Label: CLOZARIL- clozapine tablet 

  • Label RSS
  • NDC Code(s): 0078-0126-05, 0078-0126-06, 0078-0126-08, 0078-0126-61, view more
    0078-0127-05, 0078-0127-06, 0078-0127-08, 0078-0127-61
  • Packager: Novartis Pharmaceuticals Corporation
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: New Drug Application

Drug Label Information

Updated 11/13

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  • BOXED WARNING(What is this?)

    WARNING: AGRANULOCYTOSIS; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

    Agranulocytosis

    CLOZARIL treatment has caused agranulocytosis, defined as an absolute neutrophil count (ANC) less than 500/mm3. Agranulocytosis can lead to serious infection and death. Prior to initiating treatment with CLOZARIL, obtain a baseline white blood cell (WBC) count and ANC. The ANC must be greater than or equal to 2000/mm3 and the WBC must be greater than or equal to 3500/mm3 for a patient to begin treatment with CLOZARIL. During treatment, patients must have regular monitoring of ANC and WBC. Discontinue CLOZARIL and do not rechallenge if the ANC is less than 1000/mm3 or the WBC is less than 2000/mm3. Advise patients to immediately report symptoms consistent with agranulocytosis or infection (e.g., fever, weakness, lethargy, or sore throat) [see Dosage and Administration (2.1) and Warnings and Precautions (5.1)].

    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, and pharmacies must enroll in the program [see Warnings and Precautions (5.2)].

    Orthostatic Hypotension, Bradycardia, Syncope

    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 dosages. Use CLOZARIL cautiously in patients with cardiovascular or cerebrovascular disease or conditions predisposing to hypotension (e.g., dehydration, use of antihypertensive medications) [see Dosage and Administration (2.2, and 2.5) and Warnings and Precautions (5.3)].

    Seizures

    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 [see Dosage and Administration (2.2), Warnings and Precautions (5.4)].

    Myocarditis and Cardiomyopathy

    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 [see Warnings and Precautions (5.5)].

    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 is not approved for use in patients with dementia-related psychosis [see Warnings and Precautions (5.6)].

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use CLOZARIL safely and effectively. See full prescribing information for CLOZARIL.
    CLOZARIL® (clozapine) tablets, for oral use
    Initial U.S. Approval: 1989

    WARNING: AGRANULOCYTOSIS; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

    See full prescribing information for complete boxed warning.

    • Agranulocytosis: Can lead to serious infection and death. Monitor white blood cell count and absolute neutrophil count prior to and during treatment. Monitor for symptoms of agranulocytosis and infection. (2.1, 5.1)
    • Because of risk of agranulocytosis, CLOZARIL is available only through a restricted program called the CLOZARIL National Registry. Prescribers, patients, and pharmacies must enroll in the program. (5.2)
    • Orthostatic Hypotension, Bradycardia, and Syncope: Risk is dose-related. Starting dose is 12.5 mg. Titrate gradually and use divided dosages. (2.2, 2.5, 5.3)
    • Seizure: Risk is dose-related. Titrate gradually and use divided doses. Use with caution in patients with history of seizure or risk factors for seizure. (2.2, 5.4)
    • Myocarditis and Cardiomyopathy: Can be fatal. Discontinue and obtain cardiac evaluation if findings suggest these cardiac reactions. (5.5)
    • Increased Mortality in Elderly Patients with Dementia-Related Psychosis: CLOZARIL is not approved for this condition. (5.6)

    RECENT MAJOR CHANGES

    Dosage and Administration (2.1, 2.6, 2.7)       07/2013

    Contraindications (4)       07/2013

    Warnings and Precautions (5.2, 5.3)       07/2013

    INDICATIONS AND USAGE

    CLOZARIL is an atypical antipsychotic indicated for:

    • Treatment-resistant schizophrenia. Efficacy was established in an active-controlled study. (1.1, 14.1)
    • Reducing suicidal behavior in patients with schizophrenia or schizoaffective disorder. Efficacy was established in an active-controlled study. (1.2, 14.2)

    DOSAGE AND ADMINISTRATION

    • Starting Dose: 12.5 mg once daily or twice daily. (2.2)
    • Use cautious titration and divided dosage schedule. (2.2, 5.3)
    • Titration: increase the total daily dosage in increments of 25 mg to 50 mg per day, if well-tolerated. (2.2)
    • Target dose: 300 mg to 450 mg per day, in divided doses, by the end of 2 weeks. (2.2)
    • Subsequent increases: increase in increments of 100 mg or less, once or twice weekly. (2.2)
    • Maximum daily dose: 900 mg (2.2)

    DOSAGE FORMS AND STRENGTHS

    25 mg and 100 mg tablets with a facilitated score on one side (3)

    CONTRAINDICATIONS

    • History of clozapine-induced agranulocytosis or severe Granulocytopenia. (4)
    • Known hypersensitivity to clozapine or any other component of CLOZARIL. (4)

    WARNINGS AND PRECAUTIONS

    • Eosinophilia: Assess for organ involvement (e.g., myocarditis, pancreatitis, hepatitis, colitis, nephritis). Discontinue if these occur. (5.7)
    • QT Interval Prolongation: Can be fatal. Consider additional risk factors for prolonged QT interval (disorders and drugs). (5.8)
    • Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/ cerebrovascular risk.

      These metabolic changes include:
      • Hyperglycemia and Diabetes Mellitus: Monitor for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes. (5.9)
      • Dyslipidemia: Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics. (5.9)
      • Weight Gain: Significant weight gain has occurred. Monitor weight gain. (5.9)
    • Neuroleptic Malignant Syndrome (NMS): Immediately discontinue and monitor closely. Assess for co-morbid conditions. (5.10)
    • Fever: Evaluate for infection, agranulocytosis, NMS. (5.11)
    • Pulmonary Embolism (PE): Consider PE if respiratory distress, chest pain, or deep vein thrombosis occur. (5.12)
    • Anticholinergic Toxicity: Use cautiously in presence of specific conditions (e.g., narrow angle glaucoma, use of anticholinergic drugs). (5.13)
    • Interference with Cognitive and Motor Performance: Advise caution when operating machinery, including automobiles. (5.14)

    ADVERSE REACTIONS

    Most common adverse reactions (≥5%) were: CNS reactions (sedation, dizziness/vertigo, headache, and tremor); cardiovascular reactions (tachycardia, hypotension, and syncope); autonomic nervous system reactions (hypersalivation, sweating, dry mouth, and visual disturbances); gastrointestinal reactions (constipation and nausea); and fever. (6.1)

    To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    DRUG INTERACTIONS

    • Concomitant use of Strong CYP1A2 Inhibitors: Reduce CLOZARIL dose to one-third when coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, enoxacin). (2.6, 7.1)
    • Concomitant use of Strong CYP3A4 Inducers is not recommended. (2.6, 7.1)
    • Discontinuation of CYP1A2 or CYP3A4 Inducers: Consider reducing CLOZARIL dose when CYP1A2 (e.g., tobacco smoke) or CYP3A4 inducers (e.g., carbamazepine) are discontinued. (2.6, 7.1)

    USE IN SPECIFIC POPULATIONS

    • Nursing Mothers: Discontinue drug or discontinue nursing, taking into consideration importance of drug to mother. (8.3)


    See 17 for PATIENT COUNSELING INFORMATION.

