WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Assess for organ involvement (e.g., myocarditis, pancreatitis, hepatitis, colitis, nephritis).

Discontinue if these occur.

( ) Eosinophilia: 5.7 Can be fatal.

Consider additional risk factors for prolonged QT interval (disorders and drugs).

( ) QT Interval Prolongation: 5.8 Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/ cerebrovascular risk.

These metabolic changes include: Metabolic Changes: Monitor for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.

Monitor glucose regularly in patients with diabetes or at risk for diabetes.

( ) Hyperglycemia and Diabetes Mellitus: 5.9 Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics.

( ) Dyslipidemia: 5.9 Significant weight gain has occurred.

Monitor weight gain.

( ) Weight Gain: 5.9 Immediately discontinue and monitor closely.

Assess for co-morbid conditions.

( ) Neuroleptic Malignant Syndrome (NMS): 5.10 Evaluate for infection, agranulocytosis, NMS.

( ) Fever: 5.11 Consider PE if respiratory distress, chest pain, or deep vein thrombosis occur.

( ) Pulmonary Embolism (PE): 5.12 Use cautiously in presence of specific conditions (e.g., narrow angle glaucoma, use of anticholinergic drugs).

( ) Anticholinergic Toxicity: 5.13 Advise caution when operating machinery, including automobiles.

( ) Interference with Cognitive and Motor Performance: 5.14 5.1 Agranulocytosis Background Agranulocytosis, defined as an ANC of less than 500/mm , has been estimated to occur in association with clozapine use at a cumulative incidence at 1 year of approximately 1.3%, based on the occurrence of 15 US cases out of 1743 patients exposed to CLOZARIL during its clinical testing prior to domestic marketing.

All of these cases occurred at a time when the need for close monitoring of WBC counts was already recognized.

A hematologic risk analysis was conducted based upon the available information in the CLOZARIL National Registry for US patients.

Based upon a cut-off date of April 30, 1995, the incidence rates of agranulocytosis based upon a weekly monitoring schedule rose steeply during the first 2 months of therapy, peaking in the third month.

Among clozapine patients who continued the drug beyond the third month, the weekly incidence of agranulocytosis fell a substantial degree.

After 6 months, the weekly incidence of agranulocytosis declines still further; however, it never reaches zero.

It should be noted that any type of reduction in the frequency of monitoring WBC counts may result in an increased incidence of agranulocytosis.

3 Risk Factors Experience from clinical development, as well as from examples in the medical literature, suggests that patients who have developed agranulocytosis during clozapine therapy are at increased risk of subsequent episodes of agranulocytosis.

Analysis of WBC count data from the CLOZARIL National Registry also suggests that patients who have an initial episode of moderate leukopenia (3000/mm >WBC count ≥2000/mm ) are at an increased risk of subsequent episodes of agranulocytosis.

Except for bone-marrow suppression during initial clozapine therapy, there are no other established risk factors based on worldwide experience for the development of agranulocytosis in association with clozapine use.

However, a disproportionate number of the US cases of agranulocytosis occurred in patients of Jewish background compared to the overall proportion of such patients exposed during domestic development of clozapine.

Most of the US cases of agranulocytosis occurred within 4–10 weeks of exposure, but neither dose nor duration is a reliable predictor of this problem.

Agranulocytosis associated with other antipsychotic drugs has been reported to occur with a greater frequency in women, the elderly, and in patients who are cachectic or have serious underlying medical illness; such patients may also be at particular risk with clozapine, although this has not been definitively demonstrated.

3 3 WBC Count and ANC Clinical Monitoring Schedule CLOZARIL is available only through a distribution system that ensures monitoring of WBC count and ANC according to the schedule described below prior to delivery of the next supply of medication.

As described in Table 2, patients who are being treated with CLOZARIL must have a baseline WBC count and ANC before initiation of treatment, and a WBC count and ANC every week for the first 6 months.

Thereafter, if acceptable WBC counts and ANCs (WBC count ≥3500/mm and ANC ≥2000/mm ) have been maintained during the first 6 months of continuous therapy, WBC counts and ANCs can be monitored every 2 weeks for the next 6 months.

Thereafter, if acceptable WBC counts and ANCs (WBC count ≥3500/mm and ANC ≥2000/mm ) have been maintained during the second 6 months of continuous therapy, WBC count and ANC can be monitored every 4 weeks.

