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Uses

Psychotic Disorders

Clozapine is used for the symptomatic management of psychotic disorders (e.g., schizophrenia). Drug therapy is integral to the management of acute psychotic episodes in patients with schizophrenia and generally is required for long-term stabilization to sustain symptom remission or control and to minimize the risk of relapse. Antipsychotic agents are the principal class of drugs used for the management of all phases of schizophrenia. Patient response and tolerance to antipsychotic agents are variable, and patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.

Clozapine has been shown to be an effective, relatively rapid-acting, broad-spectrum antipsychotic agent in both uncontrolled and controlled studies of patients with schizophrenia. In these studies, improvement in manifestations of schizophrenia was based on the results of various psychiatric rating scales, principally the Brief Psychiatric Rating Scale (BPRS) that assesses factors such as anergy, thought disturbance, activation, hostility/suspiciousness, and anxiety/depression. In clinical studies, clozapine improved both positive (florid symptomatology such as hallucinations, conceptual disorganization, and suspiciousness) and negative (''deficit'' symptomatology such as emotional withdrawal, motor retardation, blunted affect, and disorientation) manifestations of schizophrenia; conventional (typical) antipsychotic agents appear to have lesser effects on negative manifestations of the disorder. In comparative studies, clozapine was at least as effective as, or more effective than several conventional antipsychotic agents, including chlorpromazine, haloperidol, perphenazine, or trifluoperazine.

Unlike conventional antipsychotic agents, however, clozapine generally does not induce extrapyramidal effects and has not been clearly implicated as a causative agent in tardive dyskinesia.

While the risks of adverse neurologic effects with long-term clozapine therapy remain to be fully elucidated, other adverse effects, including some potentially serious effects (e.g., severe neutropenia, seizures), may occur more frequently with clozapine therapy. Consequently, the manufacturers and most clinicians state that use of clozapine should be reserved for patients with severe disease that fails to respond adequately to other antipsychotic therapy. The American Psychiatric Association (APA) recommends that a trial of clozapine be considered in patients with schizophrenia who fail to respond or experience a partial or suboptimal response to adequate trials of 2 antipsychotic agents (including at least one second-generation [atypical] antipsychotic), in patients with a history of chronic and persistent suicidal ideation and behavior that has not responded to other treatments, and in patients with persistent hostility and aggression.

Treatment-resistant Schizophrenia

Clozapine is used for the management of schizophrenia in severely ill patients who fail to respond adequately to standard antipsychotic therapy. Because of the risk of severe neutropenia and seizures associated with its use, clozapine should be used only in patients who have failed to respond adequately to standard antipsychotic treatment. (See Severe Neutropenia under Cautions: Hematologic Effects and also under Cautions: Precautions and Contraindications.)

Schizophrenia is a major psychotic disorder that frequently has devastating effects on various aspects of the patient's life and carries a high risk of suicide and other life-threatening behaviors. Manifestations of schizophrenia involve multiple psychologic processes, including perception (e.g., hallucinations), ideation, reality testing (e.g., delusions), emotion (e.g., flatness, inappropriate affect), thought processes (e.g., loose associations), behavior (e.g., catatonia, disorganization), attention, concentration, motivation (e.g., avolition, impaired intention and planning), and judgment. The principal manifestations of this disorder usually are described in terms of positive and negative (deficit) symptoms, and more recently, disorganized symptoms. Positive symptoms include hallucinations, delusions, bizarre behavior, hostility, uncooperativeness, and paranoid ideation, while negative symptoms include restricted range and intensity of emotional expression (affective flattening), reduced thought and speech productivity (alogia), anhedonia, apathy, and decreased initiation of goal-directed behavior (avolition). Disorganized symptoms include disorganized speech (thought disorder) and behavior and poor attention.

Evidence from both retrospective and controlled prospective studies indicates that clozapine is effective in many patients who fail to respond adequately to other antipsychotic therapy and/or in whom such therapy produces intolerable adverse effects. In a controlled, comparative study in patients with at least moderately severe schizophrenia whose disease was refractory to at least 3 antipsychotic agents from at least 2 different chemical classes during the past 5 years, an adequate clinical response (a 20% or greater decrease in total BPRS score and either a posttreatment Clinical Global Impressions [CGI] scale rating of mildly ill or a posttreatment BPRS score of 35 or less) was noted after 1-6 weeks of therapy in 30% of patients receiving clozapine (mean maximum dosage exceeding 600 mg daily) compared with 4% of patients receiving chlorpromazine (mean maximum dosage exceeding 1200 mg daily) plus benztropine. In addition, clozapine was substantially more effective than chlorpromazine plus benztropine in improving both positive and negative manifestations of schizophrenia. In this study, resistance to antipsychotic treatment prior to entry into the clozapine/chlorpromazine comparative phase was confirmed by a 6-week trial of haloperidol (mean dosage of 61 mg daily) combined with benztropine. This study provides evidence from both categorical and continuous measures not only of clozapine's efficacy as an antipsychotic agent but also of its superiority over conventional antipsychotic drug therapy in a well-defined group of antipsychotic-resistant patients. Similar 6-week response rates in treatment-resistant schizophrenia have been reported in other studies with the drug. Clinically important improvement in quality of life and social functioning, including deinstitutionalization, interpersonal relationships, and ability to hold a job or attend school, also have been reported following initiation of clozapine therapy in patients with antipsychotic-resistant schizophrenia.

For additional information on the symptomatic management of schizophrenia, including treatment recommendations,

Pediatric Considerations

Although the manufacturers state that the safety and efficacy of clozapine in pediatric patients have not been established, the drug has been successfully used for the management of childhood-onset schizophrenia in a limited number of treatment-resistant children and adolescents. While the lower risk of extrapyramidal adverse effects and tardive dyskinesia during treatment with atypical antipsychotic agents such as clozapine compared with conventional antipsychotic agents represents an advantage in the treatment of childhood-onset schizophrenia, concerns regarding serious adverse effects (e.g., neutropenia, seizures) associated with clozapine limit its use in clinical practice.(See Cautions: Pediatric Precautions.) Therefore, the American Academy of Child and Adolescent Psychiatry (AACAP) states that clozapine is not considered a first-line agent, and should be reserved for treatment-refractory patients who have failed to respond to adequate therapeutic trials (i.e., use of sufficient dosages over a period of 6 weeks) of at least 2 other first-line antipsychotic agents. For additional information on the symptomatic management of childhood-onset schizophrenia,

In one randomized, double-blind, clinical study conducted by the National Institute of Mental Health (NIMH), a limited number of children and adolescents (mean: 14 years of age) with childhood-onset schizophrenia (i.e., development of the disorder by 12 years of age or younger) who were intolerant and/or nonresponsive to at least 2 different antipsychotic agents were treated with either clozapine (up to 525 mg daily; mean final dosage 176 mg daily) or haloperidol (up to 27 mg daily; mean final dosage 16 mg daily) for 6 weeks. In this study, children and adolescents receiving clozapine had substantially greater reductions in both positive and negative symptoms of schizophrenia than those receiving haloperidol. Additional follow-up of these patients over a 2-year period indicated that, as reported in adults, maximal antipsychotic effects in schizophrenic children and adolescents may not be evident until after 6-9 months of clozapine therapy. For most children and adolescents in the study, clozapine improved interpersonal functioning and enabled a return to a less restrictive setting. However, mild to moderate neutropenia occurred in 24% of the patients, and 29% required therapy with an anticonvulsant.

Suicide Risk Reduction in Schizophrenia and Schizoaffective Disorder

Clozapine is used to reduce the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for such behavior, based on history and recent clinical state. Efficacy of clozapine for this indication has been established in a multicenter, randomized, open-label clinical study (the International Suicide Prevention Trial [InterSePT]) of 2 years' duration comparing clozapine and olanzapine in patients with schizophrenia (62%) or schizoaffective disorder (38%) who were judged to be at risk for recurrent suicidal behavior. These patients either had attempted suicide or had been hospitalized to prevent a suicide attempt within the 3 years prior to their baseline evaluation or had demonstrated moderate-to-severe suicidal ideation with a depressive component or command hallucinations to do self-harm within 1 week prior to their baseline evaluation. Treatment resistance (i.e., resistance to standard antipsychotic drug therapies) was not a requirement for inclusion in this study, and only 27% of the total patient population was identified as being treatment resistant at baseline.

In the InterSePT study, patients who received flexible dosages of clozapine (mean dosage: 274.2 mg daily) for approximately 2 years had a 26% reduction in their risk for suicide attempts or hospitalization to prevent suicide compared with those who received flexible dosages of olanzapine (mean dosage: 16.6 mg daily); the treatment-resistant status of patients was not predictive of response to clozapine or olanzapine. The cumulative probability of experiencing a suicide attempt, including a completed suicide, or hospitalization due to imminent suicide risk (including increased level of surveillance for suicidal behavior for patients already hospitalized) also was lower for patients receiving clozapine (24%) than for those receiving olanzapine (32%) at year 2. In addition, patients receiving clozapine had a statistically significant longer delay in the time to recurrent suicidal behavior than those receiving olanzapine. These results, however, may have been confounded by extensive use of other treatments to reduce the suicide risk, including concomitant psychotropic agents (84% with antipsychotics; 65% with anxiolytics; 53% with antidepressants; 28% with mood stabilizers), hospitalization, and psychotherapy, the contributions of which to clozapine's efficacy are unknown.

Some clinicians state that methodologic problems (e.g., lack of actively suicidal patients in the study, possible bias and unblinding of suicide monitoring board members during the study, use of concomitant psychotropic agents) associated with the InterSePT study limit definitive conclusions about the efficacy of clozapine for prevention of suicide in patients with schizophrenia or schizoaffective disorder. The FDA advises clinicians to interpret the results of the InterSePT study only as evidence of the efficacy of clozapine in delaying time to recurrent suicidal behavior, and not as efficacy of the drug for treatment of suicidal behaviors or as a demonstration of the superior efficacy of clozapine over olanzapine. However, the APA states that, based on the available evidence from the InterSePT study, clozapine should be preferentially considered for schizophrenia patients with a history of chronic and persistent suicidal ideation and behaviors. Decisions to initiate clozapine therapy or switch patients from other antipsychotics to clozapine, therefore, should be individualized. In addition, safety and efficacy of clozapine in actively suicidal patients have yet to be determined.

Parkinsonian Syndrome

Clozapine has been used in a limited number of patients with advanced, idiopathic parkinsonian syndrome for the management of dopaminomimetic psychosis associated with antiparkinsonian drug therapy, but adverse effects such as sedation, confusion, and increased parkinsonian manifestations may limit the benefit of clozapine therapy in these patients. Attempts to relieve antiparkinsonian drug-induced delusions, paranoia, and hallucinations by reduction of antiparkinsonian drug dosage or administration of typical antipsychotic agents often aggravate parkinsonian symptoms. Limited data suggest that administration of clozapine in dosages of 6.25-400 mg daily can improve psychotic symptoms within a few days, reportedly without exacerbating parkinsonian manifestations. However, in a controlled study in a limited number of patients receiving clozapine dosages up to 250 mg daily, exacerbation of parkinsonian manifestations and development of delirium occurred frequently despite prevention of antiparkinsonian drug-induced deterioration of psychosis; it has been suggested that rapid clozapine dosage escalation may have contributed to the observed negative effect on parkinsonian manifestations and delirium. Clozapine dosages of 100-250 mg daily reportedly have been associated with hypersalivation, hypophonia, bradykinesia, and considerable sedation in patients with idiopathic parkinsonian syndrome, and withdrawal of clozapine therapy or a decrease in dosage also has exacerbated parkinsonian manifestations. Some clinicians suggest that the dosage of clozapine required to treat drug-induced dopaminomimetic psychosis may be substantially less than that required for treatment of psychosis in young, otherwise healthy individuals and that clozapine therapy should be initiated at low dosages (e.g., 6.25-50 mg daily) with cautious upward titration (e.g., to a maximum of 100-200 mg daily). Other clinicians have suggested that clozapine be used only as a last resort in patients with drug-induced dopaminomimetic psychosis.

