Clozapine, a tricyclic dibenzodiazepine derivative, is an atypical antipsychotic agent.1, 395, 400, 406
Treatment-resistant Schizophrenia
Clozapine conventional oral tablets, orally disintegrating tablets, and oral suspension are used for treatment of schizophrenia in severely ill adults who fail to respond adequately to standard antipsychotic treatment.1, 395, 400, 406 Due to the risks of severe neutropenia and seizure associated with its use, clozapine should only be used in patients who have failed to respond adequately to standard antipsychotic treatment.1, 395, 400, 406
Clozapine has also been used for the management of childhood- and early-onset treatment-resistant schizophrenia in pediatric patients† .319, 434
The efficacy of clozapine for treatment-resistant schizophrenia in adults was established in a multicenter, randomized, double-blind, active-controlled study in patients with schizophrenia who had been treated with at least 3 different antipsychotics from at least 2 different chemical classes during the preceding 5 years.1, 10, 395, 406 To be enrolled, patients had to have a baseline score of at least 45 on the investigator-rated Brief Psychiatric Rating Scale (BPRS), an 18-item survey where each item is scored on a scale of 1 (indicating the absence of symptoms) to 7 (indicating severe symptoms).1, 10, 395, 406 Patients also had to have a Clinical Global Impressions-Severity Scale (CGI-S) score of at least 4 (moderately ill).1, 10, 395, 406 A total of 305 patients received initial single-blind treatment with haloperidol (at a mean dosage of 61 mg/day) and benztropine mesylate (6 mg/day) for 6 weeks.1, 10, 395, 406 Of these patients, 268 had an inadequate response to haloperidol and were enrolled in the double-blind treatment phase; these patients were randomized to either clozapine (up to 900 mg/day) or chlorpromazine hydrochloride (up to 1800 mg/day).1, 10, 395, 406 Patients in the chlorpromazine group also received benztropine mesylate, up to 6 mg per day, for the duration of the study period.10 One of the efficacy measures was treatment response, defined as a ≥20% decrease in BPRS score and either a CGI-S score ≤3 (mildly ill) or a BPRS score ≤35 after 6 weeks of treatment.1, 10, 395, 406 Rates of treatment response were substantially higher among clozapine-treated patients (30% versus 4% among patients treated with chlorpromazine plus benztropine).1, 10, 395, 406 Patients treated with clozapine also had substantially greater changes in total BPRS and CGI-S scores from baseline to week 6.1, 10, 395, 406
A meta-analysis of individual patient data from 12 clinical studies (1052 patients) compared clozapine with other second-generation antipsychotics (e.g., olanzapine, risperidone, ziprasidone) in adults with treatment-resistant schizophrenia.433 The main efficacy outcome was the change in overall schizophrenia symptoms at 6-8 weeks, as measured by the Positive and Negative Syndrome Scale (PANSS).433 Results revealed that the estimated mean change from baseline in PANSS total score was not substantially different for clozapine compared to other second-generation antipsychotics (collectively and individually).433
Another meta-analysis assessed the efficacy and safety of clozapine for the treatment of early-onset schizophrenia† (i.e., diagnosis before 17 years of age) and childhood-onset schizophrenia† (i.e., diagnosis before 13 years of age).434 An analysis of 3 randomized controlled studies of 6-12 weeks' duration found that clozapine was associated with a substantial improvement in BPRS score compared with an active comparator (olanzapine or haloperidol).434 In an extension study, patients who received clozapine maintained clinical improvement of symptoms over 2-6 years of follow-up.434
The American Psychiatric Association (APA) recommends that patients with schizophrenia be treated with an antipsychotic agent.347 The APA states that, with the possible exception of clozapine, there currently is no definitive evidence that one atypical antipsychotic agent will have superior efficacy compared with another agent in the class, although meaningful differences in response may be observed in individual patients.347 The choice of an antipsychotic agent should be individualized, considering patient preference, past response to therapy, concurrent medical conditions, and drug-specific factors (e.g., adverse effect profile, available formulations, potential drug interactions, receptor binding profiles, pharmacokinetic considerations).347 Patients whose symptoms improve on an antipsychotic agent should continue treatment long-term; in most patients, it is appropriate to continue the same antipsychotic agent rather than switch to another antipsychotic for maintenance therapy.347 For patients with treatment-resistant schizophrenia, the APA recommends treatment with clozapine.347 For patients with schizophrenia at risk for aggressive behavior despite other treatments, the APA suggests treatment with clozapine.347