    Revised: 11/2013

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  • FULL PRESCRIBING INFORMATION: CONTENTS*

    WARNING: AGRANULOCYTOSIS; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

    1     INDICATIONS AND USAGE

    1.1     Treatment Resistant Schizophrenia

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

    2     DOSAGE AND ADMINISTRATION

    2.1     Required Laboratory Testing Prior to Initiation and During Therapy

    2.2     Dosing Information

    2.3     Maintenance Treatment

    2.4     Discontinuation of Treatment

    2.5     Re-Initiation of Treatment

    2.6     Dosage Adjustments with Concomitant use of CYP1A2, CYP2D6, CYP3A4 Inhibitors or CYP1A2, CYP3A4 Inducers

    2.7     Renal or Hepatic Impairment or CYP2D6 Poor Metabolizers

    3     DOSAGE FORMS AND STRENGTHS

    4     CONTRAINDICATIONS

    5     WARNINGS AND PRECAUTIONS

    5.1     Agranulocytosis

    5.2     CLOZARIL National Registry Because of the Risk of Agranulocytosis

    5.3     Orthostatic Hypotension, Bradycardia, and Syncope

    5.4     Seizures

    5.5     Myocarditis and Cardiomyopathy

    5.6     Increased Mortality in Elderly Patients with Dementia-Related Psychosis

    5.7     Eosinophilia

    5.8     QT Interval Prolongation

    5.9     Metabolic Changes

    5.10     Neuroleptic Malignant Syndrome

    5.11     Fever

    5.12     Pulmonary Embolism

    5.13     Anticholinergic Toxicity

    5.14     Interference with Cognitive and Motor Performance

    5.15     Tardive Dyskinesia

    5.16     Cerebrovascular Adverse Reactions

    5.17     Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation of CLOZARIL

    6     ADVERSE REACTIONS

    6.1     Clinical Trials Experience

    6.2     Postmarketing Experience

    7     DRUG INTERACTIONS

    7.1     Potential for Other Drugs to Affect CLOZARIL

    7.2     Potential for CLOZARIL to Affect Other Drugs

    8     USE IN SPECIFIC POPULATIONS

    8.1     Pregnancy

    8.3     Nursing Mothers

    8.4     Pediatric Use

    8.5     Geriatric Use

    8.6     Patients with Renal or Hepatic Impairment

    8.7     CYP2D6 Poor Metabolizers

    10     OVERDOSAGE

    10.1     Overdosage Experience

    10.2     Management of Overdosage

    11     DESCRIPTION

    12     CLINICAL PHARMACOLOGY

    12.1     Mechanism of Action

    12.2     Pharmacodynamics

    12.3     Pharmacokinetics

    13     NONCLINICAL TOXICOLOGY

    13.1     Carcinogenesis, Mutagenesis, Impairment of Fertility

    14     CLINICAL STUDIES

    14.1     Treatment Resistant Schizophrenia

    14.2     Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder

    16     HOW SUPPLIED/STORAGE AND HANDLING

    16.1     How Supplied

    16.2     Storage and Handling

    17     PATIENT COUNSELING INFORMATION

    *
    Sections or subsections omitted from the full prescribing information are not listed.
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  • 1     INDICATIONS AND USAGE

    1.1     Treatment Resistant Schizophrenia

    CLOZARIL is indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the significant risk of agranulocytosis and seizure associated with its use, CLOZARIL should be used only in patients who have failed to respond adequately to standard antipsychotic treatment [see Warnings and Precautions (5.1, 5.4)].

    The effectiveness of CLOZARIL in treatment-resistant schizophrenia was demonstrated in a 6-week, randomized, double-blind, active-controlled study comparing CLOZARIL and chlorpromazine in patients who had failed other antipsychotics [see Clinical Studies (14.1)].

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

    CLOZARIL is indicated 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 CLOZARIL in reducing the risk of recurrent suicidal behavior was demonstrated over a 2-year treatment period in the InterSePTTM trial [see Clinical Studies (14.2)].

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  • 2     DOSAGE AND ADMINISTRATION

    2.1     Required Laboratory Testing Prior to Initiation and During Therapy

    Prior to initiating treatment with CLOZARIL, obtain a complete blood count (CBC) with differential. The absolute neutrophil count (ANC) must be greater than or equal to 2000/mm3 and the WBC must be greater than or equal to 3500 mm3 in order to initiate treatment. To continue treatment, the ANC and WBC must be monitored regularly [see Warnings and Precautions (5.1)].

    2.2     Dosing Information

    The starting dose is 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 achieve 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 once weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. To minimize the risk of orthostatic hypotension, bradycardia, and syncope, it is necessary to use this low starting dose, gradual titration schedule, and divided dosages [see Warnings and Precautions (5.3)].

    CLOZARIL can be taken with or without food [see Pharmacokinetics (12.3)].

    2.3     Maintenance Treatment

    Generally, it is recommended that patients responding to CLOZARIL continue maintenance treatment on their effective dose beyond the acute episode.

    2.4     Discontinuation of Treatment

    In the event of planned termination of CLOZARIL therapy, reduce the dose gradually over a period of 1 to 2 weeks. If abrupt discontinuation is necessary (because of agranulocytosis or another medical condition, for example), monitor carefully for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound such as profuse sweating, headache, nausea, vomiting, and diarrhea.

    2.5     Re-Initiation of Treatment

    When restarting CLOZARIL in patients who have discontinued CLOZARIL (i.e., 2 days or more since the last dose), re-initiate with 12.5-mg once daily or twice daily. This is necessary to minimize the risk of hypotension, bradycardia, and syncope [see Warnings and Precautions (5.3)]. If that dose is well tolerated, the dose may be increased to the previously therapeutic dose more quickly than recommended for initial treatment.