Dosage and Administration

Administration

Clozapine is administered orally without regard to meals; administration in divided doses may help minimize the risk of certain adverse effects. If daytime sleepiness occurs during therapy, bedtime administration may be helpful. The orally disintegrating tablets and conventional tablets of clozapine are bioequivalent; the oral suspension and conventional tablets of the drug also are bioequivalent. Clozapine also has been administered IM, but a parenteral preparation currently is not commercially available in the US.

Prior to initiating clozapine therapy, a baseline complete blood cell (CBC) count, including the absolute neutrophil count (ANC), must be obtained to ensure the presence of a normal baseline neutrophil count and for later comparisons. In the general population, the baseline ANC must be at least 1500/mm before clozapine therapy can be initiated. In patients with documented benign ethnic neutropenia (BEN), the baseline ANC must be at least 1000/mm in order to be eligible for clozapine therapy. Regular ANC monitoring is required during clozapine therapy because of the risk of severe neutropenia associated with the drug.(See Severe Neutropenia under Cautions: Hematologic Effects.)

Patients receiving clozapine orally disintegrating tablets (e.g., FazaClo) should be instructed not to remove a tablet from the blister until just prior to dosing. The tablet should not be pushed through the foil; instead, the foil blister backing should be peeled from the blister. The tablet should then be gently removed and immediately placed on the tongue, where it rapidly disintegrates in saliva, and then subsequently swallowed with or without liquid, or the tablet can be chewed as desired.

Clozapine oral suspension (Versacloz) should be shaken for 10 seconds prior to each use. The bottle adapter and calibrated oral dosing syringe supplied by the manufacturer should be used to administer the suspension. After withdrawing the appropriate dose into the calibrated oral dosing syringe, the dose should be administered directly into the patient's mouth; clozapine oral suspension should not be stored in the syringe for later use.

Restricted Distribution Program

Because of the risk of severe neutropenia, clozapine is available only through a restricted distribution program, the Clozapine REMS program. As of October 12, 2015, all previous clozapine registries, which had been maintained individually by each manufacturer of clozapine, were replaced by the Clozapine REMS program. Under this single, shared program, only ANC is used to monitor patients for clozapine-induced neutropenia; white blood cell (WBC) count, which previously also was required, was considered to be less relevant for monitoring neutropenia and is no longer required. In addition, ANC thresholds for clozapine treatment interruption were lowered from the previous clozapine registry requirements. Furthermore, the shared Clozapine REMS program established lower acceptable ANC levels for patients with documented benign ethnic neutropenia (BEN) and discontinued the National Non-Rechallenge Master File, allowing patients who previously were ineligible to receive clozapine due to low ANC or WBC count to be treated with the drug.(See Severe Neutropenia under Cautions: Hematologic Effects.)

Prescribers and pharmacies must be certified with the Clozapine REMS program; to be certified, physicians or an authorized representative of a pharmacy must enroll and complete training before they can prescribe or dispense clozapine, respectively. Certified prescribers must enroll patients in the Clozapine REMS program and report patients' ANC values according to the recommended monitoring guidelines. Pharmacies that are certified to dispense clozapine must train their staff members to verify that the prescriber is certified and the patient is enrolled in the program, and must verify that the ANC is current and acceptable for each patient or that continued treatment has been authorized by the prescriber before dispensing the drug to the patient. For additional information and to enroll in the program, clinicians, patients, and caregivers may visit the Clozapine REMS program website at http://www.clozapinerems.com or contact 844-267-8678.

Dosage

Cautious dosage titration and administration of clozapine in divided doses are necessary to minimize the risk of certain adverse effects such as orthostatic hypotension, bradycardia, syncope, seizures, and sedation.(See Cautions: Nervous System Effects and also see Cautions: Cardiovascular Effects.)

Treatment-resistant Schizophrenia

Adult Dosage

For the management of treatment-resistant schizophrenia, the usual initial adult dosage of clozapine is 12.5 mg given orally once or twice daily. If the drug is well tolerated, dosage may be increased in increments of 25-50 mg daily over a 2-week period until a target dosage of 300-450 mg daily (administered in divided doses) is achieved. Subsequent dosage increases can be made once or twice weekly in increments of up to 100 mg. The manufacturers state that use of a low initial daily dosage, a gradual titration schedule, and administration of the drug in divided doses are necessary to minimize the risks of orthostatic hypotension, bradycardia, syncope, seizures, and sedation.(See Cautions: Nervous System Effects and also see Cautions: Cardiovascular Effects.)

Daily administration of clozapine in divided doses should continue until an effective and tolerable dosage is reached, usually within 2-5 weeks. Although many patients may respond adequately to dosages between 200-600 mg daily, a dosage of 600-900 mg daily may be required in some patients. In the multicenter study that provides the principal support for the effectiveness of clozapine in patients resistant to standard antipsychotic therapy, the maximum dosage of clozapine was 900 mg daily, which was given in 3 divided doses. The mean and median clozapine dosages in this study both were approximately 600 mg daily. Although some clinicians suggest that dosages exceeding 450-500 mg daily have not been shown to be associated with increased therapeutic benefit, others state that added response is observed at higher dosages in some patients and stress the need for individualized therapy. The manufacturers and most clinicians recommend that the maximum daily dosage of clozapine not exceed 900 mg. Because of the possibility that high dosages of clozapine may be associated with an increased risk of adverse reactions, particularly seizures, patients generally should be given adequate time to respond to a given dosage before dosage escalation is considered.

Pediatric Dosage

The dosage of clozapine for the management of schizophrenia in children and adolescents has not been established. However, the National Institute of Mental Health (NIMH) protocol used an initial dosage of 6.25-25 mg given orally daily depending on the patient's weight. Dosages could be increased in this study every 3-4 days by 1-2 times the initial dose on an individual basis up to a maximum of 525 mg daily.

Duration of Therapy

While some clinicians state that clozapine therapy should be continued for longer than 6 weeks only in patients who exhibit substantial benefit within this period, others state that even less than substantial degrees of benefit may warrant continued therapy and that an adequate trial of clozapine may require at least 12 weeks (e.g., at daily dosages of 200-600 mg daily) or possibly 5-9 months or longer unless clinical deterioration or intolerable or potentially serious toxicity precludes it. The manufacturers state that patients who respond to clozapine therapy generally should continue to receive maintenance treatment with the drug at their effective dosage beyond the acute episode. Extended therapy in patients failing to show an acceptable response to clozapine generally should be avoided because of the substantial, continuing risks of neutropenia and seizures.(See Severe Neutropenia under Cautions: Hematologic Effects and also see Seizures under Cautions: Nervous System Effects.)

The American Psychiatric Association (APA) states that prudent long-term treatment options in patients with schizophrenia with remitted first or multiple episodes include either indefinite maintenance therapy or gradual discontinuance of the antipsychotic agent with close follow-up and a plan to reinstitute treatment upon symptom recurrence. Discontinuance of antipsychotic therapy should be considered only after a period of at least 1 year of symptom remission or optimal response while receiving the antipsychotic agent. In patients who have had multiple previous psychotic episodes or 2 psychotic episodes within 5 years, indefinite maintenance antipsychotic treatment is recommended.

Suicide Risk Reduction

For suicide risk reduction in schizophrenia and schizoaffective disorder, the usual initial adult dosage of clozapine is 12.5 mg given orally once or twice daily. If the drug is well tolerated, dosage may be increased in increments of 25-50 mg daily over a 2-week period until a target dosage of 300-450 mg daily (administered in divided doses) is achieved. Subsequent dosage increases can be made once or twice weekly in increments of up to 100 mg. The manufacturers state that use of a low initial daily dosage, a gradual titration schedule, and administration of the drug in divided doses are necessary to minimize the risks of orthostatic hypotension, bradycardia, syncope, seizures, and sedation.(See Cautions: Nervous System Effects and also see Cautions: Cardiovascular Effects.) In the multicenter InterSePT study that provides the principal support for the effectiveness of clozapine for suicide risk reduction, mean dosage was about 300 mg daily (range: 12.5-900 mg daily).

The manufacturers state that patients who respond to clozapine therapy generally should continue to receive maintenance treatment with the drug at their effective dosage beyond the acute episode; efficacy of clozapine for this indication was demonstrated over a 2-year treatment period in the InterSePT study.

Discontinuance of Therapy

In the event of planned discontinuance of clozapine therapy, gradual reduction in dosage over a 1- to 2-week period is recommended if there is no evidence of moderate to severe neutropenia. However, if abrupt discontinuance of therapy is required because of moderate to severe neutropenia, ANC should be monitored according to the neutropenia monitoring recommendations. If abrupt discontinuance of clozapine is required for reasons unrelated to neutropenia, continuation of the existing ANC monitoring schedule is recommended; patients in the general population should be monitored until their ANC is in the normal range (i.e., at least 1500/mm) while patients with BEN should be monitored until their ANC is at least 1000/mm or above their baseline. Additional ANC monitoring is necessary in any patient reporting onset of fever (temperature of 38.5°C or greater) during the 2 weeks after clozapine discontinuance.(See Severe Neutropenia under Cautions: Hematologic Effects.) Patients should be observed carefully for recurrence of psychotic symptoms and symptoms related to cholinergic rebound such as profuse sweating, headache, nausea, vomiting, and diarrhea. Sudden withdrawal from clozapine therapy can lead to rapid decompensation and rebound psychosis.(See Other Nervous System Effects under Cautions: Nervous System Effects.)

Reinitiation of Therapy

If clozapine therapy is restarted in patients who have had even brief interruptions (i.e., 2 days or more since the last dose) in therapy, dosage generally should be titrated as with initial therapy (i.e., starting with 12.5 mg once or twice daily) to minimize the risk of hypotension, bradycardia, and syncope. If this dosage is well tolerated, dosage may be titrated back to the previous therapeutic dosage more quickly than recommended during initial treatment.

For clozapine treatment interruptions of less than 30 days in patients with normal ANC values, the same ANC monitoring schedule as before the treatment interruption may be continued. If clozapine treatment is interrupted for 30 days or more, the ANC monitoring schedule must be restarted as with initial therapy.(See Severe Neutropenia under Cautions: Hematologic Effects.)

Patients who develop severe neutropenia (ANC less than 500/mm) during clozapine therapy generally should not be restarted on the drug unless the clinician determines that the benefits of the drug outweigh the risks.(See Severe Neutropenia under Cautions: Hematologic Effects.)