Guidelines from the Department of Veterans Affairs and Department of Defense similarly recommend the use of antipsychotic agents for acute and maintenance treatment of schizophrenia.435 Choice of antipsychotic agent should be based on patient-specific factors and the side effect profiles of the different antipsychotics.435 Clozapine should generally be reserved for individuals with treatment-resistant schizophrenia.435
A practice parameter from the American Academy of Child and Adolescent Psychiatry (AACAP) recommends antipsychotic drugs as a primary treatment for schizophrenia spectrum disorders in children and adolescents.319 The AACAP states that most atypical and typical antipsychotic agents, with the exception of clozapine, can be used as primary treatment in early-onset schizophrenia (i.e., onset of schizophrenia before 18 years of age).319 Choice of antipsychotic medication in pediatric patients should be individualized based on FDA-labeling, side effect profiles, patient and family preferences, cost, and clinician familiarity.319 For youth with treatment-resistant (i.e., failed trials of 2 or more first-line antipsychotic agents) schizophrenia spectrum disorders, a trial of clozapine should be considered.319
Reduction of Suicidal Behavior in Schizophrenia and Schizoaffective Disorder
Clozapine conventional oral tablets, orally disintegrating tablets, and oral suspension are used for the reduction of risk of recurrent suicidal behavior in adults with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for reexperiencing suicidal behavior, based on history and recent clinical state; suicidal behavior refers to actions by a patient that puts them at risk for death.1, 395, 400, 406
The efficacy of clozapine for the reduction of risk of suicidality in schizophrenia or schizoaffective disorder was 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, 406 Enrolled patients had either attempted suicide or were hospitalized to prevent a suicide attempt within the 3 years prior to their baseline evaluation, or had demonstrated moderate-to-severe suicidal ideation with either a depressive component or command hallucinations to do self-harm within 1 week prior to their baseline evaluation.1, 327, 395, 406 At baseline, 27% of patients were considered resistant to standard antipsychotic drug treatment.1, 327, 395, 406
In the InterSePT study, patients were randomized to receive either clozapine or olanzapine daily for up to 2 years; dosing regimens were determined by investigators and individualized for each patient.1, 395, 406 The mean daily dosage was 274.2 mg for patients who received clozapine and 16.6 mg for patients who received olanzapine.327 Many patients received other psychiatric medications in addition to study treatment; 84% used concomitant antipsychotics, 65% used concomitant anxiolytics, 53% used concomitant antidepressants, and 28% used concomitant mood stabilizers.1, 395, 406 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) was lower for patients receiving clozapine (24%) than for those receiving olanzapine (32%) at year 2.1, 327, 395, 406 In addition, patients receiving clozapine had a substantially longer delay in the time to recurrent suicidal behavior than those receiving olanzapine.1, 327, 395, 406
Guidelines from the APA recommend that patients with schizophrenia at substantial risk for suicide attempts or suicide despite other treatments should be treated with clozapine.347 Clozapine can be effective for reducing suicide risk regardless of whether or not schizophrenia is treatment-resistant.347
Treatment-resistant Bipolar Disorder
Clozapine has been used for the management of treatment-resistant bipolar disorder† .436, 437
A meta-analysis assessed the efficacy and safety of clozapine for the treatment of bipolar disorder.436 An analysis of 3 clinical trials found clozapine to be similar in efficacy to other antipsychotics for the treatment of manic episodes in bipolar disorder.436 There were 2 studies in the analysis that included patients with treatment-resistant bipolar disorder; in these studies, clozapine was associated with substantial improvement in symptoms, with the exception of depressive symptoms, compared to other treatments (i.e., usual treatment, lithium plus other antipsychotics).436
Legacy practice guidelines from APA recommend lithium plus an antipsychotic or valproate plus an antipsychotic for first-line treatment of patients with severe manic or mixed episodes associated with bipolar I disorder; patients with less severe symptoms may be treated with lithium, valproate, or antipsychotic monotherapy.437 Selection of a specific treatment should be based on clinical factors such as illness severity, associated features (e.g., rapid cycling, psychosis), and patient preference, with particular attention to side effect profiles.437 If a first-line medication at optimal dosages fails to control symptoms, addition of another first-line medication is recommended; alternative options include adding carbamazepine or oxcarbazepine, adding an antipsychotic if not already prescribed, or changing from one antipsychotic to another.437 For treatment-refractory illness, clozapine may be particularly effective.437
