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Introduction ⬇

VA Class:CN709

AHFS Class:

Generic Name(s):

Chemical Name:

Notification

REMS:

FDA approved a shared REMS for clozapine. The REMS may consist of the following: elements to assure safe use and implementation system. See the FDA REMS page ([Web]). (See General under Dosage and Administration.)

Clozapine has been referred to as an atypical or second-generation antipsychotic agent.1,2,4,5,7,8,9,10,11,12,65,67,181,197,235,239,248,253,347

Uses ⬆ ⬇

[Section Outline]

Psychotic Disorders !!navigator!!

Clozapine is used for the symptomatic management of psychotic disorders (e.g., schizophrenia).1,2,5,10,12,83,84,90,129,221 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.347 Antipsychotic agents are the principal class of drugs used for the management of all phases of schizophrenia.347 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.10,21,29,83,84,89,115,121,184,190,197,212,223,224

Clozapine has been shown to be an effective, relatively rapid-acting, broad-spectrum antipsychotic agent in both uncontrolled5,7,33,37,52,59,60,75,87,89,124,225,226 and controlled studies of patients with schizophrenia.10,21,34,53,54,55,56,61,62,63,64,65,66,74,118,120,121,122,123,135,156,172,190,196 In these studies, improvement in manifestations of schizophrenia was based on the results of various psychiatric rating scales, 5,7,13,14,21,33,34,37,52,54,59,61,62,63,64,65,115,120,121,123,156,190 principally the Brief Psychiatric Rating Scale (BPRS) that assesses factors such as anergy, thought disturbance, activation, hostility/suspiciousness, and anxiety/depression.5,10,33,52,59,60,87,89,161,225,226 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;2,10,13,21,34,54,64,65,121,128,156,237 conventional (typical) antipsychotic agents appear to have lesser effects on negative manifestations of the disorder.2,10,13,292 In comparative studies, clozapine was at least as effective as,53,55,62,63,74,135,196 or more effective than several conventional antipsychotic agents, including10,21,34,54,55,56,64,65,66,118,120,121,123,156,172,190 chlorpromazine,10,34,54,56,62,63,64,65,118,120,121,172,190,196 haloperidol,10,21,55,56,120,123,135,156 perphenazine,53,74 or trifluoperazine.56

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.5,10,67,82,89,104,111,137,182

While the risks of adverse neurologic effects with long-term clozapine therapy remain to be fully elucidated,1,12,84 other adverse effects, including some potentially serious effects (e.g., severe neutropenia, seizures), may occur more frequently with clozapine therapy.1,2,5,12,14,20,76,130,136,157,172,181,292,347 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.1,5,10,12,14,21,33,34,61,63,64,87,121,156,292,347,395,400,406 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.347

Treatment-resistant Schizophrenia

Clozapine is used for the management of schizophrenia in severely ill patients who fail to respond adequately to standard antipsychotic therapy.1,2,10,14,21,33,34,61,63,64,87,121,156,347,395,406 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.1,395,406 (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.347 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.347 The principal manifestations of this disorder usually are described in terms of positive and negative (deficit) symptoms, and more recently, disorganized symptoms.347 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).347 Disorganized symptoms include disorganized speech (thought disorder) and behavior and poor attention.347

Evidence from both retrospective57,58,66,103,122,128,187 and controlled prospective studies10,34,53,54,61,62,63,64,65,66,74,120,121,123,156,190,196 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.10 In addition, clozapine was substantially more effective than chlorpromazine plus benztropine in improving both positive and negative manifestations of schizophrenia.10 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.10 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.1,5,10,11,121 Similar 6-week response rates in treatment-resistant schizophrenia have been reported in other studies with the drug.5,61,63,65,66,83,225 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.5,58,187,225,226,227

For additional information on the symptomatic management of schizophrenia, including treatment recommendations, see Schizophrenia and Other Psychotic Disorders under Uses: Psychotic Disorders, in the Phenothiazines General Statement 28:16.08.24.

Pediatric Considerations

Although the manufacturers state that the safety and efficacy of clozapine in pediatric patients have not been established,1,395,400,406 the drug has been successfully used for the management of childhood-onset schizophrenia in a limited number of treatment-resistant children and adolescents†.319,323 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.319,322,323 (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.319 For additional information on the symptomatic management of childhood-onset schizophrenia, see Pediatric Considerations under Psychotic Disorders: Schizophrenia, in Uses in the Phenothiazines General Statement 28:16.08.24.

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.323 In this study, children and adolescents receiving clozapine had substantially greater reductions in both positive and negative symptoms of schizophrenia than those receiving haloperidol.322,323 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.323 For most children and adolescents in the study, clozapine improved interpersonal functioning and enabled a return to a less restrictive setting.323 However, mild to moderate neutropenia occurred in 24% of the patients, and 29% required therapy with an anticonvulsant.323

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.1,327,328,347,395,406 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.1,327,395 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.1,327,395 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.1,327,395

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.1,327,328 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 2.1,327,395 In addition, patients receiving clozapine had a statistically significant longer delay in the time to recurrent suicidal behavior than those receiving olanzapine.1,327 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.1,327,329

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.328,329 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.1,328,329 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.347 Decisions to initiate clozapine therapy or switch patients from other antipsychotics to clozapine, therefore, should be individualized.328,329 In addition, safety and efficacy of clozapine in actively suicidal patients have yet to be determined.329

Parkinsonian Syndrome !!navigator!!

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.16,69,88,132,193,194,237,251,254,292 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.16,69,88,125,126,134,251 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.16,68,69,125,126,132,134,292 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;88 it has been suggested that rapid clozapine dosage escalation may have contributed to the observed negative effect on parkinsonian manifestations and delirium.292 Clozapine dosages of 100-250 mg daily reportedly have been associated with hypersalivation, hypophonia, bradykinesia, and considerable sedation in patients with idiopathic parkinsonian syndrome,16 and withdrawal of clozapine therapy or a decrease in dosage also has exacerbated parkinsonian manifestations.81,132,194 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 titration194,292 (e.g., to a maximum of 100-200 mg daily).292 Other clinicians have suggested that clozapine be used only as a last resort in patients with drug-induced dopaminomimetic psychosis.16,88,292

Dosage and Administration ⬆ ⬇

[Section Outline]

General !!navigator!!

Cautions ⬆ ⬇

[Section Outline]

Although clozapine differs chemically from the phenothiazines, the drug may be capable of producing many of the toxic manifestations of phenothiazine derivatives.5,292,347 Not all adverse effects of the phenothiazines have been reported with clozapine, but the possibility that they may occur should be considered.5,11,292,347 Adverse effects of clozapine and the phenothiazines are numerous and may involve nearly all organ systems.5,12,34,166,347 Although these effects usually are reversible when dosage is reduced or the drug is discontinued,5,12,292 some effects may be irreversible and, rarely, fatal.5,57,292,296,303 In some patients, unexpected death associated with antipsychotic therapy has been attributed to cardiac arrest or asphyxia resulting from failure of the gag reflex.2,5,57 (See Cautions: Cardiovascular Effects.) In other cases, the cause of death could not be determined or definitely attributed to antipsychotic drug therapy.57 An increased risk of death has been observed in geriatric patients with dementia-related psychoses receiving antipsychotic agents.1,385,394,395,406 (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).1,5 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,2,5,12 other potentially serious adverse effects (e.g., severe neutropenia, seizures) may occur more frequently with clozapine therapy,2,5,12,14,20,76,130,136,157,172,181,292 and the potential risks and benefits should be evaluated carefully whenever therapy with the drug is considered.5,10,12,21,58,142,166,187 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).1,395,400,406,407 (See General under Dosage and Administration and also see Severe Neutropenia under Cautions: Hematologic Effects.)

Hematologic Effects !!navigator!!

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.1,395,400,406 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.1,395,400,406 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.1,395,400,406 Severe neutropenia is defined as an ANC value of less than 500/mm3 and occurs in a small percentage of patients receiving clozapine therapy.1,395,400,406

Previously described agranulocytosis, which was defined as an ANC less than 500/mm3 and characterized by leukopenia (WBC count less than 2000/mm3) and relative lymphopenia,139 has been reported to have an estimated cumulative incidence of 1-2% after 1 year of clozapine therapy,5,6,20,139 as compared with an estimated incidence of 0.1-1% for phenothiazine-induced agranulocytosis.34,76,136,157,172 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,5,136,256 although it also has been suggested that the incidence of clozapine-induced agranulocytosis may be no higher than that associated with phenothiazines.67,146,157

The precise mechanism by which clozapine induces neutropenia is not known and is not dose-dependent,1,395,400,406 but both immunologic and toxic mechanisms (including a direct myelotoxic effect of the drug and/or its metabolites)303,325 have been implicated.2,12,22,139,237 Some evidence suggests that granulocyte antibodies may be involved.138

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.411,415 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;230 the incidence of some phenotypes common among Ashkenazi Jews has been found to be greatly increased in patients with clozapine-induced agranulocytosis.230

The risk of clozapine-induced neutropenia appears to be greatest during the first 18 weeks of therapy and declines thereafter.1 However, rare cases of neutropenia or agranulocytosis have been reported after several years of treatment with the drug.414

Benign ethnic neutropenia (BEN) is a condition observed in certain ethnic groups whose average ANC values are lower than standard laboratory ranges for neutrophils.1,408,409,410 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.1,408,409,410 Patients with BEN have normal hematopoietic stem cell numbers and myeloid maturation, are healthy, and do not suffer from repeated or severe infections.1,408,409 Such patients are not at increased risk for developing clozapine-induced neutropenia.1,408 BEN may be diagnosed by repeated low ANC measurements (less than 1500/mm3 and usually 1000/mm3 or below) for several months without identifiable causes of the neutropenia.409,410 Additional evaluation may be necessary in some patients to determine whether their baseline neutropenia is caused by BEN.1,408 Consultation with a hematologist should be considered in patients with low baseline ANC values before initiating or during clozapine therapy, if necessary.1,408 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.1,408 (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.1 Clozapine therapy should not be initiated if baseline ANC is less than 1500/mm3 (or less than 1000/mm3 in patients with documented BEN).1,408

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.1,408 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.1,408 If clozapine treatment is interrupted for 30 days or longer, the initial ANC monitoring schedule should be restarted beginning with once-weekly ANC monitoring.1

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

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.1,395,406,408 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.1,395,406,408

Table 1. Clozapine Treatment Recommendations based on ANC Monitoring in the General Patient Population1,395,400,406,408

ANC Value

Treatment Recommendations

Frequency of ANC Monitoring

Normal range (ANC ≥1500/mm3)

Initiate treatment

Weekly from initiation to 6 months

If treatment interrupted <30 days, continue monitoring as before

Every 2 weeks from 6-12 months

If treatment interrupted ≥30 days, monitor as if new patient

Monthly after 12 months

Discontinuance for reasons other than neutropenia

(See Discontinuance of Therapy under Dosage and Administration.)

Mild neutropenia (ANC 1000-1499/mm3)a

Continue treatment

3 times weekly until ANC ≥1500/mm3

When ANC ≥1500/mm3, return to patient's last normal range ANC monitoring interval, if clinically appropriate

Moderate neutropenia (ANC 500-999/mm3)a

Recommend hematology consultation

Daily until ANC ≥1000/mm3

Interrupt treatment for suspected clozapine-induced neutropenia

3 times weekly until ANC ≥1500/mm3

Resume treatment once ANC ≥1000/mm3

When ANC ≥1500/mm3, monitor weekly for 4 weeks, then return to the patient's last normal range ANC monitoring interval, if clinically appropriate

Severe neutropenia (ANC <500/mm3)a

Recommend hematology consultation

Daily until ANC ≥1000/mm3

Interrupt treatment for suspected clozapine-induced neutropenia

3 times weekly until ANC ≥1500/mm3

Do not rechallenge unless prescriber determines benefits outweigh risks

If patient rechallenged, resume treatment and monitor as new patient under normal range monitoring once ANC ≥1500/mm3

aConfirm 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/mm3)

Obtain ≥2 baseline ANC values before initiating treatment

Weekly from initiation to 6 months

If treatment interrupted <30 days, continue monitoring as before

Every 2 weeks from 6-12 months

If treatment interrupted ≥30 days, monitor as if new patient

Monthly after 12 months

Discontinuance of treatment for reasons other than neutropenia

(See Discontinuance of Therapy and Dosage and Administration.)