Dosage in Renal and Hepatic Impairment or Poor CYP2D6 Metabolizers

Although the pharmacokinetics of clozapine have not been specifically studied in patients with renal or hepatic impairment, increased plasma clozapine concentrations are possible in such patients since the drug is almost completely metabolized and then excreted. The manufacturers state that dosage reduction may be necessary in patients with substantial impairment of renal or hepatic function.

The manufacturers state that dosage reduction of clozapine also may be necessary in patients who are known poor metabolizers of cytochrome P-450 isoenzyme 2D6 (CYP2D6).

Cautions

Although clozapine differs chemically from the phenothiazines, the drug may be capable of producing many of the toxic manifestations of phenothiazine derivatives. Not all adverse effects of the phenothiazines have been reported with clozapine, but the possibility that they may occur should be considered. Adverse effects of clozapine and the phenothiazines are numerous and may involve nearly all organ systems. Although these effects usually are reversible when dosage is reduced or the drug is discontinued, some effects may be irreversible and, rarely, fatal. In some patients, unexpected death associated with antipsychotic therapy has been attributed to cardiac arrest or asphyxia resulting from failure of the gag reflex.(See Cautions: Cardiovascular Effects.) In other cases, the cause of death could not be determined or definitely attributed to antipsychotic drug therapy. An increased risk of death has been observed in geriatric patients with dementia-related psychoses receiving antipsychotic agents.(See Cautions: Geriatric Precautions.)

The most frequent adverse effects of clozapine involve the central and autonomic nervous systems (e.g., drowsiness or sedation, hypersalivation) and the cardiovascular system (e.g., tachycardia, orthostatic hypotension, syncope). While the frequency and severity of some adverse effects (e.g., extrapyramidal reactions, tardive dyskinesia) appear to be less with clozapine than with other antipsychotic agents, other potentially serious adverse effects (e.g., severe neutropenia, seizures) may occur more frequently with clozapine therapy, and the potential risks and benefits should be evaluated carefully whenever therapy with the drug is considered. Because of the risk of severe clozapine-associated neutropenia, which may lead to serious and potentially fatal infections, clozapine is available only through a restricted distribution program that ensures appropriate monitoring of absolute neutrophil count (ANC). (See REMS and also see Severe Neutropenia under Cautions: Hematologic Effects.)

Hematologic Effects

Severe Neutropenia

Clozapine has been associated with neutropenia (i.e., a low absolute neutrophil count [ANC]) which can, when severe, increase the risk of serious and potentially fatal infections. Previously, the terms ''severe leukopenia,'' ''severe granulocytopenia,'' and ''agranulocytosis'' were used in the clozapine prescribing information (labeling) to describe this hematologic effect; however, to improve and standardize understanding, these terms have been replaced with ''severe neutropenia'' throughout the labeling for the drug. The ANC is usually available as a component of the complete blood count (CBC), including differential, and is considered more clinically relevant for drug-induced neutropenia than the white blood cell (WBC) count. Severe neutropenia is defined as an ANC value of less than 500/mm and occurs in a small percentage of patients receiving clozapine therapy.

Previously described agranulocytosis, which was defined as an ANC less than 500/mm and characterized by leukopenia (WBC count less than 2000/mm) and relative lymphopenia, has been reported to have an estimated cumulative incidence of 1-2% after 1 year of clozapine therapy, as compared with an estimated incidence of 0.1-1% for phenothiazine-induced agranulocytosis. Some evidence has suggested that the incidence of clozapine-induced agranulocytosis is at least 10 times greater than the incidence associated with other antipsychotic agents, although it also has been suggested that the incidence of clozapine-induced agranulocytosis may be no higher than that associated with phenothiazines.

The precise mechanism by which clozapine induces neutropenia is not known and is not dose-dependent, but both immunologic and toxic mechanisms (including a direct myelotoxic effect of the drug and/or its metabolites) have been implicated. Some evidence suggests that granulocyte antibodies may be involved.

Identified risk factors for clozapine-induced neutropenia or agranulocytosis include advanced age, female gender, and African-American and Asian ethnicity; pediatric patients also are at an increased risk. Results of genetic typing indicate that genetic factors marked by a major histocompatibility complex haplotype (HLA-B38, DR4, DQw3) may be associated with the susceptibility of certain Jewish patients with schizophrenia to develop agranulocytosis when treated with clozapine; the incidence of some phenotypes common among Ashkenazi Jews has been found to be greatly increased in patients with clozapine-induced agranulocytosis.

The risk of clozapine-induced neutropenia appears to be greatest during the first 18 weeks of therapy and declines thereafter. However, rare cases of neutropenia or agranulocytosis have been reported after several years of treatment with the drug.

Benign ethnic neutropenia (BEN) is a condition observed in certain ethnic groups whose average ANC values are lower than standard laboratory ranges for neutrophils. BEN has an approximate prevalence of 25-50% in individuals of African descent and also is observed in some Middle Eastern ethnic groups and in other non-Caucasian ethnic groups with darker skin; the condition is more common in men than women. Patients with BEN have normal hematopoietic stem cell numbers and myeloid maturation, are healthy, and do not suffer from repeated or severe infections. Such patients are not at increased risk for developing clozapine-induced neutropenia. BEN may be diagnosed by repeated low ANC measurements (less than 1500/mm and usually 1000/mm or below) for several months without identifiable causes of the neutropenia. Additional evaluation may be necessary in some patients to determine whether their baseline neutropenia is caused by BEN. Consultation with a hematologist should be considered in patients with low baseline ANC values before initiating or during clozapine therapy, if necessary. Patients with documented BEN have different ANC monitoring and treatment recommendations during clozapine therapy than the general population because of their lower baseline ANC levels.(See Table 2.)

Because of the risk of severe neutropenia associated with clozapine use, patients must have a baseline CBC and ANC performed before initiation of therapy and regular ANC monitoring during treatment with the drug. (See Restricted Distribution Program under Dosage and Administration: Administration.) Clozapine therapy should not be initiated if baseline ANC is less than 1500/mm (or less than 1000/mm in patients with documented BEN).

When initiating clozapine therapy, ANC must be monitored every week for the first 6 months of therapy and then every 2 weeks for the next 6 months if ANC values remain in the normal range. If ANC values continue to be maintained in the normal range after an additional 6 months (i.e., following 12 months of continuous treatment), the frequency of monitoring may be reduced to once every 4 weeks thereafter. If clozapine treatment is interrupted for 30 days or longer, the initial ANC monitoring schedule should be restarted beginning with once-weekly ANC monitoring.

See Tables 1and 2 for clozapine treatment recommendations based on ANC monitoring in the general patient population and in patients with BEN, respectively.

For hospice patients (i.e., patients who are terminally ill with an estimated life expectancy of 6 months or less) receiving clozapine therapy, the ANC monitoring frequency may be reduced by the clinician to once every 6 months, after a discussion with the patient and caregiver. Treatment decisions in such individuals should weigh the importance of ANC monitoring in the context of the need to control psychiatric symptoms and the patient's terminal illness.

Table 1. Clozapine Treatment Recommendations based on ANC Monitoring in the General Patient Population[1 ][395 ][400 ][406 ][408 ]
ANC Value Treatment Recommendations Frequency of ANC Monitoring
Normal range (ANC >=1500/mm) Initiate treatmentIf treatment interrupted <30 days, continue monitoring as beforeIf treatment interrupted >=30 days, monitor as if new patient Weekly from initiation to 6 monthsEvery 2 weeks from 6-12 monthsMonthly after 12 months
Discontinuance for reasons other than neutropenia See Discontinuance of Therapy under Dosage and Administration: Dosage
Mild neutropenia (ANC 1000-1499/mm) Continue treatment 3 times weekly until ANC >=1500/mmWhen ANC >=1500/mm, return to patient's last normal range ANC monitoring interval, if clinically appropriate
Moderate neutropenia (ANC 500-999/mm) Recommend hematology consultationInterrupt treatment for suspected clozapine-induced neutropeniaResume treatment once ANC >=1000/mm Daily until ANC >=1000/mm3 times weekly until ANC >=1500/mmWhen ANC >=1500/mm, monitor weekly for 4 weeks, then return to the patient's last normal range ANC monitoring interval, if clinically appropriate
Severe neutropenia (ANC <500/mm) Recommend hematology consultationInterrupt treatment for suspected clozapine-induced neutropeniaDo not rechallenge unless prescriber determines benefits outweigh risks Daily until ANC >=1000/mm3 times weekly until ANC >=1500/mmIf patient rechallenged, resume treatment and monitor as new patient under normal range monitoring once ANC >=1500/mm

Confirm all initial reports of ANC <1500/mm3 with a repeat ANC measurement within 24 hours.

Table 2. Clozapine Treatment Recommendations based on ANC Monitoring in Patients with Benign Ethnic Neutropenia (BEN)[1 ][395 ][400 ][406 ][408 ]
ANC Value Treatment Recommendations Frequency of ANC Monitoring
Normal BEN range (established ANC baseline >=1000/mm) Obtain >=2 baseline ANC values before initiating treatmentIf treatment interrupted <30 days, continue monitoring as beforeIf treatment interrupted >=30 days, monitor as if new patient Weekly from initiation to 6 monthsEvery 2 weeks from 6-12 monthsMonthly after 12 months
Discontinuance of treatment for reasons other than neutropenia See Discontinuance of Therapy under Dosage and Administration: Dosage
BEN neutropenia (ANC 500-999/mm) Recommend hematology consultationContinue treatment 3 times weekly until ANC >=1000/mm or at patient's known baselineWhen ANC >=1000/mm or at patient's known baseline, monitor weekly for 4 weeks, then return to the patient's last normal BEN range ANC monitoring interval, if clinically appropriate
BEN severe neutropenia (ANC <500/mm) Recommend hematology consultationInterrupt treatment for suspected clozapine-induced neutropeniaDo not rechallenge unless prescriber determines benefits outweigh risks Daily until ANC >=500/mm3 times weekly until ANC at or above patient's baselineIf patient rechallenged, resume treatment as a new patient under normal range monitoring once ANC >=1000/mm or at patient's baseline

Confirm all initial reports of ANC <1500/mm3 with a repeat ANC measurement within 24 hours.

If a patient develops fever (temperature of 38.5°C or higher) during therapy, clozapine should be interrupted and an ANC should be obtained. Fever is often the first sign of neutropenic infection. If fever occurs in any patient with an ANC value less than 1000/mm, the patient should be appropriately evaluated (see Tables 1and 2) and treated for infection. A hematology consultation should be considered in all clozapine-treated patients with fever or neutropenia.

Although some clinicians have suggested that body temperature be measured at least once daily for the first 18 weeks of clozapine therapy, others state that such monitoring is not an adequate means of assessing infection in clozapine-treated patients because of the drug's pharmacologic potential for causing temperature elevation (see Cautions: Fever). Patients receiving clozapine should be advised to immediately report the appearance of lethargy, weakness, fever, sore throat, or any other potential manifestations of infection.

Supportive therapy with biosynthetic hematopoietic agents, including filgrastim, a recombinant human granulocyte colony-stimulating factor (G-CSF), and sargramostim, a recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), has been effective in a limited number of patients with clozapine-induced neutropenia and agranulocytosis. Consultation with a hematologist and infectious disease expert is recommended.