Clozapine has been used for the management of psychosis associated with Parkinson disease†.438 Clozapine has also been used for the management of dyskinesia associated with Parkinson disease†.439 International experts state that clozapine and pimavanserin, with appropriate safety monitoring, are efficacious and clinically useful in treating psychosis in Parkinson disease.438 All atypical antipsychotics must be used with caution in patients with dementia and psychosis because of the risk of falls, cognitive worsening, pneumonia, cardiovascular effects, stroke, and death.438 For dyskinesia in Parkinson disease, international experts state that amantadine and clozapine, with appropriate safety monitoring, are efficacious and clinically useful pharmacotherapies when added to optimized oral levodopa.439
Dispensing and Administration Precautions
Clozapine is administered orally as conventional tablets, disintegrating tablets, or as a suspension without regard to meals; administration in divided doses may help minimize the risk of certain adverse effects.1, 395, 400, 406
The orally disintegrating tablets and conventional tablets of clozapine are bioequivalent;395 the oral suspension and conventional tablets of the drug also are bioequivalent.406
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
Patients receiving clozapine orally disintegrating tablets should be instructed not to remove a tablet from the blister until just prior to dosing.395 The tablet should not be pushed through the foil; instead, the foil blister backing should be peeled from the blister.395 The tablet should then be gently removed and immediately placed on the tongue, where it rapidly disintegrates in saliva, and then subsequently swallowed with or without liquid, or the tablet can be chewed as desired.395
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 should be shaken for 10 seconds prior to each use.406 The bottle adapter and calibrated oral dosing syringe supplied by the manufacturer should be used to administer the suspension.406 After withdrawing the appropriate dose into the calibrated oral dosing syringe, the dose should be administered directly into the patient's mouth; clozapine oral suspension should not be stored in the syringe for later use.406
Clozapine oral suspension 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
Cautious dosage titration and administration of clozapine in divided doses are necessary to minimize the risk of certain adverse effects such as orthostatic hypotension, bradycardia, syncope, seizures, and sedation.1
Treatment-resistant Schizophrenia
For the management of treatment-resistant schizophrenia, the usual initial adult dosage of clozapine is 12.5 mg given orally once or twice daily.1, 395, 406 If the drug is well tolerated, dosage may be increased in increments of 25-50 mg daily over a 2-week period until a target dosage of 300-450 mg daily (administered in divided doses) is achieved.1, 395, 406 Subsequent dosage increases can be made once or twice weekly in increments of up to 100 mg.1, 395, 406, 395, 406
In the principal efficacy study of clozapine in patients resistant to standard antipsychotic therapy, the maximum dosage of clozapine was 900 mg daily, which was given in 3 divided doses.1 The mean clozapine dosage in this study was over 600 mg daily.1 The manufacturers recommend that the daily dosage of clozapine not exceed 900 mg.1, 395, 400, 406
The manufacturers state that patients who respond to clozapine therapy generally should continue to receive maintenance treatment with the drug at their effective dosage beyond the acute episode.1, 395, 400, 406
Reduction of Suicidal Behavior in Schizophrenia and Schizoaffective Disorder
For reduction of suicidal behavior in schizophrenia and schizoaffective disorder, the usual initial adult dosage of clozapine is 12.5 mg given orally once or twice daily.1, 395, 406 If the drug is well tolerated, dosage may be increased in increments of 25-50 mg daily over a 2-week period until a target dosage of 300-450 mg daily (administered in divided doses) is achieved.1, 395, 406 Subsequent dosage increases can be made once or twice weekly in increments of up to 100 mg.1, 395, 406, 395, 400, 406 In the multicenter InterSePT study that provides the principal support for the effectiveness of clozapine for suicide risk reduction, mean dosage was about 300 mg daily (range: 12.5-900 mg daily).327
The manufacturers state that patients who respond to clozapine therapy generally should continue to receive maintenance treatment with the drug at their effective dosage beyond the acute episode; efficacy of clozapine for this indication was demonstrated over a 2-year treatment period in the InterSePT study.1, 395, 400, 406
