Clozapine (Monograph)

Brand names: Clozaril, Versacloz
Drug class: Atypical Antipsychotics
VA class: CN709
Chemical name: 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4] diazepine
CAS number: 5786-21-0

Medically reviewed by Drugs.com on Nov 20, 2023. Written by ASHP.

Warning

Risk Evaluation and Mitigation Strategy (REMS):

FDA approved a shared REMS for clozapine to ensure that the benefits outweigh the risks. The REMS consists of the following: elements to assure safe use and implementation system. See https://www.accessdata.fda.gov/scripts/cder/rems/. (Also see REMS under Dosage and Administration.)

Warning

Clozapine can cause severe neutropenia (ANC <500/mm³), which may lead to serious and potentially fatal infections.¹
Patients initiating or continuing treatment with clozapine must have a baseline blood ANC before initiating clozapine therapy and regular ANC monitoring during treatment.¹ (See Severe Neutropenia under Cautions.)
Because of this risk, clozapine is available only through a restricted distribution program called the Clozapine REMS program, which ensures periodic monitoring of ANC.¹ (See General under Dosage and Administration.)

Orthostatic hypotension, bradycardia, syncope, and cardiac arrest reported.¹ Risk is highest during initial titration period, particularly with rapid dosage escalation; these reactions may occur with the first clozapine dose and with doses as low as 12.5 mg.¹
Initiate clozapine therapy at 12.5 mg once or twice daily, titrate slowly, and administer in divided doses.¹ (See Dosage under Dosage and Administration.)
Use with caution in patients with cardiovascular or cerebrovascular disease or conditions predisposing to hypotension (e.g., dehydration, concurrent antihypertensive therapy).¹ (See Orthostatic Hypotension, Bradycardia, and Syncope under Cautions.)

Seizures have occurred; risk is dose-related.¹
Initiate clozapine therapy at 12.5 mg, titrate gradually, and administer in divided doses.¹ ³⁹⁵ ⁴⁰⁶
Use with caution in patients with a history of seizures or other predisposing factors (e.g., CNS pathology, concurrent use of other drugs that lower seizure threshold, alcohol abuse).¹
Advise patients to use caution when engaging in activities where sudden loss of consciousness could cause serious risk to patient or others.¹ (See Seizures under Cautions.)

Risk of potentially fatal myocarditis and cardiomyopathy.¹
Promptly discontinue clozapine and obtain cardiac evaluation if myocarditis or cardiomyopathy is suspected.¹ (See Myocarditis, Cardiomyopathy, and Mitral Valve Incompetence under Cautions.)

Geriatric patients with dementia-related psychosis are at an increased risk of death.¹
Analyses of 17 placebo-controlled trials in geriatric patients mainly receiving atypical antipsychotic agents revealed an approximate 1.6- to 1.7-fold increase in mortality compared with that in patients receiving placebo.¹
Most fatalities resulted from cardiovascular-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).¹
Observational studies suggest that conventional or first-generation antipsychotic agents also may increase mortality in such patients.¹
Antipsychotic agents, including clozapine, are not approved for the treatment of dementia-related psychosis.¹

Introduction

Dibenzodiazepine-derivative; 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 for Clozapine

Treatment-resistant Schizophrenia

Management of treatment-resistant 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, use only in patients who have failed to respond adequately to standard antipsychotic treatment.¹ ³⁹⁵ ⁴⁰⁶ (See Boxed Warning and also see Severe Neutropenia under Cautions.)

APA recommends considering a trial of clozapine in patients with schizophrenia who had no response or a partial or suboptimal response to adequate trials of 2 antipsychotic agents (including at least one second-generation [atypical] antipsychotic agent), 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

Has been used in the management of childhood-onset schizophrenia in a limited number of treatment-resistant children and adolescents^{† [off-label]}.³¹⁹ ³²³ Because of the risk of severe toxicity, the American Academy of Child and Adolescent Psychiatry (AACAP) states that clozapine should be reserved for treatment-refractory pediatric patients who have failed to respond to adequate therapeutic trials of at least 2 other first-line antipsychotic agents.³¹⁹

Suicide Risk Reduction in Schizophrenia and Schizoaffective Disorder

Reduction in risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for reexperiencing suicidal behavior, based on history and recent clinical state.¹ ³²⁷ ³²⁸ ³⁴⁷ ³⁹⁵ ⁴⁰⁶

In the principal supportive study for this use, most patients also received other treatments to reduce suicide risk, including concomitant psychotropic agents (i.e., antipsychotics, anxiolytics, antidepressants, mood stabilizers), hospitalization, and/or psychotherapy; contributions to efficacy unknown.¹ ³²⁷ ³²⁹

Parkinsonian Syndrome

Has been used in a limited number of patients with advanced, idiopathic parkinsonian syndrome for management of dopaminomimetic psychosis^{† [off-label]} associated with antiparkinsonian drug therapy, but adverse effects (e.g., sedation, confusion, increased parkinsonian manifestations) may limit benefit.¹⁶ ⁶⁹ ⁸⁸ ¹³² ¹⁹³ ¹⁹⁴ ²³⁷ ²⁵¹ ²⁵⁴ ²⁹²

Clozapine Dosage and Administration

General

Prior to initiating clozapine therapy, obtain a baseline complete blood cell (CBC) count, including absolute neutrophil count (ANC).¹ In the general population, baseline ANC must be ≥1500/mm³ before clozapine therapy can be initiated.¹ ⁴⁰⁸ In patients with documented benign ethnic neutropenia (BEN), baseline ANC must be ≥1000/mm³ to be eligible for clozapine therapy.¹ ⁴⁰⁸

Regular ANC monitoring is required during clozapine therapy.¹ ⁴⁰⁸

Because of risk of severe neutropenia, clozapine is available only through a restricted distribution program (Clozapine REMS program).¹ ³⁹⁵ ⁴⁰⁰ ⁴⁰⁶ ⁴³⁰ As of October 12, 2015, all previous clozapine registries were replaced by a single, shared centralized system called the Clozapine REMS program.⁴⁰⁷ Under this shared program, only ANC is used to monitor patients for clozapine-induced neutropenia; white blood cell (WBC) count monitoring is no longer required.¹ ⁴⁰⁷ ⁴⁰⁸ In addition, ANC thresholds for clozapine treatment interruption were lowered from previous requirements to allow continued treatment for a greater number of patients, and patients with benign ethnic neutropenia (BEN) who were previously ineligible to receive clozapine are now eligible.¹ ⁴⁰⁷ ⁴⁰⁸
Prescribers (who prescribe clozapine for outpatient use or initiate treatment for inpatients) must be certified with the Clozapine REMS program before they can prescribe clozapine; pharmacies must also certify with the program before they can receive and dispense the drug.¹ ³⁹⁵ ⁴⁰⁰ ⁴⁰⁶ ⁴³⁰ ⁴³² Certified prescribers must enroll patients in the Clozapine REMS program and submit patients' ANC values to the program.⁴⁰⁸ ⁴³⁰
On July 29, 2021, the Clozapine REMS program was modified to include changes to the authorization process for dispensing clozapine and changes to ANC reporting requirements.⁴³⁰ ⁴³¹ ⁴³² Starting November 15, 2021, pharmacists will no longer be able to use telecommunication verification (also known as the switch system) and will need to contact the REMS program by phone (888-586-0758) or online (www.clozapinerems.com) to verify safe use conditions and obtain authorization to dispense clozapine.⁴³¹ In addition, prescribers will no longer need to submit ANC results according to the patient's monitoring frequency; the new process requires that ANC results be submitted monthly through a new Patient Status form, which will be used to document monitoring for all outpatients receiving the drug.⁴³¹ Prescribers must re-enroll their existing patients, and pharmacies must re-certify in the revised Clozapine REMS program by November 15, 2021 before they can prescribe and dispense clozapine.⁴³¹

Administration

Oral Administration

Administer orally as conventional tablets, orally disintegrating tablets, ¹ ² ⁵ ¹⁰ ¹¹ ¹² ⁵⁴ ⁵⁹ ⁶¹ ⁶² ⁶³ ⁸⁷ ¹⁰² ¹²⁰ ¹⁵⁶ ²³⁷ ²⁵³ ²⁵⁵ ³⁹⁵ ⁴⁰⁰ or oral suspension⁴⁰⁶ without regard to meals.¹ ⁵ ²¹⁸ ²¹⁹ ³⁹⁵ ⁴⁰⁶ (See Food under Pharmacokinetics.)

Administer in divided doses to minimize risk of certain adverse effects (e.g., orthostatic hypotension, bradycardia, syncope, seizures).¹ ⁵ ¹² ¹⁵⁶ ²⁵⁵ ²⁸¹ ²⁹⁶ ²⁹⁷ If daytime sleepiness occurs, consider bedtime administration.⁵ ¹²

Just prior to administration of orally disintegrating tablet, peel foil blister backing completely off the blister and gently remove tablet; do not push tablet through the foil.³⁹⁵ Immediately place on the tongue to dissolve and swallow with or without liquid; tablet also can be chewed.³⁹⁵

Prior to each use of clozapine oral suspension (Versacloz), shake bottle for 10 seconds.⁴⁰⁶ Use the bottle adapter and calibrated oral dosing syringe supplied by the manufacturer to administer the dose directly into the mouth; do not store in syringe for later use.⁴⁰⁶

Dosage

Orally disintegrating tablets and conventional tablets are bioequivalent;³⁹⁵ oral suspension and conventional tablets also are bioequivalent.⁴⁰⁶

Carefully adjust dosage according to individual requirements and response using lowest possible effective dosage.⁵ ¹¹ ⁸⁷

To minimize the risks of orthostatic hypotension, bradycardia, syncope, and seizures, titrate dosage cautiously and administer in divided doses.¹ (See Orthostatic Hypotension, Bradycardia, and Syncope under Cautions.)

Pediatric Patients

Schizophrenia† [off-label]

Oral

Dosage not established.¹ ³²²

In a clinical study conducted by the National Institute of Mental Health (NIMH) in children (mean: 14 years of age), an initial dosage of 6.25–25 mg daily (depending on patient’s weight) was used; ³²² ³²³ dosages 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

Adults

Schizophrenia

Oral

Initially, 12.5 mg once or twice daily.¹ ³⁰² ³⁹⁵ ⁴⁰⁶ If well tolerated, increase by 25–50 mg daily over a 2-week period until the target dosage of 300–450 mg daily (administered in divided doses) is achieved.¹ ¹² ³⁸ ²⁵⁶ ³⁹⁵ ⁴⁰⁶

Make subsequent dosage increases no more than once or twice weekly, in increments ≤100 mg.¹ ¹² ³⁸ ²⁵³ ²⁵⁵ ²⁵⁶ ³⁹⁵ ⁴⁰⁶

Continue daily administration in divided doses (e.g., 2–3 times daily) until effective and tolerable dosage reached,⁵ usually within 2–5 weeks, up to a maximum dosage of 900 mg daily.¹ ¹⁰ ¹¹ ¹² ²³⁷ ²⁵⁶ ²⁹²

Many respond adequately to dosages between 200–600 mg daily,² ⁵ ¹¹ ³⁸ ⁶⁷ ²⁵³ but 600–900 mg daily may be required in some patients.⁵ ¹² ³⁸

In responsive patients, continue maintenance treatment at the effective dosage beyond the acute episode.¹ ³⁹⁵ ⁴⁰⁶

In patients with remitted first or multiple episodes, APA recommends either indefinite maintenance therapy or gradual discontinuance of the antipsychotic with close follow-up and a plan to reinstitute treatment upon symptom recurrence.³⁴⁷ Consider antipsychotic therapy discontinuance only after ≥1 year of symptom remission or optimal response while receiving the drug.³⁴⁷ Indefinite maintenance treatment recommended if patient has experienced multiple previous psychotic episodes or 2 episodes within 5 years.³⁴⁷

Suicide Risk Reduction

Oral

Initially, 12.5 mg once or twice daily.¹ ³⁹⁵ ⁴⁰⁶ If well tolerated, increase by 25–50 mg daily over a 2-week period until a dosage of 300–450 mg daily (administered in divided doses) is achieved.¹ ³⁹⁵ ⁴⁰⁶

Make subsequent dosage increases no more than once or twice weekly, in increments ≤100 mg.¹ ³⁹⁵ ⁴⁰⁶

In the principal supportive study, mean dosage was about 300 mg daily (range: 12.5–900 mg daily).³²⁷

Efficacy established over the 2 year study; ¹ ³²⁷ ³⁹⁵ ⁴⁰⁶ in responsive patients, continue maintenance treatment at the effective dosage beyond the acute episode.¹ ³⁹⁵ ⁴⁰⁶

Discontinuance of Therapy

Oral

For planned discontinuance of therapy, if no evidence of moderate to severe neutropenia, reduce dosage gradually over a 1- to 2-week period.¹ ¹³ ²⁵⁶ ³⁹⁵ ⁴⁰⁶

If abrupt discontinuance is required because of moderate to severe neutropenia, monitor ANC according to neutropenia monitoring recommendations (see Severe Neutropenia under Cautions).¹ ³⁹⁵ ⁴⁰⁶ If clozapine is discontinued abruptly for reasons unrelated to neutropenia, continue most recent ANC monitoring schedule until ANC is in the normal range (i.e., ≥1500/mm³ in the general population; in patients with BEN, ≥1000/mm³ or above their baseline).¹ Monitor ANC if fever occurs during the 2 weeks after discontinuance.¹ Observe carefully for recurrence of psychotic symptoms and symptoms related to cholinergic rebound (e.g., profuse sweating, headache, nausea, vomiting, diarrhea).¹ ³⁹⁵ ⁴⁰⁶ (See Withdrawal of Therapy under Cautions.)

Reinitiation of Therapy

Oral

If restarted after brief interruption (i.e., ≥2 days) in therapy, reinitiate at dosage of 12.5 mg once or twice daily.¹ ²⁵⁶ If dosage well tolerated, may titrate back to therapeutic dosage more quickly than during initial treatment.¹

If treatment interrupted for ≥30 days, restart ANC monitoring schedule as with initial therapy.¹ ³⁹⁵ ⁴⁰⁶ For treatment interruptions <30 days, may continue the same ANC monitoring schedule as before treatment interruption.¹ ³⁹⁵ ⁴⁰⁸ (See Severe Neutropenia under Cautions.)

Generally, do not reinitiate clozapine in patients who develop severe neutropenia (ANC <500/mm³); however, clinician may determine that benefits outweigh risks.¹ (see Severe Neutropenia under Cautions)

Prescribing Limits

Adults

Oral

Maximum 900 mg daily.¹ ³⁹⁵ ⁴⁰⁶

Special Populations

Hepatic Impairment

Clozapine concentrations may be increased; dosage reduction may be necessary in patients with clinically important hepatic impairment.¹ ³⁹⁵ ⁴⁰⁶

Renal Impairment

Clozapine concentrations may be increased; dosage reduction may be necessary in patients with clinically important renal impairment.¹ ³⁹⁵ ⁴⁰⁶

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

Pharmacogenomics: Poor CYP2D6 Metabolizer Phenotype

Clozapine concentrations may be increased; dosage reduction may be necessary in patients who are known poor metabolizers of CYP2D6.¹ ³⁹⁵ ⁴⁰⁶

Cautions for Clozapine

Contraindications

History of serious hypersensitivity to clozapine (e.g., photosensitivity, vasculitis, erythema multiforme, Stevens-Johnson syndrome) or any ingredient in the formulation.¹ ³⁹⁵ ⁴⁰⁶

Warnings/Precautions

Warnings

Severe Neutropenia

Neutropenia reported in clozapine-treated patients.¹ Neutropenia is sometimes severe (ANC <500/mm³) and increases the risk of serious and potentially fatal infections.¹

Previously “severe leukopenia,” “severe granulocytopenia,” and “agranulocytosis” were used in the clozapine prescribing information to describe this hematologic effect; however, for standardization purposes, previous terms have been replaced with “severe neutropenia.”¹

Unless patient is at risk for recurrent suicidal behavior, use clozapine only in patients who have failed to respond adequately to standard antipsychotic treatment.¹ (See Uses.)

Mechanism of clozapine-induced neutropenia not known; risk is not dose-dependent.¹ Risk of neutropenia appears greatest during first 18 weeks of therapy and declines thereafter.¹ Not known whether concurrent use of other drugs known to cause neutropenia increases the risk or severity of clozapine-induced neutropenia.¹ (See Interactions.)

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 is also observed in some Middle Eastern ethnic groups and in other non-Caucasian ethnic groups with darker skin; the condition is more common in men.¹ ⁴⁰⁸ ⁴⁰⁹ ⁴¹⁰ Patients with BEN have normal hematopoietic stem cell number 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 (<1500/mm³ and usually ≤1000/mm³) for several months without identifiable causes.⁴⁰⁹ ⁴¹⁰ Consult with hematology specialist to determine if neutropenia is due to BEN.¹ ⁴⁰⁸ Patients with documented BEN have different ANC monitoring and treatment recommendations than the general population due to their lower baseline ANC.¹ ⁴⁰⁸ (See Table 2.)

Determine baseline CBC and ANC before initiation of therapy.¹ Do not initiate therapy if baseline ANC <1500/mm³ (or <1000/mm³ in patients with documented BEN).¹ ⁴⁰⁸

For first 6 months, monitor ANC every week; after 6 months of continuous therapy, if ANC remains in normal range, may monitor every 2 weeks.¹ ⁴⁰⁸ After a further 6 months, if ANC continues to be in normal range, may reduce monitoring to every 4 weeks for the remainder of therapy.¹ ⁴⁰⁸ If clozapine is discontinued abruptly for reasons unrelated to neutropenia, continue the patient's most recent ANC monitoring schedule until ANC is in the normal range (i.e., ≥1500/mm³ or in patients with BEN, ≥1000/mm³ or above baseline).¹ If clozapine is discontinued because of moderate to severe neutropenia, monitor ANC according to neutropenia monitoring recommendations.¹ Monitor ANC if fever occurs during the 2 weeks after clozapine discontinuance.¹

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

In hospice patients (i.e., terminally ill with estimated life expectancy of ≤6 months), clinician may reduce frequency of ANC monitoring to once every 6 months after discussion with the patient and/or caregiver, taking into account the patient's terminal illness, the importance of monitoring ANC, and the need to control psychiatric symptoms.¹ ³⁹⁵ ⁴⁰⁰ ⁴⁰⁸

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

Table 1. Clozapine Treatment Recommendations Based on ANC Monitoring for the General Patient Population1395400406408
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 6 months Every 2 weeks from 6–12 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)	Continue treatment	3 times weekly until ANC ≥1500/mm³ When ANC ≥1500/mm³, return to the patient's last “normal range” ANC monitoring interval (if clinically appropriate)
Moderate neutropenia (ANC 500–999/mm³)	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)	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 a new patient under “normal range” monitoring once ANC ≥1500/mm³

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

Table 2. Clozapine Treatment Recommendations Based on ANC Monitoring in Patients with BEN1395400406408
ANC Value	Treatment Recommendations	Frequency of ANC Monitoring
Normal BEN range (established ANC baseline ≥1000/mm³)	Obtain ≥2 baseline ANCs 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 6–12 months Monthly after 12 months
Discontinuance for reasons other than neutropenia	See Discontinuance of Therapy under Dosage and Administration
BEN neutropenia (ANC 500–999/mm³)	Recommend hematology consultation Continue treatment	3 times weekly until ANC ≥1000/mm³ or at patient's known baseline 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)	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 is at patient's baseline or higher If patient rechallenged, once ANC ≥1000/mm³ or at patient's baseline, resume treatment as a new patient under “normal range” monitoring

If a patient develops fever (temperature ≥38.5°C), interrupt therapy and obtain ANC.¹ If fever occurs in any patient with ANC <1000/mm³, evaluate for infection and initiate appropriate treatment.¹ Consider hematology consultation in patients with fever or neutropenia.¹

Orthostatic Hypotension, Bradycardia, and Syncope

Orthostatic hypotension, bradycardia, syncope, and cardiac arrest reported.¹ Such reactions, which can be fatal, are more likely to occur during initial titration period, particularly with rapid dosage escalation.¹ Reactions may occur with the first dose, at doses as low as 12.5 mg; reactions are consistent with neurally-mediated reflex bradycardia.¹

Titrate dosage cautiously and administer in divided doses.¹ (See Dosage under Dosage and Administration.) If hypotension occurs, consider dosage reduction.¹ If therapy interrupted ≥2 days, reinitiate at dosage of 12.5 mg once or twice daily.¹ (See Reinitiation of Therapy under Dosage and Administration.)