BEN neutropenia (ANC 500-999/mm3)a

Recommend hematology consultation

3 times weekly until ANC ≥1000/mm3 or at patient's known baseline

Continue treatment

When ANC ≥1000/mm3 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/mm3)a

Recommend hematology consultation

Daily until ANC ≥500/mm3

Interrupt treatment for suspected clozapine-induced neutropenia

3 times weekly until ANC at or above patient's baseline

Do not rechallenge unless prescriber determines benefits outweigh risks

If patient rechallenged, resume treatment as a new patient under normal range monitoring once ANC ≥1000/mm3 or at patient's baseline

aConfirm 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.1 Fever is often the first sign of neutropenic infection.1 If fever occurs in any patient with an ANC value less than 1000/mm3, the patient should be appropriately evaluated (see Tables 1 and 2) and treated for infection.1 A hematology consultation should be considered in all clozapine-treated patients with fever or neutropenia.1

Although some clinicians have suggested that body temperature be measured at least once daily for the first 18 weeks of clozapine therapy,66,67,142,292 others292 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).2,5,11,12,57,62,67,87,103,124,127,128,130,195,237 Patients receiving clozapine should be advised to immediately report the appearance of lethargy, weakness, fever, sore throat, or any other potential manifestations of infection.1

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.307,308,309,310,311,312,313,314,315,316,317 Consultation with a hematologist and infectious disease expert is recommended.90,292

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.411,412,413,414 However, lithium should be used concurrently with clozapine with caution because, in addition to the possible increased risk of NMS148,200,204,205,206,210,211,402 and seizures,292,330 the drug can mask the development or delay the detection of severe neutropenia and other blood dyscrasias.411,412,413 (See Drug Interactions: Other CNS-active Agents.)

When neutropenia is diagnosed and clozapine therapy is discontinued, patients usually recover in 7-28 days.12,38,67,121,139 Most of these patients require further antipsychotic therapy because of a recurrence of psychotic symptoms.139 (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.2,139 Patients who develop severe clozapine-induced neutropenia generally should not be rechallenged with clozapine.1 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 rechallen in such cases, consultation with a hematology specialist may be helpful in deciding whether to rechallenge a patient with clozapine.1

Eosinophilia

Eosinophilia1,12,37,60 (defined as blood eosinophil count exceeding 700/mm3) has been reported in approximately 1% of patients who received clozapine therapy in clinical trials.1 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.1 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).1

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.1,395,400,406 If clozapine-associated systemic disease is suspected, the drug should be immediately discontinued.1 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.1

Clozapine-associated eosinophilia also has occurred without organ involvement and can resolve without intervention.1 In such cases, clozapine therapy may be continued with careful monitoring.1 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.1 There have been reports of successful rechallenge after discontinuance of clozapine without recurrence of eosinophilia.1

Other Hematologic Effects

Other hematologic effects reported with clozapine therapy include leukopenia/decreased WBC count1,1,5,12,124,237 and neutropenia,1,60 which has been reported in 3% of patients.1 Other clozapine-induced hematologic effects reportedly include basophilia110 and a substantial reduction in B cells.140 Elevated hemoglobin/hematocrit,1 elevated erythrocyte sedimentation rate (ESR),1 sepsis,1 thrombocytosis,1 and thrombocytopenia1 have been reported in patients receiving clozapine during postmarketing surveillance; however, a causal relationship to the drug has not been established.1

Nervous System Effects !!navigator!!

Seizures

Clozapine lowers the seizure threshold13,16,176,177,253,255 and can cause EEG changes, including the occurrence of spike and wave complexes.1 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%).1 In contrast, a seizure incidence of approximately 1% has been reported in patients treated with other antipsychotic agents.177 The risk of seizures with clozapine therapy is dose related,1 with a reported incidence of approximately 0.6-2% at dosages less than 300 mg daily,2,5,12,38,177,181,234,255 1.4-5% at 300-600 mg daily,2,5,12,38,177,181,234,244 and 5-14% at high dosages (600-900 mg daily).2,5,12,37,177,181,234,237,244,255 Clozapine-induced seizures may be associated with rapid dosage escalations,90,347 particularly in patients receiving concomitant therapy with drugs that may cause increased plasma concentrations of clozapine.5,293 (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.159 Results of plasma clozapine determinations obtained at the time of the seizures revealed plasma clozapine concentrations of approximately 2000 ng/mL in each case.44 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.44 One hour after the seizure, the patient's plasma clozapine concentration was 1313 ng/mL.44

Discontinuance of clozapine therapy, at least temporarily,292 should be seriously considered in patients who experience seizures while receiving the drug;177,292 however, some clinicians state that reduced clozapine dosage and/or, occasionally, addition of anticonvulsant therapy may adequately ameliorate this effect.38,177,234,292 If clozapine therapy is to be continued in such patients, many clinicians recommend obtaining additional informed consent from the patient.177,234,292 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.90 Clozapine dosage may then be increased gradually, if clinically indicated, and the need for concomitant anticonvulsant therapy should be considered.177,234,292 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;177,234,292 others suggest addition of anticonvulsant therapy and/or consultation with a neurologist in managing such patients.292 In patients with preexisting seizure disorders who are treated concomitantly with certain anticonvulsants and clozapine, the anticonvulsant dosage may need to be increased.1,151 (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).2,5,347,404 Such effects, when they occur, have been limited principally to tremor,1,5,7,11,56,61,87,120,176 restlessness,1,5,12,132 rigidity,1,5,11 and akathisia.5,7,11,56,76,103,176,292,347 In addition, marked or total remission of such manifestations induced by other antipsychotics has occurred during treatment with clozapine in some patients.2,10,89,292

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.404

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome, has been reported in patients receiving antipsychotic agents, including clozapine.1,199,200,201,202,203,204,205,206,207,208,209,210,284,395,401,402,403 NMS attributable to clozapine therapy alone has been reported in some patients,1,284,299,300,395 and there also have been reports of NMS in patients treated concomitantly with clozapine and lithium or other CNS drugs;1,2,148,395,401,402,403 some clinicians suggest that NMS may be more likely to occur when clozapine or other antipsychotic agents are used concomitantly with lithium.148,200,204,205,206,210,211,402 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,1,292 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.147,148,284 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.149 Atypical presentations of NMS (e.g., absence of or lessened rigidity, absence of fever) also have been reported in some patients receiving clozapine.401,402

The diagnostic evaluation of patients with NMS is complicated.1,395 In arriving at a diagnosis, serious medical illnesses (e.g., severe neutropenia, infection) and extrapyramidal symptoms must be excluded.1,395 Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary CNS pathology.1,395

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.1,395,401,402,403 There currently is no specific drug therapy for NMS,1 although dantrolene, bromocriptine, amantadine, and benzodiazepines have been used in a limited number of patients.347 If a patient requires antipsychotic therapy following recovery from NMS, the potential reintroduction of drug therapy should be carefully considered.1,395 In addition, such patients should be carefully monitored since NMS may recur.1,395 For additional information on NMS, including treatment, see Neuroleptic Malignant Syndrome under Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.

Tardive Dyskinesia

Use of antipsychotic agents, including clozapine, may be associated with tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements.1 However, clozapine is considered less likely to cause tardive dyskinesia than many other antipsychotic agents,5,10,67,82,89,104,111,137,182,347 and dyskinetic movements in some patients have reportedly improved with clozapine therapy.347

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.1,347 However, the syndrome can develop following relatively brief treatment periods at low dosages.1 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.347,417,418,419,420 The syndrome may remit, partially or completely, if antipsychotic therapy is discontinued.1,347 However, antipsychotic therapy itself may suppress or partially suppress the signs and symptoms of the syndrome and thereby may possibly mask the underlying process.1 The effect that such symptomatic suppression has upon the long-term course of tardive dyskinesia is unknown.1 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.417,418,419,420,421,422,423,424 (See Deutetrabenazine 28:56 and Valbenazine Tosylate 28:56.)

Clozapine should be prescribed in a manner that is most likely to minimize the occurrence of this syndrome.1,395 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.1

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.347 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.1

For additional information on tardive dyskinesia, including manifestations and treatment, see Tardive Dyskinesia under Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.

Other Nervous System Effects

Drowsiness and/or sedation occurs frequently in patients receiving clozapine.1,5,11,12,32,34,56,57,62,87,103,120,124,128,181,237 (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.1,327,395 The sedative-hypnotic effect of clozapine is most pronounced initially, diminishes after 1-4 weeks, and then generally,156,189 but not always,292 disappears during continued therapy. Daytime sleepiness may be minimized by administration of clozapine at bedtime.5,12 (See Dosage and Administration and also see Cognitive and Motor Impairment under Cautions: Precautions and Contraindications.)

Dizziness and vertigo,1,5,11,12,17,56,61,87 headache,1,5,11,12,52,56,87 syncope,1,5,12,33,62,87 disturbed sleep (e.g., insomnia) or nightmares,1,5,7 hypokinesia1,5,12,17,56 or akinesia,1,11,120 and agitation1,5 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.1,327,395 Clozapine also may cause confusion or delirium,1,5,12,52,56,87,88,128,130 which may be related to central anticholinergic effects5,107,292 and has been ameliorated in some cases by IV administration of physostigmine.5,107 Depression,87 fatigue,1,12,237 hyperkinesia,5,56 weakness or lethargy,5 and slurred speech also have been reported.5,32

Delirium,1 abnormal EEG,1 myoclonus,1 paresthesia,1 possible cataplexy,1 status epilepticus,1 obsessive-compulsive symptoms,1 and post-discontinuation cholinergic rebound reactions1 have been reported in patients receiving clozapine during postmarketing surveillance; however, a causal relationship to the drug has not been established.1,395

Abrupt discontinuance of clozapine (e.g., because of hematologic toxicity or other medical condition) may result in recurrence of psychotic symptoms or behavior,1,11,131,173,174 including autism,131 auditory hallucinations,131,173 suicide attempts,131 development of parkinsonian symptoms,173 anxiety,173 insomnia,173 delusions,173 and violent behavior.174 It has been suggested that this “rebound psychosis” may result, at least in part, from clozapine-induced supersensitivity of mesolimbic dopamine receptors131,173,174 (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.131 Patients who develop rebound psychosis following discontinuance of clozapine may improve with initiation of other antipsychotic therapy;131 however, clozapine generally should not be reinstituted in patients in whom severe neutropenia has occurred.1 (See Cautions: Hematologic Effects.)

Fever !!navigator!!

Fever or transient temperature elevations exceeding 38°C generally have been reported in 5% or more of patients receiving clozapine.1,2,5,11,12,57,62,67,87,103,124,127,128,130,195,237 The peak incidence of fever occurs within the first 3 weeks of therapy,1,2 usually between days 5-20 of treatment.5,65,67,127,189,195 Fever generally is benign and self-limiting,1,2,5,11 responds to supportive measures,347 and usually diminishes within a few (4-8)195 days despite continued clozapine therapy;67 however, it may necessitate discontinuance of the drug.1 Fever occasionally may be associated with an increase or decrease in WBC count.1 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.1 In addition, ANC should be monitored in any patient who develops fever within 2 weeks after discontinuance of clozapine.1 (See Cautions: Hematologic Effects.) Neuroleptic malignant syndrome also must be considered.1 (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.7,189 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.7 Clozapine-induced hyperthermia may be a hypersensitivity reaction, a common mechanism underlying drug fevers.7,292 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;7,292 however, recurrence is possible despite such dosage adjustment.292

Cardiovascular Effects !!navigator!!

Myocarditis, Cardiomyopathy, and Mitral Valve Incompetence

Myocarditis and cardiomyopathy, which are sometimes fatal, have been reported in patients receiving clozapine.1 Myocarditis most frequently presents within the first 2 months of clozapine treatment.1 Symptoms of clozapine-associated cardiomyopathy generally occur later than clozapine-associated myocarditis, usually after 8 weeks of treatment.1 However, myocarditis and cardiomyopathy can occur at any time during clozapine therapy.1 Overt manifestations of heart failure commonly are preceded by nonspecific flu-like symptoms (e.g., malaise, myalgia, pleuritic chest pain, low-grade fever).1 Typical laboratory findings include elevated troponin I or T concentrations, elevated CK-MB concentrations, peripheral eosinophilia, and elevated C-reactive protein (CRP) concentrations.1 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.1

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).1 If myocarditis or cardiomyopathy is suspected, clozapine therapy should be discontinued and a cardiac evaluation should be obtained.1 Patients with a history of clozapine-associated myocarditis or cardiomyopathy generally should not be rechallenged with the drug.1 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.1

Mitral valve incompetence with mild or moderate mitral regurgitation has been reported in patients diagnosed with clozapine-associated cardiomyopathy.1 In patients with suspected cardiomyopathy, consideration should be given to performing a 2-dimensional Doppler echocardiogram to identify mitral valve incompetence.1

Thromboembolic Effects

Deep-vein thrombosis and pulmonary embolism have been reported in patients receiving clozapine.1,405 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.1 (See Thromboembolic Events under Cautions: Precautions and Contraindications.)