    2.6     Dosage Adjustments with Concomitant use of CYP1A2, CYP2D6, CYP3A4 Inhibitors or CYP1A2, CYP3A4 Inducers

    Dose adjustments may be necessary in patients with concomitant use of: strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin); moderate or weak CYP1A2 inhibitors (e.g., oral contraceptives, or caffeine); CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline); CYP3A4 inducers (e.g., phenytoin, carbamazepine, St. John’s wort, and rifampin); or CYP1A2 inducers (e.g., tobacco smoking) (Table 1) [see Drug Interactions (7)].

    Table 1. Dose Adjustment in Patients Taking Concomitant Medications
    Comedications Scenarios
    Initiating CLOZARIL while taking a comedication Adding a comedication while taking CLOZARIL Discontinuing a comedication while continuing CLOZARIL
    Strong CYP1A2 Inhibitors Use one-third of the CLOZARIL dose. Increase CLOZARIL dose based on clinical response.
    Moderate or Weak CYP1A2 Inhibitors Monitor for adverse reactions.
    Consider reducing the CLOZARIL dose if necessary.
    Monitor for lack of effectiveness. Consider increasing CLOZARIL dose if necessary.
    CYP2D6 or CYP3A4 Inhibitors
    Strong CYP3A4 Inducers Concomitant use is not recommended.
    However, if the inducer is necessary, it may be necessary to increase the CLOZARIL dose.
    Monitor for decreased effectiveness.
    Reduce CLOZARIL dose based on clinical response.
    Moderate or weak CYP1A2 or CYP3A4 Inducers Monitor for decreased effectiveness. Consider increasing the CLOZARIL dose if necessary. Monitor for adverse reactions.
    Consider reducing the CLOZARIL dose if necessary.

    2.7     Renal or Hepatic Impairment or CYP2D6 Poor Metabolizers

    It may be necessary to reduce the CLOZARIL dose in patients with significant renal or hepatic impairment, or in CYP2D6 poor metabolizers [see Use in Specific Populations (8.6, 8.7)].

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  • 3     DOSAGE FORMS AND STRENGTHS

    CLOZARIL (clozapine) is available as 25 mg and 100 mg round, pale-yellow, uncoated tablets with a facilitated score on one side.

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  • 4     CONTRAINDICATIONS

    • History of Clozapine-induced Agranulocytosis or Severe Granulocytopenia

    CLOZARIL is contraindicated in patients with a history of clozapine-induced agranulocytosis or severe granulocytopenia [see Warnings and Precautions (5.1)].

    • Hypersensitivity

    CLOZARIL is contraindicated in patients with a history of hypersensitivity to clozapine (e.g., photosensitivity, vasculitis, erythema multiforme, or Stevens-Johnson syndrome) or any other component of CLOZARIL [see Adverse Reactions (6.2)].

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  • 5     WARNINGS AND PRECAUTIONS

    5.1     Agranulocytosis

    Background

    Agranulocytosis, defined as an ANC of less than 500/mm3, 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.

    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/mm3>WBC count ≥2000/mm3) 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.

    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/mm3 and ANC ≥2000/mm3) 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/mm3 and ANC ≥2000/mm3) have been maintained during the second 6 months of continuous therapy, WBC count and ANC can be monitored every 4 weeks.

    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/mm3 and ANC ≥2000/mm3.

    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/mm3
    and
    ANC≥2000/mm3
    Note: Do not initiate in patients with a history of clozapine-induced agranulocytosis or severe granulocytopenia.
    Weekly for 6 months
    6 to 12 months of therapy WBC ≥3500/mm3
    and
    ANC ≥2000/mm3
    Every 2 weeks for 6 months
    12 months of therapy WBC ≥3500/mm3
    and
    ANC ≥2000/mm3
    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/mm3 and ANC ≥2000/mm3
    Substantial drop in WBC or ANC Single drop or cumulative drop within 3 weeks of:
    WBC ≥3000/mm3 or
    ANC ≥1500/mm3
    1. Repeat WBC and ANC
    2. If repeat values are: WBC 3000/mm3 to 3500 and ANC >2000/mm3, then monitor twice weekly
    Mild leukopenia
    and/or
    Mild granulocytopenia
    If WBC 3000 mm3 to
    <3500/mm3
    and/or
    ANC 1500/mm3 to
    <2000/mm3
    Twice weekly until WBC >3500/mm3 and ANC >2000/mm3 then return to previous monitoring frequency
    Moderate leukopenia
    and/or
    Moderate granulocytopenia
    WBC 2000/mm3 to
    <3000/mm3
    and/or
    ANC 1000/mm3 to
    <1500/mm3
    1. Interrupt therapy
    2. Daily until WBC >3000/mm3 and ANC >1500/mm3
    3. Twice weekly until WBC >3500/mm3 and ANC >2000/mm3
    4. May rechallenge when WBC >3500/mm3 and ANC >2000/mm3
    5. 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/mm3
    and/or
    ANC <1000/mm3
    1. Discontinue treatment and do not rechallenge patient
    2. Monitor until normal and for at least 4 weeks from day of discontinuation as follows:
      • Daily until WBC >3000/mm3 and ANC >1500/mm3
      • Twice weekly until WBC >3500/mm3 and ANC >2000/mm3
      • Weekly after WBC >3500/mm3
    Agranulocytosis ANC <500/mm3
    1. Discontinue treatment and do not rechallenge patient
    2. Monitor until normal and for at least 4 weeks from day of discontinuation as follows:
      • Daily until WBC >3000/mm3 and ANC >1500/mm3
      • Twice weekly until WBC >3500/mm3 and ANC >2000/mm3
      • Weekly after WBC >3500/mm3

    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/mm3 or the ANC falls below 1000/mm3, 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.

    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/mm3 and the ANC does not fall below 1000/mm3. However, analysis of the data from the CLOZARIL National Registry suggests that patients who have an initial episode of moderate leukopenia (3000/mm3>WBC count ≥2000/mm3) 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/mm3 and the ANC rises above 2000/mm3, prescribers are strongly advised to consider whether the benefit of continuing CLOZARIL treatment outweighs the increased risk of agranulocytosis.

    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/mm3 and ANC ≥2000/mm3) 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/mm3 and ANC ≥2000/mm3) continue to be maintained during the 6 months of every 2-week monitoring, WBC counts can be monitored every 4 weeks thereafter, ad infinitum.

    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 http://www.clozarilregistry.com or 1-888-669-6682.

    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 [see Dosage and Administration (2.2)]. 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 (2.5)].

    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/mm3, 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.

    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.