Use with caution in patients with known cardiovascular disease (e.g., history of MI or ischemic heart disease, heart failure, conduction abnormalities), cerebrovascular disease, or conditions that would predispose to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy).¹

Seizures

Risk of seizures, particularly at high dosages (>600 mg daily) and/or in patients with elevated plasma clozapine concentrations;⁴⁴ ⁹⁰ ¹⁵⁹ ²⁹² use with caution in patients with history of seizures or other predisposing factors (e.g., head trauma or other CNS pathology, concomitant use of drugs that lower the seizure threshold, alcohol abuse).¹

Avoid activity where sudden loss of consciousness could cause serious risk to patient or others (e.g., driving automobile, operating complex machinery, swimming, climbing).¹ ²

Myocarditis, Cardiomyopathy, and Mitral Valve Incompetence

Myocarditis and cardiomyopathy, sometimes fatal, reported.¹ Although these events can occur at any time during therapy, myocarditis most often presents within the first 2 months while cardiomyopathy usually occurs after 8 weeks of treatment.¹ Nonspecific flu-like symptoms (e.g., malaise, myalgia, pleuritic chest pain, low-grade fever) often precede more overt manifestations of heart failure.¹ Common laboratory findings include elevated troponin I or T concentrations, elevated CK-MB concentrations, peripheral eosinophilia, and elevated C-reactive protein (CRP) concentrations.¹ Cardiac imaging may reveal evidence of left ventricular dysfunction and chest radiographs may reveal cardiac silhouette enlargement.¹

Consider possibility of myocarditis or cardiomyopathy in patients with chest pain, dyspnea, persistent tachycardia at rest, palpitations, fever, flu-like symptoms, hypotension, or other manifestations of heart failure or ECG findings (e.g., low voltages, ST-T wave abnormalities, arrhythmias, right axis deviation, poor R wave progression).¹

Discontinue promptly and obtain cardiac evaluation if myocarditis or cardiomyopathy suspected.¹ Generally should not rechallenge patients with clozapine-related myocarditis or cardiomyopathy unless benefit outweighs risks of recurrence; however, may consider rechallenge in consultation with a cardiologist, after a complete cardiac evaluation and with close monitoring.¹

Mitral valve incompetence with mild to moderate mitral regurgitation reported in patients diagnosed with clozapine-associated cardiomyopathy.¹ In patients with suspected cardiomyopathy, consider performing a 2-dimensional Doppler echocardiogram to identify mitral valve incompetence.¹

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Increased risk of death with use of antipsychotics in geriatric patients with dementia-related psychosis.¹

Antipsychotic agents, including clozapine, are not approved for the treatment of dementia-related psychosis.¹ ³⁹⁵ ⁴⁰⁶ (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Other Warnings and Precautions

Falls

May cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries.¹

In patients with diseases, conditions, or other drugs that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic therapy and repeat such testing periodically during long-term therapy.¹

GI Hypomotility with Severe Complications

Severe adverse GI reactions reported, primarily due to clozapine's 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 Such reactions have resulted in hospitalization, surgery, and death.¹ ⁴²⁵ ⁴²⁷ ⁴²⁸ ⁴²⁹

Increased risk of severe complications with concurrent use of anticholinergic agents and other drugs that decrease GI peristalsis (e.g., opiate agonists); avoid combined use whenever possible.¹ ⁴²⁵ ⁴²⁶ (See Interactions.)

Prior to initiating clozapine therapy, screen patients for constipation and treat, if necessary.¹ ⁴²⁵ Subjective symptoms of constipation may not accurately reflect degree of GI hypomotility in clozapine-treated patients.¹ ⁴²⁵ ⁴²⁶ Therefore, frequently reassess bowel function and pay careful attention to any changes in the frequency or character of bowel movements as well as to possible signs and symptoms of hypomotility complications (e.g., nausea, vomiting, abdominal distension, abdominal pain).¹

If constipation or GI hypomotility is identified, closely monitor the patient and treat promptly with appropriate laxatives, as needed, to prevent severe complications.¹ Consider use of prophylactic laxatives in high-risk patients (e.g., those with a history of constipation or bowel obstruction).¹ ⁴²⁵ Some clinicians recommend prophylactic laxatives in all patients during clozapine therapy.⁴²⁶ (See Advice to Patients.)

Eosinophilia

Eosinophilia (blood eosinophil count >700/mm³)¹ ¹² ³⁷ ⁶⁰ reported in approximately 1% of clozapine-treated patients in clinical trials.¹ Usually occurs during first month of therapy.¹ In some patients, eosinophilia has been associated with myocarditis, pancreatitis, hepatitis, colitis, and/or nephritis.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

If eosinophilia develops during clozapine therapy, promptly evaluate patient for possible signs and symptoms of systemic reactions (e.g., rash or other allergic symptoms, myocarditis, other organ-specific disease associated with eosinophilia).¹ If clozapine-associated eosinophilia with systemic involvement is suspected, immediately discontinue clozapine.¹ If cause of eosinophilia unrelated to clozapine is identified (e.g., asthma, allergies, collagen vascular disease, parasitic infections, specific neoplasms), treat the underlying cause and continue clozapine therapy.¹

Clozapine-associated eosinophilia without organ involvement also may occur and can resolve without intervention.¹ In such cases, may continue clozapine therapy with careful monitoring.¹ If total eosinophil count continues to increase over several weeks in the absence of systemic disease, base decision whether to interrupt clozapine therapy and rechallenge after the eosinophil count decreases on the overall clinical assessment, in consultation with an internist or hematologist.¹ Successful rechallenge after discontinuance of clozapine, without recurrence of eosinophilia, reported.¹

Prolongation of QT Interval

Prolongation of the QT interval, torsades de pointes and other life-threatening ventricular arrhythmias, cardiac arrest, and sudden death reported in clozapine-treated patients.¹ Risk factors include a history of QT-interval prolongation, long QT syndrome, family history of long QT syndrome or sudden cardiac death, significant cardiac arrhythmia, recent MI, uncompensated heart failure, and concomitant use of other drugs that prolong the QT interval or the metabolism of clozapine.¹ ³⁹⁵ ⁴⁰⁶ (See Interactions.) Hypokalemia and hypomagnesemia also increase risk of QT-interval prolongation.¹

Prior to initiating clozapine, perform a careful physical examination and obtain a medical and concomitant medication history.¹ Also obtain baseline serum potassium and magnesium concentrations and correct any electrolyte abnormalities prior to therapy.¹ Consider obtaining a baseline ECG and serum chemistry panel before starting clozapine.¹

Periodically monitor serum electrolytes during clozapine therapy.¹

In patients who experience symptoms consistent with torsades de pointes or other arrhythmias (e.g., syncope, presyncope, dizziness, palpitations), discontinue clozapine and obtain cardiac evaluation.¹ Discontinue clozapine if corrected QT (QT_c) interval >500 msec.¹

Metabolic Changes

Atypical antipsychotic agents are associated with metabolic changes that can increase cardiovascular and cerebrovascular risk (e.g., hyperglycemia and diabetes mellitus, dyslipidemia, weight gain).¹ While all atypical antipsychotics produce some metabolic changes, each drug has its own specific risk profile.¹ (See Hyperglycemia and Diabetes Mellitus, see Dyslipidemia, and also see Weight Gain under Cautions.)

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, reported in patients receiving atypical antipsychotic agents,³³¹ ³³² ³³³ including clozapine.¹

Periodically monitor patients with preexisting diabetes mellitus for worsening of glycemic control and perform fasting blood glucose testing at baseline and periodically in patients with risk factors for diabetes (e.g., obesity, family history of diabetes).¹ ³³¹ ³³² ³⁹⁵ ⁴⁰⁶ If manifestations of hyperglycemia occur in any patient, perform fasting blood glucose testing.¹ ³³¹ ³³² (See Advice to Patients.)

Some patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the suspect drug; in other patients, hyperglycemia resolved with discontinuance of the antipsychotic.¹

Dyslipidemia

Undesirable changes in lipid parameters observed in patients treated with some atypical antipsychotics, including clozapine.¹ Clinically important elevations in serum total cholesterol and triglyceride concentrations have occurred in clozapine-treated patients.¹

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

Weight Gain

Weight gain observed with atypical antipsychotic therapy.¹ In schizophrenia clinical trials, 35% of clozapine-treated adults gained ≥7% of their baseline body weight.¹ Manufacturers recommend clinical monitoring of weight during therapy.¹ ³⁹⁵ ⁴⁰⁰ ⁴⁰⁶ (See Hyperglycemia and Diabetes Mellitus under Cautions.)

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability, reported with antipsychotic agents, including some cases with clozapine therapy alone or during concomitant therapy with carbamazepine, lithium, or other CNS-active agents.¹ ¹⁴⁷ ¹⁴⁸ ²³⁷ ²⁵⁵ ²⁸⁴ ²⁹⁹ ³⁰⁰ ³⁹⁵ ⁴⁰¹ ⁴⁰² ⁴⁰³

If NMS occurs, immediately discontinue therapy and initiate supportive and symptomatic treatment.¹ Careful monitoring recommended if therapy is reinstituted following recovery; the risk that NMS can recur must be considered.¹

Hepatotoxicity

Severe, life-threatening, and sometimes fatal hepatotoxicity, including hepatic failure, hepatic necrosis, and hepatitis, reported in postmarketing studies.¹

Monitor patients for possible signs and symptoms of liver injury (e.g., fatigue, malaise, anorexia, nausea, jaundice, hyperbilirubinemia, coagulopathy, hepatic encephalopathy).¹ Monitor liver function tests during therapy.¹

Consider permanent discontinuance of the drug if hepatitis or elevated aminotransferase concentrations combined with other systemic symptoms are caused by clozapine.¹

Fever

Possible transient temperature elevations exceeding 38°C, with peak incidence within first 3 weeks of therapy.¹ ⁵ ¹¹ ¹² ⁵⁷ ⁶² ⁶⁷ ⁸⁷ ¹⁰³ ¹²⁴ ¹²⁷ ¹²⁸ ¹³⁰ ¹⁹⁵ ²³⁷ Fever usually is benign and self-limiting, but may necessitate discontinuance of therapy.¹ Occasionally, fever accompanied by an increase or decrease in WBC count.¹

If fever (temperature ≥38.5°C) occurs in any patient, interrupt clozapine therapy and obtain an ANC; carefully evaluate for severe neutropenia or infection.¹ Monitor ANC in any patient who develops fever within 2 weeks after discontinuance of clozapine.¹ If high fever is present, also consider possibility of NMS.¹ (See Neuroleptic Malignant Syndrome under Cautions.)

Thromboembolic Events

PE and DVT reported in clozapine-treated patients; causal relationship not established.¹ Consider possibility of PE in patients presenting with DVT, chest pain, acute dyspnea, or other respiratory symptoms.¹

Anticholinergic Effects

Clozapine has potent anticholinergic activity; therapy with the drug may result in CNS and peripheral anticholinergic toxicity, particularly at higher dosages or in overdosage situations.¹

Use with caution in patients with conditions that 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

Avoid concomitant use of clozapine with other drugs that have anticholinergic activity, if possible.¹ ⁴²⁵ ⁴²⁶ (See GI Hypomotility with Severe Complications under Cautions and also see Interactions.)

Cognitive and Motor Impairment

Cognitive and motor performance may be impaired.¹ Somnolence or sedation reported in 21–46% of clozapine-treated patients in clinical trials.¹ ³²⁷ Effects may be dose-related; consider dosage reduction in patients experiencing such effects.¹ (See Advice to Patients.)

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary dyskinetic movements, may occur in patients receiving antipsychotic agents.¹ Clozapine generally has not been clearly implicated as a causative agent in tardive dyskinesia.⁵ ¹⁰ ⁶⁷ ⁸² ⁸⁹ ¹⁰⁴ ¹¹¹ ¹³⁷ ¹⁸² ³⁴⁷

Reserve long-term antipsychotic treatment for patients with chronic illness known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.¹ In patients requiring chronic treatment, use smallest dosage and shortest duration of treatment producing a satisfactory clinical response; periodically reassess need for continued therapy.¹ Consider discontinuance of clozapine if signs and symptoms of tardive dyskinesia occur.¹ However, some patients may require treatment despite the presence of the syndrome.¹

Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis

Increased incidence of adverse cerebrovascular events (stroke and TIAs), including fatalities, observed in geriatric patients with dementia-related psychosis treated with some atypical antipsychotic agents in placebo-controlled studies.¹ Use with caution in patients with risk factors for stroke.¹ Clozapine is not approved for the treatment of patients with dementia-related psychosis.¹ (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Withdrawal of Therapy

If abrupt discontinuance of clozapine is required, observe patients carefully for recurrence of psychotic symptoms and symptoms related to cholinergic rebound (e.g., profuse sweating, headache, nausea, vomiting, diarrhea).¹ Sudden withdrawal from clozapine therapy can lead to rapid decompensation and rebound psychosis.¹¹ ¹³¹ ¹⁷³ ¹⁷⁴

Phenylketonuria

Clozapine orally disintegrating tablets contain aspartame, which is metabolized in the GI tract to phenylalanine; consult manufacturer's labeling for specific information regarding aspartame content of individual preparations and dosage strengths. ³⁸⁶ ³⁸⁸ ³⁸⁹ ³⁹⁰ ³⁹¹ ³⁹⁵

Specific Populations

Pregnancy

Category B.¹ ³⁹⁵ ⁴⁰⁶

Risk for extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, feeding disorder) in neonates exposed to antipsychotic agents during the third trimester; monitor neonates exhibiting such symptoms.¹ ³⁹⁷ ³⁹⁸ ³⁹⁹ Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive support and prolonged hospitalization.¹ ³⁹⁷ ³⁹⁸ ³⁹⁹

Lactation

Distributed into milk.¹ ³⁹⁵ ⁴⁰⁶ Discontinue nursing or the drug.¹ ³⁹⁵ ⁴⁰⁶

Pediatric Use

Safety and efficacy not established in pediatric patients.¹ ³⁹⁵ ⁴⁰⁶

Mild to moderate neutropenia and clinically important seizure activity (e.g., epileptiform spikes, myoclonus, tonic-clonic seizures) reported in children and adolescents receiving clozapine.³²² ³²³

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage with caution and consider greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients.¹

Geriatric patients may be particularly susceptible to cardiovascular (e.g., orthostatic hypotension, tachycardia) and anticholinergic (e.g., urinary retention, constipation) adverse effects.¹

Geriatric patients with dementia-related psychosis treated with antipsychotic agents, including clozapine, are at an increased risk of death;¹ ³⁸⁵ increased incidence of adverse cerebrovascular events also observed in geriatric patients with dementia-related psychosis receiving clozapine.¹ ³⁹⁵ ⁴⁰⁶ Clozapine is not approved for the treatment of patients with dementia-related psychosis.¹ ³⁹⁵ ⁴⁰⁶ (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning and also see Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions.)

Hepatic Impairment

Clozapine concentrations may be increased in patients with clinically important hepatic impairment.¹ (See Special Populations under Dosage and Administration.)

Renal Impairment

Clozapine concentrations may be increased in patients with clinically important renal impairment.¹ (See Special Populations under Dosage and Administration.)

Common Adverse Effects

Sedation,¹ dizziness/vertigo,¹ headache,¹ tremor,¹ tachycardia,¹ hypotension,¹ syncope,¹ hypersalivation,¹ sweating,¹ dry mouth,¹ visual disturbances,¹ constipation,¹ nausea,¹ fever.¹

Drug Interactions

Metabolized by many CYP isoenzymes, particularly 1A2, 2D6, and 3A4.¹ ³²⁰ May inhibit CYP2D6.¹

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP1A2, CYP2D6, or CYP3A4: Potential pharmacokinetic interaction (altered clozapine metabolism).¹

Potent CYP1A2 inhibitors: Reduce clozapine to one-third of original dosage when a potent CYP1A2 inhibitor is added to therapy.¹ Increase back to the original clozapine dosage when the potent CYP1A2 inhibitor is discontinued.¹

Moderate or weak CYP1A2 inhibitors or inhibitors of CYP2D6 or CYP3A4: Monitor for adverse effects and consider dosage reduction of clozapine.¹ If a moderate or weak CYP1A2 inhibitor or CYP2D6 or CYP3A4 inhibitor is discontinued, monitor for decreased efficacy of clozapine and consider increasing clozapine dosage.¹

Potent CYP3A4 inducers: Concomitant use generally not recommended.¹ If concomitant use necessary, monitor for decreased efficacy of clozapine and consider increasing clozapine dosage.¹

Inducers of CYP1A2 or 3A4: Monitor for decreased efficacy of clozapine and consider increasing clozapine dosage.¹ If a CYP1A2 or CYP3A4 inducer is discontinued during clozapine therapy, monitor for adverse effects and consider dosage reduction of clozapine.¹

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2D6: Potential pharmacokinetic interaction (increased systemic exposure of substrate); dosage reduction of substrate may be required.¹

Drugs Affecting Seizure Threshold

Possible increased risk of seizures; use concomitantly with caution.¹ ³⁹⁵ ⁴⁰⁶

Drugs that Prolong the QT Interval

Potential additive effect on QT-interval prolongation; use concomitantly with caution.¹ (See Prolongation of QT Interval under Cautions and also see Specific Drugs under Interactions.)

Drugs with Anticholinergic Activity and Drugs that Decrease GI Peristalsis

Because of the risk of anticholinergic toxicity and severe adverse GI reactions related to hypomotility, avoid concurrent use of drugs with anticholinergic activity and/or drugs that decrease GI peristalsis and can cause constipation, if possible.¹ ⁴²⁵ (See GI Hypomotility with Severe Complications and also see Anticholinergic Effects under Cautions and Specific Drugs under Interactions.)

