General

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. FAZACLO® (clozapine, USP) IS NOT APPROVED FOR THE TREATMENT OF PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS. (SEE BOXED WARNING.)

AGRANULOCYTOSIS

BECAUSE OF THE SIGNIFICANT RISK OF AGRANULOCYTOSIS, A POTENTIALLY LIFE-THREATENING ADVERSE EVENT (SEE FOLLOWING), FAZACLO® (clozapine, USP) SHOULD BE RESERVED FOR USE IN THE FOLLOWING INDICATIONS: 1) FOR 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. CONSEQUENTLY, BEFORE INITIATING TREATMENT WITH FAZACLO® (clozapine, USP), 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. 2) FOR REDUCING THE RISK FOR RECURRENT SUICIDAL BEHAVIOR IN PATIENTS WITH SCHIZOPHRENIA OR SCHIZOAFFECTIVE DISORDER WHO ARE JUDGED TO BE AT RISK OF RE-EXPERIENCING SUICIDAL BEHAVIOR.

FAZACLO® (clozapine, USP) 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 1, PATIENTS WHO ARE BEING TREATED WITH FAZACLO® (clozapine, USP) 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 FAZACLO® (clozapine, USP) 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.

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 clozapine 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. Agranulocytosis could prove fatal if not detected early and therapy interrupted. Of the 149 cases of agranulocytosis reported worldwide in association with clozapine use as of December 31, 1989, 32% were fatal. However, few of these deaths occurred since 1977, at which time the knowledge of clozapineinduced agranulocytosis became more widespread, and close monitoring of WBC counts more widely practiced. In the United States, under a weekly WBC count monitoring system with clozapine, there have been 585 cases of agranulocytosis as of August 21, 1997; 19 were fatal (3%). During this period, 150,409 patients received clozapine. A hematologic risk analysis was conducted based upon the available information in the Clozapine 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 two 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 FazaClo® (clozapine, USP) therapy are at increased risk of subsequent episodes of agranulocytosis. Analysis of WBC count data from the Clozapine 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 FazaClo® (clozapine, USP), although this has not been definitively demonstrated.

WBC Count and ANC Clinical Monitoring Schedule

Table 1 provides a summary of the frequency of monitoring that should occur based on various stages of therapy (eg, initiation of therapy) or results from WBC count and ANC monitoring tests (eg, moderate leukopenia). The text that follows should be consulted for additional details regarding the treatment of patients under the various conditions (eg, severe leukopenia).

Patients should be advised to immediately report the appearance of lethargy, weakness, fever, sore throat, or any other signs of infection occurring at any time during FazaClo® (clozapine, USP) therapy. Such patients should have a WBC count and an ANC performed promptly.

Table 1: Frequency of Monitoring Based on Stage of Therapy or Results from WBC Count and ANC Monitoring Tests

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 (1) history of myeloproliferative disorder or (2) clozapine-induced agranulocytosis or granulocytopenia.	Weekly for 6 months
6-12 months of therapy	All results for WBC count ≥ 3500/mm3 and ANC ≥ 2000/mm3	Every 2 weeks for 6 months
12 months of therapy	All results for WBC count ≥ 3500/mm3 and ANC ≥ 2000/mm3	Every 4 weeks ad infinitum
Immature forms present	N/A	Repeat WBC count and ANC
Discontinuation of therapy	N/A	Weekly for at least 4 weeks from day of discontinuation or until WBC count ≥ 3500/mm3 and ANC ≥ 2000/mm3
Substantial drop in WBC count or ANC	Single drop or cumulative drop within 3 weeks of WBC count ≥ 3000/mm3 or ANC ≥ 1500/mm3	Repeat WBC count and ANC If repeat values are 3000/mm3 ≤ WBC count ≤ 3500/mm3 and ANC > 2000/mm3, then monitor twice weekly
Mild leukopenia and/or Mild granulocytopenia	3500/mm3 > WBC count ≥ 3000/mm3 and/or 2000/mm3 > ANC ≥ 1500/mm3	Twice weekly until WBC count > 3500/mm3 and ANC > 2000/mm3 then return to previous monitoring frequency
Moderate leukopenia and/or Moderate granulocytopenia	3000/mm3 > WBC count ≥ 2000/mm3 and/or 1500/mm3 > ANC ≥ 1000/mm3	Interrupt therapy Daily until WBC count > 3000/mm3 and ANC > 1500/mm3 Twice weekly until WBC count > 3500/mm3 and ANC > 2000/mm3 May rechallenge when WBC count > 3500/mm3 and ANC > 2000/mm3 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	Discontinue treatment and do not rechallenge patient Monitor until normal and for at least four weeks from day of discontinuation as follows: Daily until WBC count > 3000/mm3 and ANC > 1500/mm3 Twice weekly until WBC count > 3500/mm3 and ANC > 2000/mm3 Weekly after WBC count > 3500/mm3
Agranulocytosis	ANC < 500/mm3	Discontinue treatment and do not rechallenge patient Monitor until normal and for at least four weeks from day of discontinuation as follows: Daily until WBC count > 3000/mm3 and ANC > 1500/mm3 Twice weekly until WBC count > 3500/mm3 and ANC > 2000/mm3 Weekly after WBC count > 3500/mm3
WBC = White blood cell ANC = Absolute neutrophil count

Decrements in WBC Count and/or ANC

Consult Table 1 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 FazaClo® (clozapine, USP). 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 reexposure. To reduce the chances of rechallenge occurring in patients who have experienced significant bone-marrow suppression during FazaClo® (clozapine, USP) therapy, a single, national master file (ie, Nonrechallengeable Database) is confidentially maintained.

