Drug Safety Alerts

Clozapine Drug Safety Communication

1/28/2020

On January 28, 2020, The United States Food and Drug Administration (FDA) issued a drug safety communication announcing they are strengthening an existing warning that constipation caused by the schizophrenia medicine clozapine (Clozaril®, Fazaclo® ODT, Versacloz®, generics) can, uncommonly, progress to serious bowel complications. This can lead to hospitalization or even death if constipation is not diagnosed and treated quickly.

The FDA is requiring a new warning and updates about this risk to be added to the prescribing information of all clozapine products. The FDA has advised that, as part of its routine monitoring, it will continue to monitor clozapine and will report updated information to the public if it becomes available.

Clozapine affects how the intestines (bowels) function in the majority of patients. It produces effects ranging from constipation (trouble having a bowel movement), which is a common occurrence, to serious but uncommon bowel problems, including complete blockage of the bowel. The FDA found that because of the way clozapine works this risk is greater with clozapine than with the other schizophrenia medicines in its drug class. The risk is further increased at higher doses of clozapine and when it is co-prescribed with a type of medicine called anticholinergics, which can slow the movement in the intestines, and other medicines that cause constipation, including opioids. Many different kinds of medicines have these anticholinergic effects.

Health care professionals should evaluate bowel function before starting a patient on clozapine and avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility. Advise patients frequently of the significant risk of constipation and life-threatening bowel issues and the need to stay hydrated to prevent constipation.

Question patients about the frequency and quality of their bowel movements throughout treatment. Advise patients to contact a health care professional right away if they have difficulty having a bowel movement or passing stools, do not have a bowel movement at least three times a week or less than their normal frequency, or are unable to pass gas. Monitor patients for symptoms of potential complications associated with gastrointestinal hypomotility such as nausea, abdominal distension or pain, and vomiting. Consider prophylactic laxative treatment when starting clozapine in patients with a history of constipation or bowel obstruction.

The FDA has provided the following information for healthcare provides:

• The FDA is strengthening an existing warning that constipation caused by the schizophrenia medicine clozapine (Clozaril, Fazaclo ODT, Versacloz) can progress to serious bowel complications. This can lead to hospitalization or even death if constipation is not diagnosed and treated quickly.

• Clozapine impairs bowel function in the majority of patients. It produces effects ranging from constipation (common) to complete bowel obstruction, paralytic ileus and intestinal ischemia or infarction (uncommon). Constipation is a frequent and known side effect of clozapine, but serious and fatal events continue to be reported.

• The risk is greater with clozapine than the other schizophrenia medicines we reviewed in its drug class because of clozapine’s potent anticholinergic activity.

• The risk is further increased at higher doses of clozapine or when it is co-prescribed with anticholinergic agents and other medicines that cause constipation, including opioids.

• As a result, the FDA requiring a new warning and updates about this risk to be added to the prescribing information of all clozapine products.

• Be aware that subjective symptoms of constipation reported by patients may not accurately reflect gastrointestinal hypomotility; therefore, it is essential to question patients regarding the frequency and character of bowel movements and any changes.

• Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility.

• Consider prophylactic use of laxatives when starting clozapine in high-risk patients.

• If constipation is identified, promptly treat it with laxatives and adjust as necessary. Consult a gastroenterologist in more serious cases.

• Encourage appropriate hydration, physical activity, and foods that are high in fiber.

• Educate patients and caregivers on the risks, prevention, and treatment of clozapine-induced constipation, including medicines to avoid such as other anticholinergic medicines.

• Emphasize that prompt attention and treatment for constipation and other gastrointestinal symptoms is critical to preventing serious complications.

• Encourage patients to read the patient information leaflet they receive with their clozapine prescription, so they are aware of this additional information about the medicine.

• To help the FDA track safety issues with medicines, report adverse events involving clozapine or other medicines to the FDA MedWatch program.

CVS Caremark® Response: Please note: These products have not been recalled. CVS Caremark® Mail Service Pharmacy will continue to dispense clozapine products.

For more information about this issue, health care providers may call the FDA consumer inquiry line at 1-888-INFO-FDA (1-888-463-6332) or visit https://www.fda.gov.