Sathya Chandrakumar, BSc, PharmD Student1
Caroline Warnock, RPh, BScPhm, PharmD, BCPP2
Valerie Powell, RN, BScN2
Maria Zhang, RPh, BScPhm, PharmD, MSc1,2
1Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario
2Centre for Addiction and Mental Health, Toronto, Ontario
Clozapine is a unique atypical antipsychotic, heralded for its effectiveness in treatment-resistant schizophrenia (TRS).1 An estimated 25% to 30% of those living with schizophrenia meet the criteria for TRS, which is defined as non-responsiveness to, or intolerance of, two or more adequate trials of non-clozapine antipsychotic medications.1
In studies, clozapine consistently demonstrates superior efficacy compared to other antipsychotics, but its use has been restricted because of rare side effects such as agranulocytosis, seizures, myocarditis, and severe (sometimes fatal) cases of constipation. Due to its risk of agranulocytosis, clozapine also comes with stringent monitoring requirements such that patients are required to register with a clozapine monitoring system run by the manufacturer. Pharmacists have a key role to play in the safe use of this medication. Below are five essential components of working with clozapine, particularly for pharmacists working in outpatient or community pharmacy settings.
1. Before receiving clozapine, the patient must be enrolled in a brand-specific clozapine registry and have completed required baseline blood work.
In contrast to most medications, the prescribing physician, dispensing pharmacy, and patient must be registered in a manufacturer-specific distribution system to ensure the safe dispensing of clozapine.2 By enrolling in a distribution system registry, the manufacturer aids in tracking clozapine usage and monitoring patient health. There are presently three manufacturers of clozapine, each with their own registry (see Table 1). 3,4,5
A patient must not be switched from one brand of clozapine to another by a pharmacist unless he/she obtains a new, registry-specific patient registration form completed by the prescribing physician.2 Regular complete blood count results are recorded in patient registries to make sure that clozapine is not given to a patient with a history of clozapine-induced agranulocytosis or myocarditis.3
Before starting therapy, baseline white blood cell (WBC) and differential counts are required.3 Sometimes prescribers will issue a prescription before the patient has been cleared by the registry to start clozapine. Pharmacists should not dispense the first clozapine prescription until confirmation has been received from the registry that it is safe to start clozapine. The same recommendation applies to patients re-starting clozapine after a period of being off the medication.
Prior to dispensing subsequent clozapine prescriptions, the pharmacist should verify that the patient has completed their WBC and differential tests by checking with the registry online or by telephone. If the blood work has not been done within the required time frame, pharmacists should not dispense clozapine (i.e., “No blood, no drug”). Since clozapine adherence is important for effectiveness and safety, pharmacists are encouraged to contact the registry for guidance if blood work is delayed. Pharmacists should refer to the product monograph for guidance on interpreting hematological values. If hematological values are abnormal, contact the prescriber to collaborate on next steps. Additionally, pharmacists should not renew or adapt prescriptions for clozapine.
2. Clozapine coverage is usually different from most drugs, and this has implications on ensuring seamless care.
In order for clozapine to be covered for a patient, they must either: 1) have coverage through third-party insurance or 2) more commonly, qualify for Ontario’s Special Drugs Program. To qualify for the Special Drugs Program clozapine must be: prescribed by a hospital staff physician; recommended by a provincial psychiatric hospital regional coordinator; and prescribed to a patient with TRS.6
If a patient is obtaining their clozapine through the Special Drugs Program, they will need to fill the prescription at a designated hospital.7 Community pharmacies cannot be reimbursed for clozapine through this program. However, they may enter into an agreement with a hospital that can provide the pharmacy with a free supply of clozapine, to be used for mutual patients of the hospital and community pharmacy while patients are seen in an outpatient setting. This arrangement is encouraged if it means that the patient will get all of their medications dispensed from a single pharmacy (which helps with adherence and detection of drug interactions). If a patient continues to get their clozapine from a hospital pharmacy, both the community pharmacy and hospital pharmacy should keep the patient’s medication list up-to-date.
For hospital pharmacists or those with access to provincial drug databases, it’s important to ask specifically about clozapine when collecting a list of current and/or prior medications. Clozapine can get missed during medication reviews because it does not appear in the Ontario Drug Benefit (ODB) Drug Profile Viewer nor ConnectingOntario even though it is covered under the Special Drugs Program.
3. If a patient misses clozapine for more than 48 hours, contact the prescribing physician for an appropriate re-titration regimen.
It is important to tell patients to contact their pharmacist or prescriber if they have missed more than two days of clozapine because the dose might need to be decreased and re-titrated.3 Risks of continuing at the same dose after a period of missed doses include seizures, orthostatic hypotension, and excessive sedation. Also, if more than three days are missed, more frequent monitoring of WBC and differential counts could be required for a certain period of time.3 More information is available in the product monograph.
4. Encourage patients to report any side effect they experience, no matter how minor they think it may be.
Due to clozapine’s nonspecific and extensive receptor binding profile, several side effects must be discussed with the patient. The most common side effects are sedation, dizziness, hypersalivation, tachycardia, and constipation.3
Clozapine-induced constipation can lead to fatal complications so it is important for the pharmacist to ask about this side effect at every visit. Evidence suggests that regularly scheduled osmotic laxatives, such as lactulose (15-30 mL once or twice daily) or polyethylene glycol (17 g once or twice daily) effectively prevent and treat clozapine-induced constipation.8 Bulk-forming agents, such as psyllium, are to be avoided as they can worsen the risk of fecal impaction.8
Less common, but serious side effects of clozapine should be communicated as well, including seizures, agranulocytosis, and myocarditis.3 Agranulocytosis, as a result of clozapine, can lead to a significant decrease in white blood cells, which can predispose the body to infections.3 Patients should promptly report any flu-like symptoms (fever, chills, sore throat), mouth sores, weakness or lethargy.