3 3 3 3 When treatment with CLOZARIL is discontinued (regardless of the reason), WBC count and ANC must be monitored weekly for at least 4 weeks from the day of discontinuation or until WBC count ≥3500/mm and ANC ≥2000/mm .

3 3 Table 2 provides a summary of the frequency of monitoring that should occur based on various stages of therapy (e.g., initiation of therapy) or results from WBC count and ANC monitoring tests (e.g., moderate leukopenia).

The text that follows should be consulted for additional details regarding the treatment of patients under the various conditions (e.g., severe leukopenia).

Advise patients to immediately report the appearance of signs/symptoms consistent with agranulocytosis or infection (e.g., fever, weakness, lethargy, or sore throat) at any time during CLOZARIL therapy.

Such patients should have a WBC count and an ANC performed promptly.

Table 2.

Frequency of Monitoring Based on Stage of Therapy or Results from WBC Count and ANC Monitoring Tests WBC=White blood cell ANC=Absolute neutrophil count Situation Hematological Values for Monitoring Frequency of WBC Count and ANC Monitoring Initiation of therapy WBC count≥3500/mm and ANC≥2000/mm Note: Do not initiate in patients with a history of clozapine-induced agranulocytosis or severe granulocytopenia.

3 3 Weekly for 6 months 6 to 12 months of therapy WBC ≥3500/mm and ANC ≥2000/mm 3 3 Every 2 weeks for 6 months 12 months of therapy WBC ≥3500/mm and ANC ≥2000/mm 3 3 Every 4 weeks ad infinitum Immature forms present N/A Repeat WBC and ANC Discontinuation of therapy N/A Weekly for at least 4 weeks from day of discontinuation or until WBC ≥3500/mm and ANC ≥2000/mm 3 3 Substantial drop in WBC or ANC Single drop or cumulative drop within 3 weeks of: WBC ≥3000/mm or ANC ≥1500/mm 3 3 Repeat WBC and ANC If repeat values are: WBC 3000/mm to 3500 and ANC >2000/mm , then monitor twice weekly 3 3 Mild leukopenia and/or Mild granulocytopenia If WBC 3000 mm to <3500/mm and/or ANC 1500/mm to 3500/mm and ANC >2000/mm then return to previous monitoring frequency 3 3 Moderate leukopenia and/or Moderate granulocytopenia WBC 2000/mm to <3000/mm and/or ANC 1000/mm to 3000/mm and ANC >1500/mm 3 3 Twice weekly until WBC >3500/mm and ANC >2000/mm 3 3 May rechallenge when WBC >3500/mm and ANC >2000/mm 3 3 If rechallenged, monitor weekly for 1 year before returning to the usual monitoring schedule of every 2 weeks for 6 months and then every 4 weeks ad infinitum Severe leukopenia and/or Severe granulocytopenia WBC count <2000/mm and/or ANC 3000/mm and ANC >1500/mm 3 3 Twice weekly until WBC >3500/mm and ANC >2000/mm 3 3 Weekly after WBC >3500/mm 3 Agranulocytosis ANC 3000/mm and ANC >1500/mm 3 3 Twice weekly until WBC >3500/mm and ANC >2000/mm 3 3 Weekly after WBC >3500/mm 3 Decrements in WBC Count and/or ANC Consult Table 2 above to determine how to monitor patients who experience decrements in WBC count and/or ANC at any point during treatment.

Additionally, patients should be carefully monitored for flu-like symptoms or other symptoms suggestive of infection.

Nonrechallengeable Patients If the total WBC count falls below 2000/mm or the ANC falls below 1000/mm , bone-marrow aspiration should be considered to ascertain granulopoietic status and patients should not be rechallenged with clozapine.

Protective isolation with close observation may be indicated if granulopoiesis is determined to be deficient.

Should evidence of infection develop, the patient should have appropriate cultures performed and an appropriate antibiotic regimen instituted.

3 3 Patients discontinued from clozapine therapy due to significant granulopoietic suppression have been found to develop agranulocytosis upon rechallenge, often with a shorter latency on re-exposure.

To reduce the chances of rechallenge occurring in patients who have experienced significant bone-marrow suppression during clozapine therapy, a single, national master file (i.e., Nonrechallengeable Database) is confidentially maintained.

Treatment of Rechallengeable Patients Patients may be rechallenged with clozapine if their WBC count does not fall below 2000/mm and the ANC does not fall below 1000/mm .