Blood Pressure Effects

Hypotension1,2,5,10,11,12,17,32,33,62,103,120,121,162,181,281,296 and hypertension1,2,5,10,11,62,292 reportedly occur in less than 10% of patients receiving clozapine.65 When they occur, changes in blood pressure, principally reductions in systolic pressure,65 appear soon after initiation of clozapine therapy and may be associated with rapid dosage increases.2 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.130 Hypotension may result from clozapine's antiadrenergic effects12 (see Adrenergic Effects under Pharmacology: Nervous System Effects). However, tolerance to the hypotensive effects of clozapine often develops with continued therapy.61,256,292

Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have been reported,1,56,57,61,128,156,159,237,281,296 particularly during initial titration or rapid escalation of clozapine dosage.1,281,296 Rarely (approximately 1 case per 3000 patients), orthostatic hypotension has been accompanied by profound collapse and respiratory and/or cardiac arrest in patients receiving initial1,166,188,281,296 doses as low as 12.5 mg.1 Such reactions, which are sometimes fatal, are consistent with neurally-mediated reflex bradycardia.1 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.166,188,237,281,296

The risk of orthostatic hypotension may be reduced by initiating clozapine therapy at lower dosages, followed by gradual increases, and administration in divided doses.1,5,292 If hypotension occurs, dosage reduction of clozapine may be considered.1 In some cases, withholding the drug for 24 hours and then restarting at a lower dosage has been accomplished without recurrence of orthostatic hypotension.54 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).1,395,400,406

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.1,395,406 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.1,395,406 (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.1,395,406

Prior to initiating clozapine therapy, a careful physical examination should be performed and a medical and concomitant medication history should be obtained.1,395,406 A baseline ECG and serum chemistry panel should also be considered before initiating clozapine therapy.1,395,406 Clozapine should be discontinued if the corrected QT (QTc) interval exceeds 500 msec.1,395,406 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).1,395,406

Baseline serum potassium and magnesium concentrations should be determined and electrolyte abnormalities, if present, should be corrected prior to initiating clozapine therapy.1,395,406 In addition, serum electrolytes should be periodically monitored during clozapine therapy.1,395,406

Other Cardiovascular Effects

Tachycardia, which may persist throughout therapy in some cases,38,61 reportedly has been observed in up to 25% of patients receiving clozapine in clinical studies.1,5,7,10,11,12,38,57,121,128,162,181,237

Postexercise decreases in left ventricular output, which may indicate left ventricular failure, have been reported in patients receiving clozapine.110 Although a causal relationship has not been established, atrial or ventricular fibrillation,1 ventricular tachycardia,1 palpitations,1 and myocardial infarction1 also have been reported during postmarketing surveillance in patients receiving the drug.1

Autonomic Nervous System Effects !!navigator!!

Adverse autonomic nervous system effects occur in more than 5% of patients receiving clozapine.1 Dry mouth occurs frequently,1,12,17,32,34,61,87,253 but hypersalivation, an apparently paradoxical effect considering the drug's potent anticholinergic activity, is more common.1,2,5,10,11,12,22,33,52,56,61,62,87,103,121,124,162,176,237 (See Cautions: GI Effects.)

Other autonomic nervous system effects of clozapine include hyperhidrosis,1,2,5,7,12,17,52,87 decreased sweating,87 and visual disturbances.1,2,12,16,87 Increased salivation occurred in 31%, dry mouth and sweating in 6%, and visual disturbances in 5% of patients receiving clozapine in controlled clinical trials.1

Hepatic Effects !!navigator!!

Transient increases in liver function test results,1,10,37,52,65,103,128,127,162,231 including serum aminotransferases (transaminases),2,37,52,65,67,127,156,162,163 LDH,163 and alkaline phosphatase,67,127,159 may occur with clozapine therapy. Clozapine-induced changes in liver function test results may be more pronounced than those with other tricyclic antipsychotic agents.67 Clozapine causes slight liver hyperplasia in rats; hyperplasia was reversible and no histologic changes were detectable.163 Clozapine also occasionally causes elevations of bilirubin concentration.1,52,127,162

Cholestasis,1 hepatitis,1 jaundice,1 hepatotoxicity,1 hepatic steatosis,1 hepatic necrosis,1 hepatic fibrosis,1 hepatic cirrhosis,1 liver injury (hepatic, cholestatic, and mixed),1 and liver failure1 have been reported in patients receiving clozapine during postmarketing surveillance; however, a causal relationship to the drug has not been established.1

Severe, life-threatening, and, in some cases, fatal hepatotoxicity, including hepatic failure, hepatic necrosis, and hepatitis, has been reported in postmarketing studies in clozapine-treated patients.1 (See Hepatotoxicity under Cautions: Precautions and Contraindications.)

Endocrine and Metabolic Effects !!navigator!!

Atypical antipsychotic agents have been associated with metabolic changes, including hyperglycemia, dyslipidemia, and weight gain.1 Such metabolic changes may be associated with increased cardiovascular and cerebrovascular risk.1

Weight Gain

Weight gain has been observed with antipsychotic therapy.1 Clozapine may cause increased appetite, polyphagia, and weight gain in a substantial proportion (approximately one-third)237 of patients.1,5,7,12,57,60,103,106,128,150,162,176,189,237,241,242,243 Some clinicians suggest that the potential for weight gain with clozapine therapy may be similar to that with other antipsychotic therapy;150 others state that they have observed greater weight gain with clozapine in some patients.292 In the 2-year InterSePT trial, weight gain reportedly occurred in 31% of patients receiving clozapine compared with 56% of those receiving olanzapine.1,327 Some clozapine-treated patients reportedly have gained up to 1 kg weekly for 6 weeks.189 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.1

Weight gain may result from the drug's serotonergic-, histaminergic-, and adrenergic-blocking properties.93,150,243,292,301 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.5,106,150,241 Some clinicians suggest using exercise and active measures (e.g., dietary counseling) to control dietary intake in clozapine-treated patients.106,292

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.1,331,332,334,335,336,337,338,339,340,341,342,343,358,359,360,361,365,384,395 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).1,331,332,333,334,335,336,337,338,339,340,341,342,343,345,346,383 (See Cautions: Precautions and Contraindications.)

Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics currently are not available.1,331,332,334,335,336,337,338,339,340,341,342,343 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.292,333,344,345,346,347,348,349,351,352,353,354,355,356,357,362,363,364,366,367,368,369,370,371,372,373,374,375,376,377,378,379,380,381,382,383

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).1 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.1 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.1

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.1

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.1 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.1 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.1 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.1

The manufacturers recommend clinical monitoring, including baseline and periodic follow-up lipid evaluations, in patients receiving clozapine.1,395,400,406

Hyperprolactinemia

Clozapine causes little or no elevation in serum prolactin concentrations.1,119,283,288,300,301,315,332 The drug has been reported to cause only a brief, transient elevation of prolactin concentration.12,30 (See Pharmacology: Neuroendocrine Effects.) Therefore, prolactin-dependent adverse effects such as galactorrhea and amenorrhea usually are not associated with clozapine therapy.12,256

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.1

Small decreases in protein-bound iodine or thyroxine concentrations have been reported in some patients receiving clozapine, but these values remained within normal limits.52

GI Effects !!navigator!!

Increased salivation may occur in approximately one-third of patients receiving clozapine;1,5,10,11,12,22,33,52,56,61,62,87,103,121,124,162,176,237 in some studies, hypersalivation was reported in up to 75-85%7,54,120 of clozapine-treated patients.2 In the InterSePT trial, increased salivation reportedly occurred in 48% of patients receiving clozapine compared with 6% of those receiving olanzapine.1,327 Salivation may be profuse, very fluid, and particularly troublesome during sleep because of decreased swallowing.2,5,292 Since clozapine exhibits intrinsic anticholinergic properties, hypersalivation is an unexpected paradoxical effect.5,22,127 A muscle-relaxant effect of the drug may contribute to hypersalivation,16 but the cause has not been fully elucidated.189 Difficulty in swallowing has been reported in a few clozapine-treated patients,296,302 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.302 Some clozapine-treated patients develop tolerance to increased salivation within a few weeks.189 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.347 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.2,5,292,347 (See Anticholinergic Toxicity and see also GI Hypomotility with Severe Complications under Cautions: Precautions and Contraindications.)

Other GI effects associated with clozapine therapy include constipation,1,5,7,11,33,34,57,162,181,425 diarrhea,1,12,62 nausea and vomiting,1,5,11,32,62,87 dyspepsia or heartburn,1,120,327 and abdominal discomfort;1,5 some of these effects have been reported in more than 5% of patients.1 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.1 For additional information on clozapine-induced constipation and possible severe bowel complications, see GI Hypomotility with Severe Complications under Cautions: GI Effects and also under Cautions: Precautions and Contraindications. Although some clinicians advocate the use of metoclopramide (e.g., in doses less than 30 mg daily) for the treatment of clozapine-induced nausea,12,153,292 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.153,292

Although a causal relationship to the drug has not been established, acute pancreatitis,1 dysphagia,1 salivary gland swelling,1 colitis,1,427,428 megacolon,1,429 and intestinal ischemia or infarction1 also have been reported in patients receiving clozapine during postmarketing surveillance.1

GI Hypomotility with Severe Complications

Severe adverse GI effects have occurred with clozapine mainly due to its potent anticholinergic effects and resulting GI hypomotility.1,425,426,427,428,429 In postmarketing experience, these effects have ranged in severity from constipation to paralytic ileus.1,425 The increased frequency of constipation with clozapine and delayed diagnosis and treatment increased the risk of developing severe complications of GI hypomotility resulting in intestinal obstruction, fecal impaction, megacolon, and intestinal ischemia or infarction; these reactions have resulted in hospitalization, surgery, and death in some patients.1,425,427,428,429 The risk of severe adverse reactions in patients receiving clozapine is further increased with concomitant use of anticholinergic agents and other drugs that decrease GI peristalsis (including opiate analgesics); use of such drugs should therefore be avoided, if possible, during clozapine therapy.1,425,426

Constipation is a frequent and well-established adverse effect associated with clozapine therapy; however, FDA states that serious and fatal bowel problems continue to be reported in patients receiving the drug.1,425 In January 2020, FDA therefore strengthened an existing warning in the clozapine prescribing information that constipation caused by the drug can, uncommonly, progress to serious bowel complications.425 FDA identified 10 cases of constipation that progressed to serious complications with clozapine use that were reported in the FDA Adverse Event Reporting System (FAERS) database from July 21, 2006 through July 20, 2016 and in the medical literature from July 21, 2006 through August 2, 2016.425,427,428,429 These cases resulted in hospitalization, surgery, and 5 deaths.425,427,428,429 Adverse events included necrotizing colitis (4 cases), intestinal ischemia or necrosis (5 cases), and volvulus (1 case).425,427,428,429 The total daily dosage of clozapine in these patients ranged from 200-600 mg (median total daily dosage of 400 mg).425 The time to onset of serious bowel events ranged from 3 days to 6 months (median of 46 days).425 A preliminary review of additional FAERS data reported from July 21, 2016 through the end of 2019 identified similar findings.425 As a result of these findings, FDA is requiring a new warning and updates about this risk to be added to the prescribing information for all clozapine products.425

The risk of constipation and severe bowel complications appears to be greater with clozapine than with other antipsychotic agents.425,426 Although clozapine can cause constipation and serious bowel complications when used alone, such serious complications of constipation have been reported with other antipsychotic agents (e.g., olanzapine) only when they were used in combination with other drugs with anticholinergic activity.425 The risk of such reactions is further increased at higher dosages of clozapine and when clozapine is used concurrently with drugs that have anticholinergic activity or other drugs that can cause constipation, including opiate analgesics.425

Clozapine-induced GI hypomotility was objectively assessed and confirmed by measuring colonic transit time (CTT) using radiopaque markers in a study involving 37 patients.425,426 The study reviewed the effects of clozapine (monotherapy and combination antipsychotic therapy in 20 patients) and non-clozapine antipsychotic therapy (monotherapy and combination antipsychotic therapy in 17 patients) and concluded that nearly all patients receiving clozapine had increased CTTs.425,426 The median CTT in clozapine-treated patients was more than 4 times longer than in patients not receiving clozapine (105 hours versus 23 hours, respectively).425,426 Colonic hypomotility occurred in 80% of the patients receiving clozapine and in none of the patients receiving other antipsychotics (including aripiprazole, haloperidol, olanzapine, paliperidone, risperidone, and zuclopenthixol [not commercially available in the US]).426 An exposure-related increase in CTT was noted in this study (i.e., higher CTT observed with higher plasma clozapine concentrations).426 Patients receiving clozapine in this study did not report the hypomotility as subjective symptoms of constipation.426 (See GI Hypomotility with Severe Complications under Cautions: Precautions and Contraindications.)

