine is added to clozapine to increase levels of clozapine, and reduce the conversion of clozapine to norclozapine, as there is evidence to suggest that a clozapine:norclozapine ratio of 2 or more will increase efficacy and tolerability of clozapine treatment (i.e. - more clozapine than norclozapine).[21]
  • St. John's wort induces CYP3A4 and CYP1A2 and reduces clozapine levels
  • Caffiene can inhibit CYP1A2, and can increase clozapine levels (mild-moderate)

Smoking

Cigarette smoking induces the CYP1A2 isoenzyme which can lead to lower levels of clozapine. It can reduce clozapine plasma levels by up to 50% and higher doses may be required in smokers than in nonsmokers. The polycyclic aromatic hydrocarbons in cigarettes induce CYP1A2 activity, which increases the metabolism of clozapine.[22] Nicotine replacement products (patches, lozenges, nasal spray, inhalers, and gum) on the other hand, do not induce CYP1A2. The impact of electronic cigarettes and vaping is less clear, and there may be a potential to induce CYP1A2 as well (though less than cigarettes).[23]

Quitting, Stopping, or Starting Smoking?

Patients who are smokers and on clozapine and decide to quit smoking face a higher risk of seizures (due to sudden increases in plasma clozapine)! These individuals may need up to a 50% reduction of their dose of clozapine. A patient who smokes at least 7-12 cigarettes a day and on a stable dose of clozapine may need a lower daily clozapine dosage when admitted to a smoke-free facility. Clozapine should be lowered by 30% to 40% over 4 to 7 days to reduce the risk of clozapine toxicity. If the patient starts smoking again, clozapine may need to be increased by as much as 1.5 times over a period of 2 to 4 weeks.

Side Effects

Sedation, hypotension and seizure activity are most commonly correlated with higher plasma levels of clozapine.[24]

Fever

Clozapine-induced fever is a benign but common side-effect that can occur in up to half of all patients on treatment.[25] Fevers typically last for up to 2-3 days, and occur in the first month of treatment. Other differential diagnoses to consider include neuroleptic malignant syndrome and clozapine-induced myocarditis.

Cardiovascular

  • Orthostatic hypotension can occur during the titration of clozapine. If hypotension occurs, the titration should be held while the blood pressure stabilizes.
  • Asymptomatic tachycardia, which occurs in approximately 25% of patients

Salivation (Hypersialorrhea)

Hypersialorrhea (hypersalivation) is the excessive production of saliva. Clozapine-induced hypersalivation/sialorrhea (CIH, or CIS) is a common side effect related to clozapine use (but can also occur in other antipsychotics).[26] Sialorrhea can range from being mildly uncomfortable drooling and excessive saliva, to potentially life-threatening conditions, such as parotitis, choking, and aspiration. Sialorrhea is not dose-related and can occur at any point during treatment. Although clozapine has many anticholinergic properties, the cause of CIS is thought to be due to clozapine agonism at the muscarinic (M4) receptors and blockade of a-2 adrenergic receptors, which increases salivary production and flow.[27]

CIS can be treated with an muscarinic receptor antagonist (i.e. - an antimuscarinic/anticholinergic) such as atropine or ipratropium, which can administered sublingually at night time.[28][29] Common treatment regimens include:

  • Atropine sulfate, 1 to 2 drops of the 1% ophthalmic solution sublingually 2 to 3 times daily[30]
  • Ipratropium bromide, 1 to 2 sprays of 0.03% nasal spray sublingually at bedtime
  • Clonidine up to 0.025 mg TID

Constipation

Constipation is very common and can affect up to 50% of patients.[31] It is critical for every patient on clozapine to have bowel monitoring for constipation. Clozapine has the potential to decrease GI motility, and is associated with risk of paralytic ileus, bowel obstruction, fecal impaction, bowel perforation, and in rare cases, death.[32] If other anticholingerics are also being used, then the prescribing clinician needs to be even more vigilant about bowel monitoring, since anticholingeric effects are additive. In addition, the risk of medication-related constipation also increases with age. Other conditions like diabetes mellitus can also further worsen constipation due to autonomic neuropathy.

Don't Forget About Constipation!