Other Drugs Associated with Neutropenia

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 Currently no strong scientific rationale to avoid clozapine treatment in patients concurrently treated with such drugs.¹ ³⁹⁵ ⁴⁰⁰ ⁴⁰⁶

Monitor patients concurrently receiving other drugs that cause neutropenia (e.g., antineoplastic agents) more closely than usual (see Severe Neutropenia under Cautions).¹ ³⁹⁵ ⁴⁰⁰ ⁴⁰⁶ If used concurrently with antineoplastic agents, consult treating oncologist.¹ ³⁹⁵ ⁴⁰⁰ ⁴⁰⁶

Protein-Bound Drugs

Interaction not evaluated but may be important, since clozapine binds extensively to plasma proteins.¹

Specific Drugs

Drug	Interaction	Comments
Alcohol	Alcohol abuse: potential additive risk factor for seizures¹	Use with caution if alcohol abuse is a concern¹
Antiarrhythmics (class Ia and III; e.g., amiodarone, procainamide, quinidine, sotalol)	Increased risk of QT-interval prolongation¹	Use concomitantly with caution¹
Antiarrhythmics (class Ic; e.g., encainide, flecainide, propafenone)	Possible increased systemic exposure of drugs metabolized by CYP2D6¹	Administer concomitantly with caution; dosage reduction of antiarrhythmic may be necessary¹
Anticholinergic agents (e.g., benztropine, cyclobenzaprine, diphenhydramine)	Additive anticholinergic effects; increased risk of constipation, GI hypomotility, and severe bowel complications¹ ⁴²⁵	Avoid concurrent use, if possible¹ ⁴²⁵
Antipsychotic agents that prolong QT interval (e.g., chlorpromazine, haloperidol, iloperidone, pimozide, risperidone, thioridazine, ziprasidone)	Increased risk of QT-interval prolongation¹ ³²⁰ ⁴¹⁶ Haloperidol: At least 1 death reported with concomitant use of oral haloperidol and IM clozapine (not commercially available in US); causal relationship not established¹⁶⁶	Use concomitantly with caution¹ ⁴¹⁶
Benzodiazepines	Severe hypotension, respiratory or cardiac arrest, and loss of consciousness reported after clozapine administration concurrently with or within 24 hours of benzodiazepine; reactions developed on first or second day of therapy¹⁶⁶ ¹⁸⁸ ²³⁷ ²⁸¹ ²⁹⁶
Bupropion	Possible increased plasma clozapine concentrations¹	Monitor for adverse effects; reduce clozapine dosage if needed¹ If bupropion is discontinued, monitor for decreased clozapine efficacy and increase clozapine dosage if needed¹
Caffeine	Possible increased plasma clozapine concentrations¹ ³²⁰
Carbamazepine	Possible decreased plasma clozapine concentrations¹ ³²⁰ Possible increased plasma carbamazepine concentrations¹ NMS reported rarely with concomitant use¹⁴⁷ ¹⁴⁸	Concomitant use generally not recommended¹ Monitor for decreased efficacy of clozapine; increase clozapine dosage if needed¹ If carbamazepine is discontinued, consider reducing dosage of clozapine¹ Carbamazepine dosage reduction may be necessary¹
Cimetidine	Possible increased plasma clozapine concentrations¹ ³²⁰	Monitor for adverse effects; reduce clozapine dosage if needed¹ If cimetidine is discontinued, monitor for decreased clozapine efficacy and increase clozapine dosage if needed¹
Ciprofloxacin	Possible substantially increased plasma clozapine concentrations¹	Reduce clozapine to one-third of original dosage when ciprofloxacin is added to therapy¹ Increase back to the original clozapine dosage when ciprofloxacin is discontinued¹
Dolasetron mesylate	Increased risk of QT-interval prolongation¹	Use concomitantly with caution¹
Droperidol	Increased risk of QT-interval prolongation¹	Use concomitantly with caution¹
Drugs that decrease GI peristalsis and cause constipation (e.g., opiate analgesics)	Increased risk of constipation, GI hypomotility, and severe bowel complications¹ ⁴²⁵	Avoid concurrent use, if possible¹ ⁴²⁵
Duloxetine	Possible increased plasma clozapine concentrations¹	Monitor for adverse effects; reduce clozapine dosage if needed¹ If duloxetine is discontinued, monitor for decreased clozapine efficacy and increase clozapine dosage if needed¹
Erythromycin	Possible increased plasma clozapine concentrations¹ ³²⁰ Increased risk of QT-interval prolongation¹	Use concomitantly with caution¹ Monitor for adverse effects; reduce clozapine dosage if needed¹ If erythromycin is discontinued, monitor for decreased clozapine efficacy and increase clozapine dosage if needed¹
Escitalopram	Possible increased plasma clozapine concentrations¹	Monitor for adverse effects; reduce clozapine dosage if needed¹ If escitalopram is discontinued, monitor for decreased clozapine efficacy and increase clozapine dosage if needed¹
Fluoxetine	Possible increased plasma clozapine concentrations (potent CYP1A2 inhibitor)¹	Monitor for adverse effects; reduce clozapine dosage if needed¹ If fluoxetine is discontinued, monitor for decreased clozapine efficacy and increase clozapine dosage if needed¹
Fluvoxamine	Substantially increased trough plasma clozapine concentrations with fluvoxamine (potent CYP1A2 inhibitor)¹	Reduce clozapine to one-third of original dosage when fluvoxamine is added to therapy; may increase back to the original clozapine dosage, based on clinical response, when fluvoxamine is discontinued¹
Gatifloxacin	Increased risk of QT-interval prolongation¹	Use concomitantly with caution¹
Hypotensive agents	Additive or potentiated hypotensive effects¹	Use concomitantly with caution¹
Lithium	Possible increased risk of seizures;²⁹² ³³⁰ NMS reported rarely with concomitant use¹⁴⁷ ¹⁴⁸ ²³⁷ ²⁵⁵
Mefloquine	Increased risk of QT-interval prolongation¹	Use concomitantly with caution¹
Methadone	Increased risk of QT-interval prolongation (see also Drugs that decrease GI peristalsis and cause constipation in this table)¹	Use concomitantly with caution¹
Moxifloxacin	Increased risk of QT-interval prolongation¹	Use concomitantly with caution¹
Oral contraceptives	Possible increased plasma clozapine concentrations when used with moderate or weak CYP1A2 inhibitors¹	Monitor for adverse effects; consider reducing dosage of clozapine¹ If oral contraceptive is discontinued, monitor for decreased efficacy of clozapine and increase clozapine dosage if needed¹
Paroxetine	Possible increased plasma clozapine concentrations¹	Monitor for adverse effects; reduce clozapine dosage if needed¹ If paroxetine is discontinued, monitor for decreased clozapine efficacy and increase clozapine dosage if needed¹
Pentamidine	Increased risk of QT-interval prolongation¹	Use concomitantly with caution¹
Phenytoin	Possible substantially decreased plasma clozapine concentrations with phenytoin (potent CYP3A4 inducer)¹ ²⁸⁵ ³⁹⁵ ⁴⁰⁰ ⁴⁰⁶	Concomitant use generally not recommended¹ ³⁹⁵ ⁴⁰⁰ ⁴⁰⁶ If concomitant use necessary, monitor for decreased efficacy of clozapine and increase clozapine dosage, if needed¹ ³⁹⁵ ⁴⁰⁰ ⁴⁰⁶ If phenytoin is discontinued, monitor for adverse effects and consider reducing clozapine dosage, if necessary ¹ ³⁹⁵ ⁴⁰⁰ ⁴⁰⁶
Quinidine	Possible increased plasma clozapine concentrations¹	Monitor for adverse effects; reduce clozapine dosage if needed¹ If quinidine is discontinued, monitor for decreased clozapine efficacy and increase clozapine dosage if needed¹
Rifampin	Possible decreased plasma clozapine concentrations with rifampin (potent CYP3A4 inducer)¹	Concomitant use generally not recommended¹ If concomitant use necessary, monitor for decreased efficacy of clozapine and increase clozapine dosage, if necessary¹ If rifampin discontinued, monitor for adverse effects and consider reducing clozapine dosage, if necessary ¹
Sertraline	Possible increased plasma clozapine concentrations¹	Monitor for adverse effects; reduce clozapine dosage if needed¹ If sertraline is discontinued, monitor for decreased clozapine efficacy and increase clozapine dosage if needed¹
Smoking	Substantially decreased plasma clozapine concentrations possible (smoking is a CYP1A2 inducer);¹ ⁴⁰ ⁴⁵ ¹⁰⁸ ²³⁷ clozapine concentrations in smokers average 60–82% of those in nonsmokers⁴⁰ ¹⁰⁸	Monitor for decreased efficacy of clozapine in smokers and increase clozapine dosage, if necessary¹ ³⁹⁵ ⁴⁰⁰ ⁴⁰⁶ If smoking is discontinued, monitor for adverse effects and reduce dosage of clozapine, if necessary¹ ³⁹⁵ ⁴⁰⁰ ⁴⁰⁶
St. John's wort (Hypericum perforatum)	Possible decreased plasma clozapine concentrations¹	Concomitant use generally not recommended¹ If concomitant use necessary, monitor for decreased efficacy of clozapine and increase clozapine dosage if needed¹ If St. John's wort discontinued, monitor for adverse effects and consider reducing dosage of clozapine, if necessary¹
Tacrolimus	Increased risk of QT-interval prolongation¹	Use concomitantly with caution¹
Terbinafine	Possible increased plasma clozapine concentrations¹	Monitor for adverse effects; reduce clozapine dosage if needed¹ If terbinafine is discontinued, monitor for decreased clozapine efficacy and increase clozapine dosage if needed¹

Clozapine Pharmacokinetics

Absorption

Bioavailability

Rapidly¹² ¹⁶ ³⁸ ⁶⁷ ¹⁰² ²³⁵ and almost completely absorbed⁵ ⁴¹ ⁶⁷ after oral administration; peak plasma concentrations attained within 1.5 or an average of 2.5 hours after single (25- or 100-mg) or multiple (100 mg twice daily) doses of clozapine as conventional tablets, respectively.¹ ² ⁴⁶

After multiple doses of clozapine oral suspension (100–800 mg once daily), peak plasma concentrations 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 achieved within an average of 2.3 hours (range: 1–6 hours).³⁹⁵

Relative oral bioavailability of 25- and 100-mg tablets is equivalent (relative to an oral solution).¹ ⁵ ³⁹⁵ Conventional and orally disintegrating tablets of clozapine are bioequivalent.⁵ ³⁹⁵ Commercially available clozapine oral suspension and conventional tablets are bioequivalent.⁴⁰⁶

Onset

Pharmacologic effects (e.g., sedation)¹⁸⁹ reportedly are apparent within 15 minutes and become clinically important within 1–6 hours following oral administration of conventional tablets.²

Antipsychotic activity generally is delayed for 1 to several weeks after initiation;³⁷ maximal activity may require several months of therapy with the drug.⁵ ⁸³ ²²⁵ ²²⁶

Duration

Duration of action reportedly ranges from 4–12 hours after a single oral dose.² In one study, sedative effect was maximal within 7 days.³⁷

Food

Food does not appear to affect rate or extent of absorption of conventional tablets.¹ ⁵ ²¹⁸ ²¹⁹ High-fat meal does not have clinically important effects on the pharmacokinetics of orally disintegrating tablets or oral suspension.³⁹⁵ ⁴⁰⁶

Plasma Concentrations

Correlations between steady-state plasma concentrations and therapeutic efficacy not established.⁵ ¹⁴³ ¹⁷¹ ¹⁸⁶ ²³⁷ ²⁹²

Special Populations

Effects of renal or hepatic impairment not specifically studied, but higher plasma clozapine concentrations expected in patients with substantial renal or hepatic impairment when administered in usual dosages.¹

In patients with poor metabolizer phenotypes of CYP2D6, increased plasma clozapine concentrations possible at usual dosages.¹ ³⁹⁵ ⁴⁰⁶

In smokers, plasma clozapine concentrations appear to be approximately 60–80% of those achieved by nonsmokers after oral administration.⁴⁰ ⁴⁵ ¹⁰⁸ ²³⁷ ²³⁸

Limited evidence suggests gender may affect plasma clozapine concentrations, with concentrations being somewhat reduced (20–30%) in males compared with females.⁴⁰ ¹⁰⁸ ²³⁸

Increased plasma concentrations possible in geriatric patients compared with those in younger (e.g., 18–35 years old) adults, possibly due to age-related decreases in hepatic elimination.¹⁰⁸ ²³⁷ ²³⁸

Distribution

Extent

Rapidly and extensively distributed into human body tissues;² ¹⁶ ⁴³ metabolites also appear to be extensively distributed.⁵

Reportedly present in low concentrations in placenta and may distribute into milk in animals;² not known whether crosses placenta in humans.²⁹² Distributed into milk in humans.¹

Plasma Protein Binding

Approximately 97%.¹ ⁵

Elimination

Metabolism

Almost completely metabolized in the liver by many CYP isoenzymes, particularly CYP1A2, CYP2D6, and CYP3A4.¹ ³²⁰ Desmethyl metabolite has only limited activity, while hydroxylated and N-oxide derivatives are inactive.¹

Elimination Route

Excreted in urine (50%) and feces (30%) principally as metabolites, with only trace amounts of unchanged drug detected.¹ ² ⁶⁷

Half-life

8 hours (range: 4–12 hours) after single oral dose and 12 hours (range: 4–66 hours) at steady state.¹ ⁵ ¹¹ ³⁸ ⁶⁷ ¹⁷⁹

Stability

Storage

Oral

Conventional Tablets

Store in tight containers at 20–25°C⁴⁰⁰ (not exceeding 30°C).¹

Orally Disintegrating Tablets

Store in original package at 20–25°C (may be exposed to 15–30°C) until time of use.³⁹⁵ Protect from moisture.³⁹⁵

Oral Suspension

Store at 20–25ºC (may be exposed to 15–30°C); do not refrigerate or freeze.⁴⁰⁶ Protect from light.⁴⁰⁶ Stable for 100 days after initial bottle opening.⁴⁰⁶

Actions

Exact mechanism of antipsychotic action not fully elucidated;¹ ² ⁹ ¹⁰ ¹² ²⁰ ²² ²⁵³ may involve serotonergic, adrenergic, and cholinergic neurotransmitter systems in addition to more selective, regionally specific effects on the mesolimbic dopaminergic system.⁵ ¹⁵ ¹⁹ ⁶⁷ ¹⁷⁰ ²¹² ²³⁷ ²⁵⁶ ²⁸⁸ ²⁹⁰ ²⁹² ²⁹³
Efficacy thought to be principally mediated through antagonist activity at dopamine type 2 (D₂) and serotonin type 2A (5-HT_2A) receptors.¹
Binds to dopamine D₁, D₂, D₃, D₄, and D₅ receptors; histamine H₁ receptors; α_1A-adrenergic and α_2A-adrenergic receptors; serotonin 5-HT_1A, 5-HT_2A, 5-HT_2C, 5-HT₃, 5-HT₆, and 5-HT₇ receptors; and muscarinic M₁ receptors.¹ Antagonism of histamine H₁ receptors, cholinergic, and α₁-adrenergic receptors may contribute to other therapeutic and adverse effects (e.g., somnolence, constipation, orthostatic hypotension).¹ ⁵ ¹⁵ ¹⁹ ⁶⁷ ¹⁷⁰ ²¹² ²³⁷ ²⁵⁶ ²⁸⁸ ²⁹⁰ ²⁹² ²⁹³

Advice to Patients

Importance of advising patients and caregivers about risk of severe neutropenia and infection with clozapine.¹ Inform patients and caregivers that clozapine is only available through the Clozapine REMS program, which is designed to ensure required blood monitoring to reduce the risk of developing severe neutropenia; advise of importance of adhering to the blood monitoring schedule.¹
Importance of immediately informing clinician if any signs or symptoms of infection (e.g., flu-like illness; fever; lethargy; general weakness or malaise; mucous membrane ulceration; skin, pharyngeal, vaginal, urinary, or pulmonary infection; extreme weakness or lethargy) occur at any time during clozapine therapy to aid in evaluation for neutropenia and to institute prompt and appropriate management.¹ (See Severe Neutropenia under Cautions.)
Risk of orthostatic hypotension, particularly during initial dosage titration.¹ Importance of patients immediately informing clinician if they feel faint, lose consciousness, or have signs or symptoms suggestive of bradycardia or arrhythmia.¹
If therapy interrupted for ≥2 days, contact clinician for dosage instructions.¹
Inform patients and caregivers about substantial risk of seizures during clozapine therapy.¹ Caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others (e.g., driving, operating complex machinery, swimming, climbing).¹
Risk of GI hypomotility and severe complications.¹ ⁴²⁵ Advise patients and caregivers about the risks, prevention, and treatment of clozapine-induced constipation, including drugs to avoid when possible (e.g., drugs with anticholinergic activity).¹ ⁴²⁵ Encourage appropriate hydration, physical activity, and fiber intake.¹ ⁴²⁵ Inform patients that prompt attention to and treatment of developing constipation or other GI symptoms are essential in preventing severe complications.¹ ⁴²⁵ Advise patients and caregivers to contact clinician if the patient experiences 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.)
Importance of advising patients and caregivers that geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.¹ Patients and caregivers also should be informed that clozapine is not approved for treating geriatric patients with dementia-related psychosis.¹
Risk of QT-interval prolongation.¹ Importance of patients immediately informing their clinician if they feel faint, lose consciousness, or have signs or symptoms suggestive of an arrhythmia.¹ Importance of instructing patients not to take clozapine with other drugs that cause QT-interval prolongation.¹ Instruct patients to inform clinicians that they are taking clozapine before they take any new drug.¹ (See Interactions.)
Importance of informing patients and caregivers about the risk of metabolic changes (e.g., hyperglycemia and diabetes mellitus, dyslipidemia, weight gain) and the need for specific monitoring for such changes.¹ Importance of patients and caregivers being aware of the symptoms of hyperglycemia (e.g., increased thirst, increased urination, increased appetite, weakness).¹ Importance of informing patients who are diagnosed with diabetes or those with risk factors for diabetes (e.g., obesity, family history of diabetes) that they should have their blood glucose monitored at the beginning of and periodically during clozapine therapy; patients who develop symptoms of hyperglycemia during therapy should have their blood glucose assessed.¹
Because somnolence and impairment of judgment, thinking, or motor skills may be associated with clozapine, advise patients to exercise caution when driving or operating hazardous machinery until they gain experience with the drug’s effects.¹
Risk of NMS, which can cause high fever, stiff muscles, sweating, fast or irregular heart beat, change in BP, confusion, and kidney damage.¹
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription or OTC drugs, as well as any concomitant illnesses (e.g., diabetes mellitus, seizure disorder, dementia, cardiovascular disease).¹

Importance of informing patients with phenylketonuria that clozapine orally disintegrating tablets contain aspartame.³⁸⁶ ³⁸⁸ ³⁸⁹ ³⁹⁰ ³⁹¹ ³⁹⁵
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹
Importance of informing patients of other important precautionary information.¹ ³⁹⁵ ⁴⁰⁶ (See Cautions.)

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, that ensures appropriate monitoring and management of patients with severe neutropenia.¹ ³⁹⁵ ⁴⁰⁰ ⁴⁰⁶ ⁴⁰⁷ ⁴⁰⁸ (See General under Dosage and Administration.)

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

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
	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

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

References

1. HLS Therapeutics (USA), Inc. Clozaril (clozapine) tablets prescribing information. Rosemont, PA; 2020 Mar.

2. Sandoz Pharmaceuticals. Formulary information on Clozaril (clozapine). East Hanover, NJ; 1989.

4. Neumayer JL. Neuroleptics and anxiolytic agents. In: Foye WO, ed. Principles of medicinal chemistry. 3rd ed. Philadelphia: Lea & Febiger; 1989:208-9.

5. Ereshefsky L, Watanabe MD, Tran-Johnson TK. Clozapine: an atypical antipsychotic agent. Clin Pharm. 1989; 8:691-709. http://www.ncbi.nlm.nih.gov/pubmed/2572373?dopt=AbstractPlus

6. Sandoz Pharmaceuticals. Treatment systems requirements: Clozaril (clozapine). East Hanover, NJ; 1991 Mar.

7. Lapierre YD, Ghadirian A, St. Laurent J et al. Clozapine in acute schizophrenia—efficacy and toxicity. Curr Ther Res. 1980; 27:391-400.