Treatment-resistant Schizophrenia
The dosage of clozapine for the management of treatment-resistant schizophrenia in children and adolescents† has not been established.319 However, the National Institute of Mental Health (NIMH) protocol used an initial dosage of 6.25-25 mg given orally daily depending on the patient's weight.323 Dosages in this study could be increased every 3-4 days by 1-2 times the initial dose on an individual basis up to a maximum of 525 mg daily.323
In the event of planned discontinuance of clozapine therapy, gradual reduction in dosage over a 1- to 2-week period is recommended if there is no evidence of moderate to severe neutropenia.1, 395, 406 However, if abrupt discontinuance of therapy is required because of moderate to severe neutropenia, ANC should be monitored according to the neutropenia monitoring recommendations.1, 395, 406 If abrupt discontinuance of clozapine is required for reasons unrelated to neutropenia, continuation of the existing ANC monitoring schedule is recommended; patients in the general population should be monitored until their ANC is in the normal range (i.e., ≥1500/mm3) while patients with BEN should be monitored until their ANC is ≥1000/mm3 or above their baseline.1 Additional ANC monitoring is necessary in any patient reporting onset of fever (temperature ≥38.5°C) during the 2 weeks after clozapine discontinuance.1 Patients should be observed carefully for recurrence of psychotic symptoms and symptoms related to cholinergic rebound such as profuse sweating, headache, nausea, vomiting, and diarrhea.1, 395, 406
If clozapine therapy is restarted in patients who have had even brief interruptions (i.e., 1 day of missed doses), dosage should be resumed at 40<50% of the prior dosage to minimize the risk of hypotension, bradycardia, and syncope.1 If 2 days of dosing have been missed, dosage should be resumed at 25% of the prior dosage.1 For longer interruptions (i.e., >2 days since the last dose) in therapy, dosage generally should be titrated as with initial therapy (i.e., starting with 12.5 mg once or twice daily).1, 395, 406 If these dosages are well tolerated, dosage may be titrated back to the previous therapeutic dosage more quickly than recommended during initial treatment.1, 395, 406
For clozapine treatment interruptions of <30 days in patients with normal ANC values, the same ANC monitoring schedule as before the treatment interruption may be continued.1, 395, 406 If clozapine treatment is interrupted for ≥30 days, the ANC monitoring schedule must be restarted as with initial therapy.1, 395, 406
Patients who develop severe neutropenia (ANC <500/mm3) during clozapine therapy generally should not be restarted on the drug unless the clinician determines that the benefits of the drug outweigh the risks.1
Dosage Adjustments for Drug Interactions
Concomitant use of strong cytochrome P-450 (CYP) 1A2 inhibitors (e.g., ciprofloxacin, fluvoxamine), moderate or weak CYP1A2 inhibitors (e.g., oral contraceptives, caffeine), CYP2D6 or CYP3A4 inhibitors (e.g., bupropion, cimetidine, duloxetine, erythromycin, escitalopram, fluoxetine, paroxetine, quinidine, sertraline, terbinafine), CYP1A2 inducers (e.g., tobacco smoke), or CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort [ Hypericum perforatum ]) may warrant dosage adjustment of clozapine or monitoring for adverse effects.1 When used concomitantly with strong CYP1A2 inhibitors, 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 strong CYP1A2 inhibitor is discontinued.1
When used concomitantly with moderate or weak CYP1A2 inhibitors, or with CYP2D6 or CYP3A4 inhibitors, 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; an increase in clozapine dosage may be necessary.1
Conversely, concomitant use of clozapine with drugs or substances that induce CYP1A2 or CYP3A4 may result in decreased plasma concentrations of clozapine.1, 395 The manufacturers state that concomitant use of a strong 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; an increase in clozapine dosage may be necessary.1, 395, 406 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, 406
Although the pharmacokinetics of clozapine have not been specifically studied in patients with hepatic impairment, increased plasma clozapine concentrations are possible in such patients since the drug is almost completely metabolized and then excreted.1, 395, 406 The manufacturers state that dosage reduction may be necessary in patients with substantial hepatic impairment.1, 395, 406
Although the pharmacokinetics of clozapine have not been specifically studied in patients with renal impairment, increased plasma clozapine concentrations are possible in such patients since the drug is almost completely metabolized and then excreted.1, 395, 406 The manufacturers state that dosage reduction may be necessary in patients with substantial renal impairment.1, 395, 406
