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Limited Use
[what does this mean?]
Generic drug name:
clozapine
(KLOE za peen)
Brand name(s):
CLOZARIL,
VERSACLOZ
GENERIC:
available
FAMILY:
Atypical Antipsychotics
Find the drug label by
searching at DailyMed.
Pregnancy and Breast-feeding Warnings [top]
Pregnancy Warning
Clozapine was not tested adequately to know what the potential effects might be on the fetus. Because of the desirability of keeping all drugs to a minimum during pregnancy, this drug should be used only if clearly needed.
The FDA updated the information for the entire class of antipsychotic drugs relating to their potential risk to newborns when used during pregnancy. The drugs’ product labels have been updated to include information stating that when mothers are treated with these drugs during the third trimester of pregnancy, there is a potential risk of abnormal muscle movements (extrapyramidal signs or EPS) and withdrawal symptoms in their newborns.
Breast-feeding Warning
Clozapine appears to be excreted in breast milk and to have an effect on the nursing infant. Women receiving clozapine should not breast-feed their infants.
Safety Warnings For This Drug [top]
FDA BLACK-BOX WARNING
Severe Neutropenia (low white blood cell count)
Clozapine treatment has caused severe neutropenia, defined as an absolute neutrophil count (ANC) less than 500/µL. Severe neutropenia can lead to serious infection and death. Prior to initiating treatment with clozapine, a baseline ANC must be at least 1,500/µL for the general population and must be at least 1,000/µL for patients with documented Benign Ethnic Neutropenia (BEN). During treatment, patients must have regular ANC monitoring. Advise patients to immediately report symptoms consistent with severe neutropenia or infection (for example, fever, weakness, lethargy or sore throat).
Because of a significant risk of severe neutropenia, clozapine is available only through a restricted program called the Clozapine REMS Program.
Orthostatic Hypotension, Bradycardia, Syncope
Orthostatic hypotension (low blood pressure), bradycardia (slow heart rate), syncope (loss of consciousness), and cardiac arrest have occurred with clozapine treatment. The risk is highest during the initial titration period, particularly with rapid dose escalation. These reactions can occur with the first dose, with doses as low as 12.5 milligrams (mg) per day, or when restarting patients who have had even a brief interruption in treatment with CLOZARIL. Initiate treatment at 12.5 mg once or twice daily; titrate slowly; and use divided dosages to minimize risk. Use CLOZARIL cautiously in patients with cardiovascular or cerebrovascular disease or conditions predisposing to hypotension (e.g., dehydration, use of antihypertensive medications).[1]
Seizures
Seizures have occurred with clozapine treatment. The risk is dose-related. Initiate treatment at 12.5 mg, titrate gradually and use divided dosing. Use caution when administering clozapine to patients with a history of seizures or other predisposing risk factors for seizure (brain disease, medications that lower the seizure threshold, alcohol abuse). Caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others.
Myocarditis [inflammation of the heart], Cardiomyopathy [heart muscle damage], and Mitral Heart Valve Damage
Fatal myocarditis and cardiomyopathy have occurred with clozapine treatment. Discontinue clozapine and obtain a cardiac evaluation upon suspicion of these reactions. Generally, patients with clozapine-related myocarditis or cardiomyopathy should not be prescribed clozapine again. Consider the possibility of myocarditis or cardiomyopathy if chest pain, tachycardia (rapid heart rate), palpitations, dyspnea (shortness of breath), fever, flu-like symptoms, hypotension (low blood pressure) or ECG changes occur.
Increased mortality in elderly patients with dementia-related psychosis.
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Clozaril (clozapine) is not approved for the treatment of patients with dementia-related psychosis.
Warning
Elevations in blood sugar (glucose), in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics that include aripiprazole (ABILIFY), clozapine (CLOZARIL), olanzapine (ZYPREXA), quetiapine (SEROQUEL), risperidone (RISPERDAL) and ziprasidone (GEODON). The relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia, including polydipsia (excessive thirst/drinking of liquids), polyuria (excessive urination), polyphagia (excessive eating) and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.
