Pharmacodynamics

Clozapine, USP ODT 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 Clozapine, USP ODT 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 Clozapine, USP ODT is preferentially more active at limbic than at striatal dopamine receptors, may explain the relative freedom of Clozapine, USP ODT from extrapyramidal side effects.

Clozapine, USP ODT 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. Clozapine, USP ODT is 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.

A comparative bioequivalence/bioavailability study was conducted in 32 patients (with schizophrenia or schizoaffective disorder) comparing Clozapine, USP ODT 200 mg* to 2 × Clozapine, USP ODT 100 mg (the approved reference product) under fasted conditions. The study also evaluated the effect of food and chewing on the pharmacokinetics of the 200 mg* tablet. Under fasted conditions, the mean AUCss and Cmin,ss of clozapine for the 200 mg* tablets were equivalent to those of the 2 x 100 mg tablets. The mean Cmax,ss of clozapine for Clozapine, USP ODT 200 mg* was 85% that for 2 x 100 mg Clozapine, USP ODT. This decrease in Cmax,ss for Clozapine, USP ODT 200 mg* is not clinically significant.

For Clozapine, USP ODT 200 mg*, food significantly increased the Cmin,ss of clozapine by 21%. However, this increase is not clinically significant. The mean AUCss and Cmax,ss of clozapine under fed conditions were equivalent to those under fasted conditions. Food delayed clozapine absorption by 1.5 hours, from a median Tmax of 2.5 hours under fasted conditions to 4 hours under fed conditions.

The mean Cmax,ss of clozapine under chewed conditions for Clozapine, USP ODT 200 mg* was about 86% that for 2 x 100 mg Clozapine, USP ODT under non-chewed conditions, while the AUCss and Cmin,ss values were similar between the chewed and non-chewed conditions.

In a food-effect study, a single dose of Clozapine, USP ODT 12.5 mg was administered to healthy volunteers under fasting conditions and after a high-fat meal. When Clozapine, USP ODT was administered after a high-fat meal, the Cmax of both clozapine and its active metabolite, desmethylclozapine, were decreased by approximately 20%, compared to administration under fasting conditions, while the AUC values were unchanged. This decrease in Cmax is not clinically significant. Therefore, Clozapine, USP ODT can be taken without regard to meals.

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:

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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 (Confidence Interval) 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

Treatment-Resistant Schizophrenia

Clozapine, USP ODT 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, Clozapine, USP ODT 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

Clozapine, USP ODT 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, Clozapine, USP ODT 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.

General

Agranulocytosis

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, Clozapine, USP ODT 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 (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 clozapine doses used.

Caution should be used in administering Clozapine, USP ODT 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 (e.g., 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 Clozapine, USP ODT 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 Clozapine, USP ODT treatment is warranted upon suspicion of myocarditis. Patients with clozapine-related myocarditis should not be rechallenged with Clozapine, USP ODT.

QT Interval Prolongation

QT prolongation is associated with an increased risk for life-threatening ventricular arrhythmias including Torsades de Pointes. Treatment with Clozapine, USP ODT has been associated with QT prolongation as well as ventricular arrhythmia, Torsades de Pointes, cardiac arrest, and sudden death. Caution should be exercised when Clozapine, USP ODT 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 Clozapine, USP ODT 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, dolasetronmesylate, 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 Clozapine, USP ODT.

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. Clozapine, USP ODT treatment should be discontinued if the QTc interval exceeds 500 msec. Patients taking Clozapine, USP ODT 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 Clozapine, USP ODT concomitantly with drugs that inhibit the metabolism of Clozapine, USP ODT. Clozapine, USP ODT is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. Use caution when prescribing Clozapine, USP ODT 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 Clozapine, USP ODT 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 Clozapine, USP ODT (i.e., 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 Clozapine, USP ODT 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.

Clozapine, USP ODT 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 (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 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, USP ODT 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 (e.g., 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 Clozapine, USP ODT 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, Clozapine, USP ODT should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. As with any antipsychotic drug, chronic Clozapine, USP ODT 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 Clozapine, USP ODT, drug discontinuation should be considered. However, some patients may require treatment with Clozapine, USP ODT 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 (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

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 Clozapine, USP ODT 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 Clozapine, USP ODT 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 Clozapine, USP ODT 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 Clozapine, USP ODT 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.

Hepatitis

Caution is advised in patients using Clozapine, USP ODT 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 Clozapine, USP ODT 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 Clozapine, USP ODT should be discontinued.

Anticholinergic Toxicity

Interference with Cognitive and Motor Performance

Because of initial sedation, Clozapine, USP ODT 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. Clozapine, USP ODT 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 Clozapine, USP ODT 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 Clozapine, USP ODT therapy in a patient scheduled for surgery.