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
Pharmacogenomic Considerations
The manufacturers state that dosage reduction of clozapine may be necessary in patients who are known poor metabolizers of CYP2D6.1, 395, 406
A boxed warning is included in the prescribing information regarding the increased risk of severe neutropenia with clozapine.1, 395, 400, 406 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, 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, 406 The ANC is usually available as a component of the CBC, including differential, and is considered more clinically relevant for drug-induced neutropenia than white blood cell (WBC) count.1, 395, 406 Severe neutropenia is defined as an ANC value of <500/mm3 and occurs in a small percentage of patients receiving clozapine therapy.1, 395, 406
The precise mechanism by which clozapine induces neutropenia is not known and is not dose-dependent.1, 395, 406 The risk of clozapine-induced neutropenia appears to be greatest during the first 18 weeks of therapy and declines thereafter.1
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 BEN has an approximate prevalence of 25-50% in individuals of African descent and also is observed in some Middle Eastern ethnic groups and other non-Caucasian ethnic groups with darker skin; the condition is more common in men than women.1 Patients with BEN have normal hematopoietic stem cell numbers and myeloid maturation, are healthy, and do not suffer from repeated or severe infections.1 Such patients are not at increased risk for developing clozapine-induced neutropenia.1 The normal ANC range in individuals with BEN is ≥1000/mm3.1 The manufacturer recommends confirming at least 2 consecutive ANC levels of ≥1000/mm3 in patients with BEN before starting clozapine therapy.1 Additional evaluation may be necessary in some patients to determine whether their baseline neutropenia is caused by BEN.1 Consultation with a hematologist should be considered in patients with low baseline ANC values before initiating or during clozapine therapy, if necessary.1 Patients with documented BEN have different ANC monitoring and treatment recommendations during clozapine therapy than the general population because of their lower baseline ANC levels (See Table 2).1 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 <1500/mm3 (or <1000/mm3 in patients with documented BEN).1
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 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 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 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
ANC Value | Treatment Recommendations | Frequency of ANC Monitoring |
|---|---|---|
Normal range (ANC ≥1500/mm3 | Initiate treatment If treatment interrupted <30 days, continue monitoring as before If treatment interrupted ≥30 days, monitor as if new patient | Weekly from initiation to month 6 Every 2 weeks from 7-12 months 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 Interrupt treatment for suspected clozapine-induced neutropenia Resume treatment once ANC ≥1000/mm3 | Daily until ANC ≥1000/mm3 3 times weekly until ANC ≥1500/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 Interrupt treatment for suspected clozapine-induced neutropenia Do not rechallenge unless prescriber determines benefits outweigh risks | Daily until ANC ≥1000/mm3 3 times weekly until ANC ≥1500/mm3 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.
ANC Value | Treatment Recommendations | Frequency of ANC Monitoring |
|---|---|---|
Normal BEN range (established ANC baseline ≥1000/mm3) | Obtain ≥2 baseline ANC values before initiating treatment If treatment interrupted <30 days, continue monitoring as before If treatment interrupted ≥30 days, monitor as if new patient | Weekly from initiation to 6 months Every 2 weeks from 7-12 months Monthly after 12 months |
Discontinuance of treatment for reasons other than neutropenia | See Discontinuance of Therapy under Dosage and Administration | |
BEN neutropenia (ANC 500-999/mm3)a | Recommend hematology consultation Continue treatment | 3 times weekly until ANC ≥1000/mm3and at or above patient's known baseline When ANC ≥1000/mm3 and at or above patient's known baseline, monitor weekly for 4 weeks, then return to the patient's last normal ANC range testing frequency for patients with BEN, if clinically appropriate |
BEN severe neutropenia (ANC <500/mm3)a | Recommend hematology consultation Interrupt treatment for suspected clozapine-induced neutropenia Do not rechallenge unless prescriber determines benefits outweigh risks | Daily until ANC ≥500/mm3 3 times weekly until ANC ≥1000/mm3and at or above patient's baseline When ANC ≥1000/mm3 and at or above patient's known baseline, then resume treatment and obtain ANC tests according to the frequency for patients with BEN who initiate treatment, if clinically appropriate |
aConfirm all initial reports of ANC <1500/mm3 with a repeat measurement within 24 hours.
