Clozapine

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
Brands: Clozaril, FazaClo

Special Alerts:

[Posted 02/22/2011] ISSUE: FDA notified healthcare professionals that the Pregnancy section of drug labels for the entire class of antipsychotic drugs has been updated. The new drug labels now contain more and consistent information about the potential risk for abnormal muscle movements (extrapyramidal signs or EPS) and withdrawal symptoms in newborns whose mothers were treated with these drugs during the third trimester of pregnancy.

The symptoms of EPS and withdrawal in newborns may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty in feeding. In some newborns, the symptoms subside within hours or days and do not require specific treatment; other newborns may require longer hospital stays.

BACKGROUND: Antipsychotic drugs are used to treat symptoms of psychiatric disorders such as schizophrenia and bipolar disorder.

RECOMMENDATION: Healthcare professionals should be aware of the effects of antipsychotic medications on newborns when the medications are used during pregnancy. Patients should not stop taking these medications if they become pregnant without talking to their healthcare professional, as abruptly stopping antipsychotic medications can cause significant complications for treatment. For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for clozapine to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of clozapine and consists of the following: elements to assure safe use and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().

• Agranulocytosis


• 
  

  Substantial risk of potentially life-threatening agranulocytosis; reserve for use in the following indications: 1) for treatment of severely ill schizophrenic patients who fail to show an acceptable response to adequate courses of standard antipsychotic therapy, either because of insufficient efficacy or an inability to achieve an effective dosage due to intolerable adverse effects.^{e f g} 2) for reducing risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at risk of reexperiencing suicidal behavior.^{e f g}

  
  


• 
  

  Measure baseline WBC count and ANC before initiation of therapy and measure WBC count and ANC at regular intervals during treatment and for at least 4 weeks after discontinuance.^{e f g} (See Agranulocytosis under Cautions.)

  
  


• 
  

  Available only through distribution systems that ensure periodic monitoring of WBC count and ANC prior to provision of patient’s next supply of drug.^{e f g} (See Restricted Distribution under Dosage and Administration.)

  
  

• Seizures


• 
  

  Risk of seizures, particularly at higher dosages.¹ Use with caution in patients with a history of seizures or other predisposing factors.¹ Avoid activity where sudden loss of consciousness could cause serious risk to patient or others.¹ (See Seizures under Cautions.)

  
  

• Myocarditis


• 
  

  Increased risk of fatal myocarditis, particularly during, but not limited to, first month of therapy.¹ Promptly discontinue if myocarditis is suspected.¹ (See Myocarditis under Cautions.)

  
  

• Increased Mortality in Geriatric Patients


• 
  

  Substantially higher mortality rate (4.5%) in geriatric patients with dementia-related psychosis† receiving atypical antipsychotic agents (e.g., aripiprazole, olanzapine, quetiapine, risperidone) compared with those receiving placebo (2.6%).^{c d e}

  
  


• 
  

  Most fatalities resulted from cardiac-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).^{c d e}

  
  


• 
  

  Atypical antipsychotics are not approved for the treatment of dementia-related psychosis.^{c d e} (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Cautions.)

  
  

• Other Cardiovascular and Respiratory Effects


• 
  

  Risk of orthostatic hypotension, with or without syncope, particularly during initial titration in association with rapid dosage escalation.¹ Profound collapse may occur rarely, possibly accompanied by respiratory and/or cardiac arrest.¹

  
  


• 
  

  In patients who have had even a brief interruption of therapy (i.e., ≥2 days since last dose), reinitiate therapy at dosage of 12.5 mg once or twice daily.¹ (See Reinitiation of Therapy under Dosage and Administration.)

  
  


• 
  

  Caution advised when initiating clozapine in patients receiving benzodiazepines or other psychotropic agents since collapse, respiratory arrest, and cardiac arrest reported during initial treatment in such patients.¹ See Specific Drugs under Interactions.

  
  

Introduction

Atypical or second-generation antipsychotic agent.^{1 2 3 4 5 7 8 9 10 11 12 65 67 181 197 235 239 248 253 306}

Uses for Clozapine

Schizophrenia

Management of treatment-resistant schizophrenia in severely ill patients who fail to respond adequately to other antipsychotic therapy and/or in whom such therapy produces intolerable adverse effects.^{1 2 3 10 14 21 33 34 61 63 64 87 121 156 306} (See Boxed Warning and see Agranulocytosis under Cautions.)