Weight Gain
For a variety of reasons, including increased appetite, the newer (so-called “atypical”) antipsychotic drugs commonly cause a significant increase in weight that can be troublesome and dangerous for patients using these drugs. For various drugs in this group, the usual range of weight gain is from 5 to 20 pounds, but there are a large number of reports of people gaining much more than 20 pounds, especially with longer-term use of the drugs. In addition to and related to weight gain are metabolic disorders including elevated blood sugar, the onset of diabetes and abnormalities of fat metabolism such as elevated triglyceride levels. Patients should be informed of these effects to help prevent excessive body weight gain.[2]
Blood Sugar Elevation and Diabetes Mellitus
Elevations in blood sugar (glucose),[3],[4],[5] in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics that include aripiprazole (ABILIFY), clozapine (CLOZARIL), olanzapine (ZYPREXA), quetiapine (SEROQUEL), risperidone (RISPERDAL) and ziprasidone (GEODON).
The relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia, including polydipsia (excessive thirst/drinking of liquids), polyuria (excessive urination), polyphagia (excessive eating) and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.
Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia
Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in clinical trials of the atypical antipsychotics in elderly patients with dementia-related psychosis.[6] In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with these drugs than in patients treated with placebo. The atypical antipsychotics are not approved for the treatment of patients with dementia-related psychosis.
Warning: Life-Threatening Interaction Between Clozapine and Benzodiazepines
Public Citizen’s Health Research Group petitioned the FDA to require a box warning on the professional product information (package insert) warnings of a potential life-threatening drug interaction between clozapine and drugs like diazepam (VALIUM) or other benzodiazepines. This warning now appears in the clozapine labeling.
Facts About This Drug [top]
Clozapine (CLOZARIL, VERSACLOZ) is a drug used to treat patients with schizophrenia who have failed to respond to other standard antipsychotic treatments. It was the first atypical antipsychotic, belonging to the same family as olanzapine (SYMBYAX, ZYPREXA, ZYPREXA RELPREVV, ZYPREXA ZYDIS) and other newer antipsychotics. It also is approved for reducing the risk of suicidal behavior in patients with schizophrenia or a similar condition called schizoaffective disorder.
Clozapine is not...
Clozapine (CLOZARIL, VERSACLOZ) is a drug used to treat patients with schizophrenia who have failed to respond to other standard antipsychotic treatments. It was the first atypical antipsychotic, belonging to the same family as olanzapine (SYMBYAX, ZYPREXA, ZYPREXA RELPREVV, ZYPREXA ZYDIS) and other newer antipsychotics. It also is approved for reducing the risk of suicidal behavior in patients with schizophrenia or a similar condition called schizoaffective disorder.
Clozapine is not approved for the treatment of elderly patients with dementia-related psychosis.
Public Citizen lists clozapine as a Limited Use drug. Because the drug has several serious unique risks, it should be reserved for severely ill schizophrenia patients who have failed to respond adequately to other antipsychotic medications.
All antipsychotics usually improve symptoms such as agitation, delusions, hallucinations and suspiciousness. Atypical antipsychotics are different because they tend to improve "negative" symptoms such as apathy, disorientation, emotional withdrawal and lack of pleasure better than older antipsychotics do.
Although atypical antipsychotics do not eliminate the risk of movement disorders, these drugs have a lower risk of these types of disorders, especially at higher doses. However, there is no clear evidence that atypical antipsychotics are more effective or are better tolerated than the older conventional antipsychotics such as haloperidol (HALDOL).[7]
Clozapine is not recommended for women who are pregnant or breast-feeding or for children younger than 16.
Adverse effects
One of the most serious risks of clozapine is agranulocytosis, a lowering of the number of white blood cells. Clozapine is dispensed only in one-week supplies to ensure that white blood cells are monitored and that the dose is adjusted if necessary.