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  • 6     ADVERSE REACTIONS

    The following adverse reactions are discussed in more detail in other sections of the labeling:

    • Agranulocytosis [see Warnings and Precautions (5.1)].
    • Orthostatic Hypotension, Bradycardia, and Syncope [see Warnings and Precautions (5.3)].
    • Seizures [see Warnings and Precautions (5.4)].
    • Myocarditis and Cardiomyopathy [see Warnings and Precautions (5.5)].
    • Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions (5.6)].
    • Eosinophilia [see Warnings and Precautions (5.7)].
    • QT Interval Prolongation [see Warnings and Precautions (5.8)].
    • Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) [see Warnings and Precautions (5.9)].
    • Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.10)].
    • Fever [see Warnings and Precautions (5.11)].
    • Pulmonary Embolism [see Warnings and Precautions (5.12)].
    • Anticholinergic Toxicity [see Warnings and Precautions (5.13)].
    • Interference with Cognitive and Motor Performance [see Warnings and Precautions (5.14)].
    • Tardive Dyskinesia [see Warnings and Precautions (5.15)].
    • Cerebrovascular Adverse Reactions [see Warnings and Precautions (5.16)].
    • Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation [see Warnings and Precautions (5.17)].

    6.1     Clinical Trials Experience

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

    The most commonly reported adverse reactions (>5%) across CLOZARIL clinical trials were: CNS reactions, including sedation, dizziness/vertigo, headache, and tremor; cardiovascular reactions, including tachycardia, hypotension, and syncope; autonomic nervous system reactions, including hypersalivation, sweating, dry mouth, and visual disturbances; gastrointestinal reactions, including constipation and nausea; and fever. Table 8 summarizes the most commonly reported adverse reactions (>5%) in CLOZARIL-treated patients (compared to chlorpromazine-treated patients) in the pivotal, 6-week, controlled trial in treatment-resistant schizophrenia.

    Table 8. Common Adverse Reactions (≥5%) in the 6-Week, Randomized, Chlorpromazine-controlled Trial in Treatment-Resistant Schizophrenia
    Adverse Reaction CLOZARIL
    (N=126)
    (%)
    Chlorpromazine
    (N=142)
    (%)
    Sedation 21 13
    Tachycardia 17 11
    Constipation 16 12
    Dizziness 14 16
    Hypotension 13 38
    Fever (hyperthermia) 13 4
    Hypersalivation 13 1
    Hypertension 12 5
    Headache 10 10
    Nausea/vomiting 10 12
    Dry mouth 5 20

    Table 9 summarizes the adverse reactions reported in CLOZARIL-treated patients at a frequency of 2% or greater across all CLOZARIL studies (excluding the 2-year InterSePT™ Study). These rates are not adjusted for duration of exposure.

    Table 9. Adverse Reactions (≥2%) Reported in CLOZARIL-treated Patients (N=842) Across all CLOZARIL Studies (excluding the 2-year InterSePTTM Study)
    † Rate based on population of approximately 1700 exposed during premarket clinical evaluation of CLOZARIL.
    Body System
         Adverse Reaction*
    CLOZARIL
    N=842
    Percentage of Patients
    Central Nervous System
         Drowsiness/Sedation 39
         Dizziness/Vertigo 19
         Headache 7
         Tremor 6
         Syncope 6
         Disturbed Sleep/Nightmares 4
         Restlessness 4
         Hypokinesia/Akinesia 4
         Agitation 4
         Seizures (convulsions) 3†
         Rigidity 3
         Akathisia 3
         Confusion 3
         Fatigue 2
         Insomnia 2
    Cardiovascular
         Tachycardia 25†
         Hypotension 9
         Hypertension 4
    Gastrointestinal
         Constipation 14
         Nausea 5
         Abdominal Discomfort/Heartburn 4
         Nausea/Vomiting 3
         Vomiting 3
         Diarrhea 2
    Urogenital
         Urinary Abnormalities 2
    Autonomic Nervous System
         Salivation 31
         Sweating 6
         Dry Mouth 6
         Visual Disturbances 5
    Skin
         Rash 2
    Hemic/Lymphatic
         Leukopenia/Decreased WBC/Neutropenia 3
    Miscellaneous
         Fever 5
         Weight Gain 4

    Table 10 summarizes the most commonly reported adverse reactions (>10% of the CLOZARIL or olanzapine group) in the InterSePTTM Study. This was an adequate and well-controlled, 2-year study evaluating the efficacy of CLOZARIL relative to olanzapine in reducing the risk of suicidal behavior in patients with schizophrenia or schizoaffective disorder. The rates are not adjusted for duration of exposure.

    Table 10. Incidence of Adverse Reactions in Patients Treated with CLOZARIL or Olanzapine in the InterSePTTM Study (>10% in the CLOZARIL or olanzapine group)
    Adverse Reactions CLOZARIL
    N=479

    % Reporting
    Olanzapine
    N=477
    % Reporting
    Salivary hypersecretion 48 6
    Somnolence 46 25
    Weight increased 31 56
    Dizziness (excluding vertigo) 27 12
    Constipation 25 10
    Insomnia 20 33
    Nausea 17 10
    Vomiting 17 9
    Dyspepsia 14 8

    Dystonia

    Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

    6.2     Postmarketing Experience

    The following adverse reactions have been identified during post-approval use of clozapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

    Central Nervous System

    Delirium, EEG abnormal, myoclonus, paresthesia, possible cataplexy, status epilepticus, obsessive compulsive symptoms, and post-discontinuation cholinergic rebound adverse reactions.

    Cardiovascular System

    Atrial or ventricular fibrillation, ventricular tachycardia, QT interval prolongation, Torsades de Pointes, myocardial infarction, cardiac arrest, and periorbital edema.

    Gastrointestinal System

    Acute pancreatitis, dysphagia, salivary gland swelling.

    Hepatobiliary System

    Cholestasis, hepatitis, jaundice, hepatotoxicity, hepatic steatosis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, liver injury (hepatic, cholestatic, and mixed), and liver failure.

    Urogenital System

    Acute interstitial nephritis, nocturnal enuresis, priapism, and renal failure.

    Skin

    Hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, and Stevens-Johnson Syndrome.

    Musculoskeletal System

    Myasthenic syndrome and rhabdomyolysis.

    Respiratory System

    Aspiration, pleural effusion, pneumonia, lower respiratory tract infection.

    Hemic and Lymphatic System

    Deep-vein thrombosis, elevated hemoglobin/hematocrit, erythrocyte sedimentation rate (ESR) increased, sepsis, thrombocytosis, and thrombocytopenia.

    Vision Disorders

    Narrow-angle glaucoma.

    Miscellaneous

    Creatine phosphokinase elevation, hyperuricemia, hyponatremia, and weight loss.

