Clozapine Use in Dental Practice: Navigating Risks and Optimizing Patient Care

This article will explore the essential considerations for dentists when treating patients on clozapine therapy.

Schizophrenia is a serious mental illness that affects approximately one percent of Canadians.¹ Symptoms include hallucinations, delusions, disorganized thinking and behaviour.

There are many antipsychotics available. However, about 30% of patients fail to respond to two or more of them and are deemed treatment-resistant.² Clozapine is the next step because it has consistently demonstrated superior efficacy compared to other drugs.

Clozapine has many side effects but can be used safely if patients are appropriately monitored. Because it is so effective in treating schizophrenia, there is a push to get more patients started on clozapine as soon as they become eligible.³ The earlier symptoms of schizophrenia are treated, the better the response and prognosis.⁴

Medication List

There are many potential drug interactions with clozapine. At each visit, obtain an accurate list of the patient’s medications, including:

• prescriptions
• over-the-counter drugs
• natural health products and vitamins
• smoking status – number of cigarettes per day and any recent changes.
• cannabis – number of grams of cannabis smoked per day
• when they last took a clozapine dose, and what dose.

For each medication, ask the patient exactly how they are using it, in case it’s different than what is on the prescription label. Contact their pharmacist to help with questions.

SIDE EFFECTS

Most side effects of clozapine are mild and manageable. Serious side effects are rare but can be life-threatening. Thankfully, these can mostly be prevented or reversed if caught in time. Below are some of clozapine’s side effects most relevant to dental practice.

Sedation, orthostatic hypotension & tachycardia

Orthostatic hypotension, tachycardia, and sedation are relatively common dose-related side effects, especially at the start of therapy, if the dose is titrated up too quickly or the plasma level gets too high.⁵

Clozapine is a sedating drug, so it is not unusual for patients to fall asleep in the chair. Dim lights and soothing music might be too calming to keep the patient awake. On the other hand, some patients may be overstimulated. Adjust the environment to match the patient’s preferences and level of alertness.

Minimize the risk of an adverse event such as falls from orthostatic hypotension by assisting patients to rise slowly from a reclining or seating position.⁶ Use sedating drugs or drugs that decrease blood pressure with caution.

Severe Neutropenia (agranulocytosis)

Severe neutropenia is a rare side effect occuring in less than 1% of patients and it can lead to serious, potentially fatal infections.⁷ The risk of severe neutropenia is highest within the first few months but can occur at any time.9 Patients are enrolled with a manufacturer-specific registry (there are three brands of clozapine – see Appendix). Patients must have a regular white blood cell (WBC) test (weekly to every four weeks, depending on how long they have been on the drug.) Clozapine is stopped if the absolute neutrophil count is too low.⁸

Patients must also contact their mental health team member or prescribing doctor immediately should they develop any signs or symptoms of an infection, such as those in Table 1.⁸ They will need an urgent blood test, and if severe neutropenia is diagnosed, clozapine is stopped, and the patient is put into isolation and closely monitored.¹⁰

Table 1: Examples of signs and symptoms of infection to report to the clozapine prescriber ⁸

• Cold or flu-like symptoms (e.g., fever, chills, myalgia, fatigue, headache, cough, sore throat, shortness of breath)
• Mouth sores
• Nausea, vomiting, diarrhea
• Weakness or feeling unwell

Dentists can help by assessing patients for signs and symptoms of infection at each visit, whether it is a dental-related infection or another type, and notify the clozapine prescriber immediately. Procedures may need to be postponed if the patient has signs of infection or low absolute neutrophil count (ANC). The registry can help with questions. Before procedures that could cause infection, confirm with the patient’s brand-specific monitoring registry program that the last WBC was normal and it is OK to proceed (contact numbers are in the Appendix). And follow up with the patient after procedures to see if they have developed any signs of infection