The drug can cause serious adverse cardiovascular events, including orthostatic hypotension (sudden drop in blood pressure upon sitting up or standing, bradycardia (slow heart rate), syncope (sudden loss of consciousness), cardiac arrest, myocarditis (inflammation of the heart muscle) and cardiomyopathy (enlargement, thickening or scarring of the heart muscle).
Clozapine increases the risk of seizure. Although all atypical antipsychotic drugs have this risk, it appears to be greatest with clozapine. The manufacturer of clozapine reports that seizures are estimated to occur in approximately 5% of patients treated with the drug for one year.
The drug also is associated with constipation, intestinal obstruction, fecal impaction and intestinal paralysis.[8]
This drug may cause dry mouth or excess saliva, which can cause dental problems.
Older people are more apt to develop dizziness while taking this drug.
Neuroleptic malignant syndrome (NMS) is a rare yet severe adverse effect of antipsychotic drugs. The symptoms of NMS include fever; confusion; disorientation or other cognitive (thinking) function changes; muscle rigidity; profuse sweating; and unstable blood pressure, heart rate and gastrointestinal function. NMS can be life threatening; rapid recognition and treatment are important.[9]
Studies show...
In April 2011, the Office of Inspector General of the Department of Health and Human Services released a study called "Medicare Atypical Antipsychotic Drug Claims for Elderly Nursing Home Residents," with dismal results. The study was conducted at the request of Sen. Charles Grassley (R-Iowa) and evaluated the extent to which elderly nursing home residents receive newer, more expensive atypical antipsychotic drugs and the associated cost to the Medicare system. It also assessed the extent to which dangerous, off-label prescribing of these drugs was occurring. Click here to read the August 2011 Worst Pills, Best Pills News article about the report.
On May 24, 2013, the Centers for Medicare & Medicaid Services, as part of the National Partnership to Improve Dementia Care in Nursing Homes, issued new guidelines discouraging the use of antipsychotic drugs to treat dementia in nursing home patients. The recommendations belatedly follow the May 2011 report by the Inspector General of the Department of Health and Human Services, which found that 14% of nursing home residents had Medicare claims filed on their behalf for atypical antipsychotic medications, which have never been approved by the Food and Drug Administration (FDA) for managing dementia.
A study published in the British Medical Journal evaluated the risk of death associated with specific antipsychotic medications used in elderly residents in nursing homes. The study reviewed information relating to the risk of death when using different drug therapies and found that the risk of death varied according to the specific drug used. The authors of the study concluded:
"The evidence accumulated so far implies that use of haloperidol in this vulnerable population cannot be justified because of the excess harm. Quetiapine might be somewhat safer than other atypical drugs, but these findings will require replication in other studies."[10]
In 2015, JAMA Internal Medicine published an article showing that use of atypical antipsychotic drugs was associated with an increased risk of falls and fractures in patients 65 years and older.[11]
In 2015, a study published in JAMA Internal Medicine showed that strong anticholinergic drugs, including clozapine, were associated with an increased risk of dementia in older adults. The study also showed that higher doses and longer use of these drugs were associated with higher risk of dementia.[12]
Regulatory actions surrounding clozapine
2003: In September, the FDA ordered that the product labels for certain drugs should warn that patients need to be monitored for symptoms of diabetes. The drugs requiring the warning included clozapine, aripiprazole (ABILIFY), olanzapine, quetiapine (SEROQUEL), risperidone (RISPERDAL) and ziprasidone (GEODON).[13]
2005: The FDA issued a public health advisory on April 11 warning that atypical antipsychotic drugs are associated with an increased risk of death when used to treat dementia in elderly patients.