Lithium has been used successfully in the treatment of clozapine-induced neutropenia or to facilitate initiation of therapy or rechallenge with the drug in a limited number of patients, including in some patients with BEN. However, lithium should be used concurrently with clozapine with caution because, in addition to the possible increased risk of NMS and seizures, the drug can mask the development or delay the detection of severe neutropenia and other blood dyscrasias.(See Drug Interactions: Other CNS-active Agents.)

When neutropenia is diagnosed and clozapine therapy is discontinued, patients usually recover in 7-28 days. Most of these patients require further antipsychotic therapy because of a recurrence of psychotic symptoms.(See Other Nervous System Effects under Cautions: Nervous System Effects.) Since there appears to be no cross-sensitivity between clozapine and other antipsychotics in terms of hematologic toxicity, other antipsychotic drugs generally may be used without causing further hematologic complications in patients who develop clozapine-induced neutropenia. Patients who develop severe clozapine-induced neutropenia generally should not be rechallenged with clozapine. However, for some patients who have no acceptable alternatives to clozapine, the risk of serious psychiatric illness from discontinuing treatment may outweigh the risk of severe neutropenia upon rechallenge; in such cases, consultation with a hematology specialist may be helpful in deciding whether to rechallenge a patient with clozapine.

Eosinophilia

Eosinophilia (defined as blood eosinophil count exceeding 700/mm) has been reported in approximately 1% of patients who received clozapine therapy in clinical trials. Clozapine-associated eosinophilia usually occurs during the first month of therapy and has been associated with myocarditis, pancreatitis, hepatitis, colitis, and/or nephritis in some patients. Such organ involvement could be consistent with drug reaction with eosinophilia and systemic symptoms (DRESS; also known as multiorgan hypersensitivity or drug-induced hypersensitivity syndrome).

The manufacturers state that if eosinophilia develops during clozapine therapy, the patient should be evaluated promptly for signs and symptoms of systemic reactions such as rash or other allergic symptoms, myocarditis, or other organ-specific disease associated with eosinophilia. If clozapine-associated systemic disease is suspected, the drug should be immediately discontinued. If a cause of eosinophilia unrelated to clozapine is identified (e.g., asthma, allergies, collagen vascular disease, parasitic infections, specific neoplasms), the underlying cause should be treated and clozapine therapy may be continued.

Clozapine-associated eosinophilia also has occurred without organ involvement and can resolve without intervention. In such cases, clozapine therapy may be continued with careful monitoring. If the patient's total eosinophil count continues to increase over several weeks in the absence of organ involvement, the decision whether to interrupt clozapine therapy and rechallenge after the eosinophil count decreases should be made based on the overall clinical assessment, in consultation with an internist or hematologist. There have been reports of successful rechallenge after discontinuance of clozapine without recurrence of eosinophilia.

Other Hematologic Effects

Other hematologic effects reported with clozapine therapy include leukopenia/decreased WBC count and neutropenia, which has been reported in 3% of patients. Other clozapine-induced hematologic effects reportedly include basophilia and a substantial reduction in B cells. Elevated hemoglobin/hematocrit, elevated erythrocyte sedimentation rate (ESR), sepsis, thrombocytosis, and thrombocytopenia have been reported in patients receiving clozapine during postmarketing surveillance; however, a causal relationship to the drug has not been established.

Nervous System Effects

Seizures

Clozapine lowers the seizure threshold and can cause EEG changes, including the occurrence of spike and wave complexes. Seizures reportedly occurred in approximately 3.5% of patients exposed to the drug during clinical trials in the US (cumulative annual incidence of approximately 5%). In contrast, a seizure incidence of approximately 1% has been reported in patients treated with other antipsychotic agents. The risk of seizures with clozapine therapy is dose related, with a reported incidence of approximately 0.6-2% at dosages less than 300 mg daily, 1.4-5% at 300-600 mg daily, and 5-14% at high dosages (600-900 mg daily). Clozapine-induced seizures may be associated with rapid dosage escalations, particularly in patients receiving concomitant therapy with drugs that may cause increased plasma concentrations of clozapine.(See Seizures under Cautions: Precautions and Contraindications.)

One patient receiving clozapine experienced a generalized tonic-clonic (grand mal) seizure following accidental ingestion of an extra dose (total dose ingested within 24 hours: 1050 mg); the same patient had another seizure several weeks later, 2 hours after a usual 450-mg morning dose. Results of plasma clozapine determinations obtained at the time of the seizures revealed plasma clozapine concentrations of approximately 2000 ng/mL in each case. Another patient who had been taking clozapine for 27 months had a generalized tonic-clonic seizure following an apparent intentional overdosage (total dose ingested within 24 hours: approximately 3 g), after which the patient made an uneventful recovery. One hour after the seizure, the patient's plasma clozapine concentration was 1313 ng/mL.

Discontinuance of clozapine therapy, at least temporarily, should be seriously considered in patients who experience seizures while receiving the drug; however, some clinicians state that reduced clozapine dosage and/or, occasionally, addition of anticonvulsant therapy may adequately ameliorate this effect. If clozapine therapy is to be continued in such patients, many clinicians recommend obtaining additional informed consent from the patient. In patients in whom clozapine is withheld, it has been suggested that therapy with the drug can be reinitiated at one-half the previous dosage. Clozapine dosage may then be increased gradually, if clinically indicated, and the need for concomitant anticonvulsant therapy should be considered. Some clinicians recommend that patients who have experienced a clozapine-induced seizure not be given clozapine dosages exceeding 600 mg daily unless the results of an EEG performed prior to the anticipated dosage increase are normal; others suggest addition of anticonvulsant therapy and/or consultation with a neurologist in managing such patients. In patients with preexisting seizure disorders who are treated concomitantly with certain anticonvulsants and clozapine, the anticonvulsant dosage may need to be increased.(See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Extrapyramidal Reactions

In contrast to some other antipsychotic agents, clozapine has little or no potential for causing certain acute extrapyramidal effects (e.g., dystonias). Such effects, when they occur, have been limited principally to tremor, restlessness, rigidity, and akathisia. In addition, marked or total remission of such manifestations induced by other antipsychotics has occurred during treatment with clozapine in some patients.

One case of clozapine-associated tardive dystonia (blepharospasm) has been reported; the patient's symptoms in this case were alleviated by discontinuance of clozapine and initiation of clonazepam therapy.

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome, has been reported in patients receiving antipsychotic agents, including clozapine. NMS attributable to clozapine therapy alone has been reported in some patients, and there also have been reports of NMS in patients treated concomitantly with clozapine and lithium or other CNS drugs; some clinicians suggest that NMS may be more likely to occur when clozapine or other antipsychotic agents are used concomitantly with lithium. Manifestations of NMS (e.g., muscle rigidity, hyperpyrexia, tachycardia, increased serum creatine kinase [CK, creatine phosphokinase, CPK], diaphoresis, somnolence), all of which may not occur in all patients with the condition, have occurred in a few patients treated with clozapine alone or combined with lithium or carbamazepine; resolution of the syndrome occurred following discontinuance of clozapine. However, clozapine also has been used successfully and apparently without recurrence of NMS in at least one patient who developed the syndrome while receiving chlorpromazine. Atypical presentations of NMS (e.g., absence of or lessened rigidity, absence of fever) also have been reported in some patients receiving clozapine.

The diagnostic evaluation of patients with NMS is complicated. In arriving at a diagnosis, serious medical illnesses (e.g., severe neutropenia, infection) and extrapyramidal symptoms must be excluded. 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 immediate discontinuance of antipsychotic agents and other drugs not considered essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and treatment of any concomitant serious medical conditions for which specific treatments are available. There currently is no specific drug therapy for NMS, although dantrolene, bromocriptine, amantadine, and benzodiazepines have been used in a limited number of patients. If a patient requires antipsychotic therapy following recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. In addition, such patients should be carefully monitored since NMS may recur. For additional information on NMS, including treatment,

Tardive Dyskinesia

Use of antipsychotic agents, including clozapine, may be associated with tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements. However, clozapine is considered less likely to cause tardive dyskinesia than many other antipsychotic agents, and dyskinetic movements in some patients have reportedly improved with clozapine therapy.

The risk of developing tardive dyskinesia 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 following relatively brief treatment periods at low dosages. Management of tardive dyskinesia generally consists of gradual discontinuance of the precipitating antipsychotic agent when possible, reducing the dosage of the first-generation (conventional) antipsychotic agent or switching to a second-generation (atypical) antipsychotic agent, or switching to clozapine therapy. The syndrome may remit, partially or completely, if antipsychotic therapy is discontinued. However, antipsychotic therapy itself may suppress or partially suppress the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that such symptomatic suppression has upon the long-term course of tardive dyskinesia is unknown. Vesicular monoamine transporter 2 (VMAT2) inhibitors (e.g., deutetrabenazine, valbenazine tosylate) have been shown to be effective in reducing symptoms of tardive dyskinesia in controlled clinical studies and may allow some patients to continue receiving antipsychotic therapy. ( and .)

Clozapine should be prescribed in a manner that is most likely to minimize the occurrence of this syndrome. In patients who do require chronic treatment, the lowest dosage and the shortest duration of treatment producing a satisfactory clinical response should be sought, and the need for continued treatment should be reassessed periodically.

The American Psychiatric Association (APA) currently recommends that patients receiving atypical antipsychotic agents be assessed clinically for abnormal involuntary movements every 12 months and that patients considered to be at increased risk for tardive dyskinesia be assessed every 6 months. If signs and symptoms of tardive dyskinesia appear in a clozapine-treated patient, clozapine discontinuance should be considered; however, some patients may require continued treatment with the drug despite the presence of the syndrome.

For additional information on tardive dyskinesia, including manifestations and treatment, .

Other Nervous System Effects

Drowsiness and/or sedation occurs frequently in patients receiving clozapine.(See Effects on Sleep under Pharmacology: Nervous System Effects.) Somnolence reportedly occurred in 46% of patients receiving clozapine in the International Suicide Prevention Trial (InterSePT) compared with 25% of those receiving olanzapine. The sedative-hypnotic effect of clozapine is most pronounced initially, diminishes after 1-4 weeks, and then generally, but not always, disappears during continued therapy. Daytime sleepiness may be minimized by administration of clozapine at bedtime. (See Dosage and Administration and also see Cognitive and Motor Impairment under Cautions: Precautions and Contraindications.)

Dizziness and vertigo, headache, syncope, disturbed sleep (e.g., insomnia) or nightmares, hypokinesia or akinesia, and agitation have been reported with clozapine therapy. In the InterSePT study, dizziness (excluding vertigo) and insomnia reportedly occurred in 27 and 20% of patients receiving clozapine, respectively, compared with 12 and 33% of those receiving olanzapine, respectively. Clozapine also may cause confusion or delirium, which may be related to central anticholinergic effects and has been ameliorated in some cases by IV administration of physostigmine. Depression, fatigue, hyperkinesia, weakness or lethargy, and slurred speech also have been reported.

Delirium, abnormal EEG, myoclonus, paresthesia, possible cataplexy, status epilepticus, obsessive-compulsive symptoms, and post-discontinuation cholinergic rebound reactions have been reported in patients receiving clozapine during postmarketing surveillance; however, a causal relationship to the drug has not been established.