Genitourinary Effects !!navigator!!

Genitourinary effects reported with clozapine therapy include polyuria,87 enuresis,12,33 and impotence.253 Acute interstitial nephritis,1 renal failure,1 nocturnal enuresis,1 priapism,1 and retrograde ejaculation1 also have been reported with clozapine therapy during postmarketing surveillance, although a causal relationship to the drug has not been established.1

Respiratory Effects !!navigator!!

Although a causal relationship to the drug has not been established, aspiration, pleural effusion, sleep apnea, and pneumonia and lower respiratory tract infection have been reported with clozapine therapy during postmarketing surveillance.1

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.188,281,296 Some evidence indicates that the incidence of respiratory arrest and vascular collapse is about 1-2% of patients receiving clozapine concomitantly with a benzodiazepine.281 For additional precautionary information about this potential effect, see Benzodiazepines under Drug Interactions: CNS Depressants.

Dermatologic and Sensitivity Reactions !!navigator!!

Rash has been reported in 2% of patients receiving clozapine.1,5,7,286

Hypersensitivity reactions, including photosensitivity,1 vasculitis,1 erythema multiforme,1 skin pigmentation disorder,1 and Stevens-Johnson syndrome,1 have been reported with clozapine during postmarketing surveillance; however, a causal relationship to the drug has not been established.1

Other Adverse Effects !!navigator!!

Myasthenic syndrome,1 rhabdomyolysis,1 systemic lupus erythematosus,1 angioedema,1 periorbital edema,1 leukocytoclastic vasculitis,1 and angle-closure (narrow angle) glaucoma1 have been reported with clozapine during postmarketing surveillance, although a causal relationship to the drug has not been established.1

Precautions and Contraindications !!navigator!!

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.5,11,292,347 (See Cautions, in the Phenothiazines General Statement 28:16.08.24.)

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.1 Because such effects may be dose-related, a reduction in clozapine dosage should be considered if they occur.1

Hepatotoxicity

Severe, life-threatening, and sometimes fatal hepatotoxicity has been reported in clozapine-treated patients.1 Patients receiving clozapine should be monitored for possible signs and symptoms of liver injury such as fatigue, malaise, anorexia, nausea, jaundice, hyperbilirubinemia, coagulopathy, and hepatic encephalopathy.1 Liver function tests should also be monitored in patients receiving the drug.1 Permanent discontinuance of clozapine should be considered if hepatitis or elevated aminotransferase concentrations combined with other systemic symptoms are caused by the drug.1

Fever

During clozapine therapy, patients may experience transient temperature elevations exceeding 38°C, with the peak incidence within the first 3 weeks of therapy.1,5,11,12,57,62,67,87,103,124,127,128,130,195,237 (See Cautions: Fever.) While this fever generally is benign and self-limiting, it may necessitate discontinuance of therapy.1 Occasionally, there may be an associated increase or decrease in leukocyte count.1

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.1 In addition, ANC should be monitored in any patient who develops fever within 2 weeks after discontinuance of clozapine.1 In the presence of high fever, the possibility of neuroleptic malignant syndrome also must be considered.1 (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, particularly at higher dosages or in overdosage situations.1 (See Acute Toxicity.) Clozapine should therefore be used with caution in individuals whose condition may be aggravated by anticholinergic effects (e.g., patients with a current or previous history of constipation, clinically important prostatic hypertrophy, urinary retention, or angle-closure [narrow-angle] glaucoma).1,146,237

Concomitant use of clozapine with other drugs that have anticholinergic activity should be avoided, if possible, because of the risk of anticholinergic toxicity and severe adverse GI reactions.1,425,426 (See Drug Interactions: Drugs with Anticholinergic Activity and Drugs that Decrease GI Peristalsis.)

Thromboembolic Events

Pulmonary embolism and deep-vein thrombosis have been reported with clozapine therapy.1 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.1

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.386,388,389,390,391,395

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.1,284,299,300,395,401,402,403 If a patient requires antipsychotic therapy following recovery from NMS, the potential reintroduction of drug therapy should be carefully considered.1,395 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.347 In addition, such patients should be carefully monitored since recurrences of NMS have been reported.1,395 (See Neuroleptic Malignant Syndrome under Cautions: Nervous System Effects.) For additional information on NMS, see Neuroleptic Malignant Syndrome under Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.

Metabolic Effects

Atypical antipsychotic agents are associated with metabolic changes that may increase cardiovascular and cerebrovascular risk (e.g., hyperglycemia, dyslipidemia, weight gain).1 While all atypical antipsychotics produce some metabolic changes, each drug has its own specific risk profile.1

Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients receiving atypical antipsychotic agents, including clozapine.1,331,332,334,335,336,337,338,339,340,341,342,343,344,358,359,360,361,365,395 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.1,331,332,334,335,336,337,338,339,340,341,342,343,395,400,406 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.1,331,332,334,335,336,337,338,339,340,341,342,343 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.1,331,332,334,335,336,337,338,339,340,341,342,343,365

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.344,345,347,349,350,354 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.344,345,351,352,353,354,355,365 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).292,346,347,351,352,353,354,363,378,379,380,381,382 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.292 (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.1 (See Dyslipidemia under Cautions: Endocrine and Metabolic Effects.)

Clozapine therapy may result in weight gain.1 Patients receiving the drug should be advised that weight gain has occurred during clozapine treatment.1 The manufacturers recommend clinical monitoring of weight in patients receiving the drug.1,395,400,406 (See Weight Gain under Cautions: Endocrine and Metabolic Effects.)

Falls

Clozapine therapy may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls; as a consequence, fractures or other injuries may occur.1 For patients with diseases or conditions or receiving other drugs that could exacerbate these effects, fall risk assessments should be completed when initiating antipsychotic treatment and periodically during long-term therapy.1

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.1 The risk of orthostatic hypotension may be reduced by initiating therapy at lower dosages, followed by gradual increases, and administration in divided doses.1,5,292 If hypotension occurs, dosage reduction of clozapine may be considered.1 Patients should be informed of the risk of orthostatic hypotension associated with use of clozapine, especially during the period of initial dosage titration.1 In addition, if clozapine therapy has been discontinued for more than 2 days, patients should be advised to contact their clinician for dosing instructions. .)1

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).1

GI Hypomotility with Severe Complications

Severe adverse GI reactions have occurred in patients receiving clozapine, primarily due to its potent anticholinergic effects and resulting GI hypomotility.1,425,426,427,428,429 In postmarketing experience, reported adverse effects ranged from constipation to paralytic ileus.1,425 Increased frequency of constipation and delayed diagnosis and treatment increased the risk of severe complications of GI hypomotility, resulting in intestinal obstruction, fecal impaction, megacolon, and intestinal ischemia or infarction.1,425,427,428,429 These reactions have resulted in hospitalization, surgery, and death.1,425,427,428,429 The risk of such severe adverse reactions is further increased with concomitant use of anticholinergic agents as well as with other drugs that decrease GI peristalsis (e.g., opiate agonists); therefore, concomitant use of clozapine with such drugs should be avoided whenever possible.1,425,426

Prior to initiating clozapine therapy, patients should be screened for constipation and treated, if necessary.1,425 However, clinicians should keep in mind that subjective symptoms of constipation may not accurately reflect the degree of GI hypomotility in clozapine-treated patients.1,425,426 Therefore, clinicians should frequently reassess bowel function with careful attention to any changes in the frequency or character of bowel movements as well as possible signs and symptoms of hypomotility complications (e.g., nausea, vomiting, abdominal distension, abdominal pain).1 If constipation or GI hypomotility is identified, the patient should be closely monitored and treated promptly with appropriate laxatives, as needed, to prevent severe complications.1 In addition, the prophylactic use of laxatives in high-risk patients (e.g., those with a history of constipation or bowel obstruction) should be considered.1,425 Some clinicians recommend that laxatives should be prescribed prophylactically in all patients receiving clozapine.426

Clinicians should educate patients and caregivers about the risks, prevention, and treatment of clozapine-induced constipation, including drugs to avoid when possible during therapy (e.g., drugs with anticholinergic activity).1,425 Appropriate hydration, physical activity, and fiber intake should be encouraged, and clinicians should emphasize that prompt attention to and treatment of developing constipation or other GI symptoms are essential in preventing severe complications.1,425 Patients and caregivers should be advised to contact their clinician if they experience symptoms of constipation (e.g., difficulty passing stools, incomplete passage of stool, decreased bowel movement frequency) or other symptoms associated with GI hypomotility (e.g., nausea, abdominal distension or pain, vomiting).1,425 (See GI Hypomotility with Severe Complications under Cautions: GI 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.1,385,394,395

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.1 Clozapine should therefore be used with caution in patients with risk factors for stroke.1,395

The manufacturer states that clozapine is not approved for the treatment of patients with dementia-related psychosis.1,385,394,395

Myocarditis, Cardiomyopathy, and Mitral Valve Incompetence

Because myocarditis and cardiomyopathy, which are sometimes fatal, have been reported in patients treated with clozapine, signs and symptoms suggestive of these reactions, including chest pain, dyspnea, persistent tachycardia at rest, palpitations, fever, flu-like symptoms, hypotension, other manifestations of heart failure, or ECG changes, should alert the clinician to perform further investigations.1 If the diagnosis of myocarditis or cardiomyopathy is confirmed, clozapine therapy should be discontinued and generally should not be reinitiated unless the benefit to the patient clearly outweighs the potential risk of recurrent myocarditis or cardiomyopathy.1,1

Mitral valve incompetence with mild or moderate mitral regurgitation has been reported in patients diagnosed with cardiomyopathy during clozapine therapy.1 In patients with suspected cardiomyopathy, consideration should be given to performing a 2-dimensional Doppler echocardiogram to identify mitral valve incompetence.1

Seizures

Generalized tonic-clonic (grand mal) seizures have occurred in patients receiving clozapine, particularly in patients receiving high dosages (greater than 600 mg daily) and/or in whom plasma clozapine concentrations were elevated.44,90,159,292 Clozapine should be used with caution in patients with a history of seizure disorders or other risk factors predisposing to seizures (e.g., history of head trauma or other preexisting CNS pathology, concomitant use of other drugs that lower the seizure threshold, history of alcohol abuse).1 Because of the substantial risk of seizures associated with clozapine use, patients should be advised not to engage in any activity where sudden loss of consciousness could cause serious risk to themselves or others (e.g., driving an automobile, operating complex machinery, swimming, climbing).1

Severe Neutropenia

Because of the risk of severe neutropenia, which can lead to serious and potentially fatal infections, clozapine therapy should be reserved for use in patients who have failed to respond adequately to standard antipsychotic therapy.1,395 Patients should be warned of this risk and informed that clozapine is only available through the Clozapine REMS program that ensures baseline and periodic monitoring of neutrophil counts.1,395 (See General under Dosage and Administration and also see Cautions: Hematologic Effects.) In addition, patients receiving clozapine therapy should be advised to immediately report the development of flu-like symptoms, fever, lethargy, malaise, weakness, mucous membrane ulceration, skin, pharyngeal, vaginal, urinary, or pulmonary infection, or any other potential manifestation of infection.1 Patients who develop severe neutropenia (ANC less than 500/mm3) while receiving clozapine generally should not be rechallenged with the drug.1,395 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 rechallen in such cases, consultation with a hematology specialist may be helpful in deciding whether to rechallenge a patient with clozapine.1

It is not known whether concurrent use of other drugs known to cause neutropenia increases the risk or severity of clozapine-induced neutropenia.1,395,400,406 (See Drug Interactions: Other Drugs Associated with Neutropenia.)

Other Precautions and Contraindications

Clozapine is contraindicated in patients with a history of serious hypersensitivity to clozapine (e.g., photosensitivity, vasculitis, erythema multiforme, Stevens-Johnson syndrome) or any ingredient in the formulation.1,395,406 (See Cautions: Dermatologic and Sensitivity Reactions.)