Has been used in the management of childhood-onset schizophrenia in a limited number of treatment-resistant children and adolescents†.^{322 323}

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.^{1 306 327 328}

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† 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

Administration

Restricted Distribution

Available only through distribution systems that ensure periodic blood tests prior to delivery of next supply of medication; dispensing is contingent on results of WBC count and ANC.^{e f g} (See Agranulocytosis under Cautions.)

Upon initiating therapy, may dispense up to an additional 1-week supply to the patient to be held for emergencies (e.g., weather, holidays).^{e g} Dispense ≤1 week supply ordinarily, but may dispense supply sufficient for therapy for a period of time equal to that of the monitoring period; patients monitored weekly may receive a 1-week (7-day) supply of medication, patients monitored biweekly may receive a 2-week supply, and patients eligible for monitoring every 4 weeks may receive a 28-day supply of medication, depending on WBC count and ANC results.^{e f g}

Before initiating therapy in any patient, check Clozaril National Registry (phone number: 800-448-5938) to ensure patient does not have history of clozapine-induced agranulocytosis or severe leukopenia/granulocytopenia; do not administer to patients with such a history.^{1 3 6} (See Contraindications under Cautions.)

Contact individual manufacturers for additional information on current mechanisms for obtaining drug.^{1 a g}

Oral Administration

Administer orally as conventional or orally disintegrating tablets ^{1 2 5 10 11 12 54 59 61 62 63 87 102 120 156 237 253 255 387} without regard to meals.^{1 3 5 218 219 387}

Administer in divided doses to minimize risk of certain adverse effects (e.g., hypotension, seizures, sedation).^{1 3 5 12 156 255 281 296 297 387}

Just prior to administration of orally disintegrating tablet, peel blister backing completely off the blister and gently remove tablet; immediately place on the tongue to dissolve and swallow with or without liquid.³⁸⁷ When clozapine orally disintegrating tablets are divided, destroy the remaining half of the tablet.³⁸⁷

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Carefully adjust dosage according to individual requirements and response using lowest possible effective dosage.^{1 5 11 87} Avoid extended treatment in patients failing to show acceptable level of clinical response.¹

Due to possibility that high dosages may increase risk of adverse reactions, particularly seizures,^{1 3 5 44 90 159 177 234} allow adequate time to respond to a given dosage before dosage escalation is considered.^{1 12 256}

Pediatric Patients

Schizophrenia†

Oral

Dosage not established in children <16 years of age.^{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 (one-half of a 25-mg tablet) once or twice daily.^{1 213 281 292 296 302 306 318} If therapy is initiated with orally disintegrating tablets, destroy the remaining half tablet.³⁸⁷ If well tolerated, increase by 25–50 mg daily over a 2-week period until dosage of 300–450 mg daily is achieved.^{1 3 12 38 256 306}

Make subsequent dosage increases no more than once or twice weekly, in increments ≤50–100 mg.^{1 3 12 38 253 255 256 306}

Continue daily administration in divided doses (e.g., 2–3 times daily) until effective and tolerable dosage reached,^{1 3 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,^{1 2 3 5 11 38 67 253} but 600–900 mg daily may be required in some.^{1 3 5 12 38}

Optimum duration currently is not known, but maintenance therapy with antipsychotic agents is well established.¹ In responsive patients, continue as long as clinically necessary and tolerated, but at lowest possible effective dosage; reassess need for continued therapy periodically.¹

Suicide Risk Reduction

Oral

Initially, 12.5 mg once or twice daily.¹ If therapy is initiated with orally disintegrating tablets, destroy the remaining half tablet.³⁸⁷ If well tolerated, increase by 25–50 mg daily over a 2-week period until a dosage of 300–450 mg daily is achieved.¹

Make subsequent dosage increases no more than once or twice weekly, in increments ≤50–100 mg.¹

In the principal supportive study, mean dosage was about 300 mg daily (range: 12.5–900 mg daily).^{1 327}