Information for Patients

Physicians are advised to discuss the following issues with patients for whom they prescribe Clozapine, USP ODT:

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Patients who are to receive Clozapine, USP ODT should be warned about the significant risk of developing agranulocytosis. Patients should be advised to immediately report the appearance of lethargy, weakness, fever, sore throat, malaise, mucous membrane ulceration, or other possible signs of infection. Particular attention should be paid to any flu-like complaints or other symptoms that might suggest infection.

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Patients should be informed that Clozapine, USP ODT will be made available only through a special program designed to ensure the required blood monitoring in order to reduce the risk of developing agranulocytosis. Patients should be informed that their WBC count and ANC will be monitored as follows:

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Weekly blood tests are required for the first 6 months.

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If acceptable WBC counts and ANCs (WBC count ≥3500/mm3 and ANC ≥2000/mm3) have been maintained during the first 6 months of continuous therapy, then WBC counts and ANCs can be monitored every 2 weeks for the next 6 months.

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Thereafter, if acceptable WBC counts and ANCs have been maintained during the second 6 months of continuous therapy, WBC counts and ANCs can be monitored every 4 weeks.

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Patients should be informed of the significant risk of seizure during Clozapine, USP ODT treatment, and they should be advised to avoid driving and any other potentially hazardous activity while taking Clozapine, USP ODT.

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Patients with phenylketonuria should be aware that Clozapine, USP ODT contains phenylalanine (a component of aspartame). (See PRECAUTIONS, Phenylketonurics.)

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Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose titration.

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Patients should be informed that if they miss taking Clozapine, USP ODT for more than 2 days, they should not restart their medication at the same dosage but should contact their physician for dosing instructions.

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Patients should notify their physician if they are taking or plan to take any prescription or over-the-counter drugs or alcohol.

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Patients should notify their physician if they become pregnant or intend to become pregnant during therapy.

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Patients should not breast feed an infant if they are taking Clozapine, USP ODT.

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Patients should be advised that Clozapine, USP ODT should remain in the original package until immediately before use.

Drug Interactions

The risks of using Clozapine, USP ODT in combination with other drugs have not been systematically evaluated. Concurrent psychopharmaceuticals may affect plasma clozapine levels, thus, plasma concentrations of clozapine may fluctuate, and dosage adjustment may be required to avoid adverse effects or clinical failure.

Pharmacodynamic-Related Interactions

Although the exact mechanism of clozapine-induced agranulocytosis is unknown, the possibility that causative factors may interact synergistically with clozapine to increase the risk and/or severity of bone-marrow suppression warrants consideration. Therefore, Clozapine, USP ODT should not be used with other agents having a well-known potential to suppress bone-marrow function.

Given the primary CNS effects of clozapine, caution is advised in using it concomitantly with other CNS-active drugs or alcohol.

Orthostatic hypotension in patients taking clozapine can, in rare cases (approximately 1 case per 3000 patients), be accompanied by profound collapse and respiratory and/or cardiac arrest. 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 clozapine and benzodiazepines or other psychotropics, caution is advised when clozapine is initiated in patients taking a benzodiazepine or any other psychotropic drug.

Clozapine, USP ODT 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.

QT prolongation: Treatment with Clozapine, USP ODT, has been associated with QT interval prolongation and fatal arrhythmia. Clozapine, USP ODT should be used with caution when co-administered with medications known to prolong the QTc interval. Such medications include: Class 1A (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, certain antipsychotic medications (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, pimozide), certain antibiotics (e.g., gatifloxacin, moxifloxacin, sparfloxacin), and other medications known to prolong the QT interval (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol and tacrolimus). Use caution when co-administering Clozapine, USP ODT with medications that can cause electrolyte imbalance (e.g., diuretics) (see WARNINGS).

Pharmacokinetic-Related Interactions

Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4. The risk of metabolic interactions caused by an effect on an individual isoform is, therefore, minimized. Nevertheless, caution should be used in patients receiving concomitant treatment with Clozapine, USP ODT and other drugs which are either inhibitors or inducers of these enzymes.

Concomitant administration of drugs known to induce cytochrome P450 enzymes may decrease the plasma levels of clozapine. Phenytoin, tobacco smoke, carbamazepine, and rifampin may decrease Clozapine, USP ODT plasma levels resulting in a decrease in effectiveness of a previously effective Clozapine, USP ODT dose.

QT Prolongation: Use caution when prescribing Clozapine, USP ODT concomitantly with drugs that inhibit Clozapine, USP ODT metabolism. Clozapine, USP ODT is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. Use caution when prescribing Clozapine, USP ODT in patients with reduced activity 1A2, 2D6, and 3A4.

Concomitant administration of drugs known to inhibit the activity of cytochrome P450 isozymes may increase the plasma levels of clozapine. Cimetidine, caffeine, citalopram, ciprofloxacin, fluvoxamine, and erythromycin may increase plasma levels of Clozapine, USP ODT, potentially resulting in adverse effects. Although concomitant use of Clozapine, USP ODT and carbamazepine is not recommended, it should be noted that discontinuation of concomitant carbamazepine administration may result in an increase in Clozapine, USP ODT plasma levels.

