Black Box Warnings for the Antipsychotic Clozaril

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Clozaril (clozapine) is an atypical antipsychotic medication that has been approved for use in treatment-resistant schizophrenia and for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state.

Black Box Warnings for Clozaril

Clozaril carries five serious warnings, called black box warnings, about possible severe side effects and drug interactions. Because of these warnings, Clozaril can only be prescribed through a special program that restricts distribution called the Clozapine Risk Evaluation and Mitigation Strategies (REMS) Program.

The REMS program ensures monitoring of white blood cell (WBC) count and absolute neutrophil count (ANC) according to the schedule described below prior to delivery of the next supply of medication. Both your doctor and your pharmacist have to be registered with this program that the manufacturers created in order to prescribe and dispense your Clozaril.

Agranulocytosis

Agranulocytosis is an abnormally low WBC count. Since WBC are necessary to fight diseases, this is a potentially fatal side effect.

If you are being treated with clozapine, you must have a baseline WBC count and ANC before you can start Clozaril, as well as regular WBC counts and ANCs during treatment and for at least 4 weeks after discontinuation of treatment.

Fewer than 1% of patients taking Clozaril may develop agranulocytosis, a potentially life-threatening adverse event.

Seizures

Seizures have been associated with the use of clozapine. Dose appears to be an important predictor of seizures, with a greater likelihood at higher clozapine doses.

Patients should be advised not to engage in any activity where sudden loss of consciousness could cause serious risk to themselves or others.

Caution should be used when administering clozapine to patients having a history of seizures or other predisposing factors.

Myocarditis and Cardiomyopathy

Myocarditis is inflammation of heart muscle and cardiomyopathy is an enlarged heart. If you have shortness of breath, fever, extreme tiredness, or chest pain while taking Clozaril, be sure to contact your doctor right away.

Orthostatic Hypotension

Orthostatic hypotension is a large, sudden decrease in blood pressure upon standing that makes you feel lightheaded or dizzy. Syncope means fainting.

Orthostatic hypotension, with or without syncope, can occur with clozapine treatment, especially when you first start taking it or your dose is changed.

Rarely, this can be profound and be accompanied by respiratory and/or cardiac arrest. 

If you have severe diarrhea or vomiting or other signs of dehydration, be sure to tell your doctor. Also, if you accidentally skip two or more doses of Clozaril, talk to your doctor before taking your next dose as you may need to take a lower dose for a time.

Increased Mortality in Elderly Patients With Dementia

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. In one study, although the causes of death were varied, most of the deaths appeared to be either cardiovascular, meaning they were related to heart failure or sudden death, or infectious in nature. Clozaril is not approved for the treatment of patients with dementia-related psychosis.

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  1. MedlinePlus. Clozapine. Updated March 16, 2020.

  2. Food and Drug Administration. Clozaril label. Updated November 2004.

  3. U.S. Food and Drug Administration. Clozapine Risk Evaluation and Mitigation Strategy (REMS). Updated November 12, 2019.

  4. MedlinePlus. Agranulocytosis. Updated April 11, 2018.