Abrupt discontinuance of clozapine (e.g., because of hematologic toxicity or other medical condition) may result in recurrence of psychotic symptoms or behavior, including autism, auditory hallucinations, suicide attempts, development of parkinsonian symptoms, anxiety, insomnia, delusions, and violent behavior. It has been suggested that this ''rebound psychosis'' may result, at least in part, from clozapine-induced supersensitivity of mesolimbic dopamine receptors(see Behavioral Effects in Animals under Pharmacology: Nervous System Effects) and that the essential feature of this phenomenon appears to be recurrence of positive symptoms of schizophrenia. Patients who develop rebound psychosis following discontinuance of clozapine may improve with initiation of other antipsychotic therapy; however, clozapine generally should not be reinstituted in patients in whom severe neutropenia has occurred.(See Cautions: Hematologic Effects.)

Fever

Fever or transient temperature elevations exceeding 38°C generally have been reported in 5% or more of patients receiving clozapine. The peak incidence of fever occurs within the first 3 weeks of therapy, usually between days 5-20 of treatment. Fever generally is benign and self-limiting, responds to supportive measures, and usually diminishes within a few (4-8) days despite continued clozapine therapy; however, it may necessitate discontinuance of the drug. Fever occasionally may be associated with an increase or decrease in WBC count. Clozapine therapy should be interrupted as a precautionary measure; an ANC should be obtained in any patient who develops fever (38.5°C or higher) during treatment, and patients should be evaluated for severe neutropenia or infection. In addition, ANC should be monitored in any patient who develops fever within 2 weeks after discontinuance of clozapine.(See Cautions: Hematologic Effects.) Neuroleptic malignant syndrome also must be considered.(See Neuroleptic Malignant Syndrome under Cautions: Nervous System Effects.)

The mechanism of clozapine-induced fever (other than that occurring secondary to some other factor such as infection) is not yet known. It may result from the drug's pronounced anticholinergic activity (see Anticholinergic Effects under Pharmacology: Nervous System Effects) or a direct effect on the hypothalamic thermoregulatory center. Clozapine-induced hyperthermia may be a hypersensitivity reaction, a common mechanism underlying drug fevers. It has been suggested that decreasing the dosage of clozapine and then gradually increasing it to the previous level may reverse the hyperthermia and not be accompanied by a recurrence of elevated temperature; however, recurrence is possible despite such dosage adjustment.

Cardiovascular Effects

Myocarditis and Cardiomyopathy

Myocarditis and cardiomyopathy, which are sometimes fatal, have been reported in patients receiving clozapine. Myocarditis most frequently presents within the first 2 months of clozapine treatment. Symptoms of clozapine-associated cardiomyopathy generally occur later than clozapine-associated myocarditis, usually after 8 weeks of treatment. However, myocarditis and cardiomyopathy can occur at any time during clozapine therapy. Overt manifestations of heart failure commonly are preceded by nonspecific flu-like symptoms (e.g., malaise, myalgia, pleuritic chest pain, low-grade fever). Typical laboratory findings include elevated troponin I or T concentrations, elevated CK-MB concentrations, peripheral eosinophilia, and elevated C-reactive protein (CRP) concentrations. Left ventricular dysfunction may be evident in cardiac imaging studies (e.g., electrocardiogram [ECG], radionucleotide studies, cardiac catheterization) and cardiac silhouette enlargement may be seen in chest radiographs.

The possibility of myocarditis or cardiomyopathy should be considered in patients receiving clozapine who present with chest pain, dyspnea, persistent tachycardia at rest, palpitations, fever, flu-like symptoms, hypotension, or other manifestations of heart failure or ECG changes associated with these conditions (e.g., low voltages, ST-T wave abnormalities, arrhythmias, right axis deviation, poor R wave progression). If myocarditis or cardiomyopathy is suspected, clozapine therapy should be discontinued and a cardiac evaluation should be obtained. Patients with a history of clozapine-associated myocarditis or cardiomyopathy generally should not be rechallenged with the drug. However, if the benefit of clozapine treatment is determined to outweigh the potential risks of recurrent myocarditis or cardiomyopathy, the clinician may consider rechallenge with the drug in consultation with a cardiologist, following a complete cardiac evaluation, and with close monitoring.

Thromboembolic Effects

Deep-vein thrombosis and pulmonary embolism have been reported in patients receiving clozapine. Although a causal relationship between clozapine and these adverse effects has not been established, the possibility of pulmonary embolism should be considered in patients presenting with deep-vein thrombosis, acute dyspnea, chest pain, or respiratory symptomatology.(See Thromboembolic Events under Cautions: Precautions and Contraindications.)

Blood Pressure Effects

Hypotension and hypertension reportedly occur in less than 10% of patients receiving clozapine. When they occur, changes in blood pressure, principally reductions in systolic pressure, appear soon after initiation of clozapine therapy and may be associated with rapid dosage increases. A decrease in arterial blood pressure below 90 mm Hg was reported in 18% of male patients and 33% of female patients receiving clozapine in one retrospective study. Hypotension may result from clozapine's antiadrenergic effects(see Adrenergic Effects under Pharmacology: Nervous System Effects). However, tolerance to the hypotensive effects of clozapine often develops with continued therapy.

Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have been reported, particularly during initial titration or rapid escalation of clozapine dosage. Rarely (approximately 1 case per 3000 patients), orthostatic hypotension has been accompanied by profound collapse and respiratory and/or cardiac arrest in patients receiving initial doses as low as 12.5 mg. Such reactions, which are sometimes fatal, are consistent with neurally-mediated reflex bradycardia. In some cases when collapse and cardiac and/or respiratory arrest developed during initial therapy, benzodiazepines or other psychotropic agents were used concomitantly, suggesting a possible adverse interaction between clozapine and these agents.(See Benzodiazepines under Drug Interactions: CNS Depressants.)

The risk of orthostatic hypotension may be reduced by initiating clozapine therapy at lower dosages, followed by gradual increases, and administration in divided doses.(See Dosage and Administration: Dosage.) If hypotension occurs, dosage reduction of clozapine may be considered. In some cases, withholding the drug for 24 hours and then restarting at a lower dosage has been accomplished without recurrence of orthostatic hypotension. If clozapine therapy is temporarily interrupted (i.e., for 2 or more days), the manufacturers recommend that the drug be reinitiated at a lower dosage (12.5 mg once or twice daily).

Prolongation of QT Interval

Prolongation of the QT interval, torsades de pointes and other life-threatening ventricular arrhythmias, cardiac arrest, and sudden death have occurred in patients receiving clozapine. Patients at particular risk for these serious cardiovascular reactions include those with a history of QT-interval prolongation, long QT syndrome, family history of long QT syndrome or sudden cardiac death, significant cardiac arrhythmia, recent myocardial infarction, and uncompensated heart failure and those concurrently receiving other drugs that prolong the QT interval or inhibit the metabolism of clozapine. (See Drug Interactions: Drugs that Prolong the QT Interval and see also Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.) Electrolyte abnormalities such as hypokalemia and hypomagnesemia also increase the risk of QT-interval prolongation.

Prior to initiating clozapine therapy, a careful physical examination should be performed and a medical and concomitant medication history should be obtained. A baseline ECG and serum chemistry panel should also be considered before initiating clozapine therapy. Clozapine should be discontinued if the corrected QT (QTc) interval exceeds 500 msec. Clozapine should also be discontinued and a cardiac evaluation performed in patients who experience symptoms consistent with torsades de pointes or other arrhythmias (e.g., syncope, presyncope, dizziness, palpitations).

Baseline serum potassium and magnesium concentrations should be determined and electrolyte abnormalities, if present, should be corrected prior to initiating clozapine therapy. In addition, serum electrolytes should be periodically monitored during clozapine therapy.

Other Cardiovascular Effects

Tachycardia, which may persist throughout therapy in some cases, reportedly has been observed in up to 25% of patients receiving clozapine in clinical studies.

Postexercise decreases in left ventricular output, which may indicate left ventricular failure, have been reported in patients receiving clozapine. Although a causal relationship has not been established, atrial or ventricular fibrillation, ventricular tachycardia, and myocardial infarction also have been reported during postmarketing surveillance in patients receiving the drug.

Autonomic Nervous System Effects

Adverse autonomic nervous system effects occur in more than 5% of patients receiving clozapine. Dry mouth occurs frequently, but hypersalivation, an apparently paradoxical effect considering the drug's potent anticholinergic activity, is more common.(See Cautions: GI Effects.)

Other autonomic nervous system effects of clozapine include hyperhidrosis, decreased sweating, and visual disturbances. Increased salivation occurred in 31%, dry mouth and sweating in 6%, and visual disturbances in 5% of patients receiving clozapine in controlled clinical trials.

Hepatic Effects

Transient increases in liver function test results, including serum aminotransferases (transaminases), LDH, and alkaline phosphatase, may occur with clozapine therapy. Clozapine-induced changes in liver function test results may be more pronounced than those with other tricyclic antipsychotic agents. Clozapine causes slight liver hyperplasia in rats; hyperplasia was reversible and no histologic changes were detectable. Clozapine occasionally causes slight elevations of bilirubin concentration. Cholestasis, hepatitis, jaundice, hepatotoxicity, hepatic steatosis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, liver injury (hepatic, cholestatic, and mixed), and liver failure have been reported in patients receiving clozapine during postmarketing surveillance; however, a causal relationship to the drug has not been established.

Endocrine and Metabolic Effects

Atypical antipsychotic agents have been associated with metabolic changes, including hyperglycemia, dyslipidemia, and weight gain. Such metabolic changes may be associated with increased cardiovascular and cerebrovascular risk.

Weight Gain

Weight gain has been observed with antipsychotic therapy. Clozapine may cause increased appetite, polyphagia, and weight gain in a substantial proportion (approximately one-third) of patients. Some clinicians suggest that the potential for weight gain with clozapine therapy may be similar to that with other antipsychotic therapy; others state that they have observed greater weight gain with clozapine in some patients. In the 2-year InterSePT trial, weight gain reportedly occurred in 31% of patients receiving clozapine compared with 56% of those receiving olanzapine. Some clozapine-treated patients reportedly have gained up to 1 kg weekly for 6 weeks. Pooled data from 11 clinical studies in patients with schizophrenia indicate that 35% of clozapine-treated patients (median duration of exposure 609 days), 46% of olanzapine-treated patients (median duration of exposure 728 days), and 8% of chlorpromazine-treated patients (median duration of exposure 42 days) gained 7% or more of their baseline body weight.

Weight gain may result from the drug's serotonergic-, histaminergic-, and adrenergic-blocking properties. Weight gain has been reported to be a problem for some patients during long-term therapy with clozapine and may be a major cause of outpatient noncompliance. Some clinicians suggest using exercise and active measures (e.g., dietary counseling) to control dietary intake in clozapine-treated patients.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients receiving certain atypical antipsychotic agents, including clozapine. While confounding factors such as an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population make it difficult to establish with certainty the relationship between use of agents in this drug class and glucose abnormalities, epidemiologic studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotic agents included in the studies (e.g., clozapine, olanzapine, quetiapine, risperidone).(See Cautions: Precautions and Contraindications.)

Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics currently are not available. While some evidence suggests that the risk for diabetes may be greater with some atypical antipsychotics (e.g., clozapine, olanzapine) than with others (e.g., quetiapine, risperidone) in the class, available data are conflicting and insufficient to provide reliable estimates of relative risk associated with use of the various atypical antipsychotics.