However, analysis of the data from the CLOZARIL National Registry suggests that patients who have an initial episode of moderate leukopenia (3000/mm >WBC count ≥2000/mm ) have up to a 12-fold increased risk of having a subsequent episode of agranulocytosis when rechallenged as compared to the full cohort of patients treated with clozapine.

Although CLOZARIL therapy may be resumed if no symptoms of infection develop and when the WBC count rises above 3500/mm and the ANC rises above 2000/mm , prescribers are strongly advised to consider whether the benefit of continuing CLOZARIL treatment outweighs the increased risk of agranulocytosis.

3 3 3 3 3 3 Analyses of the CLOZARIL National Registry have shown an increased risk of having a subsequent episode of granulopoietic suppression up to a year after recovery from the initial episode.

Therefore, as noted in Table 2, patients must undergo weekly WBC count and ANC monitoring for 1 year following recovery from an episode of moderate leukopenia and/or moderate granulocytopenia regardless of when the episode develops.

If acceptable WBC counts and ANC (WBC count ≥3500/mm and ANC ≥2000/mm ) have been maintained during the year of weekly monitoring, WBC counts can be monitored every 2 weeks for the next 6 months.

If acceptable WBC counts and ANC (WBC count ≥3500/mm and ANC ≥2000/mm ) continue to be maintained during the 6 months of every 2-week monitoring, WBC counts can be monitored every 4 weeks thereafter, ad infinitum.

3 3 3 3 Interruptions in Therapy Figure 1 provides instructions regarding re-initiating therapy and subsequently the frequency of WBC count and ANC monitoring after a period of interruption.

Figure 1.

Resuming Monitoring Frequency after Interruption of Therapy Figure 1: Resuming Monitoring Frequency after Interruption in Therapy 5.2 CLOZARIL National Registry Because of the Risk of Agranulocytosis Because of the risk of agranulocytosis, CLOZARIL is available only through a restricted program called the CLOZARIL National Registry.

Under the CLOZARIL National Registry, prescribers, patients, pharmacies, and distributors must enroll in the program.

Required components of the CLOZARIL National Registry are: Healthcare professionals who prescribe CLOZARIL must enroll in the program and comply with the Registry requirements.

Pharmacies that dispense CLOZARIL must enroll in the program and comply with the Registry requirements.

Routine monitoring and submission of laboratory results (WBC and ANC) is required during treatment with CLOZARIL .

[see Warnings and Precautions (5.1)] Patients who receive CLOZARIL must be enrolled in a registry.

Further information is available at or 1-888-669-6682.

http://www.clozarilregistry.com 5.3 Orthostatic Hypotension, Bradycardia, and Syncope 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, at doses as low as 12.5 mg.

These reactions can be fatal.

The syndrome is consistent with neurally mediated reflex bradycardia (NMRB).

Treatment must begin at a maximum dose of 12.5 mg once daily or twice daily.

The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks.

Subsequently, the dose can be increased weekly or twice weekly, in increments of up to 100 mg.

The maximum dose is 900 mg per day.

Use cautious titration and a divided dosage schedule to minimize the risk of serious cardiovascular reactions .

Consider reducing the dose if hypotension occurs.

When restarting patients who have had even a brief interval off CLOZARIL (i.e., 2 days or more since the last dose), re-initiate treatment at 12.5 mg once daily or twice daily .

[see Dosage and Administration (2.2)] [see Dosage and Administration (2.5)] Use CLOZARIL cautiously in patients with cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (e.g., concomitant use of antihypertensives, dehydration and hypovolemia).

5.4 Seizures Seizure has been estimated to occur in association with clozapine use at a cumulative incidence at 1 year of approximately 5%, based on the occurrence of 1 or more seizures in 61 of 1743 patients exposed to clozapine during its clinical testing prior to domestic marketing (i.e., a crude rate of 3.5%).

The risk of seizure is dose-related.

Initiate treatment with a low dose (12.5 mg), titrate slowly, and use divided dosing.

Use caution when administering CLOZARIL to patients with a history of seizures or other predisposing risk factors for seizure (e.g., head trauma or other CNS pathology, use of medications that lower the seizure threshold, or alcohol abuse).

Because of the substantial risk of seizure associated with CLOZARIL use, caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others (e.g., driving an automobile, operating complex machinery, swimming, climbing).

5.5 Myocarditis and Cardiomyopathy Myocarditis and cardiomyopathy have occurred with the use of CLOZARIL.

These reactions can be fatal.