Constipation can be life-threatening. Severe constipation can cause bowel obstruction, sepsis and death. More deaths are caused by clozapine-induced ileus/megacolon than by agranulocytosis.[33]

Before Starting Clozapine

  • Obtain a baseline bowel movement history
  • Counsel patients on recognition and reporting of constipation.
  • Review all current medications and anticholinergic medications and stop other constipating medications wherever possible.
  • If baseline constipation exists, begin laxative treatment immediately.

Constipation Management

1st line Osmostic agents:
• Polyethylene glycol (PEG): start 17 grams daily, and increase to 17 grams BID as needed (this is
beyond manufacturers’ recommended dose).
• Lactulose: start 15-30 mL daily, and increase to 30 mL BID
Note: Combining lactulose and PEG 3350 combined is not a rational pharmacotherapy due to overlapping mechanisms.
2nd line Stimulant laxatives:
• Sennosides
• Bisacodyl
3rd line Fibre and bulk-forming products may be helpful, but can also worsen constipation in underlying dehydration and should be used cautiously.
Adjunctive Dietary and exercise interventions should be considered as adjunct to laxative therapy as they are not likely to improve clozapine-induced constipation alone.
Not recommended There is no evidence for the use of surfactant agents (“stool softeners”) like docusate sodium for chronic constipation. These agents only lower the surface tension of stool, but are not effective at preventing and treating medication-induced constipation.[34]

Adverse Events

Agranulocytosis and Neutropenia

  • Agranulocytosis (absolute neutrophil count, or ANC, less than 500/µL) is the most serious adverse reaction to clozapine.
  • To prevent this from occurring, regular hematological monitoring is required, which reduces the risk of agranulocytosis by 20-fold.
  • Agranulocytosis tends to develop during the first 4 to 6 months of treatment, whereas neutropenia (ANC between 0.5-1.5 x 109/L) can occur at any time.[35]
    • The risk for agranulocytosis become negligible after 2 years of clozapine exposure.[36]

Myocarditis and Cardiomyopathy

Myocarditis and cardiomyopathy are the two serious cardiac-related adverse events to monitor for, both during initiation of treatment and throughout the course of treatment.[37]

Clozapine-induced Myocarditis and Cardiomyopathy

Onset % of patients Signs and Symptoms Pathophysiology Bloodwork Investigations and Treatment
Myocarditis Generally occurs within first few weeks (14-21 days) of clozapine initiation. Mortality rates as high as 50% have been reported, when undetected. 0.2% Myocarditis has non-specific symptoms, including fever, tachycardia and chest pain. There may be signs of heart failure such as dyspnea (especially while supine) or dry cough. Other symptoms include diarrhoea, vomiting, dysuria or rashes. The pathophysiology of clozapine-associated myocarditis not well understood but is not dose-dependent. • CBC (↑ WBC, ↑ eosinophils)
• CRP (↑)*
• Troponin, BNP, CK, ESR 		Echocardiogram, CXR. Treatment includes stopping clozapine, and usual treatment for myocarditis. Diagnosis is not straightforward, and suspected cases should be referred urgently for a cardiology opinion.
Cardiomyopathy Usually occurs later in clozapine treatment compared to myocarditis. Clinicians need to maintain a high index of suspicion for cardiomyopathy throughout clozapine treatment, regardless of how long a patient has been on clozapine. 0.02–0.1%[38] Signs of heart failure, flu-like symptoms, cough, fever, sinus tachycardia/ palpitations, fatigue, hypotension and chest discomfort.[39] Poorly understood, may be secondary to untreated, acute clozapine-induced myocarditis.[40] • CBC (↑ WBC, ↑ eosinophils)
• CRP (↑)*
• Troponin, BNP, CK, ESR 		Echocardiogram (reduced ejection fraction), ECG. Treatment includes stopping clozapine and usual treatment for heart failure.
* = CRP elevation is one of earliest signs of myocarditis and can appear up to 5 days prior to troponin elevation.

Bloodwork and monitoring for the first month

When doing clozapine monitoring, remember that elevated CRP means general inflammation, and when there is also elevated troponin this means there is localization of that inflammation (to the heart).