    Close
  • 7     DRUG INTERACTIONS

    7.1     Potential for Other Drugs to Affect CLOZARIL

    Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6. Use caution when administering CLOZARIL concomitantly with drugs that are inducers or inhibitors of these enzymes.

    CYP1A2 Inhibitors

    Concomitant use of CLOZARIL and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. Reduce the CLOZARIL dose to one-third of the original dose when CLOZARIL is coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin). The CLOZARIL dose should be increased to the original dose when coadministration of strong CYP1A2 inhibitors is discontinued [see Dosage and Administration (2.6), Clinical Pharmacology (12.3)].

    Moderate or weak CYP1A2 inhibitors include oral contraceptives and caffeine. Monitor patients closely when CLOZARIL is coadministered with these inhibitors. Consider reducing the CLOZARIL dosage if necessary [see Dosage and Administration (2.6)].

    CYP2D6 and CYP3A4 Inhibitors

    Concomitant treatment with CLOZARIL 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 [see Clinical Pharmacology (12.3)]. Use caution and monitor patients closely when using such inhibitors. Consider reducing the CLOZARIL dose [see Dosage and Administration (2.6)].

    CYP1A2 and CYP3A4 Inducers

    Concomitant treatment with drugs that induce CYP1A2 or CYP3A4 can decrease the plasma concentration of clozapine, resulting in decreased effectiveness of CLOZARIL. 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 CLOZARIL dose if used concomitantly with inducers of these enzymes. However, concomitant use of CLOZARIL and strong CYP3A4 inducers is not recommended [see Dosage and Administration (2.6)].

    Consider reducing the CLOZARIL dosage when discontinuing coadministered enzyme inducers; because discontinuation of inducers can result in increased clozapine plasma levels and an increased risk of adverse reactions [see Dosage and Administration (2.6)].

    Drugs that Cause QT Interval Prolongation

    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) [see Warnings and Precautions (5.8)].

    7.2     Potential for CLOZARIL to Affect Other Drugs

    Concomitant use of CLOZARIL with other drugs metabolized by CYP2D6 can increase levels of these CYPD26 substrates. Use caution when coadministering 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).

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  • 8     USE IN SPECIFIC POPULATIONS

    8.1     Pregnancy

    Pregnancy Category B

    Risk Summary

    There are no adequate or well-controlled studies of clozapine in pregnant women.

    Reproduction studies have been performed in rats and rabbits at doses up to 0.4 and 0.9 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on a mg/m2 body surface area basis. The studies revealed no evidence of impaired fertility or harm to the fetus due to clozapine. Because animal reproduction studies are not always predictive of human response, CLOZARIL should be used during pregnancy only if clearly needed.

    Clinical Considerations

    Consider the risk of exacerbation of psychosis when discontinuing or changing treatment with antipsychotic medications during pregnancy and postpartum. Consider early screening for gestational diabetes for patients treated with antipsychotic medications [see Warnings and Precautions (5.9)]. 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.

    Animal Data

    In embryofetal developmental studies, clozapine had no effects on maternal parameters, litter sizes, or fetal parameters when administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 0.4 and 0.9 times, respectively, the MRHD of 900 mg/day on a mg/m2 body surface area basis.

    In peri/postnatal developmental studies, pregnant female rats were administered clozapine over the last third of pregnancy and until day 21 postpartum. Observations were made on fetuses at birth and during the postnatal period; the offspring were allowed to reach sexual maturity and mated. Clozapine caused a decrease in maternal body weight but had no effects on litter size or body weights of either F1or F2 generations at doses up to 0.4 times the MRHD of 900 mg/day on a mg/m2 body surface area basis.

    8.3     Nursing Mothers

    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.

    8.4     Pediatric Use

    Safety and effectiveness in pediatric patients have not been established.

    8.5     Geriatric Use

    There have not been sufficient numbers of geriatric patients in clinical studies utilizing CLOZARIL to determine whether those over 65 years of age differ from younger subjects in their response to CLOZARIL.

    Orthostatic hypotension and tachycardia can occur with CLOZARIL treatment [see Boxed Warning and Warnings and Precautions (5.3)]. Elderly patients, particularly those with compromised cardiovascular functioning, may be more susceptible to these effects.

    Elderly patients may be particularly susceptible to the anticholinergic effects of CLOZARIL, such as urinary retention and constipation [see Warnings and Precautions (5.13)].

    Carefully select CLOZARIL doses in elderly patients, taking into consideration their greater frequency of decreased hepatic, renal, or cardiac function, as well as other concomitant disease and other drug therapy. Clinical experience suggests that the prevalence of tardive dyskinesia appears to be highest among the elderly; especially elderly women [see Warnings and Precautions (5.15)].

    8.6     Patients with Renal or Hepatic Impairment

    Dose reduction may be necessary in patients with significant impairment of renal or hepatic function. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted [see Dosage and Administration (2.7), Clinical Pharmacology (12.3)].

    8.7     CYP2D6 Poor Metabolizers

    Dose reduction may be necessary in patients who are CYP2D6 poor metabolizers. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted [see Dosage and Administration (2.7), Clinical Pharmacology (12.3)].

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  • 10     OVERDOSAGE

    10.1     Overdosage Experience

    The most commonly reported signs and symptoms associated with clozapine overdose are: sedation, delirium, coma, tachycardia, hypotension, respiratory depression or failure; and hypersalivation. There are reports of aspiration pneumonia, cardiac arrhythmias, and seizure. Fatal overdoses have been reported with clozapine, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g.

    10.2     Management of Overdosage

    For the most up-to-date information on the management of CLOZARIL overdosage, contact a certified Regional Poison Control Center (1-800-222-1222). Telephone numbers of certified Regional Poison Control Centers are listed in the **Physicians’ Desk Reference®, a registered trademark of Thomson PDR. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. There are no specific antidotes for CLOZARIL.

    In managing overdosage, consider the possibility of multiple-drug involvement.

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  • 11     DESCRIPTION

    CLOZARIL® (clozapine), an atypical antipsychotic drug, is a tricyclic dibenzodiazepine derivative, 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine. The structural formula is:

    Clozapine structural formula

    CLOZARIL is available in pale yellow tablets of 25 mg and 100 mg for oral administration.

    Active Ingredient: clozapine

    Inactive Ingredients: colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch (corn), and talc.

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  • 12     CLINICAL PHARMACOLOGY

    12.1     Mechanism of Action

    The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D2) and the serotonin type 2A (5-HT2A) receptors. CLOZARIL also acts as an antagonist at adrenergic, cholinergic, histaminergic and other dopaminergic and serotonergic receptors.