If a patient develops fever (temperature of ≥38.5°C) 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 <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 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
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
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
Orthostatic Hypotension, Bradycardia, and Syncope
A boxed warning is included in the prescribing information regarding the risks of orthostatic hypotension, bradycardia, and syncope with clozapine.1, 395, 400, 406 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 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 If hypotension occurs, dosage reduction of clozapine may be considered.1 Patients should be informed of the risk of orthostatic hypotension, especially during the period of initial dosage titration.1 In addition, if clozapine therapy has been missed for even 1 day, 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
A boxed warning is included in the prescribing information regarding the risk of seizures with clozapine.1, 395, 400, 406 The reported annual prevalence of seizures associated with clozapine use is approximately 5%, and is dose-related.1 Because of this risk, treatment with clozapine should be initiated at lower dosages of 12.5 mg, with gradual increases, and administered in divided doses.1
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
Myocarditis, Pericarditis, Cardiomyopathy, and Mitral Valve Incompetence
A boxed warning is included in the prescribing information regarding the risks of myocarditis, pericarditis, cardiomyopathy, and mitral valve incompetence with clozapine.1, 395, 400, 406 Myocarditis, pericarditis and cardiomyopathy, which are sometimes fatal, have been reported in patients receiving clozapine.1 Myocarditis and pericarditis most frequently present 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, pericarditis, and cardiomyopathy can occur at any time during clozapine therapy.1 Mitral valve incompetence has been reported in patients diagnosed with cardiomyopathy during clozapine therapy.1
The possibility of myocarditis, pericarditis, 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, pericarditis, 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, pericarditis, 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
Increased Mortality in Geriatric Patients with Dementia-related Psychosis
A boxed warning is included in the prescribing information regarding the increased risk of mortality in elderly patients with dementia-related psychosis.1, 395, 400, 406 Geriatric patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death compared with patients receiving placebo.1, 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, 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, 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, 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, 395
Other Warnings and Precautions
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
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 In postmarketing experience, reported adverse effects ranged from constipation to paralytic ileus.1 Increased frequency of constipation and delayed diagnosis and treatment increased the risk of severe complications of GI hypomotility, resulting in fecal impaction, megacolon, and intestinal obstruction, ischemia, infarction, perforation, ulceration, or necrosis.1 These reactions have resulted in hospitalization, surgery, and death.1 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
Prior to initiating clozapine therapy, patients should be screened for constipation and treated, if necessary.1 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 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
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 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 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
Eosinophilia (defined as blood eosinophil count >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
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, uncompensated heart failure, and those concurrently receiving other drugs that prolong the QT interval or inhibit the metabolism of clozapine.1, 395, 406 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 therapy.1, 395, 406
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, 395 The manufacturers state that patients with preexisting diabetes mellitus in whom therapy with an atypical antipsychotic is initiated should be regularly 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, 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 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
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
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
Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability, has been reported in patients receiving antipsychotic agents, including clozapine.1, 395 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 after NMS recovery, the antipsychotic agent being introduced should be carefully considered.1, 395 In addition, such patients should be carefully monitored since recurrence of NMS has been reported.1, 395 NMS has occurred in patients receiving clozapine monotherapy and in those receiving concomitant medications with CNS activity, including lithium.1, 395
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
During clozapine therapy, patients may experience transient temperature elevations exceeding 38°C, with the peak incidence within the first 3 weeks of therapy.1 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) 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 NMS also must be considered.1
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
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 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, or urinary retention).1
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
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 result in adverse effects.1 Because such effects may be dose-related, a reduction in clozapine dosage should be considered if they occur.1
Use of antipsychotic agents, including clozapine, may be associated with tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements.1
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 However, the syndrome can develop following relatively brief treatment periods at low dosages.1 The syndrome may remit, partially or completely, if antipsychotic therapy is discontinued.1 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
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
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
Cerebrovascular Adverse Reactions
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
In the event of planned discontinuance of clozapine therapy, gradual reduction in dosage over a 1- to 2-week period is recommended if there is no evidence of moderate to severe neutropenia.1, 395, 406 However, if abrupt discontinuance of therapy is required because of moderate to severe neutropenia, ANC should be monitored according to the neutropenia monitoring recommendations.1, 395, 406 If abrupt discontinuance of clozapine is required for reasons unrelated to neutropenia, continuation of the existing ANC monitoring schedule is recommended; patients in the general population should be monitored until their ANC is in the normal range (i.e., ≥1500/mm3) while patients with BEN should be monitored until their ANC is ≥1000/mm3 or above their baseline.1 Additional ANC monitoring is necessary in any patient reporting onset of fever (temperature ≥38.5°C) during the 2 weeks after clozapine discontinuance.1 Patients should be observed carefully for recurrence of psychotic symptoms and symptoms related to cholinergic rebound such as profuse sweating, headache, nausea, vomiting, and diarrhea.1, 395, 406
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; the respective manufacturer's labeling should be consulted for specific information regarding aspartame content of individual preparations and dosage strengths.395
A pregnancy registry is available that monitors pregnancy outcomes of women exposed to antipsychotics, including clozapine, during pregnancy.1 Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or by visiting [Web].