8. Steiner G, Franke A, Hadicke E. Tricyclic epines: novel (E)- and (Z)-11 H-dibenzo[b,e]azepines as potential central nervous system agents. Variation of the basic side chain. J Med Chem. 1986; 29:1877-88. http://www.ncbi.nlm.nih.gov/pubmed/2876098?dopt=AbstractPlus

9. Coward DM, Imperato A, Urwyler S et al. Biochemical and behavioural properties of clozapine. Psychopharmacology. 1989; 99(Suppl):S6-12. http://www.ncbi.nlm.nih.gov/pubmed/2573106?dopt=AbstractPlus

10. Kane J, Honigfeld G, Singer J et al. Clozapine for the treatment-resistant schizophrenic: a double- blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988; 45:789-96. http://www.ncbi.nlm.nih.gov/pubmed/3046553?dopt=AbstractPlus

11. Bablenis E, Weber SS, Wagner RL. Clozapine: a novel antipsychotic agent. DICP. 1989; 23:109-15. http://www.ncbi.nlm.nih.gov/pubmed/2658370?dopt=AbstractPlus

12. Lieberman JA, Kane JM, Johns CA. Clozapine: guidelines for clinical management. J Clin Psychiatry. 1989; 50:329-38. http://www.ncbi.nlm.nih.gov/pubmed/2670914?dopt=AbstractPlus

13. Ereshefsky L, Crismon ML, Saklad SR. Intraindividual pharmacokinetic assessment of clozapine. Pharmacotherapy. 1988; 8:137.

14. Marder SR, Van Putten T. Who should receive clozapine? Arch Gen Psychiatry. 1988; 45:856- 7.

15. Gedelsky GA, Nash JF, Berry SA et al. Basic biology of clozapine: electrophysiological and neuroendocrinological studies. Psychopharmacology. 1989; 99(Suppl):S13-7. http://www.ncbi.nlm.nih.gov/pubmed/2682728?dopt=AbstractPlus

16. Wolters EC, Hurwitz TA, Peppard RF et al. Clozapine: an antipsychotic agent in Parkinson’s disease? Clin Neuropharmacol. 1989; 12:83-90.

17. Zapletalek M, Pazdirek S, Hubsch T et al. Clinical experience with clozapine in psychosis. Act Nerv Super. 1974; 16:203-4.

18. Criswell HE, Mueller RA, Breese GA. Clozapine antagonism of D-1 and D-2 dopamine receptor-mediated behaviors. Eur J Pharmacol. 1989; 159:141-7. http://www.ncbi.nlm.nih.gov/pubmed/2495973?dopt=AbstractPlus

19. Burki HR, Sayers AC, Ruch W et al. Effects of clozapine and other dibenzo-epines on central dopaminergic and cholinergic systems. Arzneimittelforschung. 1977; 27:1561-5. http://www.ncbi.nlm.nih.gov/pubmed/20900?dopt=AbstractPlus

20. Anon. Clozapine. Lancet. 1989; 2:1430-2. http://www.ncbi.nlm.nih.gov/pubmed/2574365?dopt=AbstractPlus

21. Honigfeld G, Patin J, Singer J. Clozapine: antipsychotic activity in treatment-resistant schizophrenics. Adv Ther. 1984; 1:77-97.

22. Meltzer HY. Clozapine: the next stage in drug treatment of schizophrenia. Fair Oaks Hosp Psychiatry Lett. 1988; 6:10-4.

24. Lee T, Tang SW. Loxapine and clozapine decrease serotonin (S₂) but do not elevate dopamine (D₂) receptor numbers in the rat brain. Psychiatry Res. 1984; 12:277-85. http://www.ncbi.nlm.nih.gov/pubmed/6239298?dopt=AbstractPlus

25. Seeger TF, Thal L, Gardner EL. Behavioral and biochemical aspects of neuroleptic-induced dopaminergic supersensitivity: studies with chronic clozapine and haloperidol. Psychopharmacology. 1982; 76:182-7. http://www.ncbi.nlm.nih.gov/pubmed/6805029?dopt=AbstractPlus

26. Wilk S, Stanley M. Clozapine concentrations in brain regions: relationship to dopamine metabolite increase. Eur J Pharmacol. 1978; 51:101-7. http://www.ncbi.nlm.nih.gov/pubmed/699976?dopt=AbstractPlus

27. Mao CC, Marco E, Revuelta A et al. The turnover of q-aminobutyric acid in the nuclei of telencephalon: implications in the pharmacology of antipsychotics and of a minor tranquilizer. Biol Psychiatry. 1977; 12:359-71. http://www.ncbi.nlm.nih.gov/pubmed/17436?dopt=AbstractPlus

28. Stimmel GL. Neuroleptics and the corpus striatum: clinical implications. Dis Nerv Syst. 1976; 37:219-24. http://www.ncbi.nlm.nih.gov/pubmed/1253676?dopt=AbstractPlus

29. Cohen BM, Benes FM, Baldessarini RJ. Atypical neuroleptics, dose-response relationships, and treatment-resistant psychosis. Arch Gen Psychiatry. 1989; 46:381-3. http://www.ncbi.nlm.nih.gov/pubmed/2564764?dopt=AbstractPlus

30. Kane JM, Cooper TB, Sachar EJ et al. Clozapine: plasma levels and prolactin response. Psychopharmacology. 1981; 73:184-7. http://www.ncbi.nlm.nih.gov/pubmed/6785813?dopt=AbstractPlus

31. Sarafoff M, Davis L, Ruther E. Clozapine induced increase in human plasma norepinephrine. J Neural Transm. 1979; 46:175-80. http://www.ncbi.nlm.nih.gov/pubmed/512652?dopt=AbstractPlus

32. Touyz SW, Beumont PJV, Saayman GS et al. A psychophysiological investigation of the short term effects of clozapine upon sleep parameters in normal young adults. Biol Psychiatry. 1977; 12:801-22. http://www.ncbi.nlm.nih.gov/pubmed/202346?dopt=AbstractPlus

33. Matz R, Rick W, Oh D et al. Clozapine—a potential antipsychotic agent without extrapyramidal manifestations. Curr Ther Res. 1974; 16:687- 95. http://www.ncbi.nlm.nih.gov/pubmed/4210458?dopt=AbstractPlus

34. Claghorn J, Honigfeld G, Abuzzahab F et al. The risks and benefits of clozapine versus chlorpromazine. J Clin Psychopharmacol. 1987; 7:377-84. http://www.ncbi.nlm.nih.gov/pubmed/3323261?dopt=AbstractPlus

35. Spatz VR, Lorenzi E, Kugler J et al. Haufigkeit und Form von EEG-Anomalien bei Clozapintherapie. (German; with English abstract.) Arzneim-Forsch. 1978; 28: 1499-500.

36. Gardner EL, Seeger TF. Neurobehavioral evidence for mesolimbic specificity of action by clozapine: studies using electrical intracranial self-stimulation. Biol Psychiatry. 1983; 18:1357-62. http://www.ncbi.nlm.nih.gov/pubmed/6661466?dopt=AbstractPlus

37. Raptopoulos P, Gaind R. Clozapine (Leponex) in schizophrenia: therapeutic efficacy and side-effects. Clin Trials J. 1976; 13:49-54.

38. Anon. Clozapine for schizophrenia. Med Lett Drugs Ther. 1990; 32:3-4. http://www.ncbi.nlm.nih.gov/pubmed/2403629?dopt=AbstractPlus

39. Bondesson U, Lindstrom LH. Determination of clozapine and its N-demethylated metabolite in plasma by use of gas chromatography-mass spectrometry with single ion detection. Psychopharmacology. 1988; 95:472-5. http://www.ncbi.nlm.nih.gov/pubmed/3145517?dopt=AbstractPlus

40. Haring C, Barnas C, Saria A et al. Dose-related plasma levels of clozapine. J Clin Psychopharmacol. 1989; 9:71-2. http://www.ncbi.nlm.nih.gov/pubmed/2708561?dopt=AbstractPlus

41. Cheng YF, Lundberg T, Bondesson U et al. Clinical pharmacokinetics of clozapine in chronic schizophrenic patients. Eur J Clin Pharmacol. 1988; 34:445-9. http://www.ncbi.nlm.nih.gov/pubmed/3203703?dopt=AbstractPlus

42. Choc MG, Lehr RG, Hsuan F et al. Multiple-dose pharmacokinetics of clozapine in patients. Pharm Res. 1987; 4:402-5. http://www.ncbi.nlm.nih.gov/pubmed/3508549?dopt=AbstractPlus

43. Gardiner TH, Lewis JM, Shore PA. Distribution of clozapine in the rat: localization in lung. J Pharmacol Exp Ther. 1987; 206:151-7.

44. Simpson GM, Cooper TA. Plasma clozapine levels and convulsions. Am J Psychiatry. 1978; 135:99-100. http://www.ncbi.nlm.nih.gov/pubmed/412427?dopt=AbstractPlus

45. Haring C, Barnas C, Humpel C et al. Dose-related plasma levels of clozapine: differences in smokers and non-smokers. Psychopharmacology. 1988; 96:S186.

46. Ackenheil M. Clozapine—pharmacokinetic investigations and biochemical effects in man. Psychopharmacology. 1989; 99(Suppl):S32-7. http://www.ncbi.nlm.nih.gov/pubmed/2682731?dopt=AbstractPlus

47. Sayers AC, Burki HR, Ruch W et al. Neuroleptic-induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesias: effects of clozapine, haloperidol, loxapine and chlorpromazine. Psychopharmacology (Berl). 1975; 41:97-104.

48. Wilmot CA, Szczepanik AM. Effects of acute and chronic treatments with clozapine and haloperidol on serotonin (5-HT₂) and dopamine (D₂) receptors in the rat brain. Brain Res. 1989; 487:288-98. http://www.ncbi.nlm.nih.gov/pubmed/2525063?dopt=AbstractPlus

49. Fink M, Irwin P, Weinhold P. EEG profile studies of clozapine in volunteers and psychiatric patients. Pharmakopsychiatr Neuro-Psychopharmakol. 1979; 12:184-90.

50. Gianutsos G, Moore KE. Dopaminergic supersensitivity in striatum and olfactory tubercle following chronic administration of haloperidol or clozapine. Life Sci. 1977; 20:1585-92. http://www.ncbi.nlm.nih.gov/pubmed/875633?dopt=AbstractPlus

51. Richelson E. Neuroleptic affinities for human brain receptors and their use in predicting adverse effects. J Clin Psychiatry. 1984; 45:331-6. http://www.ncbi.nlm.nih.gov/pubmed/6146602?dopt=AbstractPlus

52. Simpson GM, Varga E. Clozapine—a new antipsychotic agent. Curr Ther Res. 1974; 16:679-86. http://www.ncbi.nlm.nih.gov/pubmed/4210457?dopt=AbstractPlus

53. Van Praag HM, Korf J, Dols LCW. Clozapine versus perphenazine: the value of the biochemical mode of action of neuroleptics in predicting their therapeutic activity. Br J Psychiatry. 1976; 129:547-55. http://www.ncbi.nlm.nih.gov/pubmed/1000139?dopt=AbstractPlus

54. Shopsin B, Klein H, Aaronsom M et al. Clozapine, chlorpromazine, and placebo in newly hospitalized, acutely schizophrenic patients. Arch Gen Psychiatry. 1979; 36:657-64. http://www.ncbi.nlm.nih.gov/pubmed/375865?dopt=AbstractPlus

55. Gerlach J, Koppelhus P, Helweg E et al. Clozapine and haloperidol in a single-blind cross-over trial: therapeutic and biochemical aspects in the treatment of schizophrenia. Acta Psychiatr Scand. 1984; 50:410-24.

56. Fischer-Cornelssen KA, Ferner UJ. An example of European multicenter trials: multispectral analysis of clozapine. Psychopharmacol Bull. 1976; 12:34-9. http://www.ncbi.nlm.nih.gov/pubmed/769027?dopt=AbstractPlus

57. Povlsen UJ, Noring U, Fog R et al. Tolerability and therapeutic effect of clozapine. Acta Psychiatr Scand. 1985; 71:176-85. http://www.ncbi.nlm.nih.gov/pubmed/3883696?dopt=AbstractPlus

58. Lindstrom LH. The effect of long-term treatment with clozapine in schizophrenia: a retrospective study in 96 patients treated with clozapine for up to 13 years. Acta Psychiatr Scand. 1988; 77:524-9. http://www.ncbi.nlm.nih.gov/pubmed/3407421?dopt=AbstractPlus

59. Chouinard G, Annable L. Clozapine in the treatment of newly admitted schizophrenic patients: a pilot study. J Clin Pharmacol. 1976; 3:298-97.

60. Battegay R, Cotar B, Fleischhauer J et al. Results and side-effects of treatment with clozapine (Leponex). Compr Psychiatry. 1977; 18:423-8. http://www.ncbi.nlm.nih.gov/pubmed/891163?dopt=AbstractPlus

61. Singer K, Law SK. A double-blind comparison of clozapine (Leponex) and chlorpromazine in schizophrenia of acute symptomatology. J Int Med Res. 1974; 2:433-5.

62. Guirguis E, Voiseskos G, Gray J et al. Clozapine (Leponex) vs chlorpromazine (Largactil) in acute schizophrenia (a double-blind controlled study). Curr Ther Res. 1977; 21:707-19.

63. Chiu E, Burrows G, Stevenson J. Double-blind comparison of clozapine with chlorpromazine in acute schizophrenic illness. Aust NZ J Psychiatry. 1976; 10:343-7.

64. Gelenberg AJ, Doller JC. Clozapine versus chlorpromazine for the treatment of schizophrenia: preliminary results from a double-blind study. J Clin Psychiatry. 1979; 40:238-40. http://www.ncbi.nlm.nih.gov/pubmed/374401?dopt=AbstractPlus

65. Ekblom B, Haggstrom JE. Clozapine (Leponex) compared with chlorpromazine: a double-blind evaluation of pharmacological and clinical properties. Curr Ther Res. 1974; 16:945-57. http://www.ncbi.nlm.nih.gov/pubmed/4154183?dopt=AbstractPlus

66. Leon CA. Therapeutic effects of clozapine. A 4-year follow-up of a controlled clinical trial. Acta Psychiatr Scand. 1979; 59:471-80. http://www.ncbi.nlm.nih.gov/pubmed/380268?dopt=AbstractPlus

67. Sayers AC, Amsler HA. Clozapine. In: Goldberg ME, ed. Pharmacological and biochemical properties of drug substances. American Pharmacological Association Academy of Pharmaceutical Science. 1977:1-31.

68. Pakkenberg H, Pakkenberg B. Clozapine in the treatment of tremor. Acta Neurol Scand. 1986; 73:295-7. http://www.ncbi.nlm.nih.gov/pubmed/3521185?dopt=AbstractPlus

69. Scholz E, Dichgans J. Treatment of drug-induced exogenous psychosis in parkinsonism with clozapine and fluperlapine. Eur Arch Psychiatry Neurol Sci. 1985; 235:60-4. http://www.ncbi.nlm.nih.gov/pubmed/2864254?dopt=AbstractPlus

70. Honigfeld G. Sandoz and the monitoring of patients receiving clozapine. JAMA. 1991; 265:1529. http://www.ncbi.nlm.nih.gov/pubmed/1999902?dopt=AbstractPlus

71. Cold JA, Wells BG, Froemming JH. Seizure activity associated with antipsychotic therapy. DICP. 1990; 24:1012. http://www.ncbi.nlm.nih.gov/pubmed/2244402?dopt=AbstractPlus

72. Walker JM, Matsumoto RR, Bowen WD et al. Evidence of a role for haloperidol-sensitive w-″opiate’ receptors in the motor effects of antipsychotic drugs. Neurology. 1988; 38:961-5. http://www.ncbi.nlm.nih.gov/pubmed/2897093?dopt=AbstractPlus

73. Caine ED, Polinsky RJ, Kartzinel R et al. The trial use of clozapine for abnormal involuntary movement disorders. Am J Psychiatry. 1979; 136:317-20. http://www.ncbi.nlm.nih.gov/pubmed/154301?dopt=AbstractPlus

74. Rodova A, Svestka J, Nahunek K et al. A blind comparison of clozapine and perphenazine in schizophrenics. Act Nerv Super. 1973; 15:94-5.

75. Faltus F, Hynek V, Dolezalova V et al. Experience in the treatment of schizophrenia with clozapine. Act Nerv Super. 1973; 15:95.

76. Shopsin B, Feiner NF. The current status of clozapine. Psychopharmacol Bull. 1983; 19:563-4. http://www.ncbi.nlm.nih.gov/pubmed/6635130?dopt=AbstractPlus

77. Singer JM. Clozapine and tardive dyskinesia. Arch Gen Psychiatry. 1983; 40:347. http://www.ncbi.nlm.nih.gov/pubmed/6338857?dopt=AbstractPlus

78. Carroll BJ, Curtis GC, Kokmen E. Paradoxical response to dopamine agonists in tardive dyskinesia. Am J Psychiatry. 1977; 134:785-9. http://www.ncbi.nlm.nih.gov/pubmed/17308?dopt=AbstractPlus

79. Jeste DV, Wyatt RJ. Clozapine and tardive dyskinesia. Arch Gen Psychiatry. 1983; 40:347-8. http://www.ncbi.nlm.nih.gov/pubmed/6338857?dopt=AbstractPlus

80. Jeste DV, Wyatt RJ. Therapeutic strategies against tardive dyskinesia. Two decades of experience. Arch Gen Psychiatry. 1983; 39:803-16.

81. Gerlach G, Simmelsgaard H. Tardive dyskinesia during and following treatment with haloperidol, haloperidol + biperiden, thioridazine, and clozapine. Psychopharmacology. 1978; 59:105-12. http://www.ncbi.nlm.nih.gov/pubmed/103110?dopt=AbstractPlus

82. Gerbino L, Shopsin B, Collora M. Clozapine in the treatment of tardive dyskinesia: an interim report. In: Fann WE, Smith RC, Davis JM et al, eds. Tardive dyskinesia research & treatment. New York: SP Medical & Scientific Books. 1980:475-89.