    12.2     Pharmacodynamics

    Clozapine demonstrated binding affinity to the following receptors: histamine H1 (Ki 1.1 nM), adrenergic α1A (Ki 1.6 nM), serotonin 5-HT6 (Ki 4 nM), serotonin 5-HT2A (Ki 5.4 nM), muscarinic M1 (Ki 6.2 nM), serotonin 5-HT7 (Ki 6.3 nM), serotonin 5-HT2C (Ki 9.4 nM), dopamine D4 (Ki 24 nM), adrenergic α2A (Ki 90 nM), serotonin 5-HT3 (Ki 95 nM), serotonin 5-HT1A (Ki 120 nM), dopamine D2 (Ki 160 nM), dopamine D1 (Ki 270 nM), dopamine D5 (Ki 454 nM), and dopamine D3 (Ki 555 nM).

    Clozapine causes little or no prolactin elevation.

    Clinical electroencephalogram (EEG) studies demonstrated that clozapine increases delta and theta activity and slows dominant alpha frequencies. Enhanced synchronization occurs. Sharp wave activity and spike and wave complexes may also develop. Patients have reported an intensification of dream activity during clozapine therapy. REM sleep was found to be increased to 85% of the total sleep time. In these patients, the onset of REM sleep occurred almost immediately after falling asleep.

    12.3     Pharmacokinetics

    Absorption

    In man, CLOZARIL tablets (25 mg and 100 mg) are equally bioavailable relative to a CLOZARIL solution. Following oral administration of CLOZARIL 100 mg twice daily, the average steady-state peak plasma concentration was 319 ng/mL (range: 102 to 771 ng/mL), occurring at the average of 2.5 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at steady state was 122 ng/mL (range: 41 to 343 ng/mL), after 100 mg twice daily dosing. Food does not appear to affect the systemic bioavailability of CLOZARIL. Thus, CLOZARIL may be administered with or without food.

    Distribution

    Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine and other highly protein-bound drugs has not been fully evaluated but may be important [see Drug Interactions (7)].

    Metabolism and Excretion

    Clozapine is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces. Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4. Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. The demethylated, hydroxylated, and N-oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite (norclozapine) to have only limited activity, while the hydroxylated and N- oxide derivatives were inactive. The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4 to12 hours), compared to a mean elimination half-life of 12 hours (range: 4 to 66 hours), after achieving steady state with 100mg twice daily dosing.

    A comparison of single-dose and multiple-dose administration of clozapine demonstrated that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics. However, at steady state, approximately dose-proportional changes with respect to area under the curve (AUC), peak, and minimum clozapine plasma concentrations were observed after administration of 37.5, 75, and 150 mg twice daily.

    Drug-Drug Interaction Studies

    Fluvoxamine

    A pharmacokinetic study was conducted in 16 schizophrenic patients who received clozapine under steady-state conditions. After coadministration of fluvoxamine for 14 days, mean trough concentrations of clozapine and its metabolites, N-desmethylclozapine and clozapine N-oxide, were elevated about 3-fold compared to baseline steady-state concentrations.

    Paroxetine, Fluoxetine, and Sertraline

    In a study of schizophrenic patients (n=14) who received clozapine under steady-state conditions, coadministration of paroxetine produced only minor changes in the levels of clozapine and its metabolites. However, other published reports describe modest elevations (less than 2-fold) of clozapine and metabolite concentrations when clozapine was taken with paroxetine, fluoxetine, and sertraline.

    Specific Population Studies

    Renal or Hepatic Impairment

    No specific pharmacokinetic studies were conducted to investigate the effects of renal or hepatic impairment on the pharmacokinetics of clozapine. Higher clozapine plasma concentrations are likely in patients with significant renal or hepatic impairment when given usual doses.

    CYP2D6 Poor Metabolizers

    A subset (3%–10%) of the population has reduced activity of CYP2D6 (CYP2D6 poor metabolizers). These individuals may develop higher than expected plasma concentrations of clozapine when given usual doses.

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  • 13     NONCLINICAL TOXICOLOGY

    13.1     Carcinogenesis, Mutagenesis, Impairment of Fertility

    Carcinogenesis

    No carcinogenic potential was demonstrated in long-term studies in mice and rats at doses up to 0.3 times and 0.4 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on a mg/m2 body surface area basis.

    Mutagenesis

    Clozapine was not genotoxic when tested in the following gene mutation and chromosomal aberration tests: the bacterial Ames test, the in vitro mammalian V79 in Chinese hamster cells, the in vitro unscheduled DNA synthesis in rat hepatocytes or the in vivo micronucleus assay in mice.

    Impairment of Fertility

    Clozapine had no effect on any parameters of fertility, pregnancy, fetal weight or postnatal development when administered orally to male rats 70 days before mating and to female rats for 14 days before mating at doses up to 0.4 times the MRHD of 900 mg/day on a mg/m2 body surface area basis.

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  • 14     CLINICAL STUDIES

    14.1     Treatment Resistant Schizophrenia

    The efficacy of CLOZARIL in treatment-resistant schizophrenia was established in a multicenter, randomized, double-blind, active-controlled (chlorpromazine) study in patients with a DSM-III diagnosis of schizophrenia who had inadequate responses to at least 3 different antipsychotics (from at least 2 different chemical classes) during the preceding 5 years. The antipsychotic trials must have been judged adequate; the antipsychotic dosages must have been equivalent to or greater than 1000 mg per day of chlorpromazine for a period of at least 6 weeks, each without significant reduction of symptoms. There must have been no period of good functioning within the preceding 5 years. Patients must have had a baseline score of at least 45 on the investigator-rated Brief Psychiatric Rating Scale (BPRS). On the 18-item BPRS, 1 indicates the absence of symptoms, and 7 indicates severe symptoms; the maximum potential total BPRS score is 126. At baseline, the mean BPRS score was 61. In addition, patients must have had a score of at least 4 on at least 2 of the following 4 individual BPRS items: conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content. Patients must have had a Clinical Global Impressions–Severity Scale score of at least 4 (moderately ill).

    In the prospective, lead-in phase of the trial, all patients (N=305) initially received single-blind treatment with haloperidol (the mean dose was 61 mg per day) for 6 weeks. More than 80% of patients completed the 6-week trial. Patients with an inadequate response to haloperidol (n=268) were randomized to double-blind treatment with CLOZARIL (N=126) or chlorpromazine (N=142). The maximum daily CLOZARIL dose was 900 mg; the mean daily dose was >600 mg. The maximum daily chlorpromazine dose was 1800 mg; the mean daily dose was >1200 mg.