Treatment of Rechallengeable Patients

Patients may be rechallenged with FazaClo® (clozapine, USP) 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 Clozapine 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 FazaClo® (clozapine, USP) 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 FazaClo® (clozapine, USP) treatment outweighs the increased risk of agranulocytosis.

Analyses of the Clozapine 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 1, patients must undergo weekly WBC count and ANC monitoring for one 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 2 provides instructions regarding reinitiating therapy and subsequently the frequency of WBC count and ANC monitoring after a period of interruption.

Figure 2: Resuming monitoring frequency after interruption of therapy.

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, FazaClo® (clozapine, USP) therapy should be interrupted until the eosinophil count falls below 3000/mm³.

Seizures

Seizure has been estimated to occur in association with clozapine use at a cumulative incidence at one year of approximately 5%, based on the occurrence of one or more seizures in 61 of 1743 patients exposed to clozapine during its clinical testing prior to domestic marketing (ie, a crude rate of 3.5%). Dose appears to be an important predictor of seizure, with a greater likelihood of seizure at the higher clozapine doses used.

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

Myocarditis

Postmarketing surveillance data from four countries that employ hematological monitoring of clozapine-treated patients revealed: 30 reports of myocarditis with 17 fatalities in 205,493 US 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 UK patients (August 2001); 15 reports of myocarditis with 5 fatalities in 8000 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, World Health Organization (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 these four countries were 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 FazaClo® (clozapine, USP) 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 clozapine 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 FazaClo® (clozapine, USP) treatment is warranted upon suspicion of myocarditis. Patients with clozapine-related myocarditis should not be rechallenged with FazaClo® (clozapine, USP).

QT Interval Prolongation

QT prolongation is associated with an increased risk for life-threatening ventricular arrhythmias including Torsades de Pointes. Treatment with FazaClo® (clozapine, USP) has been associated with QT prolongation as well as ventricular arrhythmia, Torsades de Pointes, cardiac arrest, and sudden death. Caution should be exercised when FazaClo® (clozapine, USP) is prescribed in patients with a history of long QT syndrome or QT prolongation, or other conditions that may increase their risk for QT prolongation or sudden death, including recent acute myocardial infarction, uncompensated heart failure, or clinically significant cardiac arrhythmia. Caution is also indicated when treating patients with cardiovascular disease or family history of long QT syndrome.

Caution should be exercised when FazaClo® (clozapine, USP) is used in combination with other medications known to prolong the QTc interval. These include certain antipsychotic medications (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, pimozide), certain antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), antiarrhythmic medication in Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol), and other medications known to prolong the QT interval (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) (see DRUG INTERACTIONS).

Hypokalemia, (which can result from diuretic therapy, diarrhea, and other causes), and/or hypomagnesemia can also increase the risk of QT prolongation. Use caution when treating patients at risk for significant electrolyte disturbance, particularly hypokalemia. Baseline measurements of serum potassium and magnesium levels, as well as periodic monitoring of electrolytes, should be performed. Electrolyte abnormalities should be corrected before initiating treatment with FazaClo® (clozapine, USP).

Persistent QT prolongation predisposes patients to further QTc prolongation and potentially to significant and life-threatening cardiac arrhythmias. Routine ECG assessment may detect QTc prolongation but is not always effective in preventing arrhythmias. FazaClo® (clozapine, USP) treatment should be discontinued if the QTc interval exceeds 500 msec. Patients taking FazaClo® (clozapine, USP) who experience symptoms that could indicate the occurrence of Torsades de Pointes, (e.g., syncope, dizziness and palpitations) should have further evaluation, including cardiac monitoring.

Use caution when prescribing FazaClo® (clozapine, USP) concomitantly with drugs that inhibit the metabolism of FazaClo® (clozapine, USP). FazaClo® (clozapine, USP) is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. Use caution when prescribing FazaClo® (clozapine, USP) in patients with reduced activity of 1A2, 2D6, and 3A4 (see DRUG INTERACTIONS AND CLINICAL PHARMACOLOGY).

Other Adverse Cardiovascular and Respiratory Effects

Orthostatic hypotension with or without syncope can occur with FazaClo® (clozapine, USP) treatment and may represent a continuing risk in some patients. Rarely (approximately 1 case per 3000 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 FazaClo® (clozapine, USP) (ie, 2 days or more since the last dose), it is recommended that treatment be reinitiated with a 12.5 mg dose 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 clozapine by itself. Although it has not been established that there is an interaction between FazaClo® (clozapine, USP) 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 clozapine, 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 clozapine-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 clozapine. The clinical significance of these changes is unclear. However, in clinical trials with clozapine, several patients experienced significant cardiac events, including ischemic changes, myocardial infarction, arrhythmias, and sudden death. In addition, there have been postmarketing 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.