Pediatric Precautions !!navigator!!

The manufacturers state that the safety and efficacy of clozapine in pediatric patients have not been established.1,395,400,406 However, clozapine has been used in a limited number of children and adolescents with treatment-refractory schizophrenia (see Pediatric Considerations under Psychotic Disorders: Treatment-resistant Schizophrenia, in Uses) and results of at least one randomized, double-blind clinical study indicate that adverse hematologic effects were a major concern for children and adolescents receiving clozapine†.322,323 Although no cases of agranulocytosis occurred in this study, 24% of these children and adolescents experienced mild to moderate neutropenia during 2 years of follow-up compared with an estimated cumulative risk of 1.5-2% of developing neutropenia in adults.323 The precise mechanism by which clozapine induces agranulocytosis is not known,5,12,138,139,181,237 but a higher concentration of the metabolite norclozapine, which has been associated with hematopoietic toxicity in children and adolescents receiving clozapine, has been suggested as a possible reason for the increased risk in this age group.323,325,326 As with adult patients, adjunctive lithium has been used successfully in the management of clozapine-induced neutropenia in pediatric patients with schizophrenia†.411,412,415

In addition to adverse hematologic effects, clinically important seizure activity (e.g., epileptiform spikes, myoclonus, tonic-clonic seizures) also has been reported in children and adolescents with no previous history of epilepsy who received clozapine.323 In some cases, EEG abnormalities were associated with clinical deterioration (i.e., increased aggression, psychosis, irritability).323 Because some children and adolescents responded behaviorally to reduced dosages of clozapine and the addition of an anticonvulsant (e.g., valproate), it has been suggested that the EEG may be a sensitive indicator of clozapine toxicity in children as well as in adults.323

Geriatric Precautions !!navigator!!

Clinical studies of clozapine did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.1 Because geriatric patients may be at increased risk for certain cardiovascular (e.g., orthostatic hypotension, tachycardia) and anticholinergic effects of the drug (e.g., constipation, urinary retention in the presence of prostatic hypertrophy), clozapine should be used cautiously in this age group.1,292,301 In addition, geriatric patients generally are more sensitive than younger patients to drugs that affect the CNS.215,216 Data from clinical studies indicate that the incidence of tardive dyskinesia appears to be highest among geriatric patients, especially women.1 In general, dosage should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage ran the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.1,216,217,292

Geriatric patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death compared with patients receiving placebo.1,385,394,395 Analyses of 17 placebo-controlled trials (modal duration of 10 weeks) revealed an approximate 1.6- to 1.7- fold increase in mortality among geriatric patients receiving atypical antipsychotic drugs (i.e., aripiprazole, olanzapine, quetiapine, risperidone) compared with that observed in patients receiving placebo.1,385,394,395 Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with a rate of about 2.6% in the placebo group.1,392,394,395 Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.1,385,392,394,395 Observational studies suggest that, similar to atypical antipsychotics, treatment with conventional (first-generation) antipsychotics may increase mortality; the extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients remains unclear.1,395 Clozapine is not approved for the treatment of patients with dementia-related psychosis.1,385,394,395

An increased risk of adverse cerebrovascular events has been observed in patients with dementia treated with some atypical antipsychotic agents.1,395 The mechanism for this increased risk is not known.1,395 The manufacturers state that an increased risk cannot be excluded for other antipsychotics, including clozapine, or other patient populations.1,395 Clozapine should therefore be used with caution in patients with risk factors for stroke.1,395

Mutagenicity and Carcinogenicity !!navigator!!

Clozapine did not exhibit carcinogenic potential in long-term studies in mice and rats receiving dosages up to 0.3 and 0.4 times the maximum recommended human dosage on a mg/m2 basis, respectively.1 Clozapine also did not exhibit genotoxic or mutagenic effects when assayed in appropriate bacterial and mammalian tests.1,16

Pregnancy, Fertility, and Lactation !!navigator!!

Pregnancy

Reproduction studies in rats and rabbits using clozapine dosages up to 0.4 and 0.9 times the maximum recommended human dosage on a mg/m2 basis, respectively, have not revealed evidence of harm to the fetus.1,5,16,67

Neonates exposed to antipsychotic agents, including clozapine, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.1,395,397,398,399 There have been reports of agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder in these neonates.1,395,397,398,399 The majority of cases were also confounded by other factors, including concomitant use of other drugs known to be associated with withdrawal symptoms, prematurity, congenital malformations, and obstetrical and perinatal complications; however, some cases suggested that neonatal extrapyramidal and withdrawal symptoms may occur with exposure to antipsychotic agents alone.397,399 Some of the cases described time of symptom onset, which ranged from birth to one month after birth.397,398,399 Any neonate exhibiting extrapyramidal or withdrawal symptoms following in utero exposure to antipsychotic agents should be monitored.399 Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive care unit support and prolonged hospitalization.1,395,397,398,399 For further information on extrapyramidal and withdrawal symptoms in neonates, see Cautions: Pregnancy, Fertility, and Lactation, in the Phenothiazines General Statement 28:16.08.24.

The manufacturers state that there are no adequate and well-controlled studies to date using clozapine in pregnant women, and the drug should be used during pregnancy only when clearly needed.1,5,395,400,406 Women should be advised to notify their clinician if they become pregnant or plan to become pregnant during therapy with the drug.1,381,395,395 In addition, clinicians should advise women of childbearing potential about the benefits and risks of using antipsychotic agents during pregnancy.399 Patients should also be advised not to stop taking their antipsychotic agent if they become pregnant without first consulting with their clinician, since abruptly discontinuing the drugs can cause clinically important complications.399

Fertility

Reproduction studies in rats using clozapine dosages up to 0.4 times the maximum recommended human dosage on a mg/m2 basis have not revealed impaired fertility.1,5

Lactation

Clozapine is distributed into milk in humans.1 Because of the potential for serious adverse reactions to clozapine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1

Drug Interactions ⬆ ⬇

[Section Outline]

Drugs Affecting Hepatic Microsomal Enzymes !!navigator!!

Clozapine is a substrate for many cytochrome P-450 (CYP) isoenzymes, in particular 1A2, 2D6, and 3A4.1,320 Concomitant use of clozapine with drugs that inhibit CYP1A2, CYP2D6, or CYP3A4 may result in increased plasma concentrations of clozapine.1,320,395 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.1 The dosage should be increased back to the original dosage when the potent CYP1A2 inhibitor is discontinued.1 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.1 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.1

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.1,320,395 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.1,395,400,406 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.1,395,400,406 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.1,395,400,406

Phenytoin

Substantial reductions in plasma clozapine concentrations and exacerbation of psychosis have been reported in patients receiving concomitant therapy with clozapine and phenytoin.285 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.285 Control of psychotic manifestations was regained in both patients by gradually increasing the clozapine dosage.285

Because phenytoin is a potent inducer of CYP3A4, the manufacturers of clozapine state that concomitant use of these drugs generally is not recommended.1,395,400,406 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.1,395,400,406 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.1,395,400,406

Carbamazepine

Concomitant use of clozapine and carbamazepine has been shown to decrease clozapine concentrations by about 40-50%.321 In addition, neuroleptic malignant syndrome has been reported rarely with clozapine therapy alone and during concomitant therapy with carbamazepine.147 (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.1,395,400,406 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.1,395,400,406 Likewise, if carbamazepine is discontinued during clozapine therapy, dosage reduction of clozapine should be considered.1,395,400,406

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.1,394 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).1

Substantial (threefold) increases in trough plasma clozapine concentrations have occurred in patients receiving concomitant therapy with clozapine and the potent CYP1A2 inhibitor fluvoxamine.1 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.1

Drugs Metabolized by Hepatic Microsomal Enzymes !!navigator!!

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]).1,395,400,406 Caution should be exercised when such drugs are used concomitantly with clozapine.1 The manufacturers state that dosage reduction of the CYP2D6 substrate may be necessary.1,395,400,406

Other Drugs Associated with Neutropenia !!navigator!!

It is not known whether concurrent use of other drugs known to cause neutropenia increases the risk or severity of clozapine-induced neutropenia.1,395,400,406 The manufacturers of clozapine currently state that there is no strong scientific rationale to avoid clozapine treatment in patients concurrently treated with such drugs.1,395,400,406 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.1,395,400,406

Drugs Affecting the Seizure Threshold !!navigator!!

Clozapine may lower the seizure threshold16,176,177,253,255 and is associated with dose-related increases in the risk of seizures (see Seizures under Cautions: Nervous System Effects).1,44,90,159,234 Therefore, the manufacturers state that clozapine should be used with caution in patients receiving concomitant therapy with other agents that lower the seizure threshold.1,395,400,406 In addition, caution is advised in patients in whom alcohol abuse is a concern.1

CNS Depressants !!navigator!!

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.166,188,237,281,296 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;166,188,281,296 the reactions usually developed on the first or second day of clozapine therapy.166,188,281,296 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),281,297 death resulting from respiratory arrest reportedly has occurred in at least one patient receiving clozapine concomitantly with a benzodiazepine.213 An increased incidence of dizziness and sedation and greater increases in liver enzyme test results also have been reported with this drug combination.188,252

Other CNS-active Agents !!navigator!!

Although a causal relationship has not been established, at least one death has been reported with concomitant clozapine and haloperidol therapy.166 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.166 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.166

Neuroleptic malignant syndrome has been reported rarely with clozapine therapy alone1,284 and during concomitant therapy with clozapine and carbamazepine, lithium, or other CNS-active agents.1,147,148,237,255 (See Neuroleptic Malignant Syndrome under Cautions: Nervous System Effects.)

Concomitant use of clozapine and lithium may also increase the risk of seizures.292,330

Drugs that Prolong the QT Interval !!navigator!!

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).1,416 (See Prolongation of QT Interval under Cautions: Cardiovascular Effects.)

Drugs with Anticholinergic Activity and Drugs that Decrease GI Peristalsis !!navigator!!

Clozapine has potent anticholinergic effects.1,425 Because of the risk of anticholinergic toxicity and severe GI adverse reactions related to hypomotility, concurrent use of clozapine and drugs with anticholinergic activity (e.g., benztropine, cyclobenzaprine, diphenhydramine) or drugs that decrease GI peristalsis (e.g., opiate analgesics) should be avoided whenever possible.1,425 (See GI Hypomotility with Severe Complications and see also Anticholinergic Toxicity under Cautions: Precautions and Contraindications.)

Hypotensive Agents !!navigator!!

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.1

Smoking !!navigator!!

Smoking tobacco products (e.g., cigarettes) moderately induces CYP1A2, and may substantially reduce plasma clozapine concentrations.1,40,45,108,237 Limited data indicate that plasma clozapine concentrations following a given dose in smokers average 60-82% of those in nonsmokers.40,108 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.1,395,400,406 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.1,395,400,406

Other Information ⬆ ⬇

[Section Outline]

Acute Toxicity

Pathogenesis !!navigator!!

Acute toxicity studies in animals revealed that the LD50s for clozapine administered orally, IV, or intraperitoneally are approximately 145-325,16,67 58-61,16,67,165 and 90 mg/kg,67 respectively.

Although the acute lethal dose of clozapine in humans remains to be established, fatal overdoses with the drug generally have been associated with doses exceeding 2.5 g.1,44,107 However, there also have been reports of patients surviving overdoses that substantially exceeded 4 g of the drug.1

Manifestations !!navigator!!

In general, overdosage of clozapine may be expected to produce effects that are extensions of the drug's pharmacologic and adverse effects.1,292 The most commonly reported signs and symptoms of clozapine overdosage have been altered states of consciousness and CNS depression (e.g., sedation, delirium, coma),1,16,107,114 tachycardia,1,16,107 hypotension,1,16 respiratory depression or failure,1,16 and hypersalivation.1,107 Seizures, cardiac arrhythmias, and aspiration pneumonia also have occurred with overdosage of clozapine in some patients.1,16,44 (See Seizures under Cautions: Nervous System Effects.)

A 24-year-old woman who ingested 2 g in excess of her prescribed daily dosage (i.e., total ingestion approximately 3 g within a 24-hour period) had a tonic-clonic (grand mal) seizure; her plasma clozapine concentration 1 hour after the seizure (1313 ng/mL) was 500 ng/mL higher than usual, but she recovered uneventfully.44 In a 50-year-old woman who ingested 1 g of clozapine, the only manifestations were confusion and hallucinations lasting about 48 hours.114 A 26-year-old man who ingested approximately 3 g of clozapine became drowsy, agitated, and disoriented; he also had visual hallucinations, dysarthria, tachycardia, and hypersalivation.107 The patient was treated with gastric lavage and also received diazepam, digitalis, and anti-infectives, but continued to exhibit manifestations of severe central anticholinergic toxicity.107 Administration of physostigmine salicylate 2 mg by slow IV injection resulted in improvement in the patient's mental status within minutes; however, symptoms recurred after approximately 1 hour.107 Symptoms finally remitted 18-24 hours later with no further treatment.107

Treatment !!navigator!!