Clozapine-induced Hypersalivation

Clozapine is a highly anticholinergic drug but is unique among antipsychotics because it tends to cause hypersalivation (sialorrhea) rather than dry mouth.¹¹ It usually shows up early in therapy and is likely dose-related. Unfortunately, it does not tend to improve with time.⁵

Hypersalivation is a frequent side effect, with a prevalence of up to 90%.¹³ It is also one of the most bothersome to the patient. It is socially embarrassing and potentially stigmatizing. It causes sleep disruption and can lead to life-threatening aspiration of saliva, especially if the patient is experiencing sedation. Hypersalivation is a frequent cause of non-adherence.¹⁴

The mechanism is unknown. Theories include stimulation of M4 muscarinic acetylcholine receptors in the salivary glands, antagonism at alpha 2-adrenergic receptors, and/or inhibition of the swallowing reflex.¹⁵

Excessive salivation can make the dentist’s working environment difficult, compromise dental materials and interfere with taking impressions. It can be uncomfortable for the patient because saliva can pool in the back of their throat, and choking and aspiration are possible.¹² Hypersalivation can be monitored using the two-item Drooling Severity and Frequency Scale (DSFS) or the five-point Nocturnal Hypersalivation Rating Scale (NHRS).¹³

Hypersalivation should be managed without medication whenever possible. Some tips include:

• chewing sugarless gum during the day to stimulate the swallowing reflex, so the frequent need to swallow is not as noticeable.⁵
• covering pillows with towels to make sleeping more comfortable.⁶
• elevating the head, e.g. by adding pillows and sleeping on the side to reduce the risk of aspiration.¹¹

There are no drugs with an indication for treating clozapine-induced hypersalivation. Orally ingested anticholinergic drugs have been reported to be effective in some studies (e.g., amitriptyline, diphenhydramine, hyoscine).¹⁶ However, these should not be used first-line because they add to the already strong anticholinergic effects of clozapine.¹³ Anticholinergic effects include potentially fatal constipation, blurred vision, cognitive impairment, tachycardia, and urinary retention.¹³

Sublingual anticholinergic drugs (prescribed off-label) tend to be preferred first-line options because they are less likely to have unwanted anticholinergic side effects.¹³ Atropine 1% eye drops and ipratropium nasal spray 0.03% or 0.06% are examples.⁶

Ipratropium nasal spray applied sublingually may be easier for the patient to administer and safer than atropine. Atropine overdose can occur if the patient uses too many drops by mistake or intentionally.¹³

Some non-anticholinergic drugs have been studied, including metoclopramide and clonidine. However, these medications’ side effects limit their usefulness.¹⁷ Botulinum toxin, injected into the salivary glands, can be effective for unresponsive cases or intolerable side effects with other drugs.¹⁷ Contact the clozapine prescriber if there is a need to treat hypersalivation with a medication because adding an anticholinergic drug can lead to life-threatening gastrointestinal hypomotility.

Constipation

Constipation is very common, with a prevalence of about 30%.¹³ It is dose-related and does not tend to improve with time.

Clozapine-induced constipation is usually manageable with physical activity, fluids, and a high-fibre diet.⁶ If left undetected or untreated, constipation can be life-threatening, and a small percentage of patients can develop can develop bowel obstruction, fecal impaction of paralytic ileus.¹⁹ The risk may be higher at higher doses, and despite being rare, the case fatality associated with clozapine-induced gastrointestinal hypomotility is high at upto 28%.²⁰

Patients need regular bowel movements, and many are prescribed prophylactic laxatives. Osmotic laxatives such as polyethylene glycol 3350 (Lax A Day) and lactulose, taken daily or twice daily, help prevent clozapine-induced constipation.²¹ Bulk-forming laxatives must be avoided because they can worsen constipation.²¹

If a patient reports constipation, notify the prescriber promptly.¹⁹ As with agranulocytosis, interventions can help prevent a severe outcome if constipation is detected early.

