Clozaril

Brand Name: Clozapine

Contents:

Description
Pharmacology
Indications and Usage
Contraindications
Warnings
Precautions
Drug Interactions
Adverse Reactions
Overdose
Dosage
Supplied

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.

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

25 mg and 100 mg Tablets
Active Ingredient: clozapine is a yellow, crystalline powder, very slightly soluble in water.

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

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CLINICAL PHARMACOLOGY

Pharmacodynamics
CLOZARIL® (clozapine) is classified as an atypical antipsychotic drug because its profile of binding to dopamine receptors and its effects on various dopamine mediated behaviors differ from those exhibited by more typical antipsychotic drug products. In particular, although CLOZARIL does interfere with the binding of dopamine at D1, D2, D3 and D5 receptors, and has a high affinity for the D4 receptor, it does not induce catalepsy nor inhibit apomorphine-induced stereotypy. This evidence, consistent with the view that CLOZARIL is preferentially more active at limbic than at striatal dopamine receptors, may explain the relative freedom of CLOZARIL from extrapyramidal side effects.

CLOZARIL also acts as an antagonist at adrenergic, cholinergic, histaminergic and serotonergic receptors.

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INDICATIONS AND USAGE

Treatment-Resistant Schizophrenia
CLOZARIL (clozapine) is indicated for the management of severely ill schizophrenic patients who fail to respond adequately to standard drug treatment for schizophrenia. 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 treatment with appropriate courses of standard drug treatments for schizophrenia, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs. (See WARNINGS)

The effectiveness of CLOZARIL in a treatment resistant schizophrenic population was demonstrated in a 6-week study comparing CLOZARIL and chlorpromazine. Patients meeting DSM-III criteria for schizophrenia and having a mean BPRS total score of 61 were demonstrated to be treatment resistant by history and by open, prospective treatment with haloperidol before entering into the double-blind phase of the study. The superiority of CLOZARIL to chlorpromazine was documented in statistical analyses employing both categorical and continuous measures of treatment effect.

Because of the significant risk of agranulocytosis and seizure, events which both present a continuing risk over time, the extended treatment of patients failing to show an acceptable level of clinical response should ordinarily be avoided. In addition, the need for continuing treatment in patients exhibiting beneficial clinical responses should be periodically re-evaluated.

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 reexperiencing suicidal behavior, based on history and recent clinical state. Suicidal behavior refers to actions by a patient that puts 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 InterSePT Trial (see Clinical Trials Data under CLINICAL PHARMACOLOGY). Therefore, CLOZARIL treatment to reduce the risk of suicidal behavior should be continued for at least 2 years (see DOSAGE AND ADMINISTRATION).

The prescriber should be aware that a majority of patients in both treatment groups in InterSePT received other treatments as well to reduce suicide risk, such as antidepressants and other medications, hospitalization, and/or psychotherapy. The contributions of these additional measures are unknown.

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CONTRAINDICATIONS

CLOZARIL® (clozapine) is contraindicated in patients with a previous hypersensitivity to clozapine or any other component of this drug, in patients with myeloproliferative disorders, uncontrolled epilepsy, or a history of CLOZARIL induced agranulocytosis or severe granulocytopenia. As with more typical antipsychotic drugs, CLOZARIL is contraindicated in severe central nervous system depression or comatose states from any cause.

CLOZARIL should not be used simultaneously with other agents having a well-known potential to cause agranulocytosis or otherwise suppress bone marrow function. The mechanism of CLOZARIL induced agranulocytosis is unknown; nonetheless, it is possible that causative factors may interact synergistically to increase the risk and/or severity of bone marrow suppression.