In an analysis of 5 clinical studies in patients with schizophrenia (median treatment duration of 42 days), clozapine was associated with a greater average increase in fasting glucose concentrations compared with chlorpromazine (11 mg/dL versus 4 mg/dL, respectively). A greater proportion of patients receiving clozapine experienced shifts in fasting glucose concentrations from normal (less than 100 mg/dL) to high (126 mg/dL or higher) and from borderline (100-125 mg/dL) to high (126 mg/dL or higher) compared with those receiving chlorpromazine. Shifts in fasting glucose concentrations from normal to high were observed in 27 or 10%, and from borderline to high in 42 or 28% of patients receiving clozapine or chlorpromazine, respectively.

Dyslipidemia

Like some other antipsychotic agents, clozapine therapy has been associated with undesirable changes in lipid parameters, including elevations in serum cholesterol and triglyceride concentrations.

In a pooled analysis of 10 clinical studies in adults with schizophrenia, the mean increase in total cholesterol concentrations was 13 or 15 mg/dL in patients receiving clozapine or chlorpromazine, respectively, and in a pooled analysis of 2 studies in adults with schizophrenia, the mean increase in fasting triglyceride concentrations in clozapine-treated patients was 71 mg/dL (54%) compared with 39 mg/dL (35%) in chlorpromazine-treated patients. In these studies, the median duration of exposure was 45 or 38 days for clozapine or chlorpromazine, respectively; specific data on high-density lipoprotein (HDL)- or low-density lipoprotein (LDL)-cholesterol were not collected. An increase in serum total cholesterol concentrations (random or fasting) of 40 mg/dL or higher occurred in 33 or 25%, and increases in fasting serum triglyceride concentrations of 50 mg/dL or higher occurred in 50 or 43% of adults receiving clozapine or chlorpromazine, respectively. In addition, a greater proportion of patients receiving clozapine experienced an increase in serum total cholesterol concentrations from normal (below 200 mg/dL) to high (240 mg/dL or higher) or from borderline (200-239 mg/dL) to high (240 mg/dL or higher) compared with those receiving chlorpromazine.

The manufacturers recommend clinical monitoring, including baseline and periodic follow-up lipid evaluations, in patients receiving clozapine.

Hyperprolactinemia

Clozapine causes little or no elevation in serum prolactin concentrations. The drug has been reported to cause only a brief, transient elevation of prolactin concentration.(See Pharmacology: Neuroendocrine Effects.) Therefore, prolactin-dependent adverse effects such as galactorrhea and amenorrhea usually are not associated with clozapine therapy.

Other Endocrine and Metabolic Effects

Hyperuricemia, hyponatremia, weight loss, and pseudopheochromocytoma also have been reported in patients receiving clozapine during postmarketing surveillance, although a causal relationship to the drug has not been established.

Small decreases in protein-bound iodine or thyroxine concentrations have been reported in some patients receiving clozapine, but these values remained within normal limits.

GI Effects

Increased salivation may occur in approximately one-third of patients receiving clozapine; in some studies, hypersalivation was reported in up to 75-85% of clozapine-treated patients. In the InterSePT trial, increased salivation reportedly occurred in 48% of patients receiving clozapine compared with 6% of those receiving olanzapine. Salivation may be profuse, very fluid, and particularly troublesome during sleep because of decreased swallowing. Since clozapine exhibits intrinsic anticholinergic properties, hypersalivation is an unexpected paradoxical effect. A muscle-relaxant effect of the drug may contribute to hypersalivation, but the cause has not been fully elucidated. Difficulty in swallowing has been reported in a few clozapine-treated patients, and it has been suggested that the drug may cause esophageal dysfunction, which may contribute to or exacerbate the nocturnal hypersalivation associated with clozapine therapy. Some clozapine-treated patients develop tolerance to increased salivation within a few weeks. Nonpharmacologic interventions such as the use of a towel on the pillow at night may help reduce the discomfort associated with clozapine-associated hypersalivation during sleep. Occasionally, hypersalivation may be ameliorated by reduction of clozapine dosage or cautious use of a peripherally acting anticholinergic drug; however, some clinicians generally advise against the use of anticholinergic therapy for this adverse effect because of possible potentiation of clozapine's anticholinergic activity.(See Anticholinergic Toxicity under Cautions: Precautions and Contraindications.)

Other GI effects associated with clozapine therapy include constipation, diarrhea, nausea and vomiting, dyspepsia or heartburn, and abdominal discomfort; some of these effects have been reported in more than 5% of patients. Constipation, nausea, vomiting, and dyspepsia reportedly occurred in 14-25% of patients receiving clozapine in the InterSePT trial compared with 8-10% of those receiving olanzapine. Although some clinicians advocate the use of metoclopramide (e.g., in doses less than 30 mg daily) for the treatment of clozapine-induced nausea, other clinicians suggest that metoclopramide or other dopamine antagonists not be used or be used with extreme caution for the treatment of clozapine-induced nausea because of their potential for causing parkinsonian manifestations and tardive dyskinesia.

Although a causal relationship to the drug has not been established, acute pancreatitis, dysphagia, salivary gland swelling, and colitis also have been reported in patients receiving clozapine during postmarketing surveillance.

Genitourinary Effects

Genitourinary effects reported with clozapine therapy include polyuria, enuresis, and impotence. Acute interstitial nephritis, renal failure, nocturnal enuresis, priapism, and retrograde ejaculation also have been reported with clozapine therapy during postmarketing surveillance, although a causal relationship to the drug has not been established.

Respiratory Effects

Although a causal relationship to the drug has not been established, aspiration, pleural effusion, and pneumonia and lower respiratory tract infection have been reported with clozapine therapy during postmarketing surveillance.

Respiratory depression or failure, including arrest requiring resuscitation, also has been reported in patients receiving clozapine, usually at initiation of therapy and particularly in patients receiving concomitant benzodiazepine therapy or in those with a history of recent benzodiazepine use. Some evidence indicates that the incidence of respiratory arrest and vascular collapse is about 1-2% of patients receiving clozapine concomitantly with a benzodiazepine. For additional precautionary information about this potential effect, see Benzodiazepines under Drug Interactions: CNS Depressants.

Dermatologic and Sensitivity Reactions

Rash has been reported in 2% of patients receiving clozapine.

Hypersensitivity reactions, including photosensitivity, vasculitis, erythema multiforme, skin pigmentation disorder, and Stevens-Johnson syndrome, have been reported with clozapine during postmarketing surveillance; however, a causal relationship to the drug has not been established.

Other Adverse Effects

Myasthenic syndrome, rhabdomyolysis, systemic lupus erythematosus, angioedema, periorbital edema, leukocytoclastic vasculitis, and angle-closure (narrow angle) glaucoma have been reported with clozapine during postmarketing surveillance, although a causal relationship to the drug has not been established.

Precautions and Contraindications

Clozapine shares many of the toxic potentials of other antipsychotic agents (e.g., phenothiazines), and the usual precautions associated with therapy with these agents should be observed.

Cognitive and Motor Impairment

Because of clozapine's sedative effects and because the drug potentially may impair cognitive and motor performance, clozapine-treated patients should be cautioned about operating hazardous machinery, including driving a motor vehicle, until they are reasonably certain that the drug does not adversely affect them. Because such effects may be dose-related, a reduction in clozapine dosage should be considered if they occur.

Fever

During clozapine therapy, patients may experience transient temperature elevations exceeding 38°C, with the peak incidence within the first 3 weeks of therapy.(See Cautions: Fever.) While this fever generally is benign and self-limiting, it may necessitate discontinuance of therapy. Occasionally, there may be an associated increase or decrease in leukocyte count.

Clozapine therapy should be interrupted as a precautionary measure and an ANC obtained in any patient who develops fever (38.5°C or higher) during treatment; patients should be carefully evaluated to rule out severe neutropenia or infection. In addition, ANC should be monitored in any patient who develops fever within 2 weeks after discontinuance of clozapine. In the presence of high fever, the possibility of neuroleptic malignant syndrome also must be considered.(See Neuroleptic Malignant Syndrome under Cautions: Nervous System Effects.)

Anticholinergic Toxicity

Clozapine has potent anticholinergic activity, and therapy with the drug may result in CNS and peripheral anticholinergic toxicity. Clozapine should therefore be used with caution in individuals whose condition may be aggravated by anticholinergic effects (e.g., patients with prostatic hypertrophy, urinary retention, angle-closure [narrow-angle] glaucoma) and in those who are concurrently receiving other drugs with anticholinergic effects.(See Drug Interactions: Drugs with Anticholinergic Activity.)

Clozapine therapy has been associated with varying degrees of impairment of intestinal peristalsis, ranging from constipation to intestinal obstruction, fecal impaction, and paralytic ileus, that rarely have been fatal. The manufacturers state that constipation may be treated initially by maintaining adequate hydration and with appropriate supportive therapy such as bulk-forming laxatives. Consultation with a gastroenterologist is recommended in more severe cases.

Thromboembolic Events

Pulmonary embolism and deep-vein thrombosis have been reported with clozapine therapy. The possibility of pulmonary embolism should be considered in patients presenting with deep-vein thrombosis, acute dyspnea, chest pain, or other respiratory signs and symptoms.

Individuals with Phenylketonuria

Individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be warned that clozapine orally disintegrating tablets contain aspartame, which is metabolized in the GI tract to phenylalanine following oral administration; the respective manufacturer's labeling should be consulted for specific information regarding aspartame content of individual preparations and dosage strengths.

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported in patients receiving antipsychotic agents, including clozapine. If a patient requires antipsychotic therapy following recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. If antipsychotic therapy is reintroduced, the dosage generally should be increased gradually, and an antipsychotic agent other than the agent believed to have precipitated NMS generally should be chosen. In addition, such patients should be carefully monitored since recurrences of NMS have been reported.(See Neuroleptic Malignant Syndrome under Cautions: Nervous System Effects.) For additional information on NMS,

Metabolic Effects

Atypical antipsychotic agents are associated with metabolic changes that may increase cardiovascular and cerebrovascular risk (e.g., hyperglycemia, dyslipidemia, weight gain). While all atypical antipsychotics produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients receiving atypical antipsychotic agents, including clozapine. The manufacturers state that patients with preexisting diabetes mellitus in whom therapy with an atypical antipsychotic is initiated should be closely monitored for worsening glycemic control; those with risk factors for diabetes (e.g., obesity, family history of diabetes) should undergo fasting blood glucose testing upon therapy initiation and periodically throughout treatment. Any patient who develops manifestations of hyperglycemia (e.g., polydipsia, polyphagia, polyuria, weakness) during treatment with an atypical antipsychotic should undergo fasting blood glucose testing. In some cases, patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the suspect drug; in other cases, hyperglycemia resolved with discontinuance of the antipsychotic.

