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All about: FazaClo

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Generic Name: clozapine
Dosage Form: Tablet, orally disintegrating

Rx only

PRESCRIBING INFORMATION

Before prescribing FazaClo® (clozapine, USP), the physician should be thoroughly familiar with the details of this prescribing information.

WARNING

1. AGRANULOCYTOSIS

BECAUSE OF A SIGNIFICANT RISK OF AGRANULOCYTOSIS, A POTENTIALLY LIFE-THREATENING ADVERSE EVENT, 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 ANTIPSYCHOTIC DRUG TREATMENT, 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.

PATIENTS BEING TREATED WITH CLOZAPINE MUST HAVE A BASELINE WHITE BLOOD CELL (WBC) COUNT AND ABSOLUTE NEUTROPHIL COUNT (ANC) BEFORE INITIATION OF TREATMENT AS WELL AS REGULAR WBC COUNTS AND ANCs DURING TREATMENT AND FOR AT LEAST 4 WEEKS AFTER DISCONTINUATION OF TREATMENT. (SEE WARNINGS.)

CLOZAPINE IS AVAILABLE ONLY THROUGH A DISTRIBUTION SYSTEM THAT ENSURES MONITORING OF WBC COUNTS AND ANCs ACCORDING TO THE SCHEDULE DESCRIBED BELOW PRIOR TO DELIVERY OF THE NEXT SUPPLY OF MEDICATION. (SEE WARNINGS.)

2. SEIZURES

SEIZURES HAVE BEEN ASSOCIATED WITH THE USE OF CLOZAPINE. DOSE APPEARS TO BE AN IMPORTANT PREDICTOR OF SEIZURE, WITH A GREATER LIKELIHOOD AT HIGHER CLOZAPINE DOSES. CAUTION SHOULD BE USED WHEN ADMINISTERING CLOZAPINE TO PATIENTS HAVING A HISTORY OF SEIZURES OR OTHER PREDISPOSING FACTORS. PATIENTS SHOULD BE ADVISED NOT TO ENGAGE IN ANY ACTIVITY WHERE SUDDEN LOSS OF CONSCIOUSNESS COULD CAUSE SERIOUS RISK TO THEMSELVES OR OTHERS. (SEE WARNINGS.)

3. MYOCARDITIS

ANALYSES OF POSTMARKETING SAFETY DATABASES SUGGEST THAT CLOZAPINE IS ASSOCIATED WITH AN INCREASED RISK OF FATAL MYOCARDITIS, ESPECIALLY DURING, BUT NOT LIMITED TO, THE FIRST MONTH OF THERAPY. IN PATIENTS IN WHOM MYOCARDITIS IS SUSPECTED, CLOZAPINE TREATMENT SHOULD BE PROMPTLY DISCONTINUED. (SEE WARNINGS.)

4. OTHER ADVERSE CARDIOVASCULAR AND RESPIRATORY EFFECTS

ORTHOSTATIC HYPOTENSION, WITH OR WITHOUT SYNCOPE, CAN OCCUR WITH CLOZAPINE TREATMENT. RARELY, 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. IN PATIENTS WHO HAVE HAD EVEN A BRIEF INTERVAL OFF CLOZAPINE (ie, 2 OR MORE DAYS SINCE THE LAST DOSE) TREATMENT SHOULD BE STARTED WITH 12.5 MG ONCE OR TWICE DAILY. (SEE WARNINGS AND DOSAGE AND ADMINISTRATION.)

SINCE COLLAPSE, RESPIRATORY ARREST, AND CARDIAC ARREST DURING INITIAL TREATMENT HAS OCCURRED IN PATIENTS WHO WERE BEING ADMINISTERED BENZODIAZEPINES OR OTHER PSYCHOTROPIC DRUGS, CAUTION IS ADVISED WHEN CLOZAPINE IS INITIATED IN PATIENTS TAKING A BENZODIAZEPINE OR ANY OTHER PSYCHOTROPIC DRUG. (SEE WARNINGS.)

5. INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS TREATED WITH ATYPICAL ANTIPSYCHOTIC DRUGS ARE AT AN INCREASED RISK OF DEATH COMPARED TO PLACEBO. ANALYSES OF 17 PLACEBO-CONTROLLED TRIALS (MODAL DURATION OF 10 WEEKS) IN THESE PATIENTS REVEALED A RISK OF DEATH IN THE DRUG-TREATED PATIENTS OF BETWEEN 1.6 TO 1.7 TIMES THAT SEEN 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 (eg, HEART FAILURE, SUDDEN DEATH) OR INFECTIOUS (eg, PNEUMONIA) IN NATURE. FazaClo® (clozapine, USP) IS NOT APPROVED FOR THE TREATMENT OF PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS.

DESCRIPTION

FazaClo® (clozapine, USP), 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:

FazaClo® (clozapine, USP) is available as yellow, orally disintegrating tablets of 12.5, 25, 50, and 100 mg for oral administration without water.

Each orally disintegrating tablet contains clozapine equivalent to 12.5, 25, 50, or 100 mg.

12.5-, 25-, 50-, And 100-mg Orally Disintegrating Tablets

Active Ingredient

Clozapine is a yellow, crystalline powder, very slightly soluble in water.

Inactive Ingredients

Aminoalkyl methacrylate copolymer E, mannitol, aspartame, microcrystalline cellulose, crospovidone, natural and artificial mint flavor, sodium bicarbonate, citric acid, ferric oxide (yellow), and magnesium stearate

THIS PRODUCT CONTAINS ASPARTAME AND IS NOT INTENDED FOR USE BY INFANTS. PHENYLKETONURICS: CONTAINS PHENYLALANINE. Phenylalanine is a component of aspartame. Each 12.5-mg, orally disintegrating tablet contains 1.6 mg aspartame, thus, 0.87 mg phenylalanine. Each 25-mg, orally disintegrating tablet contains 3.1 mg aspartame, thus, 1.74 mg phenylalanine. Each 50-mg, orally disintegrating tablet contains 6.2 mg aspartame, thus, 3.48 mg phenylalanine. Each 100-mg, orally disintegrating tablet contains 12.4 mg aspartame, thus, 6.96 mg phenylalanine. The allowable daily intake of aspartame is 50 mg per kilogram of body weight per day. (See PRECAUTIONS, Phenylketonurics.)

CLINICAL PHARMACOLOGY

Pharmacodynamics

FazaClo® (clozapine, USP) 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 FazaClo® (clozapine, USP) 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 FazaClo® (clozapine, USP) is preferentially more active at limbic than at striatal dopamine receptors, may explain the relative freedom of FazaClo® (clozapine, USP) from extrapyramidal side effects.

FazaClo® (clozapine, USP) also acts as an antagonist at adrenergic, cholinergic, histaminergic, and serotonergic receptors.

Absorption, Distribution, Metabolism, and Excretion

In man, clozapine tablets (25 and 100 mg) are equally bioavailable relative to a clozapine solution. FazaClo® (clozapine, USP) orally disintegrating tablets are bioequivalent to Clozaril® (clozapine) tablets, a registered trademark of Novartis Pharmaceuticals Corporation. Following a dosage of 100 mg b.i.d., the average steady-state peak plasma concentration was 413 ng/mL (range: 132-854 ng/mL), occurring at the average of 2.3 hours (range: 1-6 hours) after dosing. The average minimum concentration at steady state was 168 ng/mL (range: 45-574 ng/mL), after 100-mg b.i.d. dosing. Food does not appear to affect the systemic bioavailability of clozapine. Thus, FazaClo® (clozapine, USP) may be administered with or without food.

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 PRECAUTIONS.)