Key Points:

• Constipation can become severe and potentially fatal.
• Avoid prescribing drugs that can worsen or cause constipation (e.g., opioids).
• Bulk-forming laxatives such as psyllium (Metamucil) can worsen constipation.
• Clozapine prescribers need to know as soon as possible if the patient has constipation so it can be quickly treated

DRUG INTERACTIONS

Clozapine has many interactions that can be broadly divided into two groups: pharmacodynamic and pharmacokinetic.

Pharmacodynamic interactions

Pharmacodynamic interactions, such as those in Table 2, occur when combining clozapine with medications that also lower blood pressure, increase anticholinergic effects, cause tachycardia, sedation, agranulocytosis, or lower the seizure threshold. Use these drugs cautiously with clozapine or avoid them altogether.

Table 2: Pharmacodynamic drug interactions ^{8, 22, 23}

• Drugs that lower the seizure threshold – e.g., tramadol, bupropion, clomipramine.
• Bone marrow suppressing drugs – e.g., sulfonamides (e.g., cotrimoxazole), carbamazepine, antineoplastics – avoid.
• Drugs that can worsen constipation – e.g., opioids, anticholinergic drugs (e.g., oxybutynin, amitriptyline, chlorpheniramine, diphenhydramine, hydroxyzine), bulk-forming laxatives.
• Drugs that increase the risk of orthostasis – e.g., alpha-blockers, beta-blockers, ACE inhibitors.
• CNS depressants and respiratory depressants – e.g., alcohol, opioids, benzodiazepines, antihistamines.

Pharmacokinetic Interactions

Clozapine is metabolized by the cytochrome P450 system, primarily by CYP1A2 and, to a lesser extent, by CYP3A4.⁸ Some drugs are known to inhibit CYP1A2 and or CYP3A4 (examples in Table 3). If an inhibitor is added or the dose is increased, especially a potent inhibitor, plasma levels of clozapine can increase to toxic levels.⁸ The clozapine dose may then need to be lowered. Some signs of clozapine toxicity are listed in Table 4.

Table 3: Clozapine plasma concentrations can be increased by: ^{13, 23, 24, 26}

Inhibitors of CYP1A2

• caffeine
• ciprofloxacin
• fluvoxamine

Inhibitors of CYP3A4

• cimetidine
• clarithromycin
• erythromycin
• fluconazole
• itraconazole
• ketoconazole
• omeprazole
• ritonavir
• voriconazole

Smoking Cessation
Infections

Table 4: Signs of toxicity ^{23, 24, 25}

• tachycardia
• hypotension
• over-sedation
• hypersalivation
• aspiration pneumonia
• gastrointestinal hypomotility/constipation
  and other anticholinergic effects
• mental status changes
• difficulty walking or talking
• myoclonic jerks
• seizures
• coma
• death

Caffeine is only a weak inhibitor of CYP1A2, but it can significantly change clozapine plasma concentrations. It is best to avoid sudden changes in caffeine consumption.⁸

Conversely, some drugs increase the activity of CYP enzymes. Inducers of CYP1A2 and CYP3A4 can lower the clozapine plasma concentration, leading to loss of efficacy and return of symptoms. See Table 5 for examples. Clozapine has a short half-life, and rebound psychosis can happen quickly. Plasma levels can also decrease when drugs that inhibit CYP enzymes are stopped abruptly.⁸

Table 5: Clozapine plasma concentrations can be decreased by: ^{13, 23, 24}

Inducers of CYP1A2

• phenytoin
• rifampin
• phenobarbital
• carbamazepine
• smoking

Inducers of CYP3A4

• carbamazepine
• phenytoin
• St. John’s wort

Smoking

Smoking is another CYP enzyme inducer. Cigarette smoking increases the clearance of clozapine from the body, reducing plasma levels by up to 50%.²⁷

Stopping smoking abruptly can decrease CYP1A2 activity, leading to rapidly increasing plasma clozapine levels and potential toxic effects. One study found a mean increase in clozapine plasma levels of 57% in participants who quit smoking.²⁸

It is the polycyclic aromatic hydrocarbons in the smoke that induce CYP enzymes, so this interaction does not occur with nicotine replacement therapy.²⁷

Despite the interaction between smoking and clozapine, patients should still be encouraged to quit, mainly because patients on clozapine often have other risk factors for periodontal disease and cardiovascular disease (e.g., obesity, sedentary lifestyle, diabetes, hyperlipidemia, etc.).