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WARNINGS

General
BECAUSE OF THE SIGNIFICANT RISK OF AGRANULOCYTOSIS, A POTENTIALLY LIFE-THREATENING ADVERSE EVENT (SEE FOLLOWING), CLOZARIL® (CLOZAPINE) SHOULD BE RESERVED FOR USE IN (1) THE TREATMENT OF SEVERELY ILL PATIENTS WITH SCHIZOPHRENIA WHO FAIL TO SHOW AN ACCEPTABLE RESPONSE TO ADEQUATE COURSES OF STANDARD DRUG TREATMENT FOR SCHIZOPHRENIA, EITHER BECAUSE OF INSUFFICIENT EFFECTIVENESS OR THE INABILITY TO ACHIEVE AN EFFECTIVE DOSE DUE TO INTOLERABLE ADVERSE EFFECTS FROM THOSE DRUGS, OR (2) FOR REDUCING THE RISK OF RECURRENT SUICIDAL BEHAVIOR IN PATIENTS WITH SCHIZOPHRENIA OR SCHIZOAFFECTIVE DISORDER WHO ARE JUDGED TO BE AT RISK OF REEXPERIENCING SUICIDAL BEHAVIOR. CONSEQUENTLY, UNLESS THE PATIENT IS AT RISK FOR RECURRENT SUICIDAL BEHAVIOR, BEFORE INITIATING TREATMENT WITH CLOZARIL, IT IS STRONGLY RECOMMENDED THAT A PATIENT BE GIVEN AT LEAST 2 TRIALS, EACH WITH A DIFFERENT STANDARD DRUG PRODUCT FOR SCHIZOPHRENIA, AT AN ADEQUATE DOSE, AND FOR AN ADEQUATE DURATION.

PATIENTS WHO ARE BEING TREATED WITH CLOZARIL MUST HAVE A BASELINE WHITE BLOOD CELL (WBC) AND DIFFERENTIAL COUNT BEFORE INITIATION OF TREATMENT, AND A WBC COUNT EVERY WEEK FOR THE FIRST SIX MONTHS. THEREAFTER, IF ACCEPTABLE WBC COUNTS (WBC ≥ 3000/MM3, ANC ≥1500/MM3) HAVE BEEN MAINTAINED DURING THE FIRST 6 MONTHS OF CONTINUOUS THERAPY, WBC COUNTS CAN BE MONITORED EVERY OTHER WEEK. WBC COUNTS MUST BE MONITORED WEEKLY FOR AT LEAST 4 WEEKS AFTER THE DISCONTINUATION OF CLOZARIL. CLOZARIL IS AVAILABLE ONLY THROUGH A DISTRIBUTION SYSTEM THAT ENSURES MONITORING OF WBC COUNTS ACCORDING TO THE SCHEDULE DESCRIBED BELOW PRIOR TO DELIVERY OF THE NEXT SUPPLY OF MEDICATION.

Agranulocytosis: Agranulocytosis, defined as an absolute neutrophil count (ANC) of less than 500/mm3, has been estimated to occur in association with CLOZARIL use at a cumulative incidence at 1 year of approximately 1.3%, based on the occurrence of 15 U.S. cases out of 1,743 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. This reaction could prove fatal if not detected early and therapy interrupted. Of the 149 cases of agranulocytosis reported worldwide in association with CLOZARIL use as of December 31, 1989, 32% were fatal. However, few of these deaths occurred since 1977, at which time the knowledge of CLOZARIL induced agranulocytosis became more widespread, and close monitoring of WBC counts more widely practiced. Nevertheless, it is unknown at present what the case fatality rate will be for CLOZARIL induced agranulocytosis, despite strict adherence to the required frequency of monitoring. In the U.S., under a weekly WBC monitoring system with CLOZARIL, there have been 585 cases of agranulocytosis as of August 21, 1997; 19 were fatal. During this period 150,409 patients received CLOZARIL. A hematologic risk analysis was conducted based upon the available information in the Clozaril® National Registry (CNR) for U.S. 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 two months of therapy, peaking in the third month. Among CLOZARIL patients who continued the drug beyond the third month, the weekly incidence of agranulocytosis fell to a substantial degree, so that by the sixth month the weekly incidence of agranulocytosis was reduced to 3 per 1,000 person-years. After six months, the weekly incidence of agranulocytosis declines still further, however, 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.

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Because of the substantial risk for developing agranulocytosis in association with CLOZARIL use, which may persist over an extended period of time, patients must have a blood sample drawn for a WBC count before initiation of treatment with CLOZARIL, and must have subsequent WBC counts done at least weekly for the first 6 months of continuous treatment. If WBC counts remain acceptable (WBC ≥3000/mm3, ANC ≥1500/mm3) during this period, WBC counts may be monitored every other week thereafter. After the discontinuation of CLOZARIL, weekly WBC counts should be continued for an additional 4 weeks.