In a study of schizophrenic patients who received clozapine under steady-state conditions, fluvoxamine or paroxetine was added in 16 and 14 patients, respectively. After 14 days of coadministration, mean trough concentrations of clozapine and its metabolites, N-desmethylclozapine and clozapine N-oxide, were elevated with fluvoxamine by about three-fold compared to baseline concentrations. Paroxetine produced only minor changes in the levels of clozapine and its metabolites. However, other published reports describe modest elevations (less than two-fold) of clozapine and metabolite concentrations when clozapine was taken with paroxetine, fluoxetine, and sertraline. Therefore, such combined treatment should be approached with caution and patients should be monitored closely when Clozapine, USP ODT is combined with these drugs, particularly with fluvoxamine. A reduced Clozapine, USP ODT dose should be considered.

A subset (3%-10%) of the population has reduced activity of certain drug metabolizing enzymes such as the cytochrome P450 isozyme CYP2D6. Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, tricyclic antidepressants, and clozapine. These individuals may develop higher than expected plasma concentrations of clozapine when given usual doses. In addition, certain drugs that are metabolized by this isozyme, including many antidepressants (clozapine, selective serotonin reuptake inhibitors, and others), may inhibit the activity of this isozyme and, thus, may make normal metabolizers resemble poor metabolizers with regard to concomitant therapy with other drugs metabolized by this enzyme system, leading to drug interaction.

Concomitant use of clozapine with other drugs metabolized by P450 CYP2D6 may require lower doses than usually prescribed for either Clozapine, USP ODT or the other drug. Therefore, coadministration of Clozapine, USP ODT with other drugs that are metabolized by this isozyme, including antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme (e.g., quinidine) should be approached with caution.

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

Clozapine, USP ODT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Animal studies suggest that clozapine may be excreted in breast milk and have an effect on the nursing infant. Therefore, women receiving Clozapine, USP ODT 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.)

Associated with Discontinuation of Treatment

Sixteen percent of 1080 patients who received clozapine in premarketing clinical trials discontinued treatment due to an adverse event, including both those that could reasonably be attributed to clozapine 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 clozapine in clinical trials at an incidence of greater than 5% were: CNS 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; 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.

Incidence in Clinical Trials

Table 2 enumerates adverse events that occurred at a frequency of 1% or greater among clozapine patients who participated in clinical trials. These rates are not adjusted for duration of exposure.

Table 3 enumerates adverse events that occurred at a frequency of 10% for either treatment group in patients who took at least one dose of study medication during their participation in InterSePT™, which was an adequate and well-controlled, two-year study evaluating the efficacy of clozapine relative to olanzapine in reducing the risk of emergent suicidal behavior in patients with schizophrenia or schizoaffective disorder. These rates are not adjusted for duration of exposure.

Other Events Observed During the Premarketing Evaluation of Clozapine

This section reports additional, less frequent adverse events which occurred among the patients taking clozapine in clinical trials. Various adverse events were reported as part of the total experience in these clinical studies; a causal relationship to clozapine treatment cannot be determined in the absence of appropriate controls in some of the studies. Table 2 enumerates adverse events that occurred at a frequency of at least 1% of patients treated with clozapine. The list below includes all additional adverse experiences reported as being temporally associated with the use of the drug which occurred at a frequency less than 1%, enumerated by organ system.

Postmarketing Clinical Experience

Postmarketing experience has shown an adverse experience profile similar to that presented above. Voluntary reports of adverse events temporally associated with clozapine not mentioned above that have been received since market introduction and that may have no causal relationship with the drug include the following:

Extrapyramidal Symptoms

Human Experience

The most commonly reported signs and symptoms associated with clozapine overdose are: altered states of consciousness, including drowsiness, delirium, and coma; tachycardia; hypotension; respiratory depression or failure; and 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 clozapine, 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 are 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 Clozapine, USP ODT. 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 Regional Poison Control Centers are listed in the Physicians’ Desk Reference®, a registered trademark of Thomson PDR.

Treatment-Resistant Schizophrenia

Clozapine, USP ODT

12.5 mg

1/4-inch diameter tablet debossed with “A05” on one side.

Bottles of 100: 100 tablets in an HDPE bottle with child-resistant cap ................ NDC No. 0093-3011-01

25 mg

5/16-inch diameter tablet debossed with “A06” on one side.

Bottles of 100: 100 tablets in an HDPE bottle with child-resistant cap ................. NDC No. 0093-3012-01

Cartons of 48 for Institutional Use Only: 8 cards, 6 non child-resistant
blisters per card ............................................................................................................ NDC No. 0093-3012-84

100 mg

1/2-inch diameter tablet debossed with “A08” on one side.

Bottles of 100: 100 tablets in an HDPE bottle with child-resistant cap ................... NDC No. 0093-3010-01

Cartons of 48 for Institutional Use Only: 8 cards, 6 non child-resistant
blisters per card .............................................................................................................. NDC No. 0093-3010-84