83. Meltzer HY. Duration of clozapine trial in neuroleptic-resistant schizophrenia. Arch Gen Psychiatry. 1989; 46:672. http://www.ncbi.nlm.nih.gov/pubmed/2567591?dopt=AbstractPlus

84. Kane JM. The current status of neuroleptic therapy. J Clin Psychiatry. 1989; 50:322-8. http://www.ncbi.nlm.nih.gov/pubmed/2570063?dopt=AbstractPlus

85. Wood MJ, Rubinstein M. An atypical responder to clozapine. Am J Psychiatry. 1990; 147:369. http://www.ncbi.nlm.nih.gov/pubmed/2309959?dopt=AbstractPlus

86. Simpson GM, Pi EH, Srmek JJ Jr. Management of tardive dyskinesia: current update. Drugs. 1982; 23:381-93. http://www.ncbi.nlm.nih.gov/pubmed/7047137?dopt=AbstractPlus

87. Panteleeva GP, Kovskaya MYT, Belyaev BS et al. Clozapine in the treatment of schizophrenic patients: an international multicenter trial. Clin Ther. 1987; 10:57-68. http://www.ncbi.nlm.nih.gov/pubmed/3329966?dopt=AbstractPlus

88. Wolters EC, Hurwitz TA, Mak E et al. Clozapine in the treatment of parkinsonian patients with dopaminomimetic psychosis. Neurology. 1990; 40:832-4. http://www.ncbi.nlm.nih.gov/pubmed/1970427?dopt=AbstractPlus

89. Small JG, Milstein V, Marhenke JD et al. Treatment outcome with clozapine in tardive dyskinesia, neuroleptic sensitivity, and treatment-resistant psychosis. J Clin Psychiatry. 1987; 48:263-7. http://www.ncbi.nlm.nih.gov/pubmed/2885310?dopt=AbstractPlus

90. Ayd FJ Jr. Clozapine update: benefits and risks. Int Drug Ther Newsl. 1989; 24:37-9.

91. Pfaus JG, Phillips AG. Differential effects of dopamine receptor antagonists on the sexual behavior of male rats. Psychopharmacology. 1989; 98:363-8. http://www.ncbi.nlm.nih.gov/pubmed/2568656?dopt=AbstractPlus

92. Blackburn JR, Phillips AG. Blockade of acquisition of one-way conditioned avoidance responding by haloperidol and metoclopramide but not by thioridazine or clozapine: implications for screening new antipsychotic drugs. Psychopharmacology. 1989; 98:453-9. http://www.ncbi.nlm.nih.gov/pubmed/2570431?dopt=AbstractPlus

93. Hu XT, Wang RY. Haloperidol and clozapine: differential effects on the sensitivity of caudate-putamen neurons to dopamine agonists and cholecystokinin following one month continuous treatment. Brain Res. 1989; 486:325-33. http://www.ncbi.nlm.nih.gov/pubmed/2786442?dopt=AbstractPlus

94. Nash JF, Meltzer HY, Gudelsky GA. Antagonism of serotonin receptor mediated neuroendocrine and temperature responses by atypical neuroleptics in the rat. Eur J Pharmacol. 1988; 151:463-9. http://www.ncbi.nlm.nih.gov/pubmed/2905661?dopt=AbstractPlus

95. Ashby CR, Wang RY. Effects of antipsychotic drugs on 5-HT₂ receptors in the medial prefrontal cortex: microiontophoretic studies. Brain Res. 1990; 506:346-8. http://www.ncbi.nlm.nih.gov/pubmed/1967969?dopt=AbstractPlus

96. Black JL, Richelson E. Antipsychotic drugs: prediction of side-effect profiles based on neuroreceptor data derived from human brain tissue. Mayo Clin Proc. 1987; 62:369-72. http://www.ncbi.nlm.nih.gov/pubmed/2883343?dopt=AbstractPlus

97. Farde L, Wiesel FA, Halldin C et al. Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry. 1988; 45:71-6. http://www.ncbi.nlm.nih.gov/pubmed/2892477?dopt=AbstractPlus

98. Ashby CR, Hitzemann R, Rubinstein JE et al. One year treatment with haloperidol or clozapine fails to alter neostriatal D1- and D2-dopamine receptor sensitivity in the rat. Brain Res. 1989; 493:194-7. http://www.ncbi.nlm.nih.gov/pubmed/2570618?dopt=AbstractPlus

99. Compton DR, Johnson KM. Effects of acute and chronic clozapine and haloperidol on in vitro release of acetylcholine and dopamine from striatum and nucleus accumbens. J Pharmacol Exp Ther. 1989; 248:521-30. http://www.ncbi.nlm.nih.gov/pubmed/2918468?dopt=AbstractPlus

100. Andersen PH, Braestrup C. Evidence for different states of dopamine D1 receptor: clozapine and fluperlapine may preferentially label an adenylate cyclase-coupled state of D1 receptor. J Neurochem. 1986; 47:1822-31. http://www.ncbi.nlm.nih.gov/pubmed/2945903?dopt=AbstractPlus

101. Matsubara S, Meltzer HY. Effect of typical and atypical antipsychotic drugs on 5-HT₂ receptor density in rat cerebral cortex. Life Sci. 1989; 45:1397-406. http://www.ncbi.nlm.nih.gov/pubmed/2571912?dopt=AbstractPlus

102. Balant-Gorgia AE, Balant L. Antipsychotic drugs: clinical pharmacokinetics of potential candidates for plasma monitoring. Clin Pharmacokinet. 1987; 13:65-90. http://www.ncbi.nlm.nih.gov/pubmed/2887326?dopt=AbstractPlus

103. Leppig M, Bosch B, Naber D et al. Clozapine in the treatment of 121 out-patients. Psychopharmacology. 1989; 99(Suppl):S77-9.

104. Casey DE. Clozapine: neuroleptic-induced EPS and tardive dyskinesia. Psychopharmacology. 1989; 99(Suppl):S47-53. http://www.ncbi.nlm.nih.gov/pubmed/2682732?dopt=AbstractPlus

105. Steiger A, Benkert O. Examination and treatment of sleep-related painful erections—a case report. Arch Sexual Behav. 1989; 18:263-7.

106. Norris DL, Israelstam K. Clozapine (Leponex) overdosage. S Afr Med J. 1975; 49:385. http://www.ncbi.nlm.nih.gov/pubmed/1145356?dopt=AbstractPlus

107. Schuster P, Gabriel E, Kufferle B et al. Reversal by physostigmine of clozapine-induced delirium. Clin Tox. 1977; 10:437-41.

108. Haring C, Meise U, Humpel C et al. Dose-related plasma levels of clozapine: influence of smoking behaviour, sex and age. Psychopharmacology. 1989; 99(Suppl):S38-40. http://www.ncbi.nlm.nih.gov/pubmed/2813665?dopt=AbstractPlus

109. Blum A, Girke W. Marked increase in REM sleep produced by a new antipsychotic compound. Clin Electroencephalography. 1973; 4:80-4.

110. Gerlach J, Jorgenson EO, Peacock L. Long-term experience with clozapine in Denmark: research and clinical practice. Psychopharmacology. 1989; 99(Suppl): S92-6. http://www.ncbi.nlm.nih.gov/pubmed/2682734?dopt=AbstractPlus

111. Lieberman J, Johns C, Cooper T et al. Clozapine pharmacology and tardive dyskinesia. Psychopharmacology. 1989; 99(Suppl):S54-9. http://www.ncbi.nlm.nih.gov/pubmed/2479047?dopt=AbstractPlus

112. Heh CW, Herrera J, DeMet E et al. Neuroleptic-induced hypothermia associated with amelioration of psychosis in schizophrenia. Neuropsychopharmacology. 1988; 1:149-56. http://www.ncbi.nlm.nih.gov/pubmed/3251495?dopt=AbstractPlus

113. Marco LA, Joshi RS, Brigham TE et al. Effects of clozapine on ketamine-induced linguopharyngeal events in rats. Eur J Pharmacol. 1989; 164:171-3. http://www.ncbi.nlm.nih.gov/pubmed/2753078?dopt=AbstractPlus

114. Levinson B. Clozapine (Leponex) overdosage. S Afr Med J. 1975; 49:21. http://www.ncbi.nlm.nih.gov/pubmed/1111134?dopt=AbstractPlus

115. Mattes J. Clozapine for refractory schizophrenia: an open study of 14 patients treated up to 2 years. J Clin Psychiatry. 1989; 50:389-91. http://www.ncbi.nlm.nih.gov/pubmed/2571612?dopt=AbstractPlus

116. Hemphill RE, Pascoe FD, Zabow T. An investigation of clozapine in the treatment of acute and chronic schizophrenia and gross behavior disorders. S Afr Med J. 1975; 49:2121-5. http://www.ncbi.nlm.nih.gov/pubmed/1209429?dopt=AbstractPlus

117. Meltzer HY, Koenig JI, Nash JF et al. Melperone and clozapine: neuroendocrine effects of atypical neuroleptic drugs. Acta Psychiatr Scand. 1989; 352(Suppl): 24-9.

118. Borison RL, Diamond BI, Sinha D et al. Clozapine withdrawal rebound psychosis. Psychopharmacol Bull. 1988; 24:260-3. http://www.ncbi.nlm.nih.gov/pubmed/3212159?dopt=AbstractPlus

119. Menon MK, Gordon LI, Fitten J. Interaction between clozapine and a lipophilic α₁-adrenergic agonist. Life Sciences. 1988; 43:1791-804. http://www.ncbi.nlm.nih.gov/pubmed/2904633?dopt=AbstractPlus

120. Conley RR, Schultz C, Baker RW et al. Clozapine efficacy in schizophrenic nonresponders. Psychopharmacol Bull. 1988; 24:269-74. http://www.ncbi.nlm.nih.gov/pubmed/3212161?dopt=AbstractPlus

121. Kane JM, Honigfeld G, Singer J et al. Clozapine in treatment-resistant schizophrenics. Psychopharmacol Bull. 1988; 24:62-7. http://www.ncbi.nlm.nih.gov/pubmed/3290950?dopt=AbstractPlus

122. Naber D, Grohmann R, Muller-Spahn F et al. Efficacy and adversive effects of clozapine in the treatment of schizophrenia and tardive dyskinesia. Psychopharmacology. 1988; 96(Suppl):S187.

123. Paunovic VR, Jasovic-Gasic MM, Bogdanovic MR et al. Clozapine in the treatment of negative symptoms in schizophrenia. Psychopharmacology. 1988; 96(Suppl):S344.

124. Kiejna A. Clinical evaluation of clozapine treatment in mental disorders. Psychopharmacology. 1988; 96(Suppl):S345.

125. Pfeiffer RF, Kang J, Graber B et al. Clozapine for psychosis in Parkinson’s disease. Neurology. 1989; 39(Suppl 1):231.

126. Ostergaard K, Dupont E. Clozapine treatment of drug-induced psychotic symptoms in late stages of Parkinson’s disease. Acta Neurol Scand. 1988; 78:349-50. http://www.ncbi.nlm.nih.gov/pubmed/3223229?dopt=AbstractPlus

127. Helmchen H. Clinical experience with clozapine in Germany. Psychopharmacology. 1989; 99(Suppl): S80-3. http://www.ncbi.nlm.nih.gov/pubmed/2573107?dopt=AbstractPlus

128. Naber D, Leppig M, Grohmann R et al. Efficacy and adverse effects of clozapine in the treatment of schizophrenia and tardive dyskinesia—a retrospective study of 387 patients. Psychopharmacology. 1989; 99(Suppl):S73-6.

129. Honigfeld G, Patin J. Predictors of response to clozapine therapy. Psychopharmacology. 1989; 99(Suppl):S64-7. http://www.ncbi.nlm.nih.gov/pubmed/2813666?dopt=AbstractPlus

130. Gaertner HJ, Fischer E, Hoss J. Side effects of clozapine. Psychopharmacology. 1989; 99(Suppl):S97-100. http://www.ncbi.nlm.nih.gov/pubmed/2813671?dopt=AbstractPlus

131. Ekblom B, Eriksson K, Lindstrom LH. Supersensitivity psychosis in schizophrenia patients after sudden clozapine withdrawal. Psychopharmacology. 1984; 83:293-4. http://www.ncbi.nlm.nih.gov/pubmed/6433395?dopt=AbstractPlus

132. Friedman JH, Lannon MC. Clozapine in the treatment of psychosis in Parkinson’s disease. Neurology. 1989; 39:1219-21. http://www.ncbi.nlm.nih.gov/pubmed/2771073?dopt=AbstractPlus

133. Friedman JH, Lannon MC. Clozapine treatment of psychosis in Parkinson’s disease. Neurology. 1989; 39(Suppl 1):389.

134. Friedman JH, Max J, Swift R. Idiopathic Parkinson’s disease in a chronic schizophrenic patient: long-term treatment with clozapine and L-DOPA. Clin Neurology. 1987; 10:470-5.

135. Classen W, Laux G. Sensorimotor and cognitive performance of schizophrenic inpatients treated with haloperidol, flupenthixol, or clozapine. Pharmacopsychiatry. 1988; 21: 295-7.

136. Krupp P, Barnes P. Leponex—associated granulocytopenia: a review of the situation. Psychopharmacology. 1989; 99:S118-21. http://www.ncbi.nlm.nih.gov/pubmed/2682727?dopt=AbstractPlus

137. Hippius H. The history of clozapine. Psychopharmacology. 1989; 99(Suppl):S3-5.

138. Claas FHJ. Drug-induced agranulocytosis; review of possible mechanisms, and prospects for clozapine studies. Psychopharmacology. 1989; 99(Suppl):S113-7.

139. Lieberman JA, Johns CA, Kane JM et al. Clozapine-induced agranulocytosis: non-cross-reactivity with other psychotropic drugs. J Clin Psychiatry. 1988; 49:271-7. http://www.ncbi.nlm.nih.gov/pubmed/3391979?dopt=AbstractPlus

140. MacAllister CG, Rapaport MH, Pickar D et al. Effects of short-term administration of antipsychotic drugs on lymphocyte subsets in schizophrenic patients. Arch Gen Psychiatry. 1989; 46:956-7. http://www.ncbi.nlm.nih.gov/pubmed/2572208?dopt=AbstractPlus

141. Heimpel H. Drug-induced agranulocytosis. Med Toxicol Adverse Drug Exp. 1988; 3:449-62. http://www.ncbi.nlm.nih.gov/pubmed/3063921?dopt=AbstractPlus

142. Amsler HA, Teerenhovi L, Barth E et al. Agranulocytosis in patients treated with clozapine: a study of the Finnish epidemic. Acta Psychiatr Scand. 1977; 56:241-8. http://www.ncbi.nlm.nih.gov/pubmed/920225?dopt=AbstractPlus

143. Ackenheil M, Beckmann H, Greil W et al. Antipsychotic efficacy of clozapine in correlation to changes in catecholamine metabolism in man. In: Forrest IS, Carr CJ, Usdin E, eds. The phenothiazines and strucurally related drugs. New York: Raven Press; 1974:647-57.

144. Baum MJ, Starr MS. Inhibition of sexual behavior by dopamine antagonist or serotonin agonist drugs in castrated male rats given estradiol or dihydrotestosterone. Pharmacol Biochem Behav. 1980; 13:57-67. http://www.ncbi.nlm.nih.gov/pubmed/7403222?dopt=AbstractPlus

145. Gerlach J, Thorsen K, Fog R. Extrapyramidal reactions and amine metabolites in cerebrospinal fluid during haloperidol and clozapine treatment of schizophrenic patients. Psychopharmacology (Berl). 1975; 40:341-50.

146. Reynolds FEF, ed. Martindale: the extra pharmacopoeia. 29th ed. London: The Pharmaceutical Press; 1987:727.

147. Muller T, Becker T, Fritze J. Neuroleptic malignant syndrome after clozapine plus carbamazepine. Lancet. 1988; 31:1500.

148. Pope HG Jr, Cole JO, Choras PT et al. Apparent neuroleptic malignant syndrome with clozapine and lithium. J Nerv Ment Dis. 1986; 174:493-5. http://www.ncbi.nlm.nih.gov/pubmed/3090198?dopt=AbstractPlus

149. Chaimowitz GA, Gomes U, Maze SS. Neuroleptic malignant syndrome. CMAJ. 1988; 138: 51-3. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1267509&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/3275480?dopt=AbstractPlus

150. Cohen S, Chiles J, MacNaughton A. Weight gain associated with clozapine. Am J Psychiatry. 1990; 147:503-4. http://www.ncbi.nlm.nih.gov/pubmed/2316740?dopt=AbstractPlus

151. Sriwatanakul K. Minimizing the risk of antipsychotic-associated seizures. Drug Therapy. 1982; 12:207-11.

152. Girke W, Blum A, Wiemann H. Rapid eye movement (REM) sleep under an antipsychotically active dibenzodiazepine derivative. Electroencephalogr Clin Neurophysiol. 1972; 32:708-9.

153. Jenkins M, Metzer WS. Avoidance of metoclopramide for the treatment of clozapine-induced nausea. J Clin Psychiatry. 1990; 51:210. http://www.ncbi.nlm.nih.gov/pubmed/2335497?dopt=AbstractPlus

154. Banki CM. Alterations of cerebrospinal fluid 5-hydroxyindoleacetic acid, and total blood serotonin content during clozapine treatment. Psychopharmacology. 1978; 56:195-8. http://www.ncbi.nlm.nih.gov/pubmed/417371?dopt=AbstractPlus

155. Pentel PR, Benowitz NL. Tricyclic antidepressant poisoning: management of arrhythmias. Med Toxicol. 1986; 1:101-21. http://www.ncbi.nlm.nih.gov/pubmed/3784839?dopt=AbstractPlus

156. Gerlach J, Koppelhus P, Helweg E et al. Clozapine and haloperidol in a single-blind cross-over trial: therapeutic and biochemical treatment of schizophrenia. Acta Psychiatr Scand. 1974; 50:410-24. http://www.ncbi.nlm.nih.gov/pubmed/4153596?dopt=AbstractPlus

157. Anderman B, Griffith RW. Clozapine-induced agranulocytosis: a situation report up to August 1976. Eur J Clin Pharmacol. 1977; 11:199-210. http://www.ncbi.nlm.nih.gov/pubmed/852497?dopt=AbstractPlus

158. Gianutsos G, Moore K. Possible significance of clozapine-induced increase in brain dopamine. Res Commun Chem Path Pharmacol. 1977; 17:29-39.

159. Simpson GM, Lee JH, Shrivastava RK. Clozapine in tardive dyskinesia. Psychopharmacology. 1978; 56:75-80. http://www.ncbi.nlm.nih.gov/pubmed/415329?dopt=AbstractPlus

160. de la Chapelle A, Kari C, Nurminen M et al. Clozapine-induced agranulocytosis: a genetic and epidemiological study. Hum Genet. 1977; 37:183-94. http://www.ncbi.nlm.nih.gov/pubmed/885538?dopt=AbstractPlus

161. Snyder SH, Greenberg D, Yamumura HI. Antischizophrenic drugs: affinity for muscarinic cholinergic receptor sites in the brain predicts extrapyramidal effects. J Psychiatr Res. 1974; 11:91-5. http://www.ncbi.nlm.nih.gov/pubmed/4156796?dopt=AbstractPlus

162. Nair NPV, Zicherman V, Schwartz G. Dopamine and schizophrenia: a reappraisal in light of clinical studies with clozapine. Can Psychiatr Assoc J. 1977; 22:285-93. http://www.ncbi.nlm.nih.gov/pubmed/21741?dopt=AbstractPlus

163. Kirkegaard A, Jensen A. An investigation of some side effects in 47 psychotic patients during treatment with clozapine and discontinuing of the treatment. Arzneimittelforschung. 1979; 29:851-8. http://www.ncbi.nlm.nih.gov/pubmed/40576?dopt=AbstractPlus

164. Snyder SH, Banerjee SP, Yamamura HI et al. Drugs, neurotransmitters, and schizophrenia. Science. 1974; 184:1243-53. http://www.ncbi.nlm.nih.gov/pubmed/17784215?dopt=AbstractPlus

165. Burki HR, Eichenberger E, Sayers AC et al. Clozapine and the dopamine hypothesis of schizophrenia, a critical appraisal. Pharmakopsychiatr Neuro-Psychopharmakol. 1975; 8:115-21.

166. Grohmann R, Ruther E, Sassim N et al. Adverse effects of clozapine. Psychopharmacology. 1989: 99(Suppl):S101-4.

167. Kalow W. Genetic variaitons in the human cytochrome P-450 system. Eur J Clin Pharmacol. 1987; 31:633-41. http://www.ncbi.nlm.nih.gov/pubmed/3549324?dopt=AbstractPlus

168. Kalow W. Ethnic differences in drug metabolism. Clin Pharmacokinet. 1982; 7:373-400. http://www.ncbi.nlm.nih.gov/pubmed/6754206?dopt=AbstractPlus

169. Roubicek J, Major I. EEG profile and behavioral changes after a single dose of clozapine in normals and schizophrenics. Biol Psychiatr. 1977; 12:613-4.

170. Chiodo LA, Bunney BS. Possible mechanisms by which repeated clozapine administration differentially affects the activity of two subpopulations of midbrain dopamine neurons. J Neoroscience. 1985; 5:2539-44.

171. Ackenheil VM, Brau H, Burkhart A et al. Antipsychotische Wirksamkeit im Verhaltnis zum Plasmaspiegel von Clozapin. (German; with English abstract.) Arzneim-Forsch. 1976; 26:1156-8.