If a patient is on CLOZARIL therapy for less than 6 months with no abnormal blood events and there is a break on therapy which is less than or equal to 1 month, then patients can continue where they left off with weekly WBC testing for 6 months. When this 6-month period has been completed, the frequency of WBC count monitoring can be reduced to every other week. If a patient is on CLOZARIL therapy for less than 6 months with no abnormal blood events and there is a break on therapy which is greater than 1 month, then patients should be tested weekly for an additional 6-month period before biweekly testing is initiated. If a patient is on CLOZARIL therapy for less than 6 months and experiences an abnormal blood event as described below but remains a rechallengeable patient (patients cannot be reinitiated on CLOZARIL therapy if WBC counts fall below 2000/mm3 or the ANC falls below 1000/mm3 during CLOZARIL therapy), the patient must restart the 6-month period of weekly WBC monitoring at Day 0.

If a patient is on CLOZARIL therapy for 6 months or longer with no abnormal blood events and there is a break on therapy which is 1 year or less, then the patient can continue WBC count monitoring every other week if CLOZARIL therapy is reinitiated.

If a patient is on CLOZARIL therapy for 6 months or longer with no abnormal blood events and there is a break on therapy which is greater than 1 year, then, if CLOZARIL therapy is reinitiated, the patient must have WBC counts monitored weekly for an additional 6 months. If a patient is on CLOZARIL therapy for 6 months or longer and subsequently has an abnormal blood event, but remains a rechallengeable patient, then the patient must restart weekly WBC count monitoring until an additional 6 months of CLOZARIL therapy has been received. The distribution of CLOZARIL is contingent upon performance of the required blood tests.

Treatment should not be initiated if the WBC count is less than 3500/mm3, or if the patient has a history of a myeloproliferative disorder, or previous CLOZARIL induced agranulocytosis or granulocytopenia. Patients should be advised to report immediately the appearance of lethargy, weakness, fever, sore throat or any other signs of infection. If, after the initial treatment, the total WBC count has dropped below 3500/mm3 or it has dropped by a substantial amount from baseline, even if the count is above 3500/mm3, or if immature forms are present, a repeat WBC count and a differential count should be done. A substantial drop is defined as a single drop of 3,000 or more in the WBC count or a cumulative drop of 3,000 or more within 3 weeks. If subsequent WBC counts and the differential count reveal a total WBC count between 3000 and 3500/mm3 and an ANC above 1500/mm3, twice weekly WBC counts and differential counts should be performed.

If the total WBC count falls below 3000/mm3 or the ANC below 1500/mm3, CLOZARIL therapy should be interrupted, WBC count and differential should be performed daily, and patients should be carefully monitored for flu-like symptoms or other symptoms suggestive of infection. CLOZARIL therapy may be resumed if no symptoms of infection develop, and if the total WBC count returns to levels above 3000/mm3 and the ANC returns to levels above 1500/mm3. However, in this event, twice-weekly WBC counts and differential counts should continue until total WBC counts return to levels above 3500/mm³.

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. 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 whose total WBC counts fall below 2000/mm3, or ANCs below 1000/mm3 during CLOZARIL therapy should have daily WBC count and differential. These patients should not be rechallenged with CLOZARIL. Patients discontinued from CLOZARIL therapy due to significant WBC 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 CLOZARIL therapy, a single, national master file will be maintained confidentially.

Except for evidence of significant bone marrow suppression during initial CLOZARIL therapy, there are no established risk factors, based on world-wide experience, for the development of agranulocytosis in association with CLOZARIL use. However, a disproportionate number of the U.S. cases of agranulocytosis occurred in patients of Jewish background compared to the overall proportion of such patients exposed during domestic development of CLOZARIL. Most of the U.S. cases occurred within 4-10 weeks of exposure, but neither dose nor duration is a reliable predictor of this problem. No patient characteristics have been clearly linked to the development of agranulocytosis in association with CLOZARIL use, but 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 CLOZARIL.

To reduce the risk of agranulocytosis developing undetected, CLOZARIL is available only through a distribution system that ensures monitoring of WBC counts according to the schedule described above prior to delivery of the next supply of medication.