In addition, with the increased risk of myocarditis, pharmacists should be vigilant of persistent tachycardia at rest when coupled with other signs and symptoms of heart failure (e.g. chest pain, shortness of breath), fatigue, flu-like symptoms, hypotension, or unexplained fever.3 This is especially important during the first month of clozapine treatment.3 In some institutions, patients receive troponin and C-reactive protein (CRP) tests before starting the drug, followed by four more weekly tests as the risk of myocarditis is highest early in therapy. Pharmacists should encourage prescribers to get these tests done at the time of initiation because symptoms of myocarditis tend to be non-specific. These lab values can be used in conjunction with a physical assessment for the physician to make a diagnosis of myocarditis.
Given clozapine’s high propensity for weight gain and metabolic disturbances, pharmacists should also recommend that patients get baseline metabolic tests done (weight, waist circumference, blood pressure, lipid profile, fasting blood glucose). These tests should be repeated periodically during therapy with clozapine and monitored by both prescriber and pharmacist.3
5. Monitor for changes in other medications and smoking status.
Clozapine is largely metabolized by CYP1A2 and CYP3A4, and pharmacists should be cautious when clozapine is combined with strong inducers or inhibitors of either enzyme.3 Drugs to consider include antibiotics, like ciprofloxacin, and erythromycin, as well as fluvoxamine, carbamazepine, phenytoin, and cimetidine.3 Tobacco smoking (and cannabis smoking) can also induce CYP1A2 through polycyclic aromatic hydrocarbons found in the smoke.9 Sudden smoking cessation (e.g., during a hospital admission) may increase the clozapine plasma level and potentiate side effects.3 Re-starting smoking (e.g., upon hospital discharge) can decrease clozapine plasma levels which can lead to a relapse in symptoms of schizophrenia. When developing a smoking cessation plan, the pharmacist should work closely with the patient to minimize drug-smoke interactions via close monitoring. Since the smoke from cigarettes affect clozapine metabolism, nicotine replacement therapies do not interfere with clozapine plasma levels.9 However, certain smoking cessation medications, like bupropion, can further lower seizure thresholds, and should be prescribed with caution.9
Pharmacodynamic interactions can also be important. Drugs with CNS depressant effects can potentiate sedation caused by clozapine.3 Concurrent use of anticholinergic drugs can potentiate the risk of constipation, and other drugs that are also associated with neutropenia and agranulocytosis (e.g. carbamazepine) should be avoided.3 If they must be used, closer monitoring of WBC and differential counts should occur.
Contact the designated clozapine registry for further questions or concerns.
For further questions on complete blood count monitoring, patient-registry status, or technical assistance, contact the designated clozapine registry, and a representative may be able to assist you.3,4,5
- CSAN (HLS Therapeutics)10
- AASPIRE Patient Care Network (AA Pharma)
- GENCan (Mylan Pharmaceuticals)
- Elnaz Haddadi, Clinical Pharmacist, Residency Program Coordinator, and Education Coordinator at the Centre for Addiction and Mental Health for her guidance.
- Jenny Jiang, Outpatient & Research Pharmacy Manager at the Centre for Addiction and Mental Health for her verbal input.
- Colette Raphael, Clinical Pharmacist at the Centre for Addiction and Mental Health for her verbal input.
- Sonia Thomas, Clinical Pharmacist at the Centre for Addiction and Mental Health for her verbal input.
- Remington, G., Addington, D., Honer, W., Ismail, Z., Raedler, T., & Teehan, M. (2017). Guidelines for the Pharmacotherapy of Schizophrenia in Adults. The Canadian Journal of Psychiatry. 62(9):604-616.
- Health Canada. 2004. Recalls and alerts - Health Canada releases important information on the dispensation of CLOZAPINE products in Canada - For Health Professionals. Retrieved from: http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2004/14249a-eng.php
- Clozaril (clozapine) [product monograph]. HLS Therapeutics Inc. Etobicoke, Ontario; 2017.
- AA-Clozapine (clozapine) [product monograph]. AA Pharma Inc. Vaughan, Ontario; 2017.
- GEN-Clozapine (clozapine) [product monograph]. Mylan Pharmaceuticals ULC. Etobicoke, Ontario; 2017.
- Ontario. 2017. Laws. Health Insurance Act - R.R.O. 1990, Reg. 552: General. Retrieved from: https://www.ontario.ca/laws/regulation/900552.
- Government of Ontario. 2017. Get full coverage for certain drugs. Retrieved from https://www.ontario.ca/page/get-full-coverage-certain-drugs
- Hibbard, K. R., Propst, A., Frank, D. E., & Wyse, J. (2009). Fatalities Associated With Clozapine-Related Constipation and Bowel Obstruction: A Literature Review and Two Case Reports. Psychosomatics. 50(4):416-419.
- Els, C. (2004). What is the role of pharmacotherapy in tobacco cessation in patients with schizophrenia? Psychopharmacology for the Clinician Psychopharmacologie pratique. Rev Psychiatr Neurosci. 29(3).
- CSAN Patient Care Portal. (n.d.). Retrieved from https://psp-force-com.pspgw.ca/