    The primary endpoint was treatment response, predefined as a decrease in BPRS score of at least 20% and either (1) a CGI-S score of <3 (mildly ill), or (2) a BPRS score of <35, at the end of 6 weeks of treatment. Approximately 88% of patients from the CLOZARIL and chlorpromazine groups completed the 6-week trial. At the end of 6 weeks, 30% of the CLOZARIL group responded to treatment, and 4% of the chlorpromazine group responded to treatment. The difference was statistically significant (p <0.001). The mean change in total BPRS score was -16 and -5 in the CLOZARIL and chlorpromazine group, respectively; the mean change in the 4 key BPRS item scores was -5 and -2 in the CLOZARIL and chlorpromazine group, respectively; and the mean change in CGI-S score was -1.2 and -0.4, in the CLOZARIL and chlorpromazine group, respectively. These changes in the CLOZARIL group were statistically significantly greater than in the chlorpromazine group (p<0.001 in each analysis).

    14.2     Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder

    The effectiveness of CLOZARIL in reducing the risk of recurrent suicidal behavior was assessed in the International Suicide Prevention Trial (InterSePT™, a trademark of Novartis Pharmaceuticals Corporation). This was a prospective, randomized, open-label, active-controlled, multicenter, international, parallel-group comparison of CLOZARIL versus olanzapine (*Zyprexa®, a registered trademark of Eli Lilly and Company) in 956 patients with schizophrenia or schizoaffective disorder (DSM-IV) who were judged to be at risk for recurrent suicidal behavior. Only about one-fourth of these patients (27%) were considered resistant to standard antipsychotic drug treatment. To enter the trial, patients must have met 1 of the following criteria:

    • They had attempted suicide within the 3 years prior to their baseline evaluation.
    • They had been hospitalized to prevent a suicide attempt within the 3 years prior to their baseline evaluation.
    • They demonstrated moderate-to-severe suicidal ideation with a depressive component within 1 week prior to their baseline evaluation.
    • They demonstrated moderate-to-severe suicidal ideation accompanied by command hallucinations to do self-harm within 1 week prior to their baseline evaluation.

    Dosing regimens for each treatment group were determined by individual investigators and were individualized by patient. Dosing was flexible, with a dose range of 200–900 mg/day for CLOZARIL and 5–20 mg/day for olanzapine. For the 956 patients who received CLOZARIL or olanzapine in this study, there was extensive use of concomitant psychotropics: 84% with antipsychotics, 65% with anxiolytics, 53% with antidepressants, and 28% with mood stabilizers. There was significantly greater use of concomitant psychotropic medications among the patients in the olanzapine group.

    The primary efficacy measure was time to (1) a significant suicide attempt, including a completed suicide; (2) hospitalization due to imminent suicide risk, including increased level of surveillance for suicidality for patients already hospitalized; or (3) worsening of suicidality severity as demonstrated by “much worsening” or “very much worsening” from baseline in the Clinical Global Impression of Severity of Suicidality as assessed by the Blinded Psychiatrist (CGI-SS-BP) scale. A determination of whether or not a reported event met criterion 1 or 2 above was made by the Suicide Monitoring Board (SMB), a group of experts blinded to patient data.

    A total of 980 patients were randomized to the study and 956 received study medication. Sixty-two percent of the patients were diagnosed with schizophrenia, and the remainder (38%) were diagnosed with schizoaffective disorder. Only about one-fourth of the total patient population (27%) was identified as “treatment-resistant” at baseline. There were more males than females in the study (61% of all patients were male). The mean age of patients entering the study was 37 years of age (range 18–69). Most patients were Caucasian (71%), 15% were black, 1% were Asian, and 13% were classified as being of “other” races.

    Patients treated with CLOZARIL had a statistically significant longer delay in the time to recurrent suicidal behavior in comparison with olanzapine. This result should be interpreted only as evidence of the effectiveness of CLOZARIL in delaying time to recurrent suicidal behavior and not a demonstration of the superior efficacy of CLOZARIL over olanzapine.

    The probability of experiencing (1) a significant suicide attempt, including a completed suicide, or (2) hospitalization because of imminent suicide risk, including increased level of surveillance for suicidality for patients already hospitalized, was lower for CLOZARIL patients than for olanzapine patients at Week 104: CLOZARIL 24% versus olanzapine 32%; 95% CI of the difference: 2%, 14% (Figure 2).

    Figure 2. Cumulative Probability of a Significant Suicide Attempt or Hospitalization to Prevent Suicide in Patients with Schizophrenia or Schizoaffective Disorder at High Risk of Suicidality

    Figure 2:  Kaplan Meier Estimates of Cumulative Probability of a Significant Suicide Attempt or Hospitalization to Prevent Suicide.

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  • 16     HOW SUPPLIED/STORAGE AND HANDLING

    16.1     How Supplied

    CLOZARIL® (clozapine) is available as 25 mg and 100 mg round, pale-yellow, uncoated tablets with a facilitated score on one side.

    CLOZARIL® (clozapine) Tablets
    25 mg
    Engraved with “CLOZARIL” once on the periphery of one side.
    Engraved with a facilitated score and “25” once on the other side.
    Bottle of 100 NDC 0078-0126-05
    Bottle of 500 NDC 0078-0126-08
    Unit dose packages of 100: 2 x 5 strips, 10 blisters per strip NDC 0078-0126-06
    100 mg
    Engraved with “CLOZARIL” once on the periphery of one side.
    Engraved with a facilitated score and “100” once on the other side.
    Bottle of 100 NDC 0078-0127-05
    Bottle of 500 NDC 0078-0127-08
    Unit dose packages of 100: 2 x 5 strips, 10 blisters per strip NDC 0078-0127-06

    16.2     Storage and Handling

    Storage temperature should not exceed 30°C (86°F).

    Keep out of reach of children.