Discontinue CLOZARIL 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 CLOZARIL.

However, if the benefit of CLOZARIL treatment is judged to outweigh the potential risks of recurrent myocarditis or cardiomyopathy, the clinician may consider rechallenge with CLOZARIL in consultation with a cardiologist, after a complete cardiac evaluation, and under close monitoring.

Consider the possibility of myocarditis or cardiomyopathy in patients receiving CLOZARIL 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 2 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 CLOZARIL.

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.

Typical laboratory findings include elevated troponin I or T, elevated creatinine kinase-MB, peripheral eosinophilia, and elevated C-reactive protein (CRP).

Chest roentgenogram may demonstrate cardiac silhouette enlargement, and cardiac imaging (echocardiogram, radionucleotide studies, or cardiac catheterization) may reveal evidence of left ventricular dysfunction.

5.6 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.

Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients.

Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.

Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.

Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality in this population.

The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

CLOZARIL is not approved for the treatment of patients with dementia-related psychosis .

[see Boxed Warning] 5.7 Eosinophilia Eosinophilia, defined as a blood eosinophil count of greater than 700/mm , has occurred with CLOZARIL treatment.

In clinical trials, approximately 1% of patients developed eosinophilia.

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.

Such organ involvement could be consistent with a drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, also known as drug induced hypersensitivity syndrome (DIHS).

If eosinophilia develops during CLOZARIL treatment, evaluate promptly for signs and symptoms of systemic reactions, such as rash or other allergic symptoms, myocarditis, or other organ-specific disease associated with eosinophilia.

If CLOZARIL-related systemic disease is suspected, discontinue CLOZARIL immediately.

3 If a cause of eosinophilia unrelated to CLOZARIL is identified (e.g., asthma, allergies, collagen vascular disease, parasitic infections, and specific neoplasms), treat the underlying cause and continue CLOZARIL.

Clozapine-related eosinophilia has also occurred in the absence of organ involvement and can resolve without intervention.

There are reports of successful rechallenge after discontinuation of clozapine, without recurrence of eosinophilia.

In the absence of organ involvement, continue CLOZARIL under careful monitoring.

If the total eosinophil count continues to increase over several weeks in the absence of systemic disease, the decision to interrupt CLOZARIL therapy and rechallenge after the eosinophil count decreases should be based on the overall clinical assessment, in consultation with an internist or hematologist.

5.8 QT Interval Prolongation QT prolongation, Torsades 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.

Prior to initiating treatment with CLOZARIL, perform a careful physical examination, medical history, and concomitant medication history.

Consider obtaining a baseline ECG and serum chemistry panel.

Correct electrolyte abnormalities.

Discontinue CLOZARIL if the QTc interval exceeds 500 msec.

If patients experience symptoms consistent with Torsades de Pointes, or other arrhythmias, (e.g., syncope, presyncope, dizziness, or palpitations), obtain a cardiac evaluation and discontinue CLOZARIL.

Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of CLOZARIL.

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 antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus).

Clozapine is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4.

Concomitant treatment with inhibitors of these enzymes can increase the concentration of CLOZARIL .

[see Drug Interactions (7.1) and Clinical Pharmacology (12.3)] 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.

Obtain baseline measurements of serum potassium and magnesium levels, and periodically monitor electrolytes.

Correct electrolyte abnormalities before initiating treatment with CLOZARIL.

5.9 Metabolic Changes 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.

Hyperglycemia and Diabetes Mellitus 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.

Assessment of 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 reactions is not completely understood.

However, epidemiological studies suggest an increased risk of treatment-emergent, hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.

Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on CLOZARIL 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, polyuria, polyphagia, and weakness.

Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing.

In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

In a pooled data analysis of 8 studies in adult subjects with schizophrenia, the mean changes in fasting glucose concentration in the CLOZARIL and chlorpromazine groups were +11 mg/dL and +4 mg/dL respectively.

A higher proportion of the CLOZARIL group demonstrated categorical increases from baseline in fasting glucose concentrations, compared to the chlorpromazine group (Table 3).

The CLOZARIL doses were 100–900 mg per day (mean modal dose: 512 mg per day).

The maximum chlorpromazine dose was 1800 mg per day (mean modal dose: 1029 mg per day).

The median duration of exposure was 42 days for CLOZARIL and chlorpromazine.

Table 3.