Various experts have developed additional recommendations for the management of diabetes risks in patients receiving atypical antipsychotics; these include initial screening measures and regular monitoring (e.g., determination of diabetes risk factors; BMI determination using weight and height; waist circumference; blood pressure; fasting blood glucose; hemoglobin A1c [HbA1c]; fasting lipid profile), as well as provision of patient education and referral to clinicians experienced in the treatment of diabetes, when appropriate. Although some clinicians state that a switch from one atypical antipsychotic agent to another that has not been associated with substantial weight gain or diabetes should be considered in patients who experience weight gain (equal to or exceeding 5% of baseline body weight) or develop worsening glycemia or dyslipidemia at any time during therapy, such recommendations are controversial because differences in risk of developing diabetes associated with use of the different atypical antipsychotics remain to be fully established. Many clinicians consider antipsychotic efficacy the most important factor when making treatment decisions and suggest that detrimental effects of switching from a beneficial treatment regimen also should be considered in addition to any potential for exacerbation or development of medical conditions (e.g., diabetes). Decisions to alter drug therapy should be made on an individual basis, weighing the potential risks and benefits of the particular drug in each patient.(See Hyperglycemia and Diabetes Mellitus under Cautions: Endocrine and Metabolic Effects.)

Because undesirable changes in serum lipids have been observed with clozapine therapy, the manufacturers recommend appropriate clinical monitoring, including baseline and periodic follow-up lipid evaluations, in all patients receiving the drug.(See Dyslipidemia under Cautions: Endocrine and Metabolic Effects.)

Clozapine therapy may result in weight gain. Patients receiving the drug should be advised that weight gain has occurred during clozapine treatment. The manufacturers recommend clinical monitoring of weight in patients receiving the drug.(See Weight Gain under Cautions: Endocrine and Metabolic Effects.)

Orthostatic Hypotension, Bradycardia, and Syncope

Orthostatic hypotension, bradycardia, syncope, and cardiac arrest can occur with clozapine therapy; these effects are more likely to occur during initial titration of the drug, particularly with rapid dose escalation, but may even occur with the first dose at clozapine dosages as low as 12.5 mg. The risk of orthostatic hypotension may be reduced by initiating therapy at lower dosages, followed by gradual increases, and administration in divided doses.(See Dosage and Administration: Dosage.) If hypotension occurs, dosage reduction of clozapine may be considered. Patients should be informed of the risk of orthostatic hypotension associated with use of clozapine, especially during the period of initial dosage titration. In addition, if clozapine therapy has been discontinued for more than 2 days, patients should be advised to contact their clinician for dosing instructions. (See Reinitiation of Therapy under Dosage: Psychotic Disorders, in Dosage and Administration.)

Clozapine should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, or conditions that would predispose to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy).(See Blood Pressure Effects under Cautions: Cardiovascular Effects.)

Geriatric Patients with Dementia-related Psychosis

Geriatric patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death compared with patients receiving placebo.

An increased risk of adverse cerebrovascular events (e.g., stroke, transient ischemic attack), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with some atypical antipsychotic agents. Clozapine should therefore be used with caution in patients with risk factors for stroke.

The manufacturer states that clozapine is not approved for the treatment of patients with dementia-related psychosis.(See Cautions: Geriatric Precautions.)

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Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Clozapine is a substrate for many cytochrome P-450 (CYP) isoenzymes, in particular 1A2, 2D6, and 3A4. Concomitant use of clozapine with drugs that inhibit CYP1A2, CYP2D6, or CYP3A4 may result in increased plasma concentrations of clozapine. When used concomitantly with potent CYP1A2 inhibitors (e.g., ciprofloxacin, enoxacin [no longer commercially available in the US], fluvoxamine), clozapine dosage should be reduced to one-third of the original dosage. The dosage should be increased back to the original dosage when the potent CYP1A2 inhibitor is discontinued. When used concomitantly with moderate or weak CYP1A2 inhibitors (e.g., oral contraceptives, caffeine) or inhibitors of CYP2D6 or CYP3A4 (e.g., bupropion, cimetidine, duloxetine, erythromycin, escitalopram, fluoxetine, paroxetine, quinidine, sertraline, terbinafine), patients should be monitored for adverse effects and dosage reduction of clozapine should be considered, if necessary. If a moderate or weak CYP1A2 inhibitor or a CYP2D6 or CYP3A4 inhibitor is discontinued during clozapine therapy, patients should be monitored for decreased efficacy of clozapine and an increase in clozapine dosage may be necessary.

Conversely, concomitant use of clozapine with drugs or substances that induce CYP1A2 (e.g., tobacco smoke) or CYP3A4 (e.g., carbamazepine, phenytoin, rifampin, St. John's wort [Hypericum perforatum]) may result in decreased plasma concentrations of clozapine. The manufacturers state that concomitant use of a potent CYP3A4 inducer with clozapine is not recommended; however, if concomitant use cannot be avoided, patients should be monitored for decreased efficacy of clozapine and consideration should be given to increasing the dosage of clozapine, if necessary. If clozapine is used concomitantly with a moderate or weak CYP1A2 inducer (e.g., tobacco smoke), patients should be monitored for decreased efficacy of clozapine and an increase in clozapine dosage may be necessary. Likewise, if a CYP1A2 or CYP3A4 inducer is discontinued during clozapine therapy, patients should be monitored for possible adverse effects and dosage reduction of clozapine should be considered, if necessary.

Phenytoin

Substantial reductions in plasma clozapine concentrations and exacerbation of psychosis have been reported in patients receiving concomitant therapy with clozapine and phenytoin. In 2 patients stabilized for 1-2 weeks on a given dosage of clozapine, addition of phenytoin for prevention of clozapine-induced seizures resulted in a 65-85% decrease in steady-state plasma clozapine concentrations. Control of psychotic manifestations was regained in both patients by gradually increasing the clozapine dosage.

Because phenytoin is a potent inducer of CYP3A4, the manufacturers of clozapine state that concomitant use of these drugs generally is not recommended. However, if concomitant use of clozapine and phenytoin is necessary, patients should be monitored for decreased efficacy of clozapine and consideration should be given to increasing the dosage of clozapine, if necessary. Likewise, if phenytoin is discontinued during clozapine therapy, patients should be monitored for possible adverse effects and dosage reduction of clozapine should be considered, if necessary.

Carbamazepine

Concomitant use of clozapine and carbamazepine has been shown to decrease clozapine concentrations by about 40-50%. In addition, neuroleptic malignant syndrome has been reported rarely with clozapine therapy alone and during concomitant therapy with carbamazepine.(See Neuroleptic Malignant Syndrome under Cautions: Nervous System Effects.) Because carbamazepine is a potent inducer of CYP3A4, the manufacturers of clozapine state that concomitant use of these agents generally is not recommended. However, if concomitant use of clozapine and carbamazepine is necessary, patients should be monitored for decreased efficacy of clozapine and consideration should be given to increasing the dosage of clozapine if necessary. Likewise, if carbamazepine is discontinued during clozapine therapy, dosage reduction of clozapine should be considered.

Selective Serotonin-reuptake Inhibitors

Concomitant use of clozapine with certain selective serotonin-reuptake inhibitors (SSRIs), including escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, can increase plasma concentrations of clozapine due to inhibition of clozapine metabolism by SSRIs. Modest (less than twofold) elevations in plasma clozapine concentrations have been reported in patients receiving clozapine concomitantly with certain SSRIs (i.e., fluoxetine, paroxetine, sertraline).

Substantial (threefold) increases in trough plasma clozapine concentrations have occurred in patients receiving concomitant therapy with clozapine and the potent CYP1A2 inhibitor fluvoxamine. Clozapine dosage should be reduced to one-third of the usual dosage when used concomitantly with fluvoxamine and should be increased back to the original dosage if fluvoxamine is discontinued.

Drugs Metabolized by Hepatic Microsomal Enzymes

Clozapine may increase systemic exposure of other drugs metabolized by CYP2D6 (e.g., some antidepressants, phenothiazines, carbamazepine, class Ic antiarrhythmics [e.g., encainide, flecainide, propafenone]). Caution should be exercised when such drugs are used concomitantly with clozapine. The manufacturers state that dosage reduction of the CYP2D6 substrate may be necessary.

Other Drugs Associated with Neutropenia

It is not known whether concurrent use of other drugs known to cause neutropenia increases the risk or severity of clozapine-induced neutropenia. The manufacturers of clozapine currently state that there is no strong scientific rationale to avoid clozapine treatment in patients concurrently treated with such drugs. However, if clozapine is used in patients concurrently receiving other drugs known to cause neutropenia (e.g., some antineoplastic agents), the manufacturers state that closer monitoring than usually recommended should be considered and, in patients concomitantly receiving antineoplastic agents, the treating oncologist should be consulted.

Drugs Affecting the Seizure Threshold

Clozapine may lower the seizure threshold and is associated with dose-related increases in the risk of seizures (see Seizures under Cautions: Nervous System Effects). Therefore, the manufacturers state that clozapine should be used with caution in patients receiving concomitant therapy with other agents that lower the seizure threshold. In addition, caution is advised in patients in whom alcohol abuse is a concern.

CNS Depressants

Benzodiazepines

Severe hypotension (including absence of measurable blood pressure), respiratory or cardiac arrest, and loss of consciousness have been reported in several patients who received clozapine concomitantly with or following benzodiazepine (i.e., flurazepam, lorazepam, diazepam) therapy. Such effects occurred following administration of 12.5-150 mg of clozapine concurrently with or within 24 hours of the benzodiazepine, but patients generally have recovered within a few minutes to hours, usually spontaneously; the reactions usually developed on the first or second day of clozapine therapy. Although a causal relationship has not been established and such effects also have been observed in clozapine-treated patients who were not receiving a benzodiazepine concomitantly (see Cautions: Cardiovascular Effects), death resulting from respiratory arrest reportedly has occurred in at least one patient receiving clozapine concomitantly with a benzodiazepine. An increased incidence of dizziness and sedation and greater increases in liver enzyme test results also have been reported with this drug combination.

Other CNS-active Agents

Although a causal relationship has not been established, at least one death has been reported with concomitant clozapine and haloperidol therapy. A 31-year-old woman with schizophrenia developed respiratory arrest, became comatose, and died 4 days after receiving 10 mg of haloperidol orally and a single 100-mg dose of clozapine IM. The patient had been maintained on oral clozapine 200 mg daily for 2 years and also had received smaller doses of haloperidol concomitantly with clozapine therapy without unusual adverse effect.

Neuroleptic malignant syndrome has been reported rarely with clozapine therapy alone and during concomitant therapy with clozapine and carbamazepine, lithium, or other CNS-active agents.(See Neuroleptic Malignant Syndrome under Cautions: Nervous System Effects.)

Concomitant use of clozapine and lithium may also increase the risk of seizures.

Drugs that Prolong the QT Interval

Because of additive effects on QT-interval prolongation, clozapine should be used with caution in patients receiving other drugs known to prolong the QT interval, including class Ia antiarrhythmics (e.g., quinidine, procainamide), class III antiarrhythmics (e.g., amiodarone, sotalol), certain antipsychotic agents (e.g., chlorpromazine, haloperidol, iloperidone, mesoridazine [no longer commercially available in the US], pimozide, risperidone, thioridazine, ziprasidone), some anti-infective agents (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin [no longer commercially available in the US]), and other drugs (e.g., dolasetron mesylate, droperidol, halofantrine [no longer commercially available in the US], levomethadyl acetate [no longer commercially available in the US], mefloquine, methadone, pentamidine, probucol [no longer commercially available in the US], tacrolimus).(See Prolongation of QT Interval under Cautions: Cardiovascular Effects.)

Drugs with Anticholinergic Activity

Clozapine has potent anticholinergic effects and therefore should be used with caution in patients concurrently receiving other drugs with anticholinergic activity.(See Anticholinergic Toxicity under Cautions: Precautions and Contraindications.)