There are risks to the mother from untreated schizophrenia, including an increased risk of relapse, hospitalization, and suicide, and from exposure to antipsychotic therapy during pregnancy.1 Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth, but it is not known if this is a direct impact of the illness or from other comorbid factors.1 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
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 There have been reports of agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder in these neonates.1, 395 Any neonate exhibiting extrapyramidal or withdrawal symptoms following in utero exposure to antipsychotic agents should be monitored and symptoms managed appropriately.1, 395 Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive care unit support and prolonged hospitalization.1, 395
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, 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, 395
Clozapine is distributed into milk in humans.1 There is one reported case of sedation and one of agranulocytosis in an infant exposed to clozapine through breast milk.1 It is not known how clozapine affects milk production.1 The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for the drug and any potential adverse effects on the breast-fed infant from clozapine or from the underlying maternal condition.1
Infants that are exposed to clozapine through breast milk should be monitored for excessive sedation and neutropenia.1
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† 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.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 When children metabolize clozapine, higher concentrations of the metabolite norclozapine, which has been associated with hematopoietic toxicity, have been suggested as a possible reason for the increased risk in this age group.323
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
Clinical studies of clozapine did not include sufficient numbers of patients ≥65 years of age 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), clozapine should be used cautiously in this age group.1 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
Geriatric patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death compared with patients receiving placebo.1, 395
The manufacturer states that clozapine is not labeled for the treatment of patients with dementia-related psychosis.1, 395
An increased risk of adverse cerebrovascular events (e.g., stroke, transient ischemic attack), including fatalities, 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
No specific pharmacokinetic studies have investigated clozapine in hepatic impairment; however, higher plasma concentrations of clozapine are expected at usual dosages when given in patients with significant hepatic impairment.1
No specific pharmacokinetic studies have investigated clozapine in renal impairment; however, higher plasma concentrations of clozapine are expected at usual dosages when given in patients with significant renal impairment.1
Adverse effects reported in at least 5% of patients receiving clozapine include CNS reactions (e.g., sedation, dizziness/vertigo, headache, tremor), cardiovascular reactions (e.g., tachycardia, hypotension, syncope), autonomic nervous system reactions (e.g., hypersalivation, sweating, dry mouth, visual disturbances), GI reactions (e.g., constipation, nausea), and fever.1
Clozapine is a substrate for many cytochrome P-450 (CYP) isoenzymes, in particular 1A2, 2D6, and 3A4; it is also an inhibitor of CYP2D6.1
Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of clozapine with drugs that inhibit CYP1A2, CYP2D6, or CYP3A4 may result in increased plasma concentrations of clozapine.1, 395 When used concomitantly with strong CYP1A2 inhibitors (e.g., ciprofloxacin, 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 strong 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, 395 The manufacturers state that concomitant use of a strong 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
Pneumonia and other inflammatory conditions have been reported to increase plasma concentrations of clozapine.1, 395, 406 While the mechanism of this increase is not completely understood, it is suspected to involve a reduction in CYP1A2 activity.1, 395, 406 The clinical relevance of these findings and the impact of treatments to modulate inflammation have not been fully characterized.1, 395, 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 Modest (less than 2-fold) elevations in plasma clozapine concentrations have been reported in patients receiving clozapine concomitantly with certain SSRIs (i.e., fluoxetine, paroxetine, sertraline).1
Substantial (3-fold) increases in trough plasma clozapine concentrations have occurred in patients receiving concomitant therapy with clozapine and the strong 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
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
Drugs Affecting the Seizure Threshold
Clozapine is associated with a dose-related increase in the risk of seizures.1 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