Eosinophilia
In clinical trials, 1% of patients developed eosinophilia, which, in rare cases, can be substantial. If a differential count reveals a total eosinophil count above 4000/mm3, CLOZARIL therapy should be interrupted until the eosinophil count falls below 3000/mm3.

Seizures
Seizure has been estimated to occur in association with CLOZARIL use at a cumulative incidence at one year of approximately 5%, based on the occurrence of one or more seizures in 61 of 1,743 patients exposed to CLOZARIL during its clinical testing prior to domestic marketing (i.e., a crude rate of 3.5%). Dose appears to be an important predictor of seizure, with a greater likelihood of seizure at the higher CLOZARIL doses used.

Caution should be used in administering CLOZARIL to patients having a history of seizures or other predisposing factors. Because of the substantial risk of seizure associated with CLOZARIL use, patients should be advised not to engage in any activity where sudden loss of consciousness could cause serious risk to themselves or others, e.g., the operation of complex machinery, driving an automobile, swimming, climbing, etc.

Myocarditis
Post-marketing surveillance data from four countries that employ hematological monitoring of clozapine-treated patients revealed: 30 reports of myocarditis with 17 fatalities in 205,493 U.S. patients (August 2001); 7 reports of myocarditis with 1 fatality in 15,600 Canadian patients (April 2001); 30 reports of myocarditis with 8 fatalities in 24,108 U.K. patients (August 2001); 15 reports of myocarditis with 5 fatalities in 8,000 Australian patients (March 1999). These reports represent an incidence of 5.0, 16.3, 43.2, and 96.6 cases/100,000 patient-years, respectively. The number of fatalities represent an incidence of 2.8, 2.3, 11.5, and 32.2 cases/100,000 patient-years, respectively.

The overall incidence rate of myocarditis in patients with schizophrenia treated with antipsychotic agents is unknown. However, for the established market economies (WHO), the incidence of myocarditis is 0.3 cases/100,000 patient-years and the fatality rate is 0.2 cases/100,000 patient-years. Therefore, the rate of myocarditis in clozapine-treated patients appears to be 17-322 times greater than the general population and is associated with an increased risk of fatal myocarditis that is 14-161 times greater than the general population. The total reports of myocarditis for

The total reports of myocarditis for these four countries was 82 of which 51 (62%) occurred within the first month of clozapine treatment, 25 (31%) occurred after the first month of therapy and 6 (7%) were unknown. The median duration of treatment was 3 weeks. Of 5 patients rechallenged with clozapine, 3 had a recurrence of myocarditis. Of the 82 reports, 31 (38%) were fatal and 25 patients who died had evidence of myocarditis at autopsy. These data also suggest that the incidence of fatal myocarditis may be highest during the first month of therapy.

Therefore, the possibility of myocarditis should be considered in patients receiving CLOZARIL who present with unexplained fatigue, dyspnea, tachypnea, fever, chest pain, palpitations, other signs or symptoms of heart failure, or electrocardiographic findings such as ST-T wave abnormalities or arrhythmias. It is not known whether eosinophilia is a reliable predictor of myocarditis. Tachycardia, which has been associated with CLOZARIL treatment, has also been noted as a presenting sign in patients with myocarditis. Therefore, tachycardia during the first month of therapy warrants close monitoring for other signs of myocarditis.

Prompt discontinuation of CLOZARIL treatment is warranted upon suspicion of myocarditis. Patients with clozapine-related myocarditis should not be rechallenged with CLOZARIL.

Other Adverse Cardiovascular and Respiratory Effects

Orthostatic hypotension with or without syncope can occur with CLOZARIL treatment and may represent a continuing risk in some patients. Rarely (approximately 1 case per 3,000 patients), collapse can be profound and be accompanied by respiratory and/or cardiac arrest. Orthostatic hypotension is more likely to occur during initial titration in association with rapid dose escalation and may even occur on first dose. In one report, initial doses as low as 12.5 mg were associated with collapse and respiratory arrest.

