Clozapine: A Primer For Pharmacists

Clozapine is an atypical antipsychotic for the treatment of schizophrenia.

Thought disorders such as schizophrenia are marked by 1 or more of the following symptoms: delusions, hallucinations, disorganized thinking, grossly disorganized or abnormal motor behaviors, and negative symptoms (disruptions to normal behavior) (see Figure).¹

Clozapine, the first atypical antipsychotic available, is widely accepted to be superior to other antipsychotics, not only for treating positive symptoms, but also for treat- ing negative symptoms.² Generally, a shortcoming of antipsychotics is their inability to treat negative symptoms, which are frequently cited as the principal culprit in preventing improved social and occupational outcomes. Clozapine is FDA approved for treatment-resistant schizophrenia and reduction in the risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorder.

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Clozapine was first synthesized in 1960 and was used in clinical studies in the early 1970s. However, it was removed from the market in the United States in 1974 after 14 cases of agranulocytosis were reported in Finland, 8 of which resulted in death.

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Because of its superiority over other antipsychotics (also known as neuroleptics), clozapine was reintroduced to the American market in 1990, with specific monitoring parameters.

Clozapine monitoring was one of the first formal Risk Evaluation and Mitigation Strategy programs. It is required that the patient, physician, and pharmacy be registered with a clozapine manufacturer registry and report white blood counts (WBC) and absolute neutrophil counts (ANC) weekly during the first 6 months of therapy, every 2 weeks during the second 6 months of therapy, and monthly after 1 year of therapy. Currently, clozapine is available in the United States from 4 manufacturers (see Table). All of these companies have online registries, making it unnecessary to fax hard copies of lab results to the manufacturer or report results by telephone.

Because of the monitoring requirements and risk of agranulocytosis, clozapine is not a first-line agent for the treatment of schizophrenia. Generally, a patient must fail or be intolerant to at least 2 other antipsychotics before a trial of clozapine is warranted.

In addition to agranulocytosis, there are other adverse effects clinicians must consider. Seizures are dose related and generally are not seen in patients taking less than 600 mg daily. For patients who are on more than 600 mg daily, prophylactic antiepileptic therapy is recommen- ded, preferably with divalproex. Concomitant carbamazapine use is contraindicated due to the cumulative risk of bone marrow suppression.

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Myocarditis is a temporally related, potentially fatal side effect that has gained more recognition in the last decade. Clozapine-induced myocarditis is an immunoglobulin E—mediated allergic response that can develop during the first 8 weeks of treatment. Its true incidence is unknown, but has been reported as high as 1% to 2%.

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Some countries require mandatory reporting of myocarditis signs and symptoms during the first 6 months of treatment. At minimum, it is prudent to empirically check cardiac enzymes, brain natriuretic peptide, eryrthrocyte sedimentation rate, and/ or C-reactive protein at baseline and weekly for the first 4 to 8 weeks with the complete blood count with differential. Any symptoms such as elevated heart rate, temperature, or chest pain/discomfort should be investigated. If myocarditis is diagnosed, the clozapine must be stopped immediately and the patient provided with supportive care. If caught early enough, clozapine-induced myocarditis is reversible. It generally is not recommended that the patient be rechallenged with clozapine if myocarditis develops.

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Small bowel obstruction is another rare side effect, but it can be fatal. Because clozapine is so highly anticholinergic and patients on clozapine are, by nature, poor historians, severe constipation leading to small bowel obstruction is a real risk. All patients on clozapine should be provided with a bowel regimen such as docusate 100 mg orally twice daily at minimum. Polyethylene glycol, both as a standing order and as needed, may be used as an alternative or in addition to a stool softener.

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All patients started on clozapine will have some degree of orthostatic hypotension initially during dose titration. Up to 20% of patients will have tachycardia. Both of these results are related to the drug’s highly anticholinergic properties and its alpha receptor affinities. Symptomatic treatment is recommended (eg, increasing fluid intake, rising slowly from seated or prone position). Beta-blockers may be used if the heart rate exceeds 120 beats per minute or the patient is uncomfortable.

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Finally, as with any atypical anti-psychotic, metabolic syndrome may develop with long-term clozapine use. Clozapine is generally regarded as the worst metabolic offender among anti-psychotics; however, this high risk is often outweighed by the immeasurable benefit of improved quality of life that many patients experience when starting clozapine. Additionally, patients who were quite sedentary prior to clozapine initiation may be able to fully participate in a diet and exercise program after some symptom resolution. While the utility is still debatable, occasionally metformin will be added on to an atypical antipsychotic such as clozapine to help mitigate the metabolic effects.

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The Pharmacist’s Role

When reviewing a clozapine order or prescription, several questions should be answered to ensure safe and appropriate prescribing. Is the patient adherent to clozapine? If so, their home dose may be continued safely. If adherence is uncertain, restarting the home dose at full strength may result in cardiovascular collapse due to severe orthostatic hypotension.

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Until adherence is confirmed, it’s best to start at 25 mg daily or, at minimum, one-half of the home dose.

Ensure that the patient has had a complete blood count with differential in the last week and that WBC and ANC counts are greater than 3500/ mm

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and 2000/mm

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, respectively. The pharmacist will need to report these laboratory values to the appropriate registry and may assist in registering the physician. An extra step to ensure safety would be to obtain myocarditis laboratory values if the patient has been started on clozapine within the last 8 weeks.

As mentioned earlier, ensuring that a bowel regimen is available is important for patient comfort. A review of the medication list to identify duplicate therapeutic indications is also warranted. For example, patients taking clozapine would never require benztropine, as clozapine has inherent anticholinergic properties. Added benztropine only increases side effects such as cognitive dulling, dry mouth, and constipation.

Finally, pharmacists may assist in transitions of care by ensuring that the patient has the appropriate laboratory values required upon discharge and that the outpatient pharmacy of choice stocks clozapine. A quick telephone call to the outpatient pharmacy can assist with a smooth transition from inpatient to outpatient.

Lindsey Hedgepeth Kennedy, PharmD, BCPS, BCPP, is a clinical specialist in psychiatry at University of North Carolina Hospitals department of pharmacy.