Clozapine is almost completely metabolized prior to excretion and only trace amounts of unchanged drug are detected in the urine and feces. 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:  4-12 hours), compared to a mean elimination half-life, after achieving steady state with 100-mg b.i.d. dosing, of 12 hours (range: 4-66 hours). A comparison of single-dose and multiple-dose administration of clozapine showed 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, linearly dose-proportional changes with respect to AUC (area under the curve), peak, and minimum clozapine plasma concentrations were observed after administration of 37.5, 75, and 150 mg b.i.d.

Human Pharmacology

In contrast to more typical antipsychotic drugs, clozapine therapy produces little or no prolactin elevation.

As is true of more typical antipsychotic drugs, clinical electroencephalogram (EEG) studies have shown 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, on rare occasions, may report 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.

Clinical Trial Data (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)

The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was assessed in the International Suicide Prevention Trial (InterSePT™, a trademark of Novartis Pharmaceuticals Corporation), which was a prospective, randomized, international, parallel-group comparison of clozapine (Clozaril®) versus olanzapine (Zyprexa®, a registered trademark of Eli Lilly and Company) in patients with schizophrenia or schizoaffective disorder (DSM-IV) who were judged to be at risk for reexperiencing suicidal behavior. Only about one-fourth of these patients (27%) were considered resistant to standard antipsychotic drug treatment and the remainder were not. Patients met one of the following criteria:

-
They had attempted suicide within the three years prior to their baseline evaluation.
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They had been hospitalized to prevent a suicide attempt within the three years prior to their baseline evaluation.
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They demonstrated moderate-to-severe suicidal ideation with a depressive component within one week prior to their baseline evaluation.
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They demonstrated moderate-to-severe suicidal ideation accompanied by command hallucinations to do self-harm within one 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 clozapine and 5–20 mg/day for olanzapine. For the 956 patients who received clozapine 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.

Data from this study indicate that clozapine 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 clozapine in delaying time to recurrent suicidal behavior and not a demonstration of the superior efficacy of clozapine over olanzapine.

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

Figure 1. Kaplan-Meier Estimates of Cumulative Probability of a Significant Suicide Attempt or Hospitalization to Prevent Suicide

INDICATIONS AND USAGE

Treatment-Resistant Schizophrenia

FazaClo® (clozapine, USP) 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, FazaClo® (clozapine, USP) 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 clozapine in a treatment-resistant schizophrenic population was demonstrated in a 6-week study comparing clozapine and chlorpromazine. Patients meeting DSM-III criteria for schizophrenia and having a mean Brief Psychiatric Rating Scale (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 clozapine to chlorpromazine was documented in statistical analyses employing both categorical and continuous measures of treatment effect.

Because of the significant risk of agranulocytosis and seizures, 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 reevaluated.

Reduction In The Risk Of Recurrent Suicidal Behavior In Schizophrenia Or Schizoaffective Disorders

FazaClo® (clozapine, USP) 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 put him/herself at risk for death.

The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was demonstrated over a two-year treatment period in the InterSePT Trial (see Clinical Trial Data under CLINICAL PHARMACOLOGY). Therefore, FazaClo® (clozapine, USP) treatment to reduce the risk of suicidal behavior should be continued for at least two 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.

CONTRAINDICATIONS

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

FazaClo® (clozapine, USP) 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 clozapine-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.

WARNINGS

General

INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS TREATED WITH ATYPICAL ANTIPSYCHOTIC DRUGS ARE AT AN INCREASED RISK OF DEATH COMPARED TO PLACEBO. 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 clozapine-induced 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
WBC = White blood cell
ANC = Absolute neutrophil count
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
  1. Repeat WBC count and ANC
  2. 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
  1. Interrupt therapy
  2. Daily until WBC count >3000/mm3 and ANC >1500/mm3
  3. Twice weekly until WBC count >3500/mm3 and ANC >2000/mm3
  4. May rechallenge when WBC count >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 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
  1. Discontinue treatment and do not rechallenge patient
  2. 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

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.

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).

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 clozapine 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 (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 100.4ºF (38ºC), 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 50-mg, orally disintegrating tablet contains 3.48 mg phenylalanine. Each 100-mg, orally disintegrating tablet contains 6.96 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.

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) th

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