When restarting patients who have had even a brief interval off CLOZARIL , i.e., 2 days or more since the last dose, it is recommended that treatment be reinitiated with one-half of a 25 mg tablet (12.5 mg) once or twice daily. (See DOSAGE AND ADMINISTRATION)

Some of the cases of collapse/respiratory arrest/cardiac arrest during initial treatment occurred in patients who were being administered benzodiazepines; similar events have been reported in patients taking other psychotropic drugs or even CLOZARIL by itself. Although it has not been established that there is an interaction between CLOZARIL and benzodiazepines or other psychotropics, caution is advised when clozapine is initiated in patients taking a benzodiazepine or any other psychotropic drug.

Tachycardia, which may be sustained, has also been observed in approximately 25% of patients taking CLOZARIL, with patients having an average increase in pulse rate of 10-15 bpm. The sustained tachycardia is not simply a reflex response to hypotension, and is present in all positions monitored. Either tachycardia or hypotension may pose a serious risk for an individual with compromised cardiovascular function.

A minority of CLOZARIL treated patients experience ECG repolarization changes similar to those seen with other antipsychotic drugs, including S-T segment depression and flattening or inversion of T waves, which all normalize after discontinuation of CLOZARIL. The clinical significance of these changes is unclear. However, in clinical trials with CLOZARIL, several patients experienced significant cardiac events, including ischemic changes, myocardial infarction, arrhythmias and sudden death. In addition there have been post-marketing reports of congestive heart failure, pericarditis, and pericardial effusions. Causality assessment was difficult in many of these cases because of serious preexisting cardiac disease and plausible alternative causes. Rare instances of sudden death have been reported in psychiatric patients, with or without associated antipsychotic drug treatment, and the relationship of these events to antipsychotic drug use is unknown.

CLOZARIL should be used with caution in patients with known cardiovascular and/or pulmonary disease, and the recommendation for gradual titration of dose should be carefully observed.

Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.

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 any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

There have been several reported cases of NMS in patients receiving CLOZARIL alone or in combination with lithium or other CNS-active agents.

Tardive Dyskinesia
A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of treatment, which patients are likely to develop the syndrome.

There are several reasons for predicting that CLOZARIL may be different from other antipsychotic drugs in its potential for inducing tardive dyskinesia, including the preclinical finding that it has a relatively weak dopamine-blocking effect and the clinical finding of a virtual absence of certain acute extrapyramidal symptoms, e.g., dystonia. A few cases of tardive dyskinesia have been reported in patients on CLOZARIL who had been previously treated with other antipsychotic agents, so that a causal relationship cannot be established. There have been no reports of tardive dyskinesia directly attributable to CLOZARIL alone. Nevertheless, it cannot be concluded, without more extended experience, that CLOZARIL is incapable of inducing this syndrome.

Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic drug treatment is withdrawn. Antipsychotic drug treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptom suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, CLOZARIL should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. As with any antipsychotic drug, chronic CLOZARIL use should be reserved for patients who appear to be obtaining substantial benefit from the drug. In such patients, the smallest dose and the shortest duration of treatment should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on CLOZARIL, drug discontinuation should be considered. However, some patients may require treatment with CLOZARIL despite the presence of the syndrome.

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PRECAUTIONS

General
Because of the significant risk of agranulocytosis and seizure, both of which present a continuing risk over time, the extended treatment of patients failing to show an acceptable level of clinical response should ordinarily be avoided. In addition, the need for continuing treatment in patients exhibiting beneficial clinical responses should be periodically reevaluated. Although it is not known whether the risk would be increased, it is prudent either to avoid CLOZARIL® (clozapine) or use it cautiously in patients with a previous history of agranulocytosis induced by other drugs.

Cardiomyopathy
Cases of cardiomyopathy have been reported in patients treated with clozapine. The reporting rate for cardiomyopathy in clozapine-treated patients in the U.S. (8.9 per 100,000 person-years) was similar to an estimate of the cardiomyopathy incidence in the U.S. general population derived from the 1999 National Hospital Discharge Survey data (9.7 per 100,000 person-years). Approximately 80% of clozapine-treated patients in whom cardiomyopathy was reported were less than 50 years of age; the duration of treatment with clozapine prior to cardiomyopathy diagnosis varied, but was >6 months in 65% of the reports. Dilated cardiomyopathy was most frequently reported, although a large percentage of reports did not specify the type of cardiomyopathy. Signs and symptoms suggestive of cardiomyopathy, particularly exertional dyspnea, fatigue, orthopnea, paroxysmal nocturnal dyspnea, and peripheral edema should alert the clinician to perform further investigations. If the diagnosis of cardiomyopathy is confirmed, the prescriber should discontinue clozapine unless the benefit to the patient clearly outweighs the risk.