A plan to quit must be done carefully, in collaboration with the clozapine prescriber, because of the risk of clozapine toxicity. Depending on the patient, the prescriber may want to decrease the clozapine dose proactively when the patient stops smoking, or they may wait and see whether side effects emerge. They may also monitor clozapine plasma levels before and after the patient quits. The goal is to avoid toxicity and loss of efficacy (should the dose be decreased too much).¹³

Patients may not be ready to quit but may find themselves in a situation where they cannot smoke, such as upon admission to a hospital. The same approach to monitoring and dosing should be followed. When the patient is discharged and chooses to return to smoking, close monitoring is required because the dose may need to be increased.²⁷

Infections

Patients on clozapine are at increased risk of developing pneumonia, likely because of side effects like hypersalivation, sedation and impaired swallowing.^29-31

Pneumonia and other infections may be associated with the release of inflammatory mediators that inhibit CYP1A2 (and possibly other enzymes), inhibiting clozapine metabolism and increasing plasma levels. The risk of toxic levels increases further if the patient stops smoking and/or the infection is treated with drug(s) inhibiting clozapine’s metabolism.²⁹

Pneumonia is a leading cause of death in patients on clozapine. An analysis of serious adverse reaction reports found pneumonia was associated with more fatal outcomes than agranulocytosis in patients taking clozapine.³² Because of this risk, patients with signs of infection must be carefully monitored.

COVID-19 infections have also been linked to increased clozapine serum levels, with reported increases in sedation, lethargy, sialorrhea, and ataxia.³¹ Dose decreases of greater than 50% were required in some cases. Also, ritonavir (a component of Paxlovid) is a potent inhibitor of CYP3A4 and can potentially raise plasma levels of clozapine. Paxlovid is not contraindicated with clozapine but must be used cautiously, especially in patients sensitive to increased clozapine levels.³³ Notify the prescriber if a patient has signs of an infection such as pneumonia or COVID-19; they need careful monitoring.

Metabolic Side Effects

Clozapine has a high incidence of glucose intolerance, lipid abnormalities and significant weight gain compared with many other antipsychotics. A high percentage of patients will be diabetic and/or obese. Along with the increased risk for cardiovascular disease, poorly controlled diabetes and obesity are linked to poorer periodontal health. A healthy lifestyle, including smoking cessation, regular physical activity, and proper nutrition should be promoted.

Conclusion

Dentists play a vital role in patients’ overall health and well-being, including those on clozapine therapy. By being aware of the unique challenges posed by clozapine, dentists can take proactive steps to manage risks, ensure patient safety, and provide effective dental care. Close collaboration with prescribers and a patient-centred approach will help optimize care for individuals on clozapine therapy, enhancing oral health and quality of life.

Oral Health welcomes this original article.

Appendix: Contact information for the three clozapine registries (for further questions or concerns).

Clozaril Support and Assistance Network (CSAN)–HLS Therapeutics (Clozaril) 1-800-267-2726

AASPIRE The AA-Clozapine Patient Care Network–AA Pharma (AA-Clozapine) 1-877-276-2569

Gen-Clozapine Access Network (GENCan)–Mylan Pharmaceuticals (Gen-Clozapine) 1-866-501-3338

