- Last edited on April 30, 2020
Clozapine (Clozaril)
Primer
Clozapine (Tradename: Clozaril) is an atypical antipsychotic. It is used to treat both the positive and negative symptoms of schizophrenia, especially in patients who are resistant to other antipsychotics. It is the 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. Norclozapine is the major metabolite of clozapine.
Management
Pre-Treatment Investigations
Pre-Treatment Investigations
| Physical | Labwork |
|---|---|
| • Height • Weight • Waist circumference • Blood pressure • Heart rate | • CBC • Glucose fasting • AST, ALT, ALP • Lipid Panel • HbA1C • CRP • High sensitivity troponin I • Baseline ECG |
Starting Dose
- Clozapine can be started at 25-50mg PO daily. The dose can be titrated by 25-50 mg per day up to 300 mg
- Once at 300mg daily, the titration should not exceed by more than 25mg each day
- Once at daily doses of 400mg, 500mg 600mg, 700mg, 800mg, and 900mg, these doses should be maintained for at least 14 days
- Once past 500mg daily, consider increasing the dose by 25-50mg only every 2 weeks
- The maximum daily dose of clozapine is 900mg
Target Plasma Level
The dose of clozapine is not correlated with clinical response, rather, it is the clozapine plasma level that matters. The lowest effective clozapine plasma levels range from 250 to 550 µg/L based on research consensus. Plasma levels below 200 μg/L may place patients at a higher risk of relapse, while above 1000 μg/L increases the risk of developing seizures. The recommended upper limit to prevent clozapine toxicity ranges from 600 to 2000 µg/L. The dose of clozapine 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. Clozapine plasma levels correlates with seizure risk. Retrospective studies have been used to create nomograms to help determine whether serum levels are therapeutic based on specific patient demographics, including smoking, age, sex, and metabolic activity.[1]
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 – Every 2 weeks for the next 26 weeks – Every 4 weeks thereafter |
| Flashing Yellow | Any of the following: • A single or sum of falls in WBC count of 3.0 x 109/L over the last 4 weeks, reaching a value <4.0 x 109/L• A single or sum of falls in ANC of 1.5 x 109/L over the last 4 weeks, reaching a value <2.5 x 109/L | • 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 |
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.[2][3] 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.[4]Guidelines
Missed Doses
Tapering or Discontinuation
The abrupt withdrawal of clozapine has been associated with cholinergic rebound symptoms and rapid onset of psychosis.[5] Discontinuation-induced supersensitivity of dopamine receptors can lead to worsening and the appearance of new and more complex symptoms.[6] Therefore, clozapine should always be gradually and slowly tapered over time.
Benefits
Low EPS
Clozapine has the same incidence of extrapyramidal symptoms as placebo.[7] 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.[8]
Side Effects
Sedation, hypotension and seizure activity are most commonly correlated with higher plasma levels of clozapine.[9]
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 6 months of treatment, whereas neutropenia (ANC between 0.5-1.5 x 109/L) can occur at any time.
Smoking
Cigarette smoking reduces 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.[10]
Find out if your patients are smoking or not!
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. Conversely, for inpatients who are admitted into hospital and stop smoking during the hospitalization, ensure you discuss with them the risks of resuming smoking. If they start smoking again after discharge, this can lead to subtherapeutic levels of clozapine due to increased clozapine metabolism.Seizures
Seizures occur more frequently in patients with serum levels above 1000 μg/L, or at doses more than 500mg per day. Clozapine-induced seizures can be treated 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.[11]
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.[12] Overall, clozapine plasma levels have a dose-dependent relationship with seizure occurrence.
Cardiovascular
Cardiomyopathy and myocarditis are the two serious cardiac-related side effects to monitor for.
Myocarditis generally occurs within the first few weeks after clozapine initiation. The absolute risk has been estimated at less than 0.2% of patients, however, mortality rates as high as 50% have been reported. Myocarditis has non-specific symptoms, including fever, tachycardia and chest pain. Other symptoms include shortness of breath, dry cough, elevated white cell count, peripheral eosinophilia, diarrhoea, vomiting, dysuria and rash. The pathophysiology of clozapine-associated myocarditis not well understood but is not dose-dependent. Diagnosis is not straightforward, and suspected cases should be referred urgently for a cardiology opinion. Elevated C-reactive protein (CRP) is one of the earliest signs of myocarditis, usually 5 days prior to any troponin elevation. An echocardiogram is recommended as an initial diagnostic step.
Cardiomyopathy usually occurs later in clozapine treatment than myocarditis. Symptoms include signs of heart failure, flu-like symptoms, cough, fever, sinus tachycardia/ palpitations, fatigue, hypotension and chest discomfort.[13] Clinicians need to maintain a high index of suspicion for cardiomyopathy throughout clozapine treatment. Diagnosis of clozapine-associated cardiomyopathy is made through a finding of reduced ejection fraction on echocardiogram. Electrocardiograms (ECGs) and blood tests, including raised B-type natriuretic peptide (BNP) is also used. Treatment includes cessation of clozapine and usual treatment for heart failure.
Hypotension
Orthostatic hypotension can occur during the titration of clozapine. If hypotension occurs, the titration should be held while the blood pressure stabilizes. Other non-fatal symptoms include asymptomatic tachycardia, which occurs in approximately 25% of patients.
Sialorrhea
Clozapine-induced sialorrhea (CIS), is a common side effect related to clozapine use. Sialorrhea can range from being mildly uncomfortable drooling and excessive saliva, to potentially life-threatening conditions, such as parotiditis, choking, and aspiration. Sialorrhea is not dose-related and can occur at any point during treatment. It is due to clozapine agonism at muscarinic (M4) receptors and blockade of a-2 adrenergic receptors, which increases salivary production and flow.[14]
CIS is treated with an muscarinic receptor antagonist (antimuscarinic) such as atropine or ipratropium, which can administered sublingually at night time.[15][16] Common treatments include:
- Atropine sulfate, 1 to 2 drops of the 1% ophthalmic solution sublingually 2 to 3 times daily[17]
- Ipratropium bromide, 1 to 2 sprays of 0.03% nasal spray sublingually at bedtime
Constipation
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.[18]Constipation is common and can affect up to 50% of patients.[19] 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.[20] 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.
First-line management and treatment includes the use of an osmotic agent, such as polyethylene glycol (PEG), and/or a stimulant laxative such as senna. There is limited 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.[21]