172. Claghorn JL, Abuzzahab FS, Wang R et al. The current status of clozapine. Psychopharmacol Bull. 1983; 19:138-40.

173. Perenyi A, Kuncz E, Bagdy G. Early relapse after sudden withdrawal or dose reduction of clozapine. Psychopharmacology. 1985; 86:244. http://www.ncbi.nlm.nih.gov/pubmed/3927364?dopt=AbstractPlus

174. Eklund K. Supersensitivity and clozapine withdrawal. Psychopharmacology. 1987; 91:135. http://www.ncbi.nlm.nih.gov/pubmed/3103155?dopt=AbstractPlus

175. Richelson E, Nelson A. Antagonism by neuroleptics of neurotransmitter receptors of normal human brain in vitro. Eur J Pharmacol. 1984; 103:197-204. http://www.ncbi.nlm.nih.gov/pubmed/6149136?dopt=AbstractPlus

176. Schmauss M, Wolff R, Erfurth A et al. Tolerability of long term clozapine treatment. Psychopharmacology. 1989; 99(Suppl):S105-8. http://www.ncbi.nlm.nih.gov/pubmed/2813663?dopt=AbstractPlus

177. Haller E, Binder RL. Clozapine and seizures. Am J Psychiatry. 1990; 147:1069-71. http://www.ncbi.nlm.nih.gov/pubmed/2375443?dopt=AbstractPlus

178. Burki HR, Ruch W, Asper H et al. Pharmakologische und neurochemische Wirkungen von Clozapin: neue Gesichtspunkte in der medikamentosen Behandlung der Schizophrenie. (German; with English abstract.) Schweiz Med Wochenschr. 1973; 103:1716-24.

179. Meltzer HY, Goode DJ, Schyve PM et al. Effect of clozapine on human serum prolactin levels. Am J Psychiatry. 1979; 136:1550-5. http://www.ncbi.nlm.nih.gov/pubmed/507205?dopt=AbstractPlus

180. Chiodo SA, Bunney BS. Typical and atypical neuroleptics: differential effects of chronic administration on the activity of A9 and A10 midbrain dopaminergic neurons. J Neuroscience. 1983; 3:1607-19.

181. Barrett N, Ormiston S, Molyneux V. Clozapine: a new drug for schizophrenia. J Psychosocial Nurs. 1990; 28:24-8.

182. Pi EH, Simpson GM. Atypical neuroleptics: clozapine and the benzamides in the prevention and treatment of tardive dyskinesia. Mod Probl Pharmacopsychiat. 1983; 21:80-6.

183. Crome P. Poisoning due to tricyclic antidepressant overdosage: clinical presentation and treatment. Med Toxicol. 1986; 1:261-5. http://www.ncbi.nlm.nih.gov/pubmed/3537621?dopt=AbstractPlus

184. Small JG, Milstein V, Small IF et al. Computerized EEG profiles of haloperidol, chlorpromazine and placebo in treatment resistant schizophrenia. Clin Encephalogr. 1987; 18:124-35.

185. Meltzer HY, Nash JF, Koenig JI. Clozapine: neuroendocrine studies of an atypical neuroleptic. Clin Neuropharmacol. 1986; 9(Suppl 4):316-8. http://www.ncbi.nlm.nih.gov/pubmed/2882843?dopt=AbstractPlus

186. Thorup M, Fog R. Clozapine treatment of schizophrenic patients: plasma concentration and coagulation factors. Acta Psychiatr Scand. 1977; 55:123-6. http://www.ncbi.nlm.nih.gov/pubmed/842385?dopt=AbstractPlus

187. Kuha S, Miettinen E. Long-term effect of clozapine in schizophrenia: a retrospective study of 108 schizophrenic patients treated with clozapine for up to 7 years. Nord Psykiat T. 1986; 40:225- 30.

188. Sassim N, Grohmann R. Adverse drug reactions with clozapine and simultaneous application of benzodiazepines. Pharmacopsychiatry. 1988; 21:306-7. http://www.ncbi.nlm.nih.gov/pubmed/2907633?dopt=AbstractPlus

189. Hemphill RE, Pascoe FD, Zabow T. Clozapine (Leponex) in psychiatric treatment. S Afr Med J. 1974; 48:2168. http://www.ncbi.nlm.nih.gov/pubmed/4428299?dopt=AbstractPlus

190. Herrera JM, Costa J, Sramek J et al. Clozapine in refractory schizophrenics: preliminary findings. Schizophrenia Res. 1988; 1:305-6.

191. Zapletalek M, Preiningerova O, Pazdirek S et al. Dlouhodoba lecba psychoz schizofrenniho okruhu clozapinem a vyznam vedlejsich priznaku. (Czech; with English abstract.) Cesk Psychiatr. 1977; 73:73-80.

192. Ichikawa J, Meltzer HY. The effect of chronic clozapine and haloperidol on basal dopamine release and metabolism in rat striatum and nucleus accumbens studied by in vivo microdialysis. Eur J Pharmacol. 1990; 176:371-4. http://www.ncbi.nlm.nih.gov/pubmed/2184042?dopt=AbstractPlus

193. Bernardi F, Del Zompo M. Clozapine in idiopathic Parkinson’s disease. Neurology. 1990; 40:1151. http://www.ncbi.nlm.nih.gov/pubmed/2393440?dopt=AbstractPlus

194. Friedman JH, Lannon MC. Clozapine in idiopathic Parkinson’s disease. Neurology. 1990; 40:1151-2. http://www.ncbi.nlm.nih.gov/pubmed/2393440?dopt=AbstractPlus

195. Blum A. Triad of hyperthermia, increased REM sleep, and cataplexy during clozapine treatment? J Clin Psychiatry. 1990; 51:259-60. Letter.

196. Dick P, Remy M, Rey-Bellet JJ. Essai de comparaison de deux antipsychotiques: la chlorpromazine et la clozapine. (French; with English abstract.) Ther Umsch. 1972; 32:497-500.

197. Pere JJ, Chaumet-Riffaud D. Clozapine et schizophrenie resistante. (French; with english abstract.) Encephale. 1990; 16:143-5.

198. Rao TS, Cler JA, Oei EJ et al. Increased release of dopamine in vivo by BMY-14802: contrasting pattern to clozapine. Neuropharmacology. 1990; 29:503-6. http://www.ncbi.nlm.nih.gov/pubmed/1972552?dopt=AbstractPlus

199. Sternberg DE. Neuroleptic malignant syndrome: the pendulum swings. Am J Psychiatr. 1986; 143:1273-5. http://www.ncbi.nlm.nih.gov/pubmed/2876648?dopt=AbstractPlus

200. Pope HG Jr, Keck PE Jr, McElroy SL. Frequency and presentation of neuroleptic malignant syndrome in a large psychiatric hospital. Am J Psychiatr. 1986; 143:1227-33. http://www.ncbi.nlm.nih.gov/pubmed/2876647?dopt=AbstractPlus

201. Anon. Neuroleptic malignant syndrome. Lancet. 1984: 545-6. Editorial.

202. Guze BH, Baxter LR Jr. Neuroleptic malignant syndrome. N Engl J Med. 1985; 313: 163-4. http://www.ncbi.nlm.nih.gov/pubmed/3892294?dopt=AbstractPlus

203. Sangal R, Dimitrijevic R. Neuroleptic malignant syndrome: successful treatment with pancuronium. JAMA. 1985; 254:2795-6. http://www.ncbi.nlm.nih.gov/pubmed/4057490?dopt=AbstractPlus

204. Szabadi E. Neuroleptic malignant syndrome. BMJ. 1984; 288:1399-400. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1441030&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/6144347?dopt=AbstractPlus

205. Pearlman CA. Neuroleptic malignant syndrome: a review of the literature. J Clin Psychopharmacol. 1986; 6:257-73. http://www.ncbi.nlm.nih.gov/pubmed/2877012?dopt=AbstractPlus

206. Harpe C, Stoudemire A. Aetiology and treatment of neuroleptic malignant syndrome. Med Toxicol Adverse Drug Exp. 1987; 2:166-76.

207. Henderson VW, Wooten GF. Neuroleptic malignant syndrome: a pathogenetic role for dopamine receptor blockade? Neurology. 1981; 31:132-7.

208. McCarron MM, Boettger ML, Peck JJ. A case of neuroleptic malignant syndrome successfully treated with amantadine. J Clin Psychiatry. 1082; 43:381-2.

209. Ayd FJ Jr. Neuroleptic malignant syndrome: new therapies. Int Drug Therapy Newsl. 1983; 18:10-2.

210. Smego RA Jr, Durack DT. The neuroleptic malignant syndrome. Arch Intern Med. 1982; 142:1183-5. http://www.ncbi.nlm.nih.gov/pubmed/6124221?dopt=AbstractPlus

211. Addonizio G, Susman VL, Roth SD. Symptoms of neuroleptic malignant syndrome in 82 consecutive inpatients. Am J Psychiatry. 1986; 143:1587- 90. http://www.ncbi.nlm.nih.gov/pubmed/3789214?dopt=AbstractPlus

212. Baldessarini RJ. Drugs and the treatment of psychiatric disorders. In: Gilman AG, Rall TW, Nies AS et al, eds. Goodman and Gilman’s the pharmacological basis of therapeutics. 8th ed. New York: Macmillan Publishing Company; 1990:387-404.

213. Anon. Clozaril concomitant use with benzodiazepines. 1991; 53(Aug 5):T&G-6.

214. Stock B, Spiteller G, Heipertz R. Austausch aromatisch gebundenen Halogens gegen OH- und SCH₃- bei der Metabolisierung des Clozapins im menschlichen Körper. Arzneimittelforschung. 1977; 27:982-90. http://www.ncbi.nlm.nih.gov/pubmed/577884?dopt=AbstractPlus

215. Lipsitz L. Orthostatic hypotension in the elderly. N Engl J Med. 1989; 321:952-7. http://www.ncbi.nlm.nih.gov/pubmed/2674714?dopt=AbstractPlus

216. Montamat SC, Cusack BJ, Vestal RE. Management of drug therapy in the elderly. N Engl J Med. 1989; 321:303-9. http://www.ncbi.nlm.nih.gov/pubmed/2664519?dopt=AbstractPlus

217. Food and Drug Administration. Specific requirements on content and format of labeling for human prescription drugs; proposed addition of “geriatric use” subsection in the labeling; proposed rule. Fed Regist. 1990; 55:46134-7.

218. Crismon ML, Ereshefsky L, Sakland SR. A comparison of clozapine absorption in the postprandial versus fasting states. Pharm Res. 1988; 10:S171.

219. Choc MG, Hsuan F, Honigfeld G. Single- vs multiple-dose pharmacokinetics of clozapine in psychiatric patients. Pharm Res. 1990; 7:347-51. http://www.ncbi.nlm.nih.gov/pubmed/2194198?dopt=AbstractPlus

220. Hartvig P, Eckernas SA, Lindstrom L et al. Receptor binding of N-(methyl-11C) clozapine in the brain of rhesus monkey studied by positron emission tomography (PET). Psychopharmacology (Berl). 1986; 89:248-52. http://www.ncbi.nlm.nih.gov/pubmed/3088645?dopt=AbstractPlus

221. Salzman C. Mandatory monitoring of side effects the “bundling” of clozapine. N Engl J Med. 1990; 323:827-9. http://www.ncbi.nlm.nih.gov/pubmed/2392135?dopt=AbstractPlus

222. Zellmer WA. An unsavory concoction. Am J Hosp Pharm. 1990; 47:783. http://www.ncbi.nlm.nih.gov/pubmed/2321652?dopt=AbstractPlus

223. Stimmel GL. Schizophrenia. In: Herfindal ET, Gourley DR, Hart LL, eds. Clinical Pharmacy and Therapeutics. 4th ed. Baltimore, MD; Williams & Wilkins: 1988:639-51.

224. Ereshefsky L, Richards A. Psychoses. In: Young LY, Koda-Kimble MA, eds. Applied therapeutics: the clinical use of drugs. Vancouver, BC: Applied Therapeutics, Inc; 1988:1189-230.

225. Meltzer HY, Bastani B, Kwon KY et al. A prospective study of clozapine in treatment-resistant schizophrenic patients. I. Preliminary report. Psychopharmacology. 1989; 99(Suppl):S68-72. http://www.ncbi.nlm.nih.gov/pubmed/2813667?dopt=AbstractPlus

226. Meltzer HY. Clozapine and electroconvulsive therapy. Arch Gen Psychiatry. 1990; 47:291. http://www.ncbi.nlm.nih.gov/pubmed/2306170?dopt=AbstractPlus

227. Meltzer HY, Burnett S, Bastani B et al. Effects of six months of clozapine treatment on the quality of life of chronic schizophrenic patients. Hosp Community Psychiatry. 1990; 41:892-7. http://www.ncbi.nlm.nih.gov/pubmed/2401480?dopt=AbstractPlus

228. Gosselin RE, Smith RP, Hodge HC et al. Clinical toxicology of commercial products. 5th ed. Baltimore: The Williams and Wilkins Co; 1984:III-205-13.

229. Goldfrank LR, Lewin NA, Flomenbaum NE et al. Psychotropics. Antidepressants: tricyclics, tetracyclics, monoamine oxidase inhibitors, and others. In: Goldfrank LR, Flomenbaum NE, Lewin NA et al, eds. Goldfrank’s toxicologic emergencies. 3rd ed. Norwalk, CT: Appleton-Century-Crofts; 1986:351-9.

230. Lieberman JA, Yunis J, Egea E et al. HLA-B38, DR4, DQw3 and clozapine-induced agranulocytosis in Jewish patients with schizophrenia. Arch Gen Psychiatry. 1990; 47:945-8. http://www.ncbi.nlm.nih.gov/pubmed/2222133?dopt=AbstractPlus

231. Borison RL, Shah C, Shelhorse M et al. Clinical pharmacology of clozapine. Pharmacologist. 1984; 26:179.

232. Ackenheil M, Blatt B, Lampart C. Biochemical changes in man and animals following clozapine treatment. J Pharmacol. 1974; 5(Suppl 2):1.

233. Murray AM, Waddington JL. Behavioral indices of the interaction of clozapine with D₁ and D₂ dopamine receptors. Br J Pharmacol. 1989; 98(Suppl):814P. http://www.ncbi.nlm.nih.gov/pubmed/2611521?dopt=AbstractPlus

234. Anon. Clozapine-induced seizures. Int Drug Ther Newsl. 1990; 25:37-8.

235. Lovdahl MJ, Perry PJ, Miller DD. The assay of clozapine and N-desmethylclozapine in human plasma by high-performance liquid chromatography. Ther Drug Monitor. 1991; 13:69-72.

236. Perry PJ, Miller DD, Arndt SV et al. Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients. Am J Psychiatry. 1991; 148:231-5. http://www.ncbi.nlm.nih.gov/pubmed/1670979?dopt=AbstractPlus

237. Baldessarini RJ, Frankenburg FR. Clozapine: a novel antipsychotic agent. N Engl J Med. 1991; 324: 746-54. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3091357&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/1671793?dopt=AbstractPlus

238. Haring C, Fleischhacker WW, Schett P et al. Influence of patient-related variables on clozapine plasma levels. Am J Psychiatry. 1990; 147:1471-5. http://www.ncbi.nlm.nih.gov/pubmed/2221158?dopt=AbstractPlus

239. Wirshing WC, Phelan CK, Van Putten T et al. Effects of clozapine on treatment-resistant akathisia and comcomitant tardive dyskinesia. Am J Psychopharmacol. 1990; 10:371-3.

240. Van Putten T, Wirshing WC, Marder S. Tardive Meige syndrome responsive to clozapine. Am J Psychopharmacol. 1990; 10:381-2.

241. Leadbetter RA, Vieweg V. Clozapine-induced weight gain. Am J Psychiatry. 1990; 147:1693-4.

242. Carson WH, Forbes RA. Clozapine-induced weight gain. Am J Psychiatry. 1990; 147:1694. http://www.ncbi.nlm.nih.gov/pubmed/2244654?dopt=AbstractPlus

243. Cohen S, Chiles J, MacNaughton A. Clozapine-induced weight gain. Am J Psychiatry. 1990; 147:1694. http://www.ncbi.nlm.nih.gov/pubmed/2244654?dopt=AbstractPlus

244. Cold JA, Wells BG, Froemming JH. Seizure activity associated with antipsychotic therapy. DICP. 1990; 24:601-6. http://www.ncbi.nlm.nih.gov/pubmed/1972826?dopt=AbstractPlus

245. Meltzer HY. Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia. Psychopharmacology (Berl). 1989; 99(Suppl):S18-27.

246. Carvey PM, Nath ST, Kao LC et al. Clozapine fails to prevent the development of haloperidol-induced behavioral hypersensitivity in a cotreatment paradigm. Eur J Pharmacol. 1990; 184:43-53. http://www.ncbi.nlm.nih.gov/pubmed/2209714?dopt=AbstractPlus

247. Watling KJ, Beer MS, Stanton JA et al. Interaction of the atypical neuroleptic clozapine with 5-HT₃ receptors in the cerebral cortex and superior cervical ganglion of the rat. Eur J Pharmacol. 1990; 182:465-72. http://www.ncbi.nlm.nih.gov/pubmed/1977590?dopt=AbstractPlus

248. Invernizzi R, Morali F, Pozzi L et al. Effects of acute and chronic clozapine on dopamine release and metabolism in the striatum and nucleus accumbens of conscious rats. Br J Pharmacol. 1990; 100:774-8. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1917584&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/2207499?dopt=AbstractPlus

249. O’Dell SJ, La Hoste GJ, Widmark CB et al. Chronic treatment with clozapine or haloperidol differentially regulates dopamine and serotonin receptors in rat brain. Synapse. 1990; 6:146-53. http://www.ncbi.nlm.nih.gov/pubmed/2237777?dopt=AbstractPlus

250. Uehlinger C, Baumann P. Clozapine as an alternative treatment for neuroleptic-induced gynecomastia. Am J Psychiatry. 1990; 148:392-3.

