Indicated for:

Treatment-Resistant Schizophrenia:

• For 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, VERSACLOZ should be used only in patients who have failed to respond adequately to standard antipsychotic treatment.

The effectiveness of clozapine in treatment-resistant schizophrenia was demonstrated in a 6-week, randomized, double-blind, active-controlled study comparing clozapine and chlorpromazine in patients who had failed other antipsychotics.

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

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

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

The maximum dose is 900 mg per day.

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

Prior to initiating treatment with VERSACLOZ, a baseline ANC must be obtained. The baseline ANC must be at least 1500/µL for the general population, and at least 1000 µL for patients with documented Benign Ethnic Neutropenia (BEN). To continue treatment, the ANC must be monitored regularly.

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 VERSACLOZ 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.

Because of the risk of severe neutropenia, VERSACLOZ is available only through a restricted program under a Risk Evaluation Mitigation Strategy (REMS) called the Clozapine REMS Program.

Reduce the dose gradually over a period of 1 to 2 weeks if termination of VERSACLOZ therapy is planned and there is no evidence of moderate to severe neutropenia.

Orthostatic hypotension, bradycardia, syncope, 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 mg per day. Initiate treatment at 12.5 mg once or twice daily; titrate slowly; and use divided doses. Use VERSACLOZ cautiously in patients with cardiovascular/cerebrovascular disease or conditions predisposing to hypotension (e.g., dehydration, use of antihypertensive medications).

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 VERSACLOZ 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.

Myocarditis and cardiomyopathy have occurred with the use of clozapine. These reactions can be fatal. Discontinue VERSACLOZ and obtain a cardiac evaluation upon suspicion of myocarditis or  cardiomyopathy. Generally, patients with a history of clozapine-associated myocarditis or cardiomyopathy should not be rechallenged with VERSACLOZ. However, if the benefit of VERSACLOZ treatment is judged to outweigh the potential risks of recurrent myocarditis or cardiomyopathy, the clinician may consider rechallenge with VERSACLOZ in consultation with a cardiologist, after a complete cardiac evaluation, and under close monitoring.

Consider the possibility of myocarditis or cardiomyopathy in patients receiving VERSACLOZ who present with chest pain, dyspnea, persistent tachycardia at rest, palpitations, fever, flu-like symptoms, hypotension, other signs or symptoms of heart failure, or electrocardiographic findings (low voltages, ST-T abnormalities, arrhythmias, right axis deviation, and poor R wave progression). Myocarditis most frequently presents within the first two months of clozapine treatment. Symptoms of cardiomyopathy generally occur later than clozapine-associated myocarditis and usually after 8 weeks of treatment. However, myocarditis and cardiomyopathy can occur at any period during treatment with VERSACLOZ. It is common for nonspecific flu-like symptoms such as malaise, myalgia, pleuritic chest pain, and low grade fevers to precede more overt signs of heart failure.

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

Eosinophilia, defined as a blood eosinophil count of greater than 700/µL, has occurred with clozapine treatment.

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

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

VERSACLOZ may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries.

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

Severe gastrointestinal adverse reactions have occurred with the use of VERSACLOZ, 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.

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

Use with caution in the presence of narrow-angle glaucoma, concomitant anticholinergic medications, prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions.

During clozapine therapy, patients have experienced transient, clozapine-related fever. The peak incidence is within the first 3 weeks of treatment.

QT prolongation, Torsades de Pointes and other life-threatening ventricular arrhythmias, cardiac arrest, and sudden death have occurred with clozapine treatment.

Hypokalemia and hypomagnesemia increase the risk of QT prolongation. Hypokalemia can result from diuretic therapy, diarrhea, and other causes. Use caution when treating patients at risk for significant electrolyte disturbance, particularly hypokalemia.

Atypical antipsychotic drugs, including VERSACLOZ, have been associated with metabolic changes that can increase cardiovascular and cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain.