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  • 17     PATIENT COUNSELING INFORMATION

    Discuss the following issues with patients and caregivers:

    • Agranulocytosis: Prior to initiating treatment, educate patients and caregivers about the significant risk of developing agranulocytosis. Advise them to immediately report the appearance of signs or symptoms consistent with agranulocytosis or infection (e.g., fever; mucus membrane ulcers; skin, pharyngeal, vaginal, urinary, or pulmonary infection; or extreme weakness or lethargy) at any time during CLOZARIL therapy [see Boxed Warning and Warnings and Precautions (5.1)].
      • Inform patients and caregivers that CLOZARIL will be made available only through a special program (CLOZARIL National Registry) designed to ensure the required blood monitoring, in order to reduce the risk of developing agranulocytosis. Inform patients and caregivers the WBC count and ANC will be monitored as follows:
        • Weekly blood tests are required for the first 6 months.
        • If acceptable WBC counts and ANCs (WBC count ≥3500/mm3 and ANC ≥2000/mm3) have been maintained during the first 6 months of continuous therapy, then WBC counts and ANCs can be monitored every 2 weeks for the next 6 months.
        • Thereafter, if acceptable WBC counts and ANCs have been maintained during the second 6 months of continuous therapy, WBC counts and ANCs can be monitored every 4 weeks.
    • Orthostatic Hypotension, Bradycardia, and Syncope: Inform patients and caregivers about the risk of orthostatic hypotension and syncope, especially during the period of initial dose titration. Instruct them to strictly follow the clinician’s instructions for dosage and administration. Advise patients to consult their clinician immediately if they feel faint, lose consciousness or have signs or symptoms suggestive of bradycardia or arrhythmia [see Dosage and Administration (2.2) and Warnings and Precautions (5.3)].
    • Seizures: Inform patients and caregivers about the significant risk of seizure during CLOZARIL treatment. Caution them about driving and any other potentially hazardous activity while taking CLOZARIL [see Warnings and Precautions (5.4)].
    • QT Interval Prolongation: Advise patients to consult their clinician immediately if they feel faint, lose consciousness or have signs or symptoms suggestive of arrhythmia. Instruct patients to not take CLOZARIL with other drugs that cause QT interval prolongation. Instruct patients to inform their clinicians that they are taking CLOZARIL before any new drug [see Warnings and Precautions (5.8.) and Drug Interactions (7.1)].
    • Metabolic Changes (hyperglycemia and diabetes mellitus, dyslipidemia, weight gain): Educate patients and caregivers about the risk of metabolic changes and the need for specific monitoring. The risks include hyperglycemia and diabetes mellitus, dyslipidemia, weight gain, and cardiovascular reactions. Educate patients and caregivers about the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus (e.g., polydipsia, polyuria, polyphagia, and weakness). Monitor all patients for these symptoms. Patients who are diagnosed with diabetes or have risk factors for diabetes (obesity, family history of diabetes) should have their fasting blood glucose monitored before beginning treatment and periodically during treatment. Patients who develop symptoms of hyperglycemia should have assessments of fasting glucose. Clinical monitoring of weight is recommended [see Warnings and Precautions (5.9)].
    • Interference with Cognitive and Motor Performance: Because CLOZARIL may have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that CLOZARIL therapy does not affect them adversely [see Warnings and Precautions (5.14)].
    • Missed Doses and Re-initiating Treatment: Inform patients and caregivers that if the patient misses taking CLOZARIL for more than 2 days, they should not restart their medication at the same dosage but should contact their physician for dosing instructions adversely [see Dosage and Administration (2.5) and Warnings and Precautions (5.3)].
    • Pregnancy: Patients and caregivers should notify the clinician if the patient becomes pregnant or intends to become pregnant during therapy [see Use in Specific Populations (8.1)].
    • Nursing: Advice patients and caregivers that the patient should not breast feed an infant if they are taking CLOZARIL [see Use in Specific Populations (8.3)].
    • Concomitant Medication: Advise patients to inform their health care provider if they are taking, or plan to take, any prescription or over-the-counter drugs; there is a potential for significant drug-drug interactions [see Dosage and Administrations (2.6) and Drug Interactions (7.1)].

    *Zyprexa® (olanzapine) is a registered trademark of Eli Lilly and Company.

    **Trademark of Thomson Healthcare, Inc.

    CLOZARIL® is a registered trademark of Novartis Pharmaceuticals Corporation.

    Novartis Pharmaceuticals Corporation
    East Hanover, New Jersey 07936

    © Novartis

    T2013-114
    November 2013

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  • PRINCIPAL DISPLAY PANEL

    Package Label  25 mg

    Rx Only             NDC 0078-0126-06

    CLOZARIL® (clozapine)

    Unit Dose Package

    100 Tablets

    This unit dose package is intended for institutional

    In-patient use only. If dispensed for out-patient use,

    an appropriate safety closure should be provided.

    PRINCIPAL DISPLAY PANEL
Package Label – 25 mg
Rx Only		NDC 0078-0126-06
CLOZARIL® (clozapine) 
Unit Dose Package
100 Tablets
This unit dose package is intended for institutional
In-patient use only.  If dispensed for out-patient use,
an appropriate safety closure should be provided.

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  • PRINCIPAL DISPLAY PANEL

    Package Label  100 mg

    Rx Only             NDC 0078-0127-06

    CLOZARIL® (clozapine)

    Unit Dose Package

    100 Tablets

    This unit dose package is intended for institutional

    In-patient use only. If dispensed for out-patient use,

    an appropriate safety closure should be provided

    PRINCIPAL DISPLAY PANEL
Package Label – 100 mg

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  • INGREDIENTS AND APPEARANCE
    CLOZARIL 
    clozapine tablet
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0078-0126
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    CLOZAPINE (CLOZAPINE) CLOZAPINE 25 mg
    Inactive Ingredients
    Ingredient Name Strength
    SILICON DIOXIDE  
    LACTOSE  
    MAGNESIUM STEARATE  
    POVIDONES  
    STARCH, CORN  
    TALC  
    Product Characteristics
    Color YELLOW (pale yellow) Score 2 pieces
    Shape ROUND Size 7mm
    Flavor Imprint Code CLOZARIL;25
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0078-0126-05 100 in 1 BOTTLE
    2 NDC:0078-0126-08 500 in 1 BOTTLE
    3 NDC:0078-0126-06 100 in 1 BOX, UNIT-DOSE
    3 NDC:0078-0126-61 1 in 1 BLISTER PACK
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA019758 09/30/1989
    CLOZARIL 
    clozapine tablet
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0078-0127
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    CLOZAPINE (CLOZAPINE) CLOZAPINE 100 mg
    Inactive Ingredients
    Ingredient Name Strength
    SILICON DIOXIDE  
    LACTOSE  
    MAGNESIUM STEARATE  
    POVIDONES  
    STARCH, CORN  
    TALC  
    Product Characteristics
    Color YELLOW (pale yellow) Score 2 pieces
    Shape ROUND Size 9mm
    Flavor Imprint Code CLOZARIL;100
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0078-0127-05 100 in 1 BOTTLE
    2 NDC:0078-0127-08 500 in 1 BOTTLE
    3 NDC:0078-0127-06 100 in 1 BOX, UNIT-DOSE
    3 NDC:0078-0127-61 1 in 1 BLISTER PACK
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA019758 09/30/1989
    Labeler - Novartis Pharmaceuticals Corporation (002147023)
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