The atypical antipsychotics affected by this FDA advisory include clozapine, aripiprazole, olanzapine, quetiapine, risperidone and ziprasidone. None of these drugs, however, is approved for the treatment of behavioral disorders in patients with dementia.[14]
2011: The FDA updated the information for all antipsychotic drugs relating to their potential risk to newborns when used during pregnancy. The drugs' product labels have been updated to state that when mothers are treated with these drugs during the third trimester of pregnancy, there is a potential risk of abnormal muscle movements (extrapyramidal signs or EPS) and withdrawal symptoms in their newborns.[15]
2015: The FDA announced that it is making changes to the monitoring, prescribing, dispensing and receiving of clozapine. These changes were based on one of the most serious adverse effects of clozapine: lowering of the number of white blood cells. The new program will require prescribers and pharmacies to be certified and patients to be enrolled in a monitoring program.[16]
2016: Health Canada, an agency similar to the FDA, updated the product label of atypical antipsychotics to warn that the drugs are associated with an increased risk of sleep apnea (a disorder that causes breaks in breathing or very shallow breathing during sleep).[17]
2017: The FDA approved a new warning in the product labeling of clozapine that stated that severe life-threatening liver injury has been reported in patients treated with clozapine.[18] Patients should be monitored for signs and symptoms of liver disease (such as fatigue, loss of appetite, nausea and yellow skin or eyes) and contact their doctor immediately if these occur.
The FDA also approved a second new warning in the product label of clozapine that stated that the drug may cause excessive sleepiness, low blood pressure upon sitting up or standing (postural hypotension) and problems with balance, all of which may increase the risk of falls and fractures in patients taking the drug.[18]
2020: The FDA strengthened the existing warning and updated the product labeling for clozapine to warn that constipation caused by clozapine can lead to severe and fatal intestinal (bowel) problems.[19],[20]
Before You Use This Drug [top]
Do not use if you have or have had:
Tell your doctor if you have or have had:
Tell your doctor about any other drugs you take, including aspirin, herbs, vitamins, and other nonprescription products.
When You Use This Drug [top]
How to Use This Drug [top]
Interactions with Other Drugs [top]
The following drugs, biologics (e.g., vaccines, therapeutic antibodies), or foods are listed in Evaluations of Drug Interactions 2003 as causing “highly clinically significant” or “clinically significant” interactions when used together with any of the drugs in this section. In some sections with multiple drugs, the interaction may have been reported for one but not all drugs in this section, but we include the interaction because the drugs in this section are similar to one another. We have also included potentially serious interactions listed in the drug’s FDA-approved professional package insert or in published medical journal articles. There may be other drugs, especially those in the families of drugs listed below, that also will react with this drug to cause severe adverse effects. Make sure to tell your doctor and pharmacist the drugs you are taking and tell them if you are taking any of these interacting drugs:
Central nervous system (CNS) depressant drugs, including alcohol, antidepressants, antihistamines, some blood pressure medications (reserpine, methyldopa, beta-blockers), motion sickness medications, muscle relaxants, narcotics, sedatives, sleeping pills, and tranquilizers.
Other drugs that can interact with clozapine are: AGENERASE, amprenavir, bone marrow depressants, carbamazepine, cimetidine, diazepam, EES, ERYTHROCIN, erythromycin, fluvoxamine, lithium, LITHOBID, LITHONATE, LUVOX, NORVIR, RIFADIN, rifampin, ritonavir, TAGAMET, TEGRETOL, VALIUM.
Adverse Effects [top]
Call your doctor immediately if you experience:
Call your doctor if these symptoms continue:
Signs of overdose:
If you suspect an overdose, call this number to contact your poison control center: (800) 222-1222.
Periodic Tests[top]
Ask your doctor which of these tests should be done periodically while you are taking this drug:
last reviewed January 31, 2024
Worst Pills, Best Pills is a project of Public Citizen's Health Research Group Group. As an independent, nonprofit organization, we take no corporate or government contributions and accept no advertising. Copyright © 2024 Public Citizen's Health Research Group. All rights reserved.
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