References

1. Government of Canada. (2020). Schizophrenia in Canada. https://www.canada.ca/en/public-health/services/publications/diseases-conditions/schizophrenia-canada.html.
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3. Ontario Health. (2023). Quality Standard. Schizophrenia Care in the Community for Adults, 2023 Update. https://www.hqontario.ca/Portals/0/documents/evidence/quality-standards/qs-schizophrenia-care-in-the-community-quality-standard-en.pdf
4. Yoshimura, B., Yada, Y., So, R., Takaki, M., & Yamada, N. (2017). The critical treatment window of clozapine in treatment-resistant schizophrenia: Secondary analysis of an observational study. Psychiatry Research, 250, 65-70. https://doi.org/10.1016/j.psychres.2017.01.064
5. Young, C. R., Bowers, Jr., M. B., & Mazure, C. M. (1998). Management of the Adverse Effects of Clozapine. Schizophrenia Bulletin, 24(3), 381–390. https://doi.org/10.1093/oxfordjournals.schbul.a033333
6. Winckel, K., & Siskind, D. (2017). Clozapine in primary care. Australian Prescriber, 40(6), 231-6. https://doi.org/10.18773/austprescr.2017.067
7. Government of Canada. (2018). Summary safety review–clozapine–assessing the effectiveness of monitoring for low numbers of white blood cells. https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/safety-reviews/clozapine-white-blood-cells.html
8. HLS Therapeutics Inc. (2022). PrClozaril® (clozapine) [Product monograph]. Etobicoke, Ontario. Date of revision: April 29, 2022.
9. Li, X. H., Zhong, X. M., Lu, L., Zheng, W., Wang, S. B., Rao, W. W., Wang, S., Ng, C. H., Ungvari, G. S., Wang, G., & Xiang, Y. T. (2020). The prevalence of agranulocytosis and related death in clozapine-treated patients: a comprehensive meta-analysis of observational studies. Psychological medicine, 50(4), 583–594. https://doi.org/10.1017/S0033291719000369
10. Taylor, D. M., et al. (2021). The Maudsley Prescribing Guidelines in Psychiatry (p. 208). John Wiley & Sons, Incorporated. Retrieved from http://ebookcentral.proquest.com/lib/rps/detail.action?docID=6607557
11. Taylor, D. M., et al. (2021). The Maudsley Prescribing Guidelines in Psychiatry (p. 227). John Wiley & Sons, Incorporated. Retrieved from http://ebookcentral.proquest.com/lib/rps/detail.action?docID=6607557
12. Page, M. M. (2007). Psychotropic drugs and dentistry. Australian Prescriber, 30, 98-101. https://doi.org/10.18773/austprescr.2007.059
13. 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
14. Gupta, S., Khastgir, U., Croft, M., & Roshny, S. (2020). Management of clozapine-induced sialorrhoea. BJPsych Advances, 26(2), 106-108. https://doi.org/10.1192/bja.2019.58
15. Taylor, D. M., et al. (2021). The Maudsley Prescribing Guidelines in Psychiatry (p. 227). John Wiley & Sons, Incorporated. Retrieved from http://ebookcentral.proquest.com/lib/rps/detail.action?docID=6607557
16. Taylor, D. M., et al. (2021). The Maudsley Prescribing Guidelines in Psychiatry (p. 229). John Wiley & Sons, Incorporated. Retrieved from http://ebookcentral.proquest.com/lib/rps/detail.action?docID=6607557
17. Taylor, D. M., et al. (2021). The Maudsley Prescribing Guidelines in Psychiatry (p. 228). John Wiley & Sons, Incorporated. Retrieved from http://ebookcentral.proquest.com/lib/rps/detail.action?docID=6607557
18. Every-Palmer, S., Nowitz, M., Stanley, J., Grant, E., Huthwaite, M., Dunn, H., & Ellis, P. M. (2016). Clozapine-treated Patients Have Marked Gastrointestinal Hypomotility, the Probable Basis of Life-threatening Gastrointestinal Complications: A Cross Sectional Study. EBioMedicine, 5, 125–134. https://doi.org/10.1016/j.ebiom.2016.02.020