Treatment of clozapine overdosage generally requires symptomatic and supportive care, including monitoring of cardiac and vital signs.1,16 There is no specific antidote for the management of clozapine overdosage.1,16

The manufacturers recommend establishing and maintaining an airway and ensuring adequate ventilation and oxygenation.1 Electrolyte and acid-base balance should be monitored and adjusted accordingly.16 Peritoneal dialysis or hemodialysis is of limited value in the treatment of clozapine overdosage because the drug is almost totally bound to serum proteins.16 While physostigmine salicylate may be useful as adjunctive treatment if severe anticholinergic toxicity is present,107 the drug should not be used routinely because of its potential adverse effects.155,183,228,229,280

In managing clozapine overdosage, the clinician should consider the possibility of multiple drug involvement.1

Chronic Toxicity

Chronic toxicity studies in mice, rats, dogs, and monkeys have revealed no specific organ toxicity.16,67 After 1 year of treatment with clozapine, a brown discoloration caused by increased lipopigment was observed in various organs in rats; this change normally appears with increasing age.16,67 Discoloration was noted in the thyroid, brain, liver, kidney, heart, spleen, and skeletal muscle of rats, but such increased pigmentation was not associated with deleterious changes.67 The liver did show slight, dose-dependent changes, including centrolobular vacuolation, hepatocyte swelling, and increased weight.67

Pharmacology

Clozapine is a dibenzodiazepine-derivative1,2,4,5,7,8,9,10,11,12,65,67,181,197,235,239,248,253 antipsychotic agent.1,2,4,5,11,12,181,182,190,192,253 Clozapine shares some of the pharmacologic actions of other antipsychotic agents2,5,9,38,237 and has been described as an atypical or second-generation antipsychotic agent since many of its CNS effects differ from those of conventional (first-generation) agents (e.g., butyrophenones, phenothiazines).1,5,7,8,9,10,11,12,15,21,25,181,253,347 In fact, these apparent differences in actions on neostriatal dopaminergic receptors have led some investigators to question the importance of the dopaminergic system in mediating the therapeutic effects of neuroleptic drugs.67,162,164,165,212,256 The exact mechanism of antipsychotic action of clozapine has not been fully elucidated,1,2,9,10,12,20,22,253 but appears to be mediated through a combination of antagonist activity at dopamine type 2 (D2) and serotonin type 2A (5-hydroxytryptamine [5-HT2A]) receptors.1,5,15,19,67,170,212,237,256,288,290,292,293,347 Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic, and other dopaminergic and serotonergic receptors.1,67,237,256,347

Nervous System Effects !!navigator!!

Although the precise mechanism of action of antipsychotic drugs has not been fully elucidated, current data suggest that the therapeutic effects of atypical antipsychotic agents involve antagonism of dopaminergic and serotonergic systems in the CNS.1,212,256,347 In animals, classic neuroleptic agents increase muscle tone or induce postural abnormalities (catalepsy), antagonize stereotyped behaviors induced by the dopamine agonists apomorphine and amphetamine, accelerate dopamine turnover in various areas of the brain, increase serum prolactin concentrations, and produce dopamine receptor hypersensitivity on repeated administration.5,47,67,162,164,165,237 These effects, many of which have been attributed to blockade of dopamine receptors in the neostriatum, form the basis for the hypothesis that idiopathic psychoses result from overactivity of dopamine in neostriatal and mesolimbic systems.5,53,67,162,164,165,212,237,256,265

Unlike typical antipsychotic agents, clozapine exerts relatively weak antidopaminergic action within the neostriatum and has a low propensity to produce extrapyramidal effects or stimulate prolactin secretion.1,5,47,212,231,233,235,237,246,247,249,250,251,255,256,347 While some studies have demonstrated that relatively high doses of clozapine suppress the conditioned avoidance response in animals, which is a characteristic of typical antipsychotic agents,9,67,256 this response is not completely blocked by clozapine,7,9,22,67,92,212,256 and tolerance to this effect develops rapidly with repeated dosing, suggesting that it is not specifically related to clozapine's antipsychotic action.237,256,262 Further research is needed to elucidate fully clozapine's antipsychotic action in terms of the drug's serotonergic, adrenergic, muscarinic, and peptidergic effects and their influences on functional alterations in dopamine receptor systems.5,165,237

Antidopaminergic Effects

The therapeutic effects of antipsychotic drugs are thought to be mediated by dopaminergic blockade in the mesolimbic and mesocortical areas of the CNS, while antidopaminergic effects in the neostriatum appear to be associated with extrapyramidal effects.5,7,9,12,15,16,21,25,36,67,93,170,180,246,255,256 Several (at least 5)289 different types or subtypes of dopamine receptors have been identified in animals and humans.288,289,290,291 The relative densities of these receptors and their distribution and function vary for different neuroanatomical regions, and clozapine's unique effects may be secondary to regionally specific receptor interactions and/or other effects on dopaminergic neurons.5,9,11,36,67,288,289,290,291,292 Results obtained from receptor binding, behavioral, metabolic, and electrophysiologic studies of clozapine as well as the apparently low incidence of extrapyramidal effects associated with clozapine therapy15,16,21,36,180,246,255 suggest that the drug is more active in the mesolimbic than the neostriatal dopaminergic system.5,7,9,12,15,16,21,25,36,93,170,180,246,255,256 Results of some studies suggest that clozapine is more effective in increasing dopamine turnover and release in the nucleus accumbens or olfactory tubercle than in the neostriatum with acute administration99,257,258,259 and that it reduces dopamine release in the accumbens but not in the neostriatum during prolonged administration,292,293,294 which suggests preferential effects on dopaminergic function in the limbic system.99,257,258,259,293,294 However, conflicting data (i.e., no preferential limbic effects) also have been reported with both acute260,261 and repeated administration of the drug,192 which may reflect differences in analytical techniques, regional differences in drug distribution or receptor affinity, or other variables.192,260

Some evidence suggests that the effects of clozapine on dopamine metabolism in the neostriatum are dose related;67,145,178,198 unlike typical antipsychotic drugs, clozapine appears to increase striatal dopamine turnover only at supratherapeutic doses.19,21,178 Single high doses (80 mg/kg intraperitoneally) of clozapine in rats interfere with dopaminergic transmission by blocking postsynaptic dopamine receptors and causing a compensatory increase in dopaminergic neuronal firing, while lower doses retard dopamine release.99,158 Clozapine appears to increase striatal dopamine content when given either in single high doses or repeated low doses,21,67,178 and low doses of the drug reportedly decrease the degradation of dopamine to 3-methoxy-4-hydroxyphenylacetic acid (homovanillic acid, HVA) in the neostriatum.145,156 In a rodent model of tardive dyskinesia, single low doses (up to 1.2 mg/kg intraperitoneally) of clozapine suppressed ketamine-induced linguopharyngeal movements, which resemble symptoms of tardive dyskinesia (e.g., tongue protrusions, retrusions, and swallows), by 15-75% compared with baseline measures.113 At clozapine doses of 4.8 mg/kg or higher, clozapine caused total suppression of these movements, and duration of suppression became dose dependent.113 Since suppression of abnormal linguopharyngeal movements occurred at doses substantially lower than those reported to alter dopamine turnover, it has been suggested that doses of the drug lower than those required for antipsychotic activity may be useful for treating antipsychotic-induced tardive dyskinesia.113

Current evidence suggests that the clinical potency and antipsychotic efficacy of both typical and atypical antipsychotic drugs generally are related to their affinity for and blockade of central dopamine D2 receptors;1,5,10,99,212,256,291,292 however, antagonism at D2 receptors does not appear to account fully for the antipsychotic effects of clozapine.1,5,16,237,256,288,290,291

In in vitro studies, clozapine is a comparatively weak antagonist at D2 receptors.51,96,132,175 Clozapine's affinity for the D2 receptor on a weight basis reportedly is approximately one-third (33%) that of loxapine,51,96,175 one-tenth (10%) that of chlorpromazine,51,96,132,175 and one-fiftieth (2%) that of haloperidol.51,96,132,175 In oral dosages of 300 mg daily, clozapine produces a 40-65% occupancy of D1 and D2 receptors.9,97,110,249 During long-term clozapine therapy, the relative occupancy of D1 receptors may become greater than that of D2 receptors,249 or the long-term effects of the drug on D2 receptors may be antagonized by its nondopaminergic properties.249 Although the in vitro affinity of clozapine for D1 and D2 receptors in brain tissue of animals appears to be similar,5,22,233,237,249 the drug's in vivo effects in many animals resemble those of D1receptor-specific antagonists.5 Compared with typical antipsychotic agents, clozapine shows greater affinity for and appears to produce greater blockade of neostriatal dopamine D1 receptors;9,21,235,246,256 other data suggest that clozapine preferentially but not selectively antagonizes D1 receptor-mediated functions.233 At clinically effective dosages, however, the drug produces comparable blockade of D1 and D2 receptors and less D2 blockade than typical antipsychotic drugs.5,18,97,256,263 Long-term administration of clozapine leads to a 35-50% “up-regulation” of D1 receptors, which is comparable to that observed with administration of selective D1 antagonists;246,249 however, the number of D2 receptors is not changed,24,48,246,249 possibly because the proportion of occupied receptors required to elicit a response is less for D1 than for D2 receptors.249 Limited evidence suggests that D1 receptors may exist either coupled to adenylate cyclase or in uncoupled form.100 Clozapine appears to be a potent, competitive inhibitor of dopamine-stimulated adenylate cyclase in vitro, and the adenylate cyclase-coupled state of the D1 receptor binds clozapine with high affinity;100,233,237,249 in contrast, typical antipsychotic agents bind preferentially to the uncoupled D1 receptor.100

Although their role in eliciting the pharmacologic effects of antipsychotic agents remains to be fully elucidated, dopamine D3, D4, and D5 receptors also have been identified;288,289,290,291,292 clozapine appears to have a much higher affinity for the D4 receptor than for D2 or D3 receptors.288 Current information on D3-receptor affinity for antipsychotic drugs suggests that most antipsychotics probably bind to both D2 and D3 receptors, although with higher affinity to D2 receptors; however, the magnitude of the difference in D3- versus D2-receptor binding is much less with atypical antipsychotics such as clozapine, suggesting that effects on D3 receptors may play a more important role in the pharmacologic actions of atypical versus typical antipsychotic drugs.290,291 The high affinity of the D4 receptor for clozapine and its preferential distribution in cortical and limbic areas in animals may explain, in part, the relative lack of tardive dyskinesia and extrapyramidal effects during clozapine therapy.288 The cloning of a gene for a neuron-specific dopamine D5 receptor, which binds antipsychotic drugs with similar affinity as the D1 receptor but has a tenfold higher affinity for dopamine, also has been reported.289

Clozapine's clinical potency appears to be twice that of chlorpromazine on a weight basis,5,16,64,237 although the drug demonstrates considerably weaker D2-receptor binding affinity than chlorpromazine and appears to be much less potent in elevating dopamine metabolite concentrations in the brain.26 Clozapine produces a more potent blockade of central serotonergic, adrenergic, histamine H1, and muscarinic receptors than typical antipsychotic agents;18,24,67,96,197,237,247,256 also, long-term administration of clozapine enhances striatal D1-receptor function in animals and results in “down-regulation” of cortical, type 2 serotonergic (5-HT2) receptors,154,247,256 suggesting that an interaction between these central neurotransmitter systems may be important for the drug's antipsychotic efficacy.256 Antagonism at cholinergic and α1-adrenergic receptors in the mesolimbic system, compensating for dopaminergic blockade in the neostriatum, may explain the apparent selectivity and low incidence of extrapyramidal effects seen with clozapine.31,111,170,256 The amygdala also may be a site of action for clozapine,237,256,264,265,266 since repeated administration of the drug selectively induces supersensitivity to locally applied dopamine in the amygdala,237,264,265,266 and amygdaloid neurons are excited by clozapine but generally unresponsive to other antipsychotic agents (e.g., haloperidol).256,264,265,266