Fever
During CLOZARIL therapy, patients may experience transient temperature elevations above 100.4°F (38°C), with the peak incidence within the first 3 weeks of treatment. While this fever is generally benign and self limiting, it may necessitate discontinuing patients from treatment. On occasion, there may be an associated increase or decrease in WBC count. Patients with fever should be carefully evaluated to rule out the possibility of an underlying infectious process or the development of agranulocytosis. In the presence of high fever, the possibility of Neuroleptic Malignant Syndrome (NMS) must be considered. There have been several reports of NMS in patients receiving CLOZARIL, usually in combination with lithium or other CNS-active drugs. [See Neuroleptic Malignant Syndrome (NMS), under WARNINGS]

Pulmonary Embolism
The possibility of pulmonary embolism should be considered in patients receiving CLOZARIL who present with deep vein thrombosis, acute dyspnea, chest pain or with other respiratory signs and symptoms. As of December 31, 1993 there were 18 cases of fatal pulmonary embolism in association with CLOZARIL therapy in users 10-54 years of age. Based upon the extent of use observed in the Clozaril National Registry, the mortality rate associated with pulmonary embolus was 1 death per 3,450 person-years of use. This rate was about 27.5 times higher than that in the general population of a similar age and gender (95% Confidence Interval; 17.1, 42.2). Deep vein thrombosis has also been observed in association with CLOZARIL therapy. Whether pulmonary embolus can be attributed to CLOZARIL or some characteristic(s) of its users is not clear, but the occurrence of deep vein thrombosis or respiratory symptomatology should suggest its presence.

Hyperglycemia
Severe hyperglycemia, sometimes leading to ketoacidosis, has been reported during CLOZARIL treatment in patients with no prior history of hyperglycemia. While a causal relationship to CLOZARIL use has not been definitively established, glucose levels normalized in most patients after discontinuation of CLOZARIL, and a rechallenge in one patient produced a recurrence of hyperglycemia. The effect of CLOZARIL on glucose metabolism in patients with diabetes mellitus has not been studied. The possibility of impaired glucose tolerance should be considered in patients receiving CLOZARIL who develop symptoms of hyperglycemia, such as polydipsia, polyuria, polyphagia, and weakness. In patients with significant treatment-emergent hyperglycemia, the discontinuation of CLOZARIL should be considered.

Hepatitis
Caution is advised in patients using CLOZARIL who have concurrent hepatic disease. Hepatitis has been reported in both patients with normal and preexisting liver function abnormalities. In patients who develop nausea, vomiting, and/or anorexia during CLOZARIL treatment, liver function tests should be performed immediately. If the elevation of these values is clinically relevant or if symptoms of jaundice occur, treatment with CLOZARIL should be discontinued.

Anticholinergic Toxicity
Eye: CLOZARIL has potent anticholinergic effects and care should be exercised in using this drug in the presence of narrow angle glaucoma.

Gastrointestinal: CLOZARIL use has been associated with varying degrees of impairment of intestinal peristalsis, ranging from constipation to intestinal obstruction, fecal impaction and paralytic ileus (see ADVERSE REACTIONS). On rare occasions, these cases have been 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.

Prostate: CLOZARIL has potent anticholinergic effects and care should be exercised in using this drug in the presence of prostatic enlargement.

Interference with Cognitive and Motor Performance
Because of initial sedation, CLOZARIL may impair mental and/or physical abilities, especially during the first few days of therapy. The recommendations for gradual dose escalation should be carefully adhered to, and patients cautioned about activities requiring alertness.

Use in Patients with Concomitant Illness
Clinical experience with CLOZARIL in patients with concomitant systemic diseases is limited. Nevertheless, caution is advisable in using CLOZARIL in patients with renal or cardiac disease.

