Indicated for:

Treatment-Resistant Schizophrenia:

• The treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, CLOZARIL should be used only in patients who have failed to respond adequately to standard antipsychotic treatment.

Reduction in the Risk of Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder:

• 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. Suicidal behavior refers to actions by a patient that put him/herself at risk for death.

The effectiveness of CLOZARIL in reducing the risk of recurrent suicidal behavior was demonstrated over a two-year treatment period in the InterSePT trial.

CLOZARIL is only available through a restricted program under a REMS called the Clozapine REMS Program because of the risk of severe neutropenia. Professionals prescribing clozapine, as well as pharmacies dispensing clozapine will need to be certified in the clozapine REMS program.

Generally, patients responding to CLOZARIL should continue maintenance treatment on their effective dose beyond the acute episode.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. CLOZARIL is not approved for use in patients with dementia-related psychosis.

CLOZARIL 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 CLOZARIL a baseline ANC must be at least 1500/μL for the general population; and must be at least 1000/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 (e.g., fever, weakness, lethargy, or sore throat).

Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have occurred with CLOZARIL 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 mg per day. Initiate treatment at 12.5 mg once or twice daily; titrate slowly; and use divided doses.

Use CLOZARIL cautiously in patients with cardiovascular or cerebrovascular disease or conditions predisposing to hypotension (e.g., dehydration, use of antihypertensive medications).

Fatal myocarditis and cardiomyopathy have occurred with CLOZARIL treatment. Discontinue CLOZARIL and obtain a cardiac evaluation upon suspicion of these reactions. Generally, patients with CLOZARIL-related myocarditis or cardiomyopathy should not be rechallenged with CLOZARIL. Consider the possibility of myocarditis or cardiomyopathy if chest pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, hypotension, or ECG changes occur.

QT prolongation, Torsade de Pointes and other life-threatening ventricular arrhythmias, cardiac arrest, and sudden death have occurred with CLOZARIL treatment. When prescribing CLOZARIL, consider the presence of additional risk factors for QT prolongation and serious cardiovascular reactions. Conditions that increase these risks include the following: history of QT prolongation, long QT syndrome, family history of long QT syndrome or sudden cardiac death, significant  cardiac arrhythmia, recent myocardial infarction, uncompensated heart failure, treatment with other medications that cause QT prolongation, treatment with medications that inhibit the metabolism of clozapine, and electrolyte abnormalities.

Seizures have occurred with CLOZARIL treatment. The risk is dose-related. Initiate treatment at 12.5 mg, titrate gradually, and use divided dosing. Use caution when administering CLOZARIL to patients with a history of seizures or other predisposing risk factors for seizure (CNS pathology, 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.

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including CLOZARIL.

Weight gain has occurred with the use of antipsychotics, including CLOZARIL.

Pulmonary embolism and deep-vein thrombosis have occurred in patients treated with CLOZARIL.

During clozapine therapy, patients have experienced transient, clozapine-related fever.

CLOZARIL has potent anticholinergic effects. Treatment with CLOZARIL can result in CNS and peripheral anticholinergic toxicity.

Severe gastrointestinal adverse reactions have occurred with the use of CLOZARIL, primarily due to its potent anticholinergic effects and resulting gastrointestinal hypomotility. In post marketing experience, reported effects range from constipation to paralytic ileus. Increased frequency of constipation and delayed diagnosis and treatment increased the risk of severe complications of gastrointestinal hypomotility, resulting in intestinal obstruction, fecal impaction, megacolon and intestinal ischemia or infarction.

Tardive dyskinesia (TD) has occurred in patients treated with antipsychotic drugs, including CLOZARIL.

Clozaril may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long–term antipsychotic therapy.

Benign ethnic neutropenia (BEN) is a condition observed in certain ethnic groups whose average ANC values are lower than “standard” laboratory ranges for neutrophils. It is most commonly observed in individuals of African descent (approximate prevalence of 25-50%), some Middle Eastern ethnic groups, and in other non–Caucasian ethnic groups with darker skin. BEN is more common in men.

Clozapine-related eosinophilia usually occurs during the first month of treatment. In some patients, it has been associated with myocarditis, pancreatitis, hepatitis, colitis, and nephritis.

Antipsychotic drugs including CLOZARIL can cause a potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS).

Severe, life threatening, and in some cases fatal hepatotoxicity including hepatic failure, hepatic necrosis, and hepatitis have been reported in post marketing studies in patients treated with clozapine.

Atypical antipsychotic drugs, including CLOZARIL have been associated with metabolic changes that can increase cardiovascular and cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While atypical antipsychotic drugs may produce some metabolic changes, each drug in the class has its own specific risk profile.