Categorical Changes in Fasting Glucose Level in Studies in Adult Subjects with Schizophrenia Laboratory Parameter Category Change (at least once) from baseline Treatment Arm N n (%) Fasting Glucose Normal (<100 mg/dL) to High (≥126 mg/dL) CLOZARIL 198 53 (27) Chlorpromazine 135 14 (10) Borderline (100 to 125 mg/dL) to High (≥126 mg/dL) CLOZARIL 57 24 (42) Chlorpromazine 43 12 (28) Dyslipidemia Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics, including CLOZARIL.

Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using CLOZARIL, is recommended.

In a pooled data analysis of 10 studies in adult subjects with schizophrenia, CLOZARIL treatment was associated with increases in serum total cholesterol.

No data were collected on LDL and HDL cholesterol.

The mean increase in total cholesterol was 13 mg/dL in the CLOZARIL group and 15 mg/dL in the chlorpromazine group.

In a pooled data analysis of 2 studies in adult subjects with schizophrenia, CLOZARIL treatment was associated with increases in fasting serum triglyceride.

The mean increase in fasting triglyceride was 71 mg/dL (54%) in the CLOZARIL group and 39 mg/dL (35%) in the chlorpromazine group (Table 4).

In addition, CLOZARIL treatment was associated with categorical increases in serum total cholesterol and triglyceride, as illustrated in Table 5.The proportion of patients with categorical increases in total cholesterol or fasting triglyceride increased with the duration of exposure.

The median duration of CLOZARIL and chlorpromazine exposure was 45 days and 38 days, respectively.

The CLOZARIL dose range was 100 mg to 900 mg daily; the maximum chlorpromazine dose was 1800 mg daily.

Table 4.

Mean Changes in Total Cholesterol and Triglyceride Concentration in Studies in Adult Subjects with Schizophrenia Treatment Arm Baseline total cholesterol concentration (mg/dL) Change from baseline mg/dL (%) CLOZARIL (N=334) 184 +13 (7) Chlorpromazine (185) 182 +15 (8) Baseline triglyceride concentration (mg/dL) Change from baseline mg/dL (%) CLOZARIL (N=6) 130 +71 (54) Chlorpromazine (N=7) 110 +39 (35) Table 5.

Categorical Changes in Lipid Concentrations in Studies in Adult Subjects with Schizophrenia Laboratory Parameter Category Change (at least once) from baseline Treatment Arm N n (%) Total Cholesterol (random or fasting) Increase by ≥40 mg/dL CLOZARIL 334 111 (33) Chlorpromazine 185 46 (25) Normal (<200 mg/dL) to High (≥240 mg/dL) CLOZARIL 222 18 (8) Chlorpromazine 132 3 (2) Borderline (200-239 mg/dL) to High (≥240 mg/dL) CLOZARIL 79 30 (38) Chlorpromazine 34 14 (41) Triglycerides (fasting) Increase by ≥50 mg/dL CLOZARIL 6 3 (50) Chlorpromazine 7 3 (43) Normal (<150 mg/dL) to High (≥200 mg/dL) CLOZARIL 4 0 (0) Chlorpromazine 6 2 (33) Borderline (≥150 mg/dL and <200 mg/dL) to High (≥200 mg/dL) CLOZARIL 1 1 (100) Chlorpromazine 1 0 (0) Weight Gain Weight gain has occurred with the use of antipsychotics, including CLOZARIL.

Monitor weight during treatment with CLOZARIL.

Table 6 summarizes the data on weight gain by the duration of exposure pooled from 11 studies with CLOZARIL and active comparators.

The median duration of exposure was 609, 728, and 42 days, in the CLOZARIL, olanzapine, and chlorpromazine group, respectively.

Table 6.

Mean Change in Body Weight (kg) by duration of exposure from studies in adult subjects with schizophrenia Metabolic parameter Exposure duration CLOZARIL (N=669) Olanzapine (N=442) Chlorpromazine (N=155) n Mean n Mean n Mean Weight change from baseline 2 weeks (Day 11–17) 6 +0.9 3 +0.7 2 -0.5 4 weeks (Day 21–35) 23 +0.7 8 +0.8 17 +0.6 8 weeks (Day 49–63) 12 +1.9 13 +1.8 16 +0.9 12 weeks (Day 70–98) 17 +2.8 5 +3.1 0 0 24 weeks (154–182) 42 – 0.6 12 +5.7 0 0 48 weeks (Day 322–350) 3 +3.7 3 +13.7 0 0 Table 7 summarizes pooled data from 11 studies in adult subjects with schizophrenia demonstrating weight gain ≥7% of body weight relative to baseline.