Further studies are needed to elucidate the mechanism of clozapine's antipsychotic effects in various areas of the CNS.237

Neurophysiologic Effects

In vitro and in vivo electrophysiologic studies in animals demonstrate different sensitivities of various brain areas to clozapine-mediated postsynaptic receptor blockade.15,99,170,180,237 While clozapine increases firing rates of both nigrostriatal (A9 pathway) and mesolimbic (A10 pathway) dopaminergic neurons after acute administration, only mesolimbic dopaminergic neurons exhibit prolonged depolarization blockade following repeated exposure to the drug.15,99,170,237 Repeated administration of typical antipsychotic agents (e.g., haloperidol) concomitantly with an anticholinergic agent (trihexyphenidyl) or an α1-adrenergic blocking drug (prazosin) mimicked these selective effects of clozapine on mesolimbic versus nigrostriatal dopaminergic neurons, suggesting that α1-adrenergic blocking and/or anticholinergic effects may be responsible, in part, for the differential effects of clozapine in these midbrain areas.170,180,256 Some evidence suggests that the nucleus accumbens has greater sensitivity for clozapine than do other regions, which may explain why the drug appears to produce depolarization blockade of dopaminergic neurons only in the mesolimbic area.99,237 However, some studies have shown that neurons in the neostriatum also may be responsive to clozapine.26 Clozapine reportedly produces an increase in dopamine metabolites in the neostriatum15 comparable to or even greater than that in the nucleus accumbens. Demonstrable dopamine-receptor supersensitivity in both striatal and limbic forebrain regions also has been reported with prolonged clozapine administration.50 Therefore, it has been suggested that there may be a dissociation between the effects of clozapine on synthesis and metabolism of dopamine within nigrostriatal neurons and the drug's effects on neuronal firing rate and dopamine release.15,287

Adrenergic Effects

Clozapine has adrenergic-blocking activity,1,96,212 which may be partially responsible for the sedation, muscle relaxation, and cardiac effects observed in patients receiving the drug.11,67,119,237,256,292 (See Cautions: Cardiovascular Effects.) Although the drug appears to have relatively weak α-adrenergic blocking effects compared with typical antipsychotic drugs such as chlorpromazine,212 clozapine's in vitro affinity (relative to dopamine D2-receptor affinity) for α1- and α2-adrenergic receptors is much higher than that of conventional antipsychotics, including chlorpromazine, haloperidol, loxapine, and thioridazine.96 Clozapine increases the number and sensitivity of α1-adrenergic, but not dopamine D2, receptors.237 The turnover rate of epinephrine and norepinephrine also may be increased by clozapine, but to a lesser extent than that of dopamine.7,11,19,36,67,247 Substantial increases in plasma norepinephrine concentrations, which decreased following discontinuance of the drug but remained above basal levels, have been noted in both schizophrenic and healthy individuals receiving clozapine;31,111 such increases may be the result of feedback mechanisms activated by adrenergic blockade.11,31,178

Clozapine's central α1-adrenergic blocking activity also may be responsible for the dose-related hypothermia observed in mice given the drug.119 Clozapine also induces ataxia and blocks amphetamine-induced hyperactivity in mice, although repeated administration of the drug results in almost complete tolerance to these effects.119 It has been suggested that clozapine's α1-adrenergic blocking properties may, in part, mediate its differential effects on midbrain dopamine receptors15,170,256 and be responsible for its relative lack of extrapyramidal effects.170,256 However, the clinical importance of the drug's α1-adrenergic effects has not been fully elucidated.292

Anticholinergic Effects

Clozapine possesses potent anticholinergic activity in vitro;1,11,28,212,237 the drug's affinity for muscarinic receptors substantially exceeds that of other antipsychotic agents67,96 (e.g., 39-50 times greater than that of chlorpromazine and 100 times that of loxapine)67,161,164 and may be similar to that of tricyclic antidepressants107 and antimuscarinic antiparkinsonian agents (e.g., benztropine, trihexyphenidyl).161 It has been suggested that clozapine's anticholinergic effects may be more potent centrally than peripherally and that adverse anticholinergic effects generally are not dose limiting;5,28,212 however, peripheral anticholinergic effects such as dry mouth are common and may be troublesome.1,2,12,17,32,34,61,87,253,292 Clozapine-induced delirium, which reportedly has occurred with rapid dosage escalation,292 has been reversed by physostigmine; this suggests that clozapine has central antimuscarinic activity.5,107 Some evidence also suggests that clozapine's anticholinergic properties may counteract the effects of dopamine receptor blockade in the neostriatum and thus prevent extrapyramidal reactions.11,15,47,161,170,256 Limited data suggest that the propensity of antipsychotic drugs to cause extrapyramidal effects varies inversely with anticholinergic potency and antimuscarinic activity;67,164 however, the relatively potent anticholinergic activity of clozapine does not appear to account adequately for its atypical actions.11,237,292

Serotonergic Effects

It has been suggested that schizophrenia may involve a dysregulation of serotonin- and dopamine-mediated neurotransmission, and clozapine may at least partially restore a normal balance of neurotransmitter function,5,245,256 possibly through serotonergic regulation of dopaminergic tone.292 Clozapine blocks central type 2A serotonergic (5-HT2A) receptors;1,22,48,94,101,117,247 the drug also antagonizes central and peripheral type 3 serotonergic (5-HT3) receptors.247 Long-term95 and acute101,249 administration of clozapine has produced down-regulation of 5-HT2 receptors in the frontal cortex and neostriatum of male rats;95,101,249 single or repeated daily injections of clozapine also reduced the number of cortical 5-HT2 receptors but did not change receptor affinity.48 In contrast to effects caused by typical antipsychotic agents, an increase in brain tryptophan, serotonin, and 5-hydroxyindoleacetic acid (5-HIAA) concentrations generally has been reported with clozapine administration in animals.67,154,271,292 It has been suggested that these effects might contribute to the pronounced sedative effects of clozapine,67,271 although increases in blood serotonin concentrations occurring during clozapine treatment in humans have been inconsistent and variable.154 (See Effects on Sleep under Pharmacology: Nervous System Effects.) Clozapine's serotonergic effects also reportedly may contribute to the drug's efficacy against negative symptoms of schizophrenia256,292 and to the weight gain observed during clozapine therapy.150,292 (See Cautions: Endocrine and Metabolic Effects.)

Effects on Other Central Neurotransmitters

Clozapine appears to have important activity on the metabolism of γ-aminobutyric acid (GABA), which has inhibitory effects on dopaminergic neurons.237 In contrast to the effects of typical antipsychotic drugs, clozapine apparently augments GABA turnover in both the neostriatum and nucleus accumbens.7,9,27,36,247 Increases in neostriatal GABA turnover and release may attenuate extrapyramidal reactions,7,9,26,27,292 while a similar action in the nucleus accumbens may be related to antipsychotic efficacy.

Clozapine appears to have central histamine H1-receptor blocking activity;1,197,247 such activity reportedly may be associated with sedation, hypotension, and weight gain.96,292 The drug's affinity (relative to dopamine D2-receptor affinity) for histamine H1-receptors is approximately 30 times that of chlorpromazine and 4 times that of loxapine.96

Behavioral Effects in Animals

Studies of the effects of clozapine on animal behavior routinely used to detect antipsychotic activity support its classification as an atypical antipsychotic drug.256 Such studies suggest that the neostriatum is relatively unresponsive to clozapine.256 Since the drug does not induce catalepsy or inhibit apomorphine-induced stereotypy, which are thought to be mediated principally by the nigrostriatal dopamine system, clozapine's antipsychotic activity appears to result from the drug's activity in other areas.5,6,7,9,11,14,18,19,21,22,34,98,237,247,256 Clozapine also does not block amphetamine-induced hyperactivity or apomorphine-induced emesis in animals as the typical antipsychotic agents do.5,237 Long-term administration of clozapine causes supersensitization of behaviors mediated by mesolimbic dopaminergic pathways (e.g., dopamine-induced locomotion) but not those mediated via neostriatal systems (e.g., dopamine-induced stereotypy).25,256,267 Long-term administration of clozapine in male rats caused a marked supersensitivity (of the same magnitude and duration as that of haloperidol) in the mesolimbic but not the nigrostriatal system.36 It has been suggested that supersensitivity of mesolimbic dopamine receptors may be associated with the apparent rebound psychosis that has been reported following clozapine therapy.131,173,174,292 (See Cautions: Other Nervous System Effects.)

EEG Effects

Clozapine may produce dose-related2,12,20,38,177,234,237,255 changes in the EEG, including increased discharge patterns similar to those associated with seizure disorders,151 and may lower the seizure threshold;16,176,177,253,255 seizures have occurred in patients receiving the drug, particularly with high dosages (greater than 600 mg daily),292 rapid dosage increases,292 and/or in the presence of high plasma concentrations.1,44,90,159,292 (See Seizures in Cautions: Nervous System Effects.) Some EEG changes associated with clozapine administration are atypical of those generally seen with other antipsychotic agents, resembling more closely those produced by antidepressants.49,184,169 Clozapine increases beta-, delta-, and theta-band amplitudes and slows dominant alpha frequencies in clinical EEG studies.1,49,67,169,244 However, in patients with severe, treatment-resistant schizophrenia, increases in delta and theta band frequencies are more pronounced with clozapine than with haloperidol or chlorpromazine therapy, a finding that appears to parallel the drugs' relative antiserotonergic, antihistaminic, and anticholinergic activities.184 Enhanced EEG synchronization, paroxysmal sharp-wave activity, and spike and wave complexes also may develop during clozapine therapy.1,17,35 Clozapine-induced EEG changes generally appear soon after initiation of the drug and return to baseline upon cessation of therapy.49,67,191 In one study, the EEG showed slight general changes or slight diffuse slowing in 75% of patients receiving clozapine; in another study, clozapine caused marked EEG changes, including a slowing of basal activity, in 5% of patients.17

Effects on Sleep

Clozapine causes a shift in the sleep-wake pattern toward dozing in animals, with marked reductions in both slow-wave and paradoxical sleep times.9,67,270 However, tolerance to the drug's sedative effect usually occurs, although slowly in some patients,292 during continuous administration of clozapine.32,156,232,272 In a controlled study of short-term (3-day) administration in healthy young men, clozapine in dosages of 25 mg nightly substantially increased total sleep time on the first night of administration, but the duration of sleep returned to baseline by the third night.32 Clozapine did not substantially affect the time spent in stage 1, 2, 3, or slow-wave sleep, nor did it affect latency to the rapid eye movement (REM) period or the percentage of time spent in REM sleep.32 However, the percentage of time spent in stage 4 sleep was reduced substantially on the second and third nights of drug administration, while a variety of REM indices were increased on the third night of the study.32

In a few patients receiving clozapine dosages of 150-800 mg daily, REM sleep increased to 85-100% of total sleep time after several days of drug therapy,109,152,195 with the onset of REM sleep occurring almost immediately after patients fell asleep.1,152 Intensification of dream activity also has been reported during clozapine therapy.1,32,152,195 Some clinicians have suggested that a correlation may exist between increases in body temperature and REM sleep and clozapine-induced improvement in psychosis.109,152,195 Cataplexy has been reported in some patients receiving clozapine.12,195,252

Neuroendocrine Effects !!navigator!!

In contrast to typical antipsychotic drugs, clozapine therapy in usual dosages generally produces little or no elevation of prolactin concentration in humans.1,5,15,22,30,67,179,237,250,347 Administration of clozapine to rats has produced a transient, dose-related increase in prolactin concentrations that is of much shorter duration than that caused by other antipsychotic agents.15,22,117 Prolactin normally is inhibited by dopamine released from tuberoinfundibular (TIDA) neurons into the pituitary portal circulation.22 In rats, clozapine acutely increases the activity of TIDA neurons, which inhibit the release of prolactin;15,22,117,185 activation of TIDA neurons may be mediated by an enhanced release of neurotensin.15 Clozapine's effect on prolactin appears to be transient, possibly because the drug appears to dissociate from dopamine receptors more rapidly than typical antipsychotic agents and is therefore eliminated from the brain more rapidly.117,179,250,292

Clozapine has an effect on corticotropin (ACTH) and corticosterone, possibly through its effects on dopamine metabolism in the hypothalamus.15,30,237 Short-term administration of clozapine (cumulative dose: 200 mg) to a few patients with schizophrenia resulted in marked inhibition of apomorphine-induced somatotropin (growth hormone) response, suggesting that clozapine may block the dopamine receptors responsible for eliciting this response.30,304 In contrast to typical antipsychotic agents, clozapine decreases22,245 or has no effect on117 basal cortisol levels. Clozapine markedly increases corticosterone concentrations in a dose-dependent fashion;15,117,185 other antipsychotic agents appear to increase corticosterone concentrations only at doses producing substantial D2-receptor blockade.15 Clozapine-induced stimulation of corticosterone secretion may result from stimulation, rather than blockade, of dopamine receptors, but the exact mechanism has not been fully elucidated.185

Other Effects !!navigator!!