251. Friedman JH. Clozapine and the mandatory monitoring system. N Engl J Med. 1991; 324:491. http://www.ncbi.nlm.nih.gov/pubmed/1703281?dopt=AbstractPlus

252. Chiles JA, Cohn S, McNaughton A. Dropping objects: possible mild cataplexy associated with clozapine. J Nerv Ment Dis. 1990; 178:663-4. http://www.ncbi.nlm.nih.gov/pubmed/2230752?dopt=AbstractPlus

253. Hamilton D. Clozapine: a new antipsychotic drug. Arch Psychiatr Nurs. 1990; 4:278-81. http://www.ncbi.nlm.nih.gov/pubmed/2241248?dopt=AbstractPlus

254. Sajatovic M, Verbanac P, Ramirez LF et al. Clozapine treatment of psychiatric symptoms resistant to neuroleptic treatment in patients with Huntington’s chorea. Neurology. 1991; 41:156. http://www.ncbi.nlm.nih.gov/pubmed/1670739?dopt=AbstractPlus

255. Ryan PM. Epidemiology, etiology, diagnosis, and treatment of schizophrenia. Am J Hosp Pharm. 1991; 48:1271-80. http://www.ncbi.nlm.nih.gov/pubmed/1677528?dopt=AbstractPlus

256. Fitton A, Heel RC. Clozapine: a review of its pharmacological properties, and therapeutic use in schizophrenia. Drugs. 1990; 40:722-47. http://www.ncbi.nlm.nih.gov/pubmed/2292234?dopt=AbstractPlus

257. Bartholini G. Differential effect of neuroleptic drugs on dopamine turnover in the extrapyramidal and limbic system. J Pharm Pharmacol. 1976; 28:429-33. http://www.ncbi.nlm.nih.gov/pubmed/6752?dopt=AbstractPlus

258. Westerink BH, Korf J. Regional rat brain levels of 3,4-dihydroxyphenylacetic acid and homovanillic acid: concurrent fluorometric measurement and influence of drugs. Eur J Pharmacol. 1976; 38:281-91. http://www.ncbi.nlm.nih.gov/pubmed/954842?dopt=AbstractPlus

259. Zivkovic B, Guidotti A, Revuelta A et al. Effect of thioridazine, clozapine and other antipsychotics on the kinetic state of tyrosine hydroxylase and on the turnover rate of dopamine in striatum and nucleus accumbens. J Pharmacol Exp Ther. 1975; 194:37-46. http://www.ncbi.nlm.nih.gov/pubmed/239221?dopt=AbstractPlus

260. Wilk S, Glick SD. Dopamine metabolism in the nucleus accumbens: the effect of clozapine. Eur J Pharmacol. 1976; 37:203-6. http://www.ncbi.nlm.nih.gov/pubmed/1278242?dopt=AbstractPlus

261. Westerink BH, Korf J. Influence of drugs on striatal and limbic homovanillic acid concentration in the rat brain. Eur J Pharmacol. 1975; 33:31-40. http://www.ncbi.nlm.nih.gov/pubmed/126169?dopt=AbstractPlus

262. Sanger DJ. The effects of clozapine on shuttle-box avoidance responding in rats: comparisons with haloperidol and chlordiazepoxide. Pharmacol Biochem Behav. 1985; 23:231-6. http://www.ncbi.nlm.nih.gov/pubmed/4059310?dopt=AbstractPlus

263. Farde L, Wiesel FA, Nordstrom AL et al. D1- and D2-dopamine receptor occupancy during treatment with conventional and atypical neuroleptics. Psychopharmacology. 1989; 99(Suppl):S28-31. http://www.ncbi.nlm.nih.gov/pubmed/2573104?dopt=AbstractPlus

264. Rebec GV, Alloway KD, Bashore T. Differential actions of classical and atypical antipsychotic drugs on spontaneous neuronal activity in the amygdaloid complex. Pharmacol Biochem Behav. 1981; 14:49-56. http://www.ncbi.nlm.nih.gov/pubmed/6110210?dopt=AbstractPlus

265. Rebec GV, Anderson GD. Regional neuropharmacology of the antipsychotic drugs: implications for the dopamine hypothesis of schizophrenia. Behav Assessment. 1986; 8:11-29.

266. Anderson GD, Rebec GV. Clozapine and haloperidol in the amygdaloid complex: differential effects on dopamine transmission with long-term treatment. Biol Psychiatry. 1988; 23:497-506. http://www.ncbi.nlm.nih.gov/pubmed/2830920?dopt=AbstractPlus

267. Halperin R, Guerin JJ, Davis KL. Regional differences in the induction of behavioral supersensitivity by prolonged treatment with atypical neuroleptics. Psychopharmacology. 1989; 98:386-91. http://www.ncbi.nlm.nih.gov/pubmed/2568659?dopt=AbstractPlus

268. Fischer PA, Baas H, Hefner R. Treatment of parkinsonian tremor with clozapine. J Neural Transm Park Dis Dement Sect. 1990; 2:233-8. http://www.ncbi.nlm.nih.gov/pubmed/2257063?dopt=AbstractPlus

269. Schott K, Ried S, Stevens I et al. Neuroleptically induced dystonia in Huntington’s disease: a case report. Eur Neurol. 1989; 29:39-40. http://www.ncbi.nlm.nih.gov/pubmed/2523309?dopt=AbstractPlus

270. Susic V, Kovacevic R, Momirov D et al. Effects of clozapine (Leponex) on sleep patterns in the cat. Arch Int Physiol Biochim. 1977; 85:455- 9. http://www.ncbi.nlm.nih.gov/pubmed/72523?dopt=AbstractPlus

271. Ruch W, Asper H, Burki HR. Effect of clozapine on the metabolism of serotonin in rat brain. Psychopharmacologia. 1976; 46:103-9. http://www.ncbi.nlm.nih.gov/pubmed/1257359?dopt=AbstractPlus

272. Touyz SW, Saayman GS, Zabow T. A psychophysiological investigation of the long-term effects of clozapine upon sleep patterns of normal young adults. Psychopharmacology. 1978: 56:69-73.

273. Friedman JH, Lannon MC. Clozapine-responsive tremor in Parkinson’s disease. Mov Dis. 1990; 5:225-9.

274. Müller P, Heipertz R. Zur Behandlung manischer Psychosen mit Clozapin. (German; with English abstract.) Fortschr Neurol Psychiatr Ihrer Grenzgeb. 1977; 45:420-4.

275. Doepp S, Buddeberg C. Extrapyramidale Symptome unter Clozapin. Nervenarzt. 1975; 46:589-90. http://www.ncbi.nlm.nih.gov/pubmed/811999?dopt=AbstractPlus

276. Schyve PM, Smithline F, Meltzer HY. Neuroleptic-induced prolactin level elevation and breast cancer: an emerging clinical issue. Arch Gen Psychiatry. 1978; 35:1291-1301. http://www.ncbi.nlm.nih.gov/pubmed/30426?dopt=AbstractPlus

277. Ingram DM, Nottage EM, Roberts AN. Prolactin and breast cancer risk. Med J Aust. 1990; 153:469-73. http://www.ncbi.nlm.nih.gov/pubmed/2215338?dopt=AbstractPlus

278. Meyer F, Brown JB, Morrison AS et al. Endogenous sex hormones, prolactin, and breast cancer in premenopausal women. J Natl Cancer Inst. 1986; 77:613-6. http://www.ncbi.nlm.nih.gov/pubmed/3462404?dopt=AbstractPlus

279. Wang DY, Sturzaker HE, Kwa HG et al. Nyctohemeral changes in plasma prolactin levels and their relationship to breast cancer risk. Int J Cancer. 1984; 33:629-32. http://www.ncbi.nlm.nih.gov/pubmed/6724738?dopt=AbstractPlus

280. Braden NJ, Jackson JE, Walson PD. Tricyclic antidepressant overdose. Ped Clin North Am. 1986; 33:287-98.

281. Public Citizen Health Research Group. Citizen’s petition to Food and Drug Administration for Dear Doctor Letter and box warning on clozapine regarding risk of respiratory arrest. Washington, DC; 1991 May 29.

282. Robins. Quinidex Extentabs prescribing information. In: Barnhart ER, publisher. Physicians’ desk reference. 45th ed. Oradell, NJ: Medical Economics Company Inc; 1991:1805-6.

283. Parke-Davis. Procan SR prescribing information. In: Barnhart ER, publisher. Physicians’ desk reference. 45th ed. Oradell, NJ: Medical Economics Company Inc; 1991:1690-2.

284. DasGupta K, Young A. Clozapine-induced neuroleptic malignant syndrome. J Clin Psychiatry. 1991; 52:105-7. http://www.ncbi.nlm.nih.gov/pubmed/2005072?dopt=AbstractPlus

285. Miller DD. Effect of phenytoin on plasma clozapine concentrations in two patients. J Clin Psychiatry. 1991; 52:23-5. http://www.ncbi.nlm.nih.gov/pubmed/1988414?dopt=AbstractPlus

286. Goumeniouk AD, Ancill RJ, MacEwan GW et al. A case of drug-drug interaction involving clozapine. Can J Psychiatry. 1991; 36:234-5. http://www.ncbi.nlm.nih.gov/pubmed/1829392?dopt=AbstractPlus

287. Iamperato A, Di Chiara G. Dopamine release and metabolism in awake rats after systemic neuroleptics as studied by trans-striatal dialysis. J Neurosci. 1985; 5:297-306. http://www.ncbi.nlm.nih.gov/pubmed/2857776?dopt=AbstractPlus

288. Van Tol HH, Bunzow JR, Guan HC et al. Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature. 1991; 350:610-4. http://www.ncbi.nlm.nih.gov/pubmed/1840645?dopt=AbstractPlus

289. Sunahara RK, Guan HC, O’Dowd BF et al. Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1. Nature. 1991; 350:614-9. http://www.ncbi.nlm.nih.gov/pubmed/1826762?dopt=AbstractPlus

290. Sokoloff P, Giros B, Martres MP et al. Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature. 1990; 347:146-51. http://www.ncbi.nlm.nih.gov/pubmed/1975644?dopt=AbstractPlus

291. Anon. Now we understand antipsychotics? Lancet. 1990; 336:1222-3. Editorial.

292. Reviewers’ comments (personal observations); 1991 Sep.

293. Chen JP, Paredes W, Gardner EL. Chronic treatment with clozapine selectively decreases basal dopamine release in nucleus accumbens but not in caudate-putamen as measured by in vivo brain microdialysis: further evidence for depolarization block. Neurosci Lett. 1991; 122:127-31. http://www.ncbi.nlm.nih.gov/pubmed/2057129?dopt=AbstractPlus

294. Blaha CD, Lane RF. Chronic treatment with classical and atypical antipsychotic drugs differentially decreases dopamine release in striatum and nucleus accumbens in vivo. Neurosci Lett. 1987; 78:199-204. http://www.ncbi.nlm.nih.gov/pubmed/2888060?dopt=AbstractPlus

295. Cohen BM, Keck PE, Satlin A et al. Prevalence and severity of akathisia in patients on clozapine. Biol Psychiatry. 1991; 29:1215-9. http://www.ncbi.nlm.nih.gov/pubmed/1888803?dopt=AbstractPlus

296. Friedman LJ, Tabb SE, Worthington JJ et al. Clozapine—a novel antipsychotic agent. N Engl J Med. 1991; 325:518. http://www.ncbi.nlm.nih.gov/pubmed/1852187?dopt=AbstractPlus

297. Finkel MJ, Schwimmer JL. Clozapine—a novel antipsychotic agent. N Engl J Med. 1991; 325: 518-9.

298. Lieberman JA, Saltz BL, Johns CA et al. The effects of clozapine on tardive dyskinesia. Br J Psychiatry. 1991; 158:503-10. http://www.ncbi.nlm.nih.gov/pubmed/1675900?dopt=AbstractPlus

299. Anderson ES, Powers PS. Neuroleptic malignant syndrome associated with clozapine use. J Clin Psychiatry. 1991; 52:102-4. http://www.ncbi.nlm.nih.gov/pubmed/2005071?dopt=AbstractPlus

300. Miller DD, Sharafuddin MJ, Kathol RG. A case of clozapine-induced neuroleptic malignant syndrome. J Clin Psychiatry. 1991; 52:99-101. http://www.ncbi.nlm.nih.gov/pubmed/1672311?dopt=AbstractPlus

301. Black JL, Richelson E, Richardson JW. Antipsychotic agents: a clinical update. Mayo Clin Proc. 1985; 60:777-89. http://www.ncbi.nlm.nih.gov/pubmed/2865413?dopt=AbstractPlus

302. Frankenburg F, Baldessarini RJ. Clozapine—a novel antipsychotic agent. N Engl J Med. 1991; 325:518. http://www.ncbi.nlm.nih.gov/pubmed/1852187?dopt=AbstractPlus

303. Gerson SL, Lieberman JA, Friedenberg WR et al. Polypharmacy in fatal clozapine-associated agranulocytosis. Lancet. 1991; 338:262. http://www.ncbi.nlm.nih.gov/pubmed/1676820?dopt=AbstractPlus

304. Nair NP, Lal S, Cervantes P et al. Effect of clozapine on apomorphine-induced growth hormone secretion and serum prolactin concentrations in schizophrenia. Neuropsychobiology. 1979; 5:136-42. http://www.ncbi.nlm.nih.gov/pubmed/431802?dopt=AbstractPlus

305. Sandoz Pharmaceuticals, East Hanover, NJ: Personal Communication.

307. van de Loosdrecht AA, Faber HJ, Hordijk P et al. Clozapine-induced agranulocytosis: a case report. Immunopathophysiological considerations. Neth J Med. 1998; 52:26-9. http://www.ncbi.nlm.nih.gov/pubmed/9573739?dopt=AbstractPlus

308. Sperner-Unterweger B, Czeipek I, Gaggl S et al. Treatment of severe clozapine-induced neutropenia with granulocyte colony-stimulating factor (G-CSF): remission despite continuous treatment with clozapine. Br J Psychiatry. 1998; 172:82-4. http://www.ncbi.nlm.nih.gov/pubmed/9534838?dopt=AbstractPlus

309. Rudolf J, Grond M, Neveling M et al. Clozapine-induced agranulocytosis and thrombopenia in a patient with dopaminergic psychosis. J Neural Transm. 1997; 104:1305-11. http://www.ncbi.nlm.nih.gov/pubmed/9503276?dopt=AbstractPlus

310. Wickramanayake PD, Scheid C, Josting A et al. Use of granulocyte colony-stimulating factor (filgrastim) in the treatment of non-cytotoxic drug-induced agranulocytosis. Eur J Med Res. 1995; 18:153-6.

311. Chin-Yee I, Bezchlibnyk-Butler K, Wong L. Use of cytokines in clozapine-induced agranulocytosis. Can J Psychiatry. 1996; 41:280-4. http://www.ncbi.nlm.nih.gov/pubmed/8793147?dopt=AbstractPlus

312. Chengappa KN, Gopalani A, Haught MK et al. The treatment of clozapine-associated agranulocytosis with granulocyte colony-stimulating factor (G-CSF). Psychopharmacol Bull. 1996; 32:111-21. http://www.ncbi.nlm.nih.gov/pubmed/8927660?dopt=AbstractPlus

313. van Melick EJ, Touw DJ, Haak HL. [Agranulocytosis caused by clozapine: the importance of leukocyte monitoring and efficacy of hematopoietic growth factors.] (Dutch; with English abstract.) Ned Tijdschr Geneeskd. 1995; 139:2437-40.

314. Gerson SL. G-CSF and the management of clozapine-induced agranulocytosis. J Clin Psychiatry. 1994; 55(Suppl B):139-42. http://www.ncbi.nlm.nih.gov/pubmed/7525542?dopt=AbstractPlus

315. Gullion G, Yeh HS. Treatment of clozapine-induced agranulocytosis with recombinant granulocyte colony-stimulating factor. J Clin Psychiatry. 1994; 55:401-5. http://www.ncbi.nlm.nih.gov/pubmed/7523362?dopt=AbstractPlus

316. Nielsen H. Recombinant human granulocyte colony-stimulating factor (rhG-CSF; filgrastim) treatment of clozapine-induced agranulocytosis. J Intern Med. 1993; 234:529-31. http://www.ncbi.nlm.nih.gov/pubmed/7693847?dopt=AbstractPlus

317. Barnas C, Zwierzina H, Hummer M et al. Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment of clozapine-induced agranulocytosis: a case report. J Clin Psychiatry. 1992; 53:245-7. http://www.ncbi.nlm.nih.gov/pubmed/1639744?dopt=AbstractPlus

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.

320. Taylor D. Pharmacokinetic interactions involving clozapine. B J Psychiatry. 1997; 171:109-12.

321. Carbamazepine interactions: clozapine (Clozaril). In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 2000:197.

322. McClellan J, Werry J, the Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with schizophrenia. J Am Acad Child Adolesc Psychiatry. 2001; 40(Suppl 7): 4-23S.

323. Kumra S, Frazier JA, Jacobsen LK et al. Childhood-onset schizophrenia: a double-blind clozapine-haloperidol comparison. Arch Gen Psychiatry. 1996; 53:1090-7. http://www.ncbi.nlm.nih.gov/pubmed/8956674?dopt=AbstractPlus

324. Bess AL, Cunningham SR. Dear health care provider letter regarding important labeling changes Clozaril. East Hanover, NJ: Novartis; 2002 Feb

325. Gerson SL, Arce C. N-desmethylclozapine: a clozapine metabolite that suppresses haemopoiesis. Br J Haematol. 1994; 86:555-61. http://www.ncbi.nlm.nih.gov/pubmed/8043437?dopt=AbstractPlus

326. Piscitelli SC, Frazier JA, McKenna K. Plasma clozapine and haloperidol concentrations in adolescents with childhood-onset schizophrenia: association with response. J Clin Psychiatry. 1994; 55(Suppl B):94-7. http://www.ncbi.nlm.nih.gov/pubmed/7961584?dopt=AbstractPlus

327. Meltzer HY, Alphs L, Green AI et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003; 60:82-91. http://www.ncbi.nlm.nih.gov/pubmed/12511175?dopt=AbstractPlus

328. Anon. Clozaril shows effect on suicidality, not definitive superiority to Zyprexa. F-D-C Rep. 2002; 64:27-8.

329. Food and Drug Administration. Review and evaluation of clinical data for clozapine for suicidality. NDA No. 19-758/S-047. Rockville, MD: 2002 Aug 1.

330. Garcia G, Crismon ML, Dorson PG. Seizures in two patients after the addition of lithium to a clozapine regimen. J Clin Psychopharmacol. 1994; 14:426-8 http://www.ncbi.nlm.nih.gov/pubmed/7884026?dopt=AbstractPlus

331. Eli Lilly and Company. Zyprexa (olanzapine) tablets and Zyprexa Zydis (olanzapine) orally disintegrating tablets prescribing information. Indianapolis, IN; 2003 Sep 16.

332. Eli Lilly and Company. Lilly announces FDA notification of class labeling for atypical antipsychotics regarding hyperglycemia and diabetes. Indianapolis, IN; 2003 Sep 17. Press release.

333. Cunningham F, Lambert B, Miller DR et al. Antipsychotic induced diabetes in veteran schizophrenic patients. In: Abstracts of the 1st International Conference on Therapeutic Risk Management and 19th International Conference on Pharmacoepidemiology, Philadelphia, PA; 2003 Aug 21-24. Pharmacoepidemiol Drug Saf. 2003; 12(suppl 1): S154-5.

334. Otsuka America Pharmaceutical, Inc. Abilify (aripiprazole) tablets prescribing information. Rockville, MD; 2004 Sep.

335. AstraZeneca Pharmaceuticals. Seroquel (quetiapine fumarate) tablets prescribing information. Wilmington, DE; 2004 Jul.

336. Janssen Pharmaceutica. Risperdal (risperidone) tablets and oral solution prescribing information. Titusville, NJ; 2003 Oct.

337. Pfizer Inc. Geodon (ziprasidone) prescribing information. New York, NY; 2004 Aug.

338. Lewis-Hall F. Dear health care professional letter regarding class labeling for atypical antipsychotics and risk of hyperglycemia and diabetes. Princeton, NJ: Bristol-Myers Squibb Company; 2004 Mar 25. From FDA website. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm153025.htm

339. Bess AL, Cunningham SR. Dear health care professional letter regarding class labeling for atypical antipsychotics and risk of hyperglycemia and diabetes. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2004 Apr 1. From the FDA website. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm154110.htm

340. Eisenberg P. Dear health care professional letter regarding safety data on Zyprexa (olanzapine) – hyperglycemia and diabetes. Indianapolis, IN: Eli Lilly and Company; 2004 Mar 1. From the FDA website. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm166542.htm

341. Macfadden W. Dear health care professional letter regarding class labeling for atypical antipsychotics and risk of hyperglycemia and diabetes. Wilmington, DE: AstraZeneca Pharmaceuticals; 2004 Apr 22. From the FDA website. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm155495.htm

342. Mahmoud RA. Dear health care professional letter regarding class labeling for atypical antipsychotics and risk of hyperglycemia and diabetes. Titusville, NJ: Janssen Pharmaceutica, Inc; 2004. From the FDA website. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm166517.htm

343. Clary CM. Dear health care practitioner letter regarding class labeling for atypical antipsychotics and risk of hyperglycemia and diabetes. New York NY: Pfizer Global Pharmaceuticals; 2004 Aug. From the FDA website. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm154977.htm

344. American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity.. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004; 27:596-601. http://www.ncbi.nlm.nih.gov/pubmed/14747245?dopt=AbstractPlus

345. Melkersson K, Dahl ML. Adverse metabolic effects associated with atypical antipsychotics. Drugs. 2004; 64:701-23. http://www.ncbi.nlm.nih.gov/pubmed/15025545?dopt=AbstractPlus

346. Citrome LL, Jaffe AB. Relationship of atypical antipsychotics with development of diabetes mellitus. Ann Pharmacother. 2003; 37:1849-57. http://www.ncbi.nlm.nih.gov/pubmed/14632602?dopt=AbstractPlus

347. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004; 161(Suppl):1-56.