Hypotensive Agents

Clozapine may be additive with or potentiate the actions of hypotensive agents; the drug should be used with particular caution in patients receiving concomitant antihypertensive therapy.

Smoking

Smoking tobacco products (e.g., cigarettes) moderately induces CYP1A2, and may substantially reduce plasma clozapine concentrations. Limited data indicate that plasma clozapine concentrations following a given dose in smokers average 60-82% of those in nonsmokers. The manufacturers state that if clozapine is used in smokers, patients should be monitored for decreased efficacy of clozapine and consideration should be given to increasing the dosage, if necessary. Likewise, if smoking is discontinued during clozapine therapy, patients should be monitored for possible adverse effects and dosage reduction of clozapine should be considered, if necessary.

Pharmacokinetics

Absorption

Clozapine is rapidly and almost completely absorbed following oral administration. However, because of extensive hepatic first-pass metabolism, only about 27-50% of an orally administered dose reaches systemic circulation unchanged. Some, but not all, evidence suggests that clozapine may exhibit nonlinear, dose-dependent pharmacokinetics, with oral bioavailability being approximately 30% less following a single 75-mg dose than at steady state following multiple dosing. GI absorption appears to occur principally in the small intestine and is approximately 90-95% complete within 3.5 hours after an oral dose. Food does not appear to have a clinically important effect on the rate or extent of GI absorption of the drug when given as conventional tablets. Administration of clozapine orally disintegrating tablets or oral suspension with a high-fat meal decreases peak plasma concentrations of clozapine by about 20%, but does not affect area under the plasma concentration-time curve (AUC). The differences in peak plasma concentrations are not considered clinically important; therefore, the manufacturers state that clozapine (as conventional tablets, orally disintegrating tablets, or oral suspension) can be taken without regard to meals.

The relative oral bioavailability of clozapine has been shown to be equivalent following administration of 25-mg and 100-mg conventional tablets; commercially available clozapine oral suspension and conventional tablets and orally disintegrating tablets and conventional tablets also are bioequivalent.

Following oral administration of a single 25- or 100-mg oral dose of clozapine as tablets in healthy adults, the drug is detectable in plasma within 25 minutes, and peak plasma clozapine concentrations occur at about 1.5 hours. Peak plasma concentrations may be delayed with higher single doses and with multiple dosing of the drug. In a multiple-dose study, peak plasma clozapine concentrations at steady state averaged 319 ng/mL (range: 102-771 ng/mL) and occurred on average at 2.5 hours (range: 1-6 hours) after a dose with 100 mg twice daily as conventional tablets; minimum plasma concentrations at steady state averaged 122 ng/mL (range: 41-343 ng/mL). Steady-state plasma concentrations ranging from 200-600 ng/mL generally are achieved with oral dosages of 300 mg daily, and steady-state peak plasma concentrations generally occur within 2-4 hours after a dose. Steady-state plasma concentrations of clozapine are achieved after 7-10 days of continuous dosing.

Following multiple-dose administration of clozapine orally disintegrating tablets at a dosage of 100 mg twice daily in adults, peak plasma clozapine concentrations at steady state averaged 413 ng/mL (range: 132-854 ng/mL) and occurred on average at 2.3 hours (range: 1-6 hours). Minimum plasma concentrations at steady state in this study averaged 168 ng/mL (range: 45-574 ng/mL). Following multiple-dose administration of clozapine oral suspension at a dosage of 100-800 mg once daily, peak plasma clozapine concentrations at steady state averaged 275 ng/mL (range: 105-723 ng/mL) and occurred on average at 2.2 hours (range: 1-3.5 hours). Minimum plasma concentrations at steady state in this study averaged 75 ng/mL (range: 11-198 ng/mL).

Considerable interindividual variation in plasma clozapine concentrations has been observed in patients receiving the drug, and some patients may exhibit either extremely high or extremely low plasma concentrations with a given dosage. Such variability may be particularly likely at relatively high dosages (e.g., 400 mg daily) of the drug. In one study, a sixfold interindividual variation in steady-state plasma clozapine concentration was observed in patients receiving such dosages. In addition, considerable intraindividual variation, particularly from week to week, may occur in some patients. However, substantial intraindividual variations in pharmacokinetic parameters typically are not observed from day to day. Although the interindividual variability in plasma clozapine concentrations is consistent with that reported for other antipsychotic drugs and may be secondary to differences in absorption, distribution, metabolism, or clearance of the drug, further study is needed to clarify whether such variation results principally from variable pharmacokinetics or other variables.

There is some evidence that interindividual differences in pharmacokinetic parameters for clozapine may result, at least in part, from nonlinear, dose-dependent pharmacokinetics of the drug. However, a linear dose-concentration relationship also has been reported. Results of a study in patients with chronic schizophrenia revealed a correlation between oral clozapine dosages of 100-800 mg daily and steady-state plasma concentrations of the drug. In addition, linearly dose-proportional changes in area under the plasma concentration-time curve (AUC) and in peak and trough plasma concentrations have been observed with oral dosages of 37.5, 75, and 150 mg twice daily in other studies.

Because clozapine is a substrate for many cytochrome P-450 (CYP) isoenzymes, including CYP1A2, CYP2D6, and CYP3A4, patients with poor-metabolizer phenotypes of CYP2D6 may have higher plasma clozapine concentrations at usual dosages. In addition, smokers appear to achieve plasma clozapine concentrations that are approximately 60-80% of those achieved by nonsmokers following oral administration of the drug, due to induction of CYP1A2 activity by tobacco smoke.(See Drug Interactions: Smoking.) There also is limited evidence that gender may affect plasma clozapine concentrations, with concentrations being somewhat reduced, perhaps by as much as 20-30%, in males compared with females. In addition, smoking has a greater effect on clozapine plasma concentrations in men than in women, although this difference could result simply from gender differences in smoking behavior. Plasma concentrations may be increased in geriatric individuals compared with relatively young (e.g., 18-35 years old) individuals, possibly secondary to age-related decreases in hepatic elimination of clozapine.

Pharmacologic effects of clozapine (e.g., sedation) reportedly are apparent within 15 minutes and become clinically important within 1-6 hours. The duration of action of clozapine reportedly ranges from 4-12 hours following a single oral dose. In one study in patients with schizophrenia, the sedative effect was apparent within hours of the first dose of the drug and was maximal within 7 days.(See Effects on Sleep under Pharmacology: Nervous System Effects.) However, antipsychotic activity generally is delayed for one to several weeks after initiation of clozapine therapy, and maximal activity may require several months of therapy with the drug.

Correlations between steady-state plasma concentrations of clozapine and therapeutic efficacy have not been established, and some evidence suggests that the degree of clinical improvement is independent of plasma concentrations ranging from 100-800 ng/mL. However, it also has been suggested that serum clozapine concentrations less than 600 ng/mL may be adequate for therapeutic effect in most patients. Results of one study of 29 patients treated with clozapine 400 mg daily for 4 weeks showed that patients were most likely to respond to therapy when their plasma clozapine concentrations were at least 350 ng/mL and/or when plasma concentrations of clozapine plus norclozapine (an active metabolite) totaled at least 450 ng/mL. Further study is needed to determine whether nonresponding patients with plasma clozapine concentrations less than 350 ng/mL will benefit from increasing their dosage in an attempt to achieve higher concentrations.

Distribution

Distribution of clozapine into human body tissues is rapid and extensive; distribution of metabolites of the drug also appears to be extensive. In mice and rats, clozapine distributes principally into the lung, spleen, liver, kidney, gallbladder, and brain, achieving concentrations in these tissues up to 50 times those in blood. At 8 hours after IV injection, clozapine was still detectable in these organs but not in blood. There is limited evidence in animals that clozapine and its metabolites may be preferentially retained in the lungs by an energy-dependent, carrier-mediated process and by cellular binding. Evidence in animals also suggests that competition between clozapine and other drugs (e.g., chlorpromazine, imipramine, certain tetracycline antibiotics) for pulmonary binding sites may potentially affect plasma and tissue concentrations of clozapine, but the clinical importance, if any, of such an effect has not been established.

The volume of distribution of clozapine has been reported to be approximately 4.65 L/kg. In one study, the volume of distribution at steady state averaged 1.6 L/kg (range: 0.4-3.6 L/kg) in schizophrenic patients. Because the volume of distribution of clozapine is smaller than that of other antipsychotic agents, it has been suggested that clozapine is less sequestered in tissues than the other drugs. Clozapine is approximately 97% bound to serum proteins.

Results of receptor-binding studies in monkeys indicate that clozapine rapidly crosses the blood-brain barrier following IV injection. The highest brain uptake of the drug was in the striatum in these animals; lesser concentrations were achieved in the thalamus and mesencephalon, although they exceeded those in the cerebellum. The pharmacokinetic characteristics of the drug in the CNS paralleled those in plasma in these monkeys, with an elimination half-life from CNS of about 5 hours. Evidence from other animal studies indicates that CNS concentrations of the drug exceed those in blood. Distribution of the drug into the CNS in humans has not been characterized.

Clozapine reportedly is present in low concentrations in the placenta in animals; information on placental transfer of the drug in humans currently is unavailable. Clozapine distributes into human milk.(See Cautions: Pregnancy, Fertility, and Lactation.)

Elimination

The decline of plasma clozapine concentrations in humans is biphasic. The elimination half-life of clozapine following a single 75-mg oral dose reportedly averages 8 hours (range: 4-12 hours); that after a 100-mg oral dose appears to be similar. The elimination half-life of clozapine at steady state following administration of 100 mg twice daily reportedly averages 12 hours (range: 4-66 hours). The rapid elimination phase may represent redistribution and is followed by a slower apparent mean terminal elimination half-life of 10.3-38 hours. Although a study comparing single and multiple dosing of clozapine demonstrated an increase in elimination half-life with multiple dosing, other evidence suggests this finding is not attributable to concentration-dependent pharmacokinetics.

Clozapine is almost completely metabolized in the liver prior to excretion by many CYP isoenzymes, particularly CYP1A2, CYP2D6, and CYP3A4. Clozapine may undergo N-demethylation,N-oxidation, 3'-carbon oxidation, epoxidation of the chlorine-containing aromatic ring, substitution of chlorine by hydroxyl or thiomethyl groups, and sulfur oxidation. A glucuronide metabolite, tentatively identified as a quaternary ammonium N-glucuronide of clozapine, also has been identified. Metabolism of clozapine may occur by one or more of these routes.

The rate of formation and biologic activity of clozapine metabolites have not been fully elucidated. The desmethyl metabolite of clozapine (norclozapine) has limited activity while the hydroxylated and N-oxide derivatives are inactive. The N-oxide and desmethyl derivatives are found in urine and plasma of humans in a proportion of 2:1.

Approximately 32% of a single oral dose of clozapine is found in plasma as the parent compound after 3 hours, 20% in 8 hours, and 10% up to 48 hours following the dose. Only limited amounts (approximately 2-5%) of unchanged drug are detected in urine and feces. Approximately 50% of an administered dose is excreted in urine and 30% in feces; maximum fecal excretion has been estimated at 38%. Approximately 46% of an oral dose of clozapine is excreted in urine within 120 hours.

Total plasma and blood clearance of clozapine reportedly average 217 and 250 mL/minute, respectively, but show considerable interindividual variation.

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