Clozapine produced a dose-dependent delay in initiation of copulation in male rats, which may be related to blockade of mesolimbic dopamine receptors;91 however, the drug had no effect on copulatory behavior once the behavior had started.91 Fertility in male and female rats reportedly is not adversely affected by clozapine.1 (See Cautions: Pregnancy, Fertility, and Lactation.)

In animals, even small oral doses of clozapine cause ptosis, relaxation, and a reduction in spontaneous activity,67 effects that are consistent with the drug's sedative activity.292 Inhibition of locomotor activity induced by clozapine diminishes with repeated administration.67 With increasing doses of the drug, reactions to acoustic and tactile stimuli decline, and disturbances in equilibrium have been reported.67 Clozapine also inhibits isolation-induced aggression in mice at doses lower than those affecting motor function, suggesting a specific antiaggressive effect.67

Studies in animals suggest that clozapine has a weak and variable diuretic effect;67 the clinical importance of this effect has not been established.292 In both rats and dogs, low doses of clozapine tend to increase the elimination of water and electrolytes, while higher doses are associated with increases in potassium excretion and sodium retention.67

Pharmacokinetics

Absorption !!navigator!!

Clozapine is rapidly12,16,38,67,102,235 and almost completely5,41,67 absorbed following oral administration. However, because of extensive hepatic237 first-pass metabolism, only about 27-50% of an orally administered dose reaches systemic circulation unchanged.5,41 Some,5 but not all,5,13,42,46,171 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.5 GI absorption appears to occur principally in the small intestine2 and is approximately 90-95% complete within 3.5 hours after an oral dose.5 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.1,5,218,219 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).395,406 The differences in peak plasma concentrations are not considered clinically important;395,406 therefore, the manufacturers state that clozapine (as conventional tablets, orally disintegrating tablets, or oral suspension) can be taken without regard to meals.1,395,406

The relative oral bioavailability of clozapine has been shown to be equivalent following administration of 25-mg and 100-mg conventional tablets;1,5 commercially available clozapine oral suspension and conventional tablets and orally disintegrating tablets and conventional tablets also are bioequivalent.395,406

Following oral administration of a single 25-5 or 100-mg46 oral dose of clozapine as tablets in healthy adults, the drug is detectable in plasma within 25 minutes,5 and peak plasma clozapine concentrations occur at about 1.5 hours.46 Peak plasma concentrations may be delayed with higher single doses41 and with multiple dosing of the drug.1,2 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).1,2 Steady-state plasma concentrations ranging from 200-600 ng/mL generally are achieved with oral dosages of 300 mg daily,5,11,16,67,143 and steady-state peak plasma concentrations generally occur within 2-4 hours after a dose.5,12,38 Steady-state plasma concentrations of clozapine are achieved after 7-10 days of continuous dosing.11,16,42,67,143,237

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).395 Minimum plasma concentrations at steady state in this study averaged 168 ng/mL (range: 45-574 ng/mL). 395 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).406 Minimum plasma concentrations at steady state in this study averaged 75 ng/mL (range: 11-198 ng/mL).406

Considerable interindividual variation in plasma clozapine concentrations has been observed in patients receiving the drug,5,39,40,41,42,46,186,237 and some patients may exhibit either extremely high or extremely low plasma concentrations with a given dosage.40,45 Such variability may be particularly likely at relatively high dosages (e.g., 400 mg daily) of the drug.39 In one study, a sixfold interindividual variation in steady-state plasma clozapine concentration was observed in patients receiving such dosages.39 In addition, considerable intraindividual variation, particularly from week to week, may occur in some patients.186 However, substantial intraindividual variations in pharmacokinetic parameters typically are not observed from day to day.13 Although the interindividual variability in plasma clozapine concentrations is consistent with that reported for other antipsychotic drugs5,39 and may be secondary to differences in absorption, distribution, metabolism, or clearance of the drug,39,237,292 further study is needed to clarify whether such variation results principally from variable pharmacokinetics or other variables.40

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.5 However, a linear dose-concentration relationship also has been reported.5,42,46,171,238 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.39 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.1,42

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.1,395,406 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.1,40,45,108,237,238,395,406 (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.40,108,238 In addition, smoking has a greater effect on clozapine plasma concentrations in men than in women,238 although this difference could result simply from gender differences in smoking behavior.238 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.108,237,238

Pharmacologic effects of clozapine (e.g., sedation)189 reportedly are apparent within 15 minutes and become clinically important within 1-6 hours.2 The duration of action of clozapine reportedly ranges from 4-12 hours2 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.37 (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,37 and maximal activity may require several months of therapy with the drug.5,83,225,226

Correlations between steady-state plasma concentrations of clozapine and therapeutic efficacy have not been established,5,143,171,186,237,292 and some evidence suggests that the degree of clinical improvement is independent of plasma concentrations ranging from 100-800 ng/mL.171 However, it also has been suggested that serum clozapine concentrations less than 600 ng/mL may be adequate for therapeutic effect in most patients.44 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.235,236,292 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.236,292

Distribution !!navigator!!

Distribution of clozapine into human body tissues is rapid and extensive;2,16,43 distribution of metabolites of the drug also appears to be extensive.5 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.43,235 At 8 hours after IV injection, clozapine was still detectable in these organs but not in blood.43 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.43 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,43 but the clinical importance, if any, of such an effect has not been established.292

The volume of distribution of clozapine has been reported to be approximately 4.65 L/kg.42 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.41 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.237 Clozapine is approximately 97% bound to serum proteins.1,5

Results of receptor-binding studies in monkeys indicate that clozapine rapidly crosses the blood-brain barrier following IV injection.16,220 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.16 The pharmacokinetic characteristics of the drug in the CNS paralleled those in plasma in these monkeys,16,220 with an elimination half-life from CNS of about 5 hours.220 Evidence from other animal studies indicates that CNS concentrations of the drug exceed those in blood.43 Distribution of the drug into the CNS in humans has not been characterized.2

Clozapine reportedly is present in low concentrations in the placenta in animals;2 information on placental transfer of the drug in humans currently is unavailable.292 Clozapine distributes into human milk.1 (See Cautions: Pregnancy, Fertility, and Lactation.)

Elimination !!navigator!!

The decline of plasma clozapine concentrations in humans is biphasic.16,67,179 The elimination half-life of clozapine following a single 75-mg oral dose reportedly averages 8 hours (range: 4-12 hours);1,5,11,67,179 that after a 100-mg oral dose appears to be similar.46 The elimination half-life of clozapine at steady state following administration of 100 mg twice daily reportedly averages 12 hours (range: 4-66 hours).1,38 The rapid elimination phase may represent redistribution5 and is followed by a slower apparent mean terminal elimination half-life of 10.3-38 hours.5,16,41,42,67,179 Although a study comparing single and multiple dosing of clozapine demonstrated an increase in elimination half-life with multiple dosing,1,219 other evidence suggests this finding is not attributable to concentration-dependent pharmacokinetics.42,292

Clozapine is almost completely metabolized in the liver prior to excretion by many CYP isoenzymes, particularly CYP1A2, CYP2D6, and CYP3A4.1,2,320 Clozapine may undergo N -demethylation,12,102,214 N -oxidation,12,102,214 3'-carbon oxidation,12 epoxidation of the chlorine-containing aromatic ring,12,214 substitution of chlorine by hydroxyl or thiomethyl groups,67,102,214 and sulfur oxidation.12 A glucuronide metabolite, tentatively identified as a quaternary ammonium N -glucuronide of clozapine, also has been identified.67 Metabolism of clozapine may occur by one or more of these routes.102

The rate of formation and biologic activity of clozapine metabolites have not been fully elucidated.12,292 The desmethyl metabolite of clozapine (norclozapine) has limited activity while the hydroxylated and N -oxide derivatives are inactive.1 The N -oxide and desmethyl derivatives are found in urine and plasma of humans5,67 in a proportion of 2:1.5

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.5 Only limited amounts (approximately 2-5%)11,67 of unchanged drug are detected in urine and feces.1 Approximately 50% of an administered dose is excreted in urine1,2,67 and 30% in feces;1,2 maximum fecal excretion has been estimated at 38%.5,11,67 Approximately 46% of an oral dose of clozapine is excreted in urine within 120 hours.5

Total plasma and blood clearance of clozapine reportedly average 217 and 250 mL/minute, respectively, but show considerable interindividual variation.41

Chemistry and Stability

Chemistry !!navigator!!

Clozapine is a dibenzodiazepine-derivative1,2,4,5,7,8,9,10,11,12,65,67,181,197,235,239,248,253 antipsychotic agent.1,2,4,5,11,12,181,182,190,192,253 The drug is a piperazine-substituted tricyclic1,4,7,8,65,67,197,198 antipsychotic agent that is structurally similar to loxapine2,4,5,10,11,12,255 but that differs pharmacologically from this and other currently available antipsychotic agents (e.g., phenothiazines, butyrophenones).5,7,8,9,10,11,12,13,15,21,25,181,253 Because of these pharmacologic differences, clozapine is considered an atypical or second-generation antipsychotic agent.1,5,10,11,15,212,237,256

While the structure-activity relationships of phenothiazine antipsychotic agents have been well described, these relationships for heterocyclic antipsychotic agents, including clozapine, have not been as fully characterized.8,67,212 Generally, the unsubstituted benzene ring seems to be important for interactions at dopamine receptors, while the chloro-substituted benzene ring seems more important for action at muscarinic receptors.237 In addition, an open carbon side chain replacing the piperazine moiety of clozapine generally leads to loss of activity.237

Clozapine differs structurally from most currently available antipsychotic agents by the presence of a seven- rather than a six-membered central ring67,156,237 and the spatial relationship between the piperazine moiety and the chloro-substituted benzene ring.67 The core tricyclic ring system of clozapine is nonplanar and allows the piperazine moiety limited freedom of rotation.237

Clozapine differs structurally from loxapine by the presence of a diazepine rather than an oxazepine central ring in the tricyclic nucleus and by the presence of a chlorine atom at position 8 rather than 2 of the tricyclic nucleus.4,67,237 The presence of a chlorine atom at position 8 of the tricyclic nucleus of clozapine appears to be associated with its distinct pharmacologic profile67 and may be responsible for the drug's antimuscarinic activity.237

Clozapine occurs as a yellow, crystalline powder2,16 and is very slightly soluble in water.2

Stability !!navigator!!

Commercially available conventional clozapine tablets should be stored in tight containers at a controlled room temperature of 20-25°C400 and not exceeding 30°C.1 Clozapine orally disintegrating tablets should be stored in their original package at a controlled room temperature of 20-25°C, but may be exposed to temperatures ranging from 15-30°C.395 The orally disintegrating tablets should be protected from moisture.395 Clozapine oral suspension (e.g., Versacloz®) should be stored at a controlled room temperature of 20-25°C, but may be exposed to temperatures ranging from 15-30°C; the oral suspension should be protected from light and should not be refrigerated or frozen.406 The oral suspension is stable for 100 days after initial bottle opening.406

Preparations ⬆ ⬇

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Clozapine is available only through a shared REMS program, the Clozapine REMS program, which ensures appropriate monitoring and management of patients with severe neutropenia.1,395,400,406,407,408 (See General under Dosage and Administration.)

cloZAPine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Suspension

50 mg/mL

Versacloz®

Jazz

Tablets

25 mg*

cloZAPine Tablets (scored)

Clozaril® (scored)

HLS

50 mg*

cloZAPine Tablets (scored)

Clozaril® (scored)

HLS

100 mg*

cloZAPine Tablets (scored)

Clozaril® (scored)

HLS

200 mg*

cloZAPine Tablets (scored)

Clozaril® (scored)

HLS

Tablets, orally disintegrating

12.5 mg*

cloZAPine Orally Disintegrating Tablets

25 mg*

cloZAPine Orally Disintegrating Tablets

100 mg*

cloZAPine Orally Disintegrating Tablets

150 mg*

cloZAPine Orally Disintegrating Tablets

200 mg*

cloZAPine Orally Disintegrating Tablets

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Copyright ⬆ ⬇

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions November 29, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References ⬆

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