Use in Patients Undergoing General Anesthesia
Caution is advised in patients being administered general anesthesia because of the CNS effects of CLOZARIL. Check with the anesthesiologist regarding continuation of CLOZARIL therapy in a patient scheduled for surgery.

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Drug Interactions

As with all drugs, the potential for interaction by a variety of mechanisms is a possibility.

BEFORE USING THIS MEDICINE: INFORM YOUR DOCTOR OR PHARMACIST of all prescription and over-the-counter medicine that you are taking. This includes monoamine oxidase inhibitors (MAOIs), cyproheptadine, selegiline, lithium, fenfluramine, dexfenfluramine, and tramadol. Inform your doctor of any other medical conditions, allergies, pregnancy, or breast-feeding.

CLOZARIL may potentiate the hypotensive effects of antihypertensive drugs and the anticholinergic effects of atropine-type drugs. The administration of epinephrine should be avoided in the treatment of drug induced hypotension because of a possible reverse epinephrine effect.

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ADVERSE REACTIONS

Associated with Discontinuation of Treatment
Sixteen percent of 1,080 patients who received CLOZARIL® (clozapine) in pre-marketing clinical trials discontinued treatment due to an adverse event, including both those that could be reasonably attributed to CLOZARIL treatment and those that might more appropriately be considered intercurrent illness. The more common events considered to be causes of discontinuation included: CNS, primarily drowsiness/sedation, seizures, dizziness/syncope; cardiovascular, primarily tachycardia, hypotension and ECG changes; gastrointestinal, primarily nausea/vomiting; hematologic, primarily leukopenia/granulocytopenia/ agranulocytosis; and fever. None of the events enumerated accounts for more than 1.7% of all discontinuations attributed to adverse clinical events.

Commonly Observed Adverse events observed in association with the use of CLOZARIL in clinical trials at an incidence of greater than 5% were: central nervous system complaints, including drowsiness/sedation, dizziness/vertigo, headache and tremor; autonomic nervous system complaints, including salivation, sweating, dry mouth and visual disturbances; cardiovascular findings, including tachycardia, hypotension and syncope; and gastrointestinal complaints, including constipation and nausea; and fever. Complaints of drowsiness/sedation tend to subside with continued therapy or dose reduction. Salivation may be profuse, especially during sleep, but may be diminished with dose reduction.

DRUG ABUSE AND DEPENDENCE

Physical and psychological dependence have not been reported or observed in patients taking CLOZARIL® (clozapine).

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OVERDOSAGE

Human Experience
The most commonly reported signs and symptoms associated with CLOZARIL® (clozapine) overdose are: altered states of consciousness, including drowsiness, delirium and coma; tachycardia; hypotension; respiratory depression or failure; hypersalivation. Aspiration pneumonia and cardiac arrhythmias have also been reported. Seizures have occurred in a minority of reported cases. Fatal overdoses have been reported with CLOZARIL, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g.

Management of Overdose
Establish and maintain an airway; ensure adequate oxygenation and ventilation. Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or lavage, and should be considered in treating overdosage. Cardiac and vital signs monitoring is recommended along with general symptomatic and supportive measures. Additional surveillance should be continued for several days because of the risk of delayed effects. Avoid epinephrine and derivatives when treating hypotension, and quinidine and procainamide when treating cardiac arrhythmia.

There are no specific antidotes for CLOZARIL. Forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.

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

Up-to-date information about the treatment of overdose can often be obtained from a certified Regional Poison Control Center. Telephone numbers of certified Poison Control Centers are listed in the Physicians� Desk Reference®.**

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DOSAGE AND ADMINISTRATION

Treatment-Resistant Schizophrenia
Upon initiation of CLOZARIL® (clozapine) therapy, up to a 1 week supply of additional CLOZARIL tablets may be provided to the patient to be held for emergencies (e.g., weather, holidays).

Initial Treatment: It is recommended that treatment with CLOZARIL begin with one-half of a 25 mg tablet (12.5 mg) once or twice daily and then be continued with daily dosage increments of 25-50 mg/day, if well tolerated, to achieve a target dose of 300-450 mg/day by the end of 2 weeks. Subsequent dosage increments should be made no more than once or twice weekly, in increments not to exceed 100 mg. Cautious titration and a divided dosage schedule are necessary to minimize the risks of hypotension, seizure, and sedation.