The median duration of exposure was 609, 728, and 42 days, in the CLOZARIL, olanzapine, and chlorpromazine group, respectively.

Table 7.

Proportion of Adult Subjects in Schizophrenia Studies with Weight Gain ≥7% Relative to Baseline Body Weight Weight change CLOZARIL Olanzapine Chlorpromazine N 669 442 155 ≥7% (inclusive) 236 (35%) 203 (46%) 13 (8%) 5.10 Neuroleptic Malignant Syndrome Antipsychotic drugs including CLOZARIL can cause a potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS).

Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).

Associated findings can include elevated creatine phosphokinase (CPK), myoglobinuria, rhabdomyolysis, and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated.

It is important to consider the presence of other serious medical conditions (e.g., agranulocytosis, infection, heat stroke, primary CNS pathology, central anticholinergic toxicity, extrapyramidal symptoms, and drug fever).

The management of NMS should include (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, (2) intensive symptomatic treatment and medical monitoring, and (3) treatment of comorbid medical conditions.

There is no general agreement about specific pharmacological treatments for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered.

NMS can recur.

Monitor closely if restarting treatment with antipsychotics.

NMS has occurred with CLOZARIL monotherapy and with concomitant CNS-active medications, including lithium.

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

The peak incidence is within the first 3 weeks of treatment.

While this fever is generally benign and self-limited, it may necessitate discontinuing treatment.

The fever can be associated with an increase or decrease in WBC count.

Carefully evaluate patients with fever to rule out agranulocytosis or infection.

Consider the possibility of NMS .

[see Warnings and Precautions (5.10)] 5.12 Pulmonary Embolism Pulmonary embolism and deep vein thrombosis have occurred in patients treated with CLOZARIL.

Consider the possibility of pulmonary embolism in patients who present with deep-vein thrombosis, acute dyspnea, chest pain, or with other respiratory signs and symptoms.

Whether pulmonary embolus and deep vein thrombosis can be attributed to clozapine or some characteristic(s) of patients is not clear.

5.13 Anticholinergic Toxicity CLOZARIL has potent anticholinergic effects.

Treatment with CLOZARIL 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.

Treatment with CLOZARIL can result in gastrointestinal adverse reactions, including constipation, intestinal obstruction, fecal impaction, and paralytic ileus.

Such reactions can be fatal.

Constipation should be initially treated by ensuring adequate hydration and use of ancillary therapy such as bulk laxatives.

Consultation with a gastroenterologist is advisable in more serious cases.

5.14 Interference with Cognitive and Motor Performance CLOZARIL can cause sedation and impairment of cognitive and motor performance.

Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that CLOZARIL does not affect them adversely.

These reactions may be dose-related.

Consider reducing the dose if they occur.

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

The syndrome consists of potentially irreversible, involuntary, dyskinetic movements.

The risk of TD and the likelihood that it will become irreversible are believed to increase with greater durations of treatment and higher total cumulative doses.

However, the syndrome can develop after relatively brief treatment periods at low doses.

Prescribe CLOZARIL in a manner that is most likely to minimize the risk of developing TD.

Use the lowest effective dose and the shortest duration necessary to control symptoms.

Periodically assess the need for continued treatment.

Consider discontinuing treatment if TD occurs.

However, some patients may require treatment with CLOZARIL despite the presence of the syndrome.

There is no known treatment for TD.

However, the syndrome may remit partially or completely if treatment is discontinued.

Antipsychotic treatment, itself, may suppress (or partially suppress) the signs and symptoms, and it has the potential to mask the underlying process.

The effect of symptom suppression on the long-term course of TD is unknown.

5.16 Cerebrovascular Adverse Reactions In controlled trials, elderly patients with dementia-related psychosis treated with some atypical antipsychotics had an increased risk (compared to placebo) of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities.

The mechanism for this increased risk is not known.

An increased risk cannot be excluded for CLOZARIL or other antipsychotics or other patient populations.

CLOZARIL should be used with caution in patients with risk factors for cerebrovascular adverse reactions.

5.17 Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation of CLOZARIL If abrupt discontinuation of CLOZARIL is necessary (because of agranulocytosis or another medical condition, for example), monitor carefully for the recurrence of psychotic symptoms and adverse reactions related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting and diarrhea.