348. Sumiyoshi T, Roy A, Anil AE et al. A comparison of incidence of diabetes mellitus between atypical antipsychotic drugs. J Clin Psychopharmacol. 2004; 24:345-8. http://www.ncbi.nlm.nih.gov/pubmed/15118492?dopt=AbstractPlus

349. Expert Group. ’Schizophrenia and Diabetes 2003’ expert consensus meeting, Dublin, 3–4 October 2003: consensus summary. Br J Psychiatry. 2004; 47(Suppl):S112-4.

350. Marder SR, Essock SM, Miller AL et al. Physical health monitoring of patients with schizophrenia. Am J Psychiatry. 2004; 161:1334-49. http://www.ncbi.nlm.nih.gov/pubmed/15285957?dopt=AbstractPlus

351. Holt RI. Consensus development conference on antipsychotic drugs and obesity and diabetes: response to consensus statement. Diabetes Care. 2004; 27:2086-7. http://www.ncbi.nlm.nih.gov/pubmed/15277449?dopt=AbstractPlus

352. Citrome L, Volavka J. Consensus development conference on antipsychotic drugs and obesity and diabetes: response to consensus statement. Diabetes Care. 2004; 27:2087-8. http://www.ncbi.nlm.nih.gov/pubmed/15277450?dopt=AbstractPlus

353. Isaac MT, Isaac MB. Consensus development conference on antipsychotic drugs and obesity and diabetes: response to consensus statement. Diabetes Care. 2004; 27:2088. http://www.ncbi.nlm.nih.gov/pubmed/15277451?dopt=AbstractPlus

354. Boehm G, Racoosin JA, Laughren TP et al. Consensus development conference on antipsychotic drugs and obesity and diabetes: response to consensus statement. Diabetes Care. 2004; 27:2088-9. http://www.ncbi.nlm.nih.gov/pubmed/15277452?dopt=AbstractPlus

355. Barrett EJ. Consensus development conference on antipsychotic drugs and obesity and diabetes: response to Holt, Citrome and Volevka, Isaac and Isaac, and Boehm et al. Diabetes Care. 2004; 27:2089-90.

356. Fuller MA, Shermock KM, Secic M et al. Comparative study of the development of diabetes mellitus in patients taking risperidone and olanzapine. Pharmacotherapy. 2002; 23:1037-43.

357. Koller EA, Cross JT, Doraiswamy PM et al. Risperidone-associated diabetes mellitus: a pharmacovigilance study. Pharmacotherapy. 2003; 23:735-44. http://www.ncbi.nlm.nih.gov/pubmed/12820816?dopt=AbstractPlus

358. Koller EA, Weber J, Doraiswamy PM et al. A survey of reports of quetiapine-associated hyperglycemia and diabetes mellitus. J Clin Psychiatry. 2004; 65:857-63. http://www.ncbi.nlm.nih.gov/pubmed/15291665?dopt=AbstractPlus

359. Ananth J, Johnson KM, Levander EM et al. Diabetic ketoacidosis, neuroleptic malignant syndrome, and myocardial infarction in a patient taking risperidone and lithium carbonate. J Clin Psychiatry. 2004; 65:724. http://www.ncbi.nlm.nih.gov/pubmed/15163265?dopt=AbstractPlus

360. Torrey EF, Swalwell CI. Fatal olanzapine-induced ketoacidosis. Am J Psychiatry. 2003; 160:2241. http://www.ncbi.nlm.nih.gov/pubmed/14638601?dopt=AbstractPlus

361. Wehring HJ, Kelly DL, Love RC et al. Deaths from diabetic ketoacidosis after long-term clozapine treatment. Am J Psychiatry. 2003; 160:2241-2. http://www.ncbi.nlm.nih.gov/pubmed/14638600?dopt=AbstractPlus

362. Koro CE, Fedder DO, L’Italien GJ et al. Assessment of independent effect of olanzapine and risperidone on risk of diabetes among patients with schizophrenia: population based nested case-control study. BMJ. 2002; 325:243. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=117636&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/12153919?dopt=AbstractPlus

363. Citrome LL. Efficacy should drive atypical antipsychotic treatment. BMJ. 2003; 326:283. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1125137&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/12561827?dopt=AbstractPlus

364. Anon. Which atypical antipsychotic for schizophrenia?. Drug Ther Bull. 2004; 42:57-60. http://www.ncbi.nlm.nih.gov/pubmed/15310154?dopt=AbstractPlus

365. Anon. Atypical antipsychotics and hyperglycaemia. Aust Adv Drug React Bull. 2004; 23:11-2.

366. Sussman N. The implications of weight changes with antipsychotic treatment. J Clin Psychopharmacol. 2003; 23 (Suppl 1):S21-6.

367. Gianfrancesco F, Grogg A, Mahmoud R et al. Differential effects of antipsychotic agents on the risk of development of type 2 diabetes mellitus in patients with mood disorders. Clin Ther. 2003; 25:1150-71. http://www.ncbi.nlm.nih.gov/pubmed/12809963?dopt=AbstractPlus

368. Bushe C, Leonard B. Association between atypical antipsychotic agents and type 2 diabetes: review of prospective clinical data. Br J Psychiatry Suppl. 2004; 47:S87-93. http://www.ncbi.nlm.nih.gov/pubmed/15056600?dopt=AbstractPlus

369. Cavazzoni P, Mukhopadhyay N, Carlson C et al. Retrospective analysis of risk factors in patients with treatment-emergent diabetes during clinical trials of antipsychotic medications. Br J Psychiatry Suppl. 2004; 47:s94-101. http://www.ncbi.nlm.nih.gov/pubmed/15056601?dopt=AbstractPlus

370. Gianfrancesco FD, Grogg AL, Mahmoud RA et al. Differential effects of risperidone, olanzapine, clozapine, and conventional antipsychotics on type 2 diabetes: findings from a large health plan database. J Clin Psychiatry. 2002; 63:920-30. http://www.ncbi.nlm.nih.gov/pubmed/12416602?dopt=AbstractPlus

371. Etminan M, Streiner DL, Rochon PA. Exploring the association between atypical neuroleptic agents and diabetes mellitus in older adults. Pharmacotherapy. 2003; 23:1411-15. http://www.ncbi.nlm.nih.gov/pubmed/14620387?dopt=AbstractPlus

372. Leslie DL, Rosenheck RA. Incidence of newly diagnosed diabetes attributable to atypical antipsychotic medications. Am J Psychiatry. 2004; 161:1709-11. http://www.ncbi.nlm.nih.gov/pubmed/15337666?dopt=AbstractPlus

373. Sernyak MJ, Leslie DL, Alarcon RD et al. Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry. 2002; 159:561-6. http://www.ncbi.nlm.nih.gov/pubmed/11925293?dopt=AbstractPlus

374. Geller WK, MacFadden W. Diabetes and atypical neuroleptics. Am J Psychiatry. 2003; 160:388. http://www.ncbi.nlm.nih.gov/pubmed/12562601?dopt=AbstractPlus

375. Gianfrancesco FD. Diabetes and atypical neuroleptics. Am J Psychiatry. 2003; 160:388-9; author reply 389. http://www.ncbi.nlm.nih.gov/pubmed/12562599?dopt=AbstractPlus

376. Lamberti JS, Crilly JF, Maharaj K. Prevalence of diabetes mellitus among outpatients with severe mental disorders receiving atypical antipsychotic drugs. J Clin Psychiatry. 2004; 65:702-6. http://www.ncbi.nlm.nih.gov/pubmed/15163259?dopt=AbstractPlus

377. Lee DW, Fowler RB. Olanzapine/risperidone and diabetes risk. J Clin Psychiatry. 2003; 64:847-8; author reply 848. http://www.ncbi.nlm.nih.gov/pubmed/12934988?dopt=AbstractPlus

378. Bristol-Myers Squibb, Princeton, NJ: Personal communication.

379. AstraZeneca, Wayne, PA: Personal communication.

380. Eli Lilly and Company, Indianapolis, IN: Personal communication.

381. Novartis Pharmaceuticals Corporation, East Hanover, NJ: Personal communication.

382. Janssen Pharmaceuticals, Titusville, NJ: Personal communication.

383. Citrome LL. The increase in risk of diabetes mellitus from exposure to second generation antipsychotic agents. Drugs Today (Barc). 2004; 40:445-64. http://www.ncbi.nlm.nih.gov/pubmed/15319799?dopt=AbstractPlus

384. Citrome L, Jaffe A, Levine J et al. Relationship between antipsychotic medication treatment and new cases of diabetes among psychiatric inpatients. Psychiatr Serv. 2004; 55:1006-13. http://www.ncbi.nlm.nih.gov/pubmed/15345760?dopt=AbstractPlus

385. Food and Drug Administration. Public health advisory: deaths with antipsychotics in elderly patients with behavioral disturbances. Rockville, MD; 2005 Apr 11. From the FDA website. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/UCM053171

386. Anon. Aspartame and other sweeteners. Med Lett Drugs Ther. 1982; 24:1 2. http://www.ncbi.nlm.nih.gov/pubmed/7054648?dopt=AbstractPlus

388. American Medical Association Council on Scientific Affairs. Aspartame: review of safety issues. JAMA. 1985; 254:400 2. http://www.ncbi.nlm.nih.gov/pubmed/2861297?dopt=AbstractPlus

389. Gossel TA. A review of aspartame: characteristics, safety and uses. US Pharm. 1984; 9:26,28 30.

390. Food and Drug Administration. Aspartame as an inactive ingredient in human drug products; labeling requirements. Proposed rule. [21 CFR Part 201] Fed Regist. 1983; 48:54993 5.

391. Food and Drug Administration. Food additives permitted for direct addition to food for human consumption; aspartame. Final rule. [21 CFR Part 172] Fed Regist. 1983; 48:31376 82.

392. Food and Drug Administration. Alert for healthcare professionals: clozapine (marketed as clozaril). Rockville, MD; undated. From the FDA website. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm151399.htm

394. Bess AL, Cunningham SR. Dear health care provider letter regarding revised prescribing information for Clozaril tablets. East Hanover, NJ: Novartis; 2005 Dec.

395. Teva Pharmaceuticals USA. Clozapine orally disintegrating tablets prescribing information. Horsham, PA; 2017 Feb.

397. Sexson WR, Barak Y. Withdrawal emergent syndrome in an infant associated with maternal haloperidol therapy. J Perinatol. 1989; 9:170-2. http://www.ncbi.nlm.nih.gov/pubmed/2738729?dopt=AbstractPlus

398. Coppola D, Russo LJ, Kwarta RF Jr. et al. Evaluating the postmarketing experience of risperidone use during pregnancy: pregnancy and neonatal outcomes. Drug Saf. 2007; 30:247-64. http://www.ncbi.nlm.nih.gov/pubmed/17343431?dopt=AbstractPlus

399. US Food and Drug Administration. FDA drug safety communication: Antipsychotic drug labels updated on use during pregnancy and risk of abnormal muscle movements and withdrawal symptoms in newborns. Rockville, MD; 2011 Feb 22. From the FDA website:. http://www.fda.gov/Drugs/DrugSafety/ucm243903.htm

400. Teva Pharmaceuticals. Clozapine tablets prescribing information. North Wales, PA; 2015 Aug.

401. Shetty S, Vize C. An unusual case of neuroleptic malignant syndrome. J Neuropsychiatry Clin Neurosci. 2010; 22:123.E21-2.

402. Karagianis JL, Phillips LC, Hogan KP et al. Clozapine-associated neuroleptic malignant syndrome: two new cases and a review of the literature. Ann Pharmacother. 1999; 33:623-30. http://www.ncbi.nlm.nih.gov/pubmed/10369628?dopt=AbstractPlus

403. Kuchibatla SS, Cheema SA, Chakravarthy KS et al. A case report of neuroleptic malignant syndrome. BMJ Case Rep. 2009; 2009 http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3027363&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/21686818?dopt=AbstractPlus

404. Duggal HS, Mendhekar DN. Clozapine-induced tardive dystonia (blepharospasm). J Neuropsychiatry Clin Neurosci. 2007; 19:86-7. http://www.ncbi.nlm.nih.gov/pubmed/17308236?dopt=AbstractPlus

405. Tripp AC. Nonfatal pulmonary embolus associated with clozapine treatment: a case series. Gen Hosp Psychiatry. 2011 Jan-Feb; 33:85.e5-6.

406. Jazz Pharmaceuticals, Inc. Versacloz (clozapine) oral suspension prescribing information. Paolo Alto, CA; 2015 Sep.

407. US Food and Drug Administration. FDA Drug Safety Communication: FDA modifies monitoring for neutropenia associated with schizophrenia medicine clozapine; approves new shared REMS program for all clozapine medicines. Silver Spring, MD; 2015 Sep 15. From FDA website. Accessed 2015 Oct 14. http://www.fda.gov/Drugs/DrugSafety/ucm461853.htm

408. Clozapine REMS Program. Clozapine and the Risk of Neutropenia: A Guide for Healthcare Providers. Phoenix, AZ; 2015 Sep.

409. Thobakgale CF, Ndung'u T. Neutrophil counts in persons of African origin. Curr Opin Hematol. 2014; 21:50-7. http://www.ncbi.nlm.nih.gov/pubmed/24257098?dopt=AbstractPlus

410. Haddy TB, Rana SR, Castro O. Benign ethnic neutropenia: what is a normal absolute neutrophil count?. J Lab Clin Med. 1999; 133:15-22. http://www.ncbi.nlm.nih.gov/pubmed/10385477?dopt=AbstractPlus

411. Raja M, Raja S. Clozapine safety, 40 years later. Curr Drug Saf. 2014; 9:163-95. http://www.ncbi.nlm.nih.gov/pubmed/24809463?dopt=AbstractPlus

412. Nooijen PM, Carvalho F, Flanagan RJ. Haematological toxicity of clozapine and some other drugs used in psychiatry. Hum Psychopharmacol. 2011; 26:112-9. http://www.ncbi.nlm.nih.gov/pubmed/21416507?dopt=AbstractPlus

413. Nykiel S, Henderson D, Bhide G et al. Lithium to allow clozapine prescribing in benign ethnic neutropenia. Clin Schizophr Relat Psychoses. 2010; 4:138-40. http://www.ncbi.nlm.nih.gov/pubmed/20643636?dopt=AbstractPlus

414. Ghaznavi S, Nakic M, Rao P et al. Rechallenging with clozapine following neutropenia: treatment options for refractory schizophrenia. Am J Psychiatry. 2008; 165:813-8. http://www.ncbi.nlm.nih.gov/pubmed/18593787?dopt=AbstractPlus

415. Mattai A, Fung L, Bakalar J et al. Adjunctive use of lithium carbonate for the management of neutropenia in clozapine-treated children. Hum Psychopharmacol. 2009; 24:584-9. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2772202&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/19743394?dopt=AbstractPlus

416. Nachimuthu S, Assar MD, Schussler JM. Drug-induced QT interval prolongation: mechanisms and clinical management. Ther Adv Drug Saf. 2012; 3:241-53. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4110870&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/25083239?dopt=AbstractPlus

417. Waln O, Jankovic J. An update on tardive dyskinesia: from phenomenology to treatment. Tremor Other Hyperkinet Mov (N Y). 2013; 3

418. Rakesh G, Muzyk A, Szabo ST et al. Tardive dyskinesia: 21st century may bring new treatments to a forgotten disorder. Ann Clin Psychiatry. 2017; 29:108-119. http://www.ncbi.nlm.nih.gov/pubmed/28207919?dopt=AbstractPlus

419. Margolese HC, Chouinard G, Kolivakis TT et al. Tardive dyskinesia in the era of typical and atypical antipsychotics. Part 2: Incidence and management strategies in patients with schizophrenia. Can J Psychiatry. 2005; 50:703-14. http://www.ncbi.nlm.nih.gov/pubmed/16363464?dopt=AbstractPlus

420. Lerner PP, Miodownik C, Lerner V. Tardive dyskinesia (syndrome): Current concept and modern approaches to its management. Psychiatry Clin Neurosci. 2015; 69:321-34. http://www.ncbi.nlm.nih.gov/pubmed/25556809?dopt=AbstractPlus

421. Neurocrine Biosciences, Inc. Ingrezza (valbenazine) capsules prescribing information. San Diego, CA; 2017 Apr.

422. Hauser RA, Factor SA, Marder SR et al. KINECT 3: a phase 3 randomized, double-blind, placebo-controlled trial of valbenazine for tardive dyskinesia. Am J Psychiatry. 2017; 174:476-84. http://www.ncbi.nlm.nih.gov/pubmed/28320223?dopt=AbstractPlus

423. Fernandez HH, Factor SA, Hauser RA et al. Randomized controlled trial of deutetrabenazine for tardive dyskinesia: The ARM-TD study. Neurology. 2017; http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=5440239&blobtype=pdf

424. Teva Pharmaceuticals USA, Inc. Austedo (deutetrabenazine) tablets prescribing information. North Wales, PA; 2017 Aug.

425. US Food and Drug Administration. FDA Drug Safety Communication: FDA strengthens warning that untreated constipation caused by schizophrenia medicine clozapine (Clozaril) can lead to serious bowel problems. Silver Spring, MD; 2020 Jan 28. From FDA website. Accessed 2020 Jul 13. https://www.fda.gov/drugs/drug-safety-and-availability/fda-strengthens-warning-untreated-constipation-caused-schizophrenia-medicine-clozapine-clozaril-can

426. Every-Palmer S, Nowitz M, Stanley J et al. Clozapine-treated Patients Have Marked Gastrointestinal Hypomotility, the Probable Basis of Life-threatening Gastrointestinal Complications: A Cross Sectional Study. EBioMedicine. 2016; 5:125-134. http://www.ncbi.nlm.nih.gov/pubmed/27532076?dopt=AbstractPlus

427. Baptista T. A fatal case of ischemic colitis during clozapine administration. Braz J Psychiatry. 2014; 36:358. http://www.ncbi.nlm.nih.gov/pubmed/25517419?dopt=AbstractPlus

428. Leong QM, Wong KS, Koh DC. Necrotising colitis related to clozapine? A rare but life threatening side effect. World J Emerg Surg. 2007; 2:21. http://www.ncbi.nlm.nih.gov/pubmed/17711574?dopt=AbstractPlus

429. Alam HB, Fricchione GL, Guimaraes ASR. Case 31-2009 — A 26-Year-Old Man with Abdominal Distention and Shock. N Engl J Med. 2009; 361:1487-1496. http://www.ncbi.nlm.nih.gov/pubmed/19812406?dopt=AbstractPlus

430. Clozapine REMS. From Clozapine REMS website. Accessed 2021 Nov 10. https://www.newclozapinerems.com/home#

431. US Food and Drug Administration. Frequently Asked Questions: Clozapine REMS Modification. Rockville, MD; updated July 29, 2021. From the FDA website. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/frequently-asked-questions-clozapine-rems-modification

432. US Food and Drug Administration. Clozapine Risk Evaluation and Mitigation Strategy (REMS) requirements will change on November 15, 2021. Rockville, MD; updated July 29, 2021. From the FDA website. https://www.fda.gov/drugs/drug-safety-and-availability/clozapine-risk-evaluation-and-mitigation-strategy-rems-requirements-will-change-november-15-2021