It may be necessary to reduce the CLOZARIL dose in patients with significant renal or hepatic impairment, or in CYP2D6 poor metabolizers.

Concomitant use of CLOZARIL with other drugs metabolized by CYP2D6 can increase levels of these CYP2D6 substrates. Use caution when co-administering CLOZARIL with other drugs that are metabolized by CYP2D6. It may be necessary to use lower doses of such drugs than usually prescribed. Such drugs include specific antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide).

When used with strong CYP1A2 inhibitors use one-third of the CLOZARIL dose.

Concomitant use with strong CYP3A4 inducers is not recommended.

When used with moderate or weak CYP1A2 or CYP3A4 Inducers, monitor for decreased effectiveness. Consider increasing the CLOZARIL dose if necessary.

Concomitant treatment with clozapine and other drugs with anticholinergic activity (e.g., benztropine, cyclobenzaprine, diphenhydramine) can increase the risk for anticholinergic toxicity and severe gastrointestinal adverse reactions related to hypomotility. Avoid concomitant use of CLOZARIL with anticholinergic drugs when possible.

Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of clozapine. Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, and pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus).

There are no adequate or well-controlled studies of clozapine in pregnant women. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Monitor neonates for symptoms of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding difficulties. The severity of complications can vary from self-limited symptoms to some neonates requiring intensive care unit support and prolonged hospitalization.

CLOZARIL is present in human milk. Because of the potential for serious adverse reactions in nursing infants from CLOZARIL, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

GoToSource

• Use in patients under the age of 18. GoToSource

• Dosage greater than 900 mg daily. GoToSource

• Use in adolescent patients with bipolar disorder, intermittent explosive disorder or post traumatic stress disorder. GoToSource

• Autism spectrum disorder. GoToSource

• Use in patients who have responded to standard antipsychotic treatment. GoToSource

• Use in patients with dementia-related psychosis. GoToSource

• Drug-induced psychosis in parkinson’s disease. GoToSource 

• HIV psychosis disorder. GoToSource

• Huntington’s disease. GoToSource

⚠️  Patients with CYP2D6 gene variation results in higher systemic concentrations of Clozapine.

Neutropenia (low number of white blood cells) and agranulocytosis (low number of neutrophils, a type of white blood cells). GoToSource

Seizures, orthostatic hypotension (decreased blood pressure after standing) respiratory and cardiac arrest. GoToSource

Myocarditis (inflammation of heart muscle) and cardiomyopathy (disease of the heart muscle). GoToSource

Double the risk of death when compared with placebo. GoToSource

Aplastic anemia (bone marrow does not make enough new blood cells), hemolytic anemia (red blood cells are destroyed faster than they can be made), leukopenia (decreased number of white blood cells), leukocytosis (elevated white blood cell count), eosinophilia (high number of eosinophils in the blood, a type of white blood cell), thrombocytosis (body produces too many platelets), disordered platelet function and impaired coagulation. GoToSource 

Acute dystonia (movement disorder). GoToSource

New-onset diabetes. GoToSource

Pancreatitis (inflammation of the pancreas). GoToSource

Nocturnal enuresis (bedwetting). GoToSource

Weight gain and dyslipidemia (high level of lipids). GoToSource

Liver injury and liver failure. GoToSource

QT interval prolongation with combined therapy. GoToSource

Serotonin syndrome (life-threatening drug interaction). GoToSource

Deep vein thrombosis (blood clot forms in a vein deep in the body) and pulmonary embolism (blockage in one of the pulmonary arteries in lungs). GoToSource

Diabetic ketoacidosis (excess blood acids), gastrointestinal hypomotility (abnormally slow movement of ingested food through the digestive tract) and hyperglycemia (high blood sugar). GoToSource 

Colitis. GoToSource

Angioedema (swelling in deep layers of skin). GoToSource

Allergic vasculitis (severe immune reaction to a medication). GoToSource

Skin pigmentation. GoToSource

Worsen myasthenia gravis (autoimmune neuromuscular disease causing weakness in skeletal muscles). GoToSource

Rhabdomyolysis (breakdown of muscle tissue). GoToSource

Systemic lupus erythematosus (autoimmune disease). GoToSource

Obsessive compulsive symptoms. GoToSource

Neuroleptic malignant syndrome (life-threatening drug reaction). GoToSource

Serious bowel complications leading to hospitalization or death. GoToSource

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. GoToSource

Lawsuits filed for strokes, heart attacks, diabetes and pancreatitis.