Drugs that Prolong the QT Interval
Because of additive effects on QT-interval prolongation, clozapine should be used with caution in patients receiving other drugs known to prolong the QT interval, including class Ia antiarrhythmics (e.g., quinidine, procainamide), class III antiarrhythmics (e.g., amiodarone, sotalol), certain antipsychotic agents (e.g., chlorpromazine, iloperidone, pimozide, droperidol, thioridazine, ziprasidone), some anti-infective agents (e.g., erythromycin, gatifloxacin, moxifloxacin, and other drugs (e.g., dolasetron mesylate, mefloquine, methadone, pentamidine, tacrolimus).1
Drugs with Anticholinergic Activity and Drugs that Decrease GI Peristalsis
Clozapine has potent anticholinergic effects.1 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 should be avoided whenever possible.1
Other Drugs Associated with Neutropenia
It is not known whether concurrent use of other drugs known to cause neutropenia increases the risk or severity of clozapine-induced neutropenia.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, the manufacturers state that closer monitoring than is usually recommended should be considered and, in patients concomitantly receiving antineoplastic agents, the treating oncologist should be consulted.1, 395, 400, 406
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
Tobacco smoke moderately induces CYP1A2, and may reduce plasma clozapine concentrations, resulting in decreased efficacy.1 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.1, 395, 400, 406
Clozapine is a dibenzodiazepine-derivative antipsychotic agent.1 Clozapine has been described as an atypical or second-generation antipsychotic agent.1 The exact mechanism of antipsychotic action of clozapine has not been fully elucidated, 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 Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic, and other dopaminergic and serotonergic receptors.1 Clozapine has little to no propensity to stimulate prolactin secretion.1
Linearly dose-proportional changes in AUC, and in peak and trough plasma concentrations, have been observed with oral dosages of 37.5, 75, and 150 mg twice daily.1 After multiple doses of clozapine oral suspension (100-800 mg once daily), peak plasma concentrations were achieved within an average of 2.2 hours (range: 1-3.5 hours).406 After multiple doses of clozapine as orally disintegrating tablets (100 mg twice daily), peak plasma concentrations were achieved within an average of 2.3 hours (range: 1-6 hours).395 The relative oral bioavailability of clozapine has been shown to be equivalent following administration of 25- and 100-mg conventional tablets.1
Commercially available clozapine oral suspension and conventional tablets are bioequivalent; orally disintegrating tablets and conventional tablets also are bioequivalent.395, 406
Food does not affect the bioavailability of the drug when given as conventional tablets.1 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 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
Clozapine is approximately 97% bound to serum proteins.1 It is almost completely metabolized in the liver prior to excretion by many CYP isoenzymes, particularly CYP1A2, CYP2D6, and CYP3A4.1 The N -desmethyl metabolite of clozapine (norclozapine) has limited activity while the hydroxylated and N -oxide derivatives are inactive.1 Only trace amounts of unchanged drug are detected in urine and feces.1 Approximately 50% of an administered dose is excreted in urine and 30% in feces.1
The elimination half-life of clozapine following a single 75-mg oral dose averages 8 hours (range: 4-12 hours).1 The elimination half-life of clozapine at steady state following administration of 100 mg twice daily averages 12 hours (range: 4-66 hours).1 A study comparing single and multiple dosing of clozapine demonstrated an increase in elimination half-life with multiple dosing, suggesting possible concentration-dependent pharmacokinetics.1
Because clozapine is a substrate for many CYP isoenzymes, including CYP2D6, patients with poor-metabolizer phenotypes of CYP2D6 may have higher plasma clozapine concentrations at usual dosages.1, 395, 406 In addition, smokers appear to have reduced concentrations of clozapine, due to induction of CYP1A2 activity by tobacco smoke.1, 395, 406
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Suspension | 50 mg/mL | ||
Tablets | 25 mg* | cloZAPine Tablets (scored) | ||
Clozaril® (scored) | ||||
50 mg* | cloZAPine Tablets (scored) | |||
100 mg* | cloZAPine Tablets (scored) | |||
Clozaril® (scored) | HLS | |||
200 mg* | cloZAPine Tablets (scored) | |||
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
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319. McClellan J, Stock S, the American Academy of Child and Adolescent Psychiatry (AACAP) Committee on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with schizophrenia. J Am Acad Child Adolesc Psychiatry . 2013; 52: 976-90.
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