Bloodwork and monitoring for the first month

Although there are no universal guidelines, some monitoring protocols suggest monitoring troponin and CRP every week for the first month, plus vital signs every other day.[41] Symptoms suggestive of myocarditis, plus elevated troponin (>2 times the upper limit of normal) and CRP (>100 mg/L) is highly sensitive for the diagnosis of clozapine-induced myocarditis.[42]

Seizures

Seizure risk increases in a dose-dependent manner with clozapine, and is most frequent in patients with serum levels above 1000 μg/L, or at doses more than 500 mg per day. Clozapine-induced seizures can be managed and prevented with either valproate or lamotrigine. Valproate has the most data to support its use and it is widely regarded as the drug of choice. Adjunctive antiepileptic treatment is recommended as prophylaxis against seizures and myoclonus when plasma levels are above 600 μg/L. There is also a relationship between clozapine dose, plasma level, and the likelihood of an abnormal EEG.[43]

Multiple factors can affect the true plasma level of clozapine. Plasma levels are generally lower in smokers, younger ages, and males. Conversely, plasma levels are generally higher in Asian patients, and they may have a higher risk of seizures even at low doses of clozapine.[44]

Clinical Pearls

Special Populations

Geriatric

Pediatric

Obstetric and Fetal

Medically Ill

Guidelines

Resources

For Clinicians
Readings
Documentation
We reviewed the common side effects of clozapine:  elevated heart rate, ECG abnormalities, orthostatic hypotension, hyperlipidemia, hyperglycemia, drowsiness, dizziness, falls, insomnia, akathisia, excess saliva production, dry mouth, weight gain, constipation, nausea, vomiting, abdominal discomfort and heartburn, enuresis, EPS. Potentially rare, but more serious risks:  agranulocytosis,  tardive dyskinesia, neuroleptic malignant syndrome (muscle stiffness, fever, sudden rise in blood pressure, agitation and confusion), myocarditis, pericarditis, cardiomyopathy, stroke, blood clots, lowered blood cells (such as platelets and eosinophils), aspiration pneumonia, dysregulation of body temperature, arrhythmias, suicidal thinking, bowel obstruction and seizures. We also reiterated that sudden cardiac death is possible with patients who are prone to arrhythmias and QTc prolongation. Reviewed that patients with dementia have a known risk for death and stroke like events with use of neuroleptics.

References

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2) Reeves, S., Bertrand, J., Obee, S. J., Hunter, S., Howard, R., & Flanagan, R. J. (2023). A population pharmacokinetic model to guide clozapine dose selection, based on age, sex, ethnicity, body weight and smoking status. British Journal of Clinical Pharmacology.
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16) Clozapine Product Monograph
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20) FDA Monograph Clozaril
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29) Bird, A. M., Smith, T. L., & Walton, A. E. (2011). Current treatment strategies for clozapine-induced sialorrhea. Annals of Pharmacotherapy, 45(5), 667-675.
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34) Paré, P., Bridges, R., Champion, M. C., Ganguli, S. C., Gray, J. R., Irvine, E. J., ... & Flook, N. (2007). Recommendations on chronic constipation (including constipation associated with irritable bowel syndrome) treatment. Canadian Journal of Gastroenterology and Hepatology, 21(Suppl B), 3B-22B.
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38) Longhi, S., & Heres, S. (2017). Clozapine-induced, dilated cardiomyopathy: a case report. BMC research notes, 10(1), 338. https://doi.org/10.1186/s13104-017-2679-5
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40) Longhi, S., & Heres, S. (2017). Clozapine-induced, dilated cardiomyopathy: a case report. BMC research notes, 10(1), 338.
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42) Sackey, B. K., Moore, T. A., Cupples, N. L., & Gutierrez, C. A. (2018). Clozapine-induced myocarditis: Two case reports and review of clinical presentation and recognition. Mental Health Clinician, 8(6), 303-308.
43) Varma, S., Bishara, D., Besag, F. M., & Taylor, D. (2011). Clozapine-related EEG changes and seizures: dose and plasma-level relationships. Therapeutic advances in psychopharmacology, 1(2), 47-66.
44) Matsuda, K. T., Cho, M. C., Lin, K. M., Smith, M. W., Young, A. S., & Adams, J. A. (1996). Clozapine dosage, serum levels, efficacy, and side-effect profiles: A comparison of Korean-American and Caucasian patients. Psychopharmacology bulletin.