19. Medicines and Healthcare products Regulatory Agency. (2017). Clozapine: reminder of potentially fatal risk of intestinal obstruction, faecal impaction, and paralytic ileus. https://www.gov.uk/drug-safety-update/clozapine-reminder-of-potentially-fatal-risk-of-intestinal-obstruction-faecal-impaction-and-paralytic-ileus
20. Cohen, D. (2017). Clozapine and gastrointestinal hypomotility. CNS Drugs, 31(12), 1083-1091.
21. 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. https://doi.org/10.1176/appi.psy.50.4.416
22. Devinsky, O., Honigfeld, G., & Patin, J. (1991). Clozapine-related seizures. Neurology, 41(3), 369-371. https://doi.org/10.1212/wnl.41.3.369
23. Hoeft, D. (2014). An overview of clinically significant drug interactions between medications used to treat psychiatric and medical conditions. Mental Health Clinician, 4(3), 118–130. https://doi.org/10.9740/mhc.n197904
24. Flockhart, D. A., Thacker, D., McDonald, C., & Desta, Z. (Updated 2021). The Flockhart Cytochrome P450 Drug-Drug Interaction Table. Division of Clinical Pharmacology, Indiana University School of Medicine. https://drug-interactions.medicine.iu.edu/ Accessed August 15, 2023.
25. Taylor, D. M., et al. (2021). The Maudsley Prescribing Guidelines in Psychiatry (p. 212-214). John Wiley & Sons, Incorporated. Retrieved from http://ebookcentral.proquest.com/lib/rps/detail.action?docID=6607557
26. Meyer, J. M., Proctor, G., Cummings, M. A., Dardashti, L. J., & Stahl, S. M. (2016). Ciprofloxacin and Clozapine: A Potentially Fatal but Underappreciated Interaction. Case reports in psychiatry.
27. Taylor, D. M., et al. (2021). The Maudsley Prescribing Guidelines in Psychiatry (p.857-858). John Wiley & Sons, Incorporated. Retrieved from http://ebookcentral.proquest.com/lib/rps/detail.action?docID=6607557
28. Meyer, J. M. (2001). Individual Changes in Clozapine Levels After Smoking Cessation: Results and a Predictive Model. Journal of Clinical Psychopharmacology, 21(6), 569-574. https://doi.org/10.1097/00004714-200112000-00005
29. Clark, S. R., Warren, N. S., Kim, G., Jankowiak, D., Schubert, K. O., Kisely, S., Forrester, T., Baune, B. T., & Siskind, D. J. (2018). Elevated clozapine levels associated with infection: A systematic review. Schizophrenia Research, 192, 50-56. https://doi.org/10.1016/j.schres.2017.03.045
30. Robinson, J. (2023). Quarter of hospitalized patients taking clozapine admitted with infection, study finds. The Pharmaceutical Journal, PJ, 310(7969). https://doi.org/10.1211/PJ.2023.1.171330
31. McCollum, B. D., Juettner, P. K., & Shelton, C. I. (2021). Proactive Modification to Clozapine Dose in a Patient With Pneumonia to Prevent Toxicity. Primary Care Companion CNS Disorders, 23(1), 20l02622. https://doi.org/10.4088/PCC.20l02622
32. de Leon, J., Sanz, E. J., Norén, G. N., et al. (2020). Pneumonia may be more frequent and have more fatal outcomes with clozapine than with other second-generation antipsychotics. World Psychiatry, 19(1), 120-121. https://doi.org/10.1002/wps.20707
33. Pfizer Canada ULC. (2022) PrPaxlovid™ (nirmatrelvir-ritonavir) [Product monograph]. Kirkland, Quebec. Date of revision: August 30, 2023.

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About the Author

Caroline Warnock is a Board-Certified Psychiatric Pharmacist who has worked at the Centre for Addiction and Mental Health (CAMH) in Toronto for over 20 years. She is currently the Medication Safety Pharmacist and provides clinical coverage on an inpatient unit. She has a Doctor of Pharmacy degree from the University of Colorado and a Postgraduate Certificate in Psychiatric Pharmacy from Aston University in the UK.