In the multicenter study that provides primary support for the effectiveness of CLOZARIL in patients resistant to standard drug treatment for schizophrenia, patients were titrated during the first 2 weeks up to a maximum dose of 500 mg/day, on a t.i.d. basis, and were then dosed in a total daily dose range of 100-900 mg/day, on a t.i.d. basis thereafter, with clinical response and adverse effects as guides to correct dosing.

Therapeutic Dose Adjustment:
Daily dosing should continue on a divided basis as an effective and tolerable dose level is sought. While many patients may respond adequately at doses between 300-600 mg/day, it may be necessary to raise the dose to the 600-900 mg/day range to obtain an acceptable response. (Note: In the multicenter study providing the primary support for the superiority of CLOZARIL in treatment-resistant patients, the mean and median CLOZARIL doses were both approximately 600 mg/day.)

Because of the possibility of increased adverse reactions at higher doses, particularly seizures, patients should ordinarily be given adequate time to respond to a given dose level before escalation to a higher dose is contemplated. CLOZARIL can cause EEG changes, including the occurrence of spike and wave complexes. It lowers the seizures threshold in a dose-dependent manner and may induce myoclonic jerks or generalized seizures. These symptoms may be likely to occur with rapid dose increase and in patients with preexisting epilepsy. In this case, the dose should be reduced and, if necessary, anticonvulsant treatment initiated.

Dosing should not exceed 900 mg/day.

Because of the significant risk of agranulocytosis and seizure, events which both present a continuing risk over time, the extended treatment of patients failing to show an acceptable level of clinical response should ordinarily be avoided.

Maintenance Treatment: While the maintenance effectiveness of CLOZARIL in schizophrenia is still under study, the effectiveness of maintenance treatment is well established for many other drugs used to treat schizophrenia. It is recommended that responding patients be continued on CLOZARIL, but at the lowest level needed to maintain remission. Because of the significant risk associated with the use of CLOZARIL, patients should be periodically reassessed to determine the need for maintenance treatment.

Discontinuation of Treatment: In the event of planned termination of CLOZARIL therapy, gradual reduction in dose is recommended over a 1-2 week period. However, should a patient�s medical condition require abrupt discontinuation (e.g., leukopenia), the patient should be carefully observed for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound such as headache, nausea, vomiting, and diarrhea.

Reinitiation of Treatment in Patients Previously Discontinued: When restarting patients who have had even a brief interval off CLOZARIL, i.e., 2 days or more since the last dose, it is recommended that treatment be reinitiated with one-half of a 25 mg tablet (12.5 mg) once or twice daily (see WARNINGS). If that dose is well tolerated, it may be feasible to titrate patients back to a therapeutic dose more quickly than is recommended for initial treatment. However, any patient who has previously experienced respiratory or cardiac arrest with initial dosing, but was then able to be successfully titrated to a therapeutic dose, should be re-titrated with extreme caution after even 24 hours of discontinuation.

Certain additional precautions seem prudent when reinitiating treatment. The mechanisms underlying CLOZARIL induced adverse reactions are unknown. It is conceivable, however, that re-exposure of a patient might enhance the risk of an untoward event�s occurrence and increase its severity. Such phenomena, for example, occur when immune mediated mechanisms are responsible. Consequently, during the reinitiation of treatment, additional caution is advised. Patients discontinued for WBC counts below 2000/mm3 or an ANC below 1000/mm3 must not be restarted on CLOZARIL. (See WARNINGS)

Reducing the Risk of Recurrent Suicidal Behavior in Patients with Schizophrenia or Schizoaffective Disorder
The dosage and administration recommendations outlined above regarding the use of CLOZARIL in patients with treatment-resistant schizophrenia should also be followed when treating patients with schizophrenia or schizoaffective disorder at risk for recurrent suicidal behavior.

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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

Store and Dispense
Storage temperature should not exceed 86°F (30°C). Drug dispensing should not ordinarily exceed a weekly supply. If a patient is eligible for WBC testing every other week, then a two-week supply of CLOZARIL can be dispensed. Dispensing should be contingent upon the results of a WBC count.

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

**Trademark of Medical Economics Company, Inc.

REV: JANUARY 2003

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