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

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

Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of VERSACLOZ. Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmic medications (e.g., quinidine, procainamide) or Class III antiarrhythmic (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). VERSACLOZ is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. Concomitant treatment with inhibitors of these enzymes can increase the concentration of VERSACLOZ.

Concomitant use of VERSACLOZ and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. Reduce the VERSACLOZ dose to one third of the original dose when VERSACLOZ is co-administered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin). The VERSACLOZ dose should be increased to the original dose when co-administration of strong CYP1A2 inhibitors is discontinued.

Concomitant treatment with VERSACLOZ and CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline) can increase clozapine levels and lead to adverse reactions.

Concomitant treatment with drugs that induce CYP1A2 or CYP3A4 can decrease the plasma concentration of clozapine, resulting in decreased effectiveness of VERSACLOZ.

Tobacco smoke is a moderate inducer of CYP1A2.

Strong CYP3A4 inducers include carbamazepine, phenytoin, St. John’s wort, and rifampin. It may be necessary to increase the VERSACLOZ dose if used concomitantly with inducers of these enzymes. However, concomitant use of VERSACLOZ and strong CYP3A4 inducers is not recommended.

There are no adequate or well-controlled studies of clozapine in pregnant women. Animal studies: decrease in maternal body weight.

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.

VERSACLOZ is present in human milk. Because of the potential for serious adverse reactions in nursing infants from VERSACLOZ, 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.

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• Use in patients under the age of 18. GoToSource

• Bipolar disorder. GoToSource

• Borderline personality disorder and aggression. GoToSource

• Refractory major depression. GoToSource

• Substance abuse disorders. GoToSource

• Obsessive-compulsive disorder. GoToSource

• Post-traumatic stress disorder. GoToSource

• Tourette’s syndrome. GoToSource

• Autism. GoToSource

• Agitation in dementia. GoToSource

• Psychotic disorders and attention-deficit hyperactivity disorder. GoToSource

• Behavioral disturbances of dementia. GoToSource 

• Insomnia. GoToSource

• Parkinson’s disease. GoToSource

• Huntington’s disease. GoToSource

• Dosage greater than 900 mg per day. GoToSource

Emergence or worsening of obsessive compulsive symptoms, agranulocytosis (low number of granulocytes, a type of white blood cell), constipation, tachycardia (rapid heart rate), hypersalivation (excess saliva) and metabolic changes such as weight gain, diabetes and hyperlipidaemia (high concentration of fats or lipids in blood). GoToSource

Binge eating and eating disorders. GoToSource

Neutropenia (low level of neutrophils, a type of white blood cell), increased risk of eosinophilia (higher than normal level of a certain type of white blood cell), anemia, lymphopenia (low level of lymphocytes, a type of white blood cell), leukocytosis (increased number of white cells in the blood) and thrombocytopenia (low blood platelet count). GoToSource

Seizures. GoToSource

QTc prolongation (heart rhythm disorder), atrial flutter (abnormal heart rhythm), myocarditis (inflammation of heart muscle), cardiomyopathy (disease of heart muscle), fever, syncope (fainting), diabetes mellitus, diabetic ketoacidosis (life-threatening complication of diabetes), diabetic hyperosmolar coma (extremely high blood sugar levels), neuroleptic malignant syndrome (life-threatening drug reaction), ileus (obstruction of intestine), liver enzyme elevation, postural hypotension (drop in blood pressure due to change in body position) and hypercholesterolaemia (high levels of cholesterol in the blood). GoToSource

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

Fatal fulminant liver failure. GoToSource

Venous thromboembolism (blood clot in a deep vein) and pulmonary embolism (blockage in one of the pulmonary arteries in lungs). GoToSource

Tardive dyskinesia (movement disorder). GoToSource

Sedation. GoToSource

Serious bowel complications including hospitalization or death. GoToSource

Panic disorder. GoToSource

Lawsuits filed for bowel obstructions, intestinal damage, aspiration and death.