FazaClo® (clozapine, USP) 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

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 (eg, 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 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 clozapine 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 FazaClo® (clozapine, USP) 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 low incidence of certain acute extrapyramidal symptoms (eg, dystonia). A few cases of tardive dyskinesia have been reported in patients on clozapine 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 clozapine alone. Nevertheless, it cannot be concluded without more extended experience that FazaClo® (clozapine, USP) 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, FazaClo® (clozapine, USP) should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. As with any antipsychotic drug, chronic FazaClo® (clozapine, USP) 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 FazaClo® (clozapine, USP), drug discontinuation should be considered. However, some patients may require treatment with FazaClo® (clozapine, USP) despite the presence of the syndrome.

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 clozapine. 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 events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent, hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (eg, 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.

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 to either avoid FazaClo® (clozapine, USP) 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 United States (8.9 per 100,000 person-years) was similar to an estimate of the cardiomyopathy incidence in the US 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 FazaClo® (clozapine, USP) 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 NMS must be considered. There have been several reports of NMS in patients receiving clozapine, usually in combination with lithium or other CNS-active drugs. (See Neuroleptic Malignant Syndrome under WARNINGS.)

Pulmonary Embolism

The possibility of pulmonary embolism should be considered in patients receiving FazaClo® (clozapine, USP) 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 clozapine therapy in users 10-54 years of age. Based upon the extent of use observed in the Clozapine National Registry, the mortality rate associated with pulmonary embolus was 1 death per 3450 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 clozapine therapy. Whether pulmonary embolus can be attributed to clozapine or some characteristic(s) of its users is not clear, but the occurrence of deep-vein thrombosis or respiratory symptomatology should suggest its presence.

Phenylketonurics

Phenylketonuric patients should be informed that FazaClo® (clozapine, USP) contains phenylalanine (a component of aspartame). Each 12.5 mg, orally disintegrating tablet contains 0.87 mg phenylalanine. Each 25 mg, orally disintegrating tablet contains 1.74 mg phenylalanine. Each 100 mg, orally disintegrating tablet contains 6.96 mg phenylalanine. Each 150 mg, orally disintegrating tablet contains 10.44 mg phenylalanine. Each 200 mg, orally disintegrating tablet contains 13.92 mg phenylalanine.

Hepatitis

Caution is advised in patients using FazaClo® (clozapine, USP) 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 FazaClo® (clozapine, USP) 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 FazaClo® (clozapine, USP) should be discontinued.

Anticholinergic Toxicity

Eye

Clozapine has potent anticholinergic effects and care should be exercised in using this drug in the presence of narrow-angle glaucoma.

Gastrointestinal

Clozapine 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

Clozapine 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, FazaClo® (clozapine, USP) 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.

Cerebrovascular Adverse Events

An increased risk of cerebrovascular adverse events has been seen in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. FazaClo® (clozapine, USP) should be used with caution in patients with risk factors for stroke.

Use in Patients with Concomitant Illness

Clinical experience with clozapine in patients with concomitant systemic diseases is limited. Nevertheless, caution is advisable in using FazaClo® (clozapine, USP) 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 clozapine. Check with the anesthesiologist regarding continuation of FazaClo® (clozapine, USP) therapy in a patient scheduled for surgery.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenic potential was demonstrated in long-term studies in mice and rats at doses approximately 7 times the typical human dose on a mg/kg basis. Fertility in male and female rats was not adversely affected by clozapine. Clozapine did not produce genotoxic or mutagenic effects when assayed in appropriate bacterial and mammalian tests.

Pregnancy

FazaClo® (clozapine, USP) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnancy Category B

Reproduction studies have been performed in rats and rabbits at doses of approximately 2-4 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to clozapine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response and in view of the desirability of keeping the administration of all drugs to a minimum during pregnancy, this drug should be used only if clearly needed.

Non-teratogenic Effects

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

Nursing Mothers

Animal studies suggest that clozapine may be excreted in breast milk and have an effect on the nursing infant. Therefore, women receiving FazaClo® (clozapine, USP) should not breast feed.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of clozapine did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently than younger subjects.

Orthostatic hypotension can occur with clozapine treatment, and tachycardia, which may be sustained, has been observed in about 25% of patients taking clozapine. (See BOXED WARNINGS, Other Adverse Cardiovascular and Respiratory Effects.) Elderly patients, particularly those with compromised cardiovascular functioning, may be more susceptible to these effects.

Also, elderly patients may be particularly susceptible to the anticholinergic effects of clozapine, such as urinary retention and constipation. (See PRECAUTIONS, Anticholinergic Toxicity.)

Dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy. Other reported clinical experience does suggest that the prevalence of tardive dyskinesia appears to be highest among the elderly, especially elderly women. (See WARNINGS, Tardive Dyskinesia.)

Last reviewed on RxList: 1/24/2012
This monograph has been modified to include the generic and brand name in many instances.