Continue therapy for ≥2 years; ^{1 327} after 2 years, reassess patient’s risk of suicidal behavior.¹ If clinician’s assessment indicates that risk for suicidal behavior is still present, continue therapy.¹ Thereafter, reevaluate need to continue therapy at regular intervals.¹

If the clinician determines the patient is no longer at risk for suicidal behavior, discontinue gradually and resume treatment of underlying disorder with an antipsychotic agent to which patient has previously responded.¹

Discontinuance of Therapy

Oral

For planned termination of therapy, reduce dosage gradually over a 1- to 2-week period.^{1 3 13 256}

If abrupt discontinuance is required (e.g., due to leukopenia or agranulocytosis), observe carefully for recurrence of psychotic symptoms and symptoms related to cholinergic rebound (e.g., headache, nausea, vomiting, diarrhea).¹ Sudden withdrawal can lead to rapid decompensation and rebound psychosis.^{1 3 11 131 173 174}

Reinitiation of Therapy

Oral

Do not reinitiate in patients in whom therapy was discontinued due to WBC count <2000/mm³ or an ANC <1000/mm³.^{1 3 6 318}

If restarted after brief interruption (i.e., ≥2 days) in therapy, reinitiate at dosage of 12.5 mg once or twice daily.^{1 3 256 318} If dosage well tolerated, it may be feasible to titrate back to therapeutic dosage more quickly than during initial treatment.^{1 318} However, reinitiate with extreme caution, even after brief interruptions of only 24 hours, in patients who have previously experienced respiratory or cardiac arrest during initial dosing but were subsequently titrated to therapeutic dosage.^{1 318}

Reexposure might enhance risk of an adverse effect and/or increase its severity (e.g., when immune-mediated mechanisms are involved); additional caution advised during reinitiation of treatment.^{1 3}

When reinitiating therapy, consider WBC count and ANC monitoring recommendations.^{e f g} (See Table 2: WBC and ANC Monitoring for Clozapine Reinitiation under Cautions.)

Prescribing Limits

Adults

Oral

Maximum 900 mg daily.¹

Special Populations

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

Cautions for Clozapine

Contraindications

• 
  

  Myeloproliferative disorders.¹

  
  


• 
  

  Uncontrolled seizure disorder.¹

  
  


• 
  

  Paralytic ileus.^{e f g}

  
  


• 
  

  History of clozapine-induced agranulocytosis or severe granulocytopenia.¹

  
  


• 
  

  Severe CNS depression or comatose states from any cause.¹

  
  


• 
  

  Concomitant use of other agents with well-known potential to cause agranulocytosis or suppress bone marrow function.¹

  
  


• 
  

  Known hypersensitivity to clozapine or any ingredient in the formulation.¹

  
  

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Possible increased risk of death with use of atypical antipsychotics in geriatric patients with dementia-related psychosis.^{c d e}

Atypical antipsychotics are not approved for the treatment of dementia-related psychosis.^{c d e} (See Boxed Warning and see Geriatric Use under Cautions.)

Agranulocytosis

Agranulocytosis, defined as an ANC <500/mm³ and characterized by leukopenia (WBC count <2000/mm³) and relative lymphopenia, reported;¹³⁹ estimated cumulative incidence of 1–2% after 1 year of therapy.^{1 5 6 20 139} Potentially fatal if not detected early and therapy interrupted.¹

Unless patient is at risk for recurrent suicidal behavior, attempt ≥2 trials, each with a different agent for schizophrenia, at an adequate dosage and duration, before clozapine initiation since there is substantial risk of agranulocytosis.^{1 e f g} (See Agranulocytosis in Boxed Warning.)

Incidence of agranulocytosis appears to rise steeply during first 2 months and peaks in third month, then falls substantially between the third and sixth months of therapy; after 6 months, incidence further declines but never reaches zero.^{e f g} Reduction in monitoring frequency may result in increased incidence.¹

Data suggest that patients who have an initial episode of moderate leukopenia (WBC ≥2000/mm³ but <3000/mm³) are at increased risk (up to 12-fold) for subsequent episodes of agranulocytosis.^{e f g}

No established risk factors for development of clozapine-induced agranulocytosis, except for evidence of substantial bone marrow suppression during initial therapy.¹ However, a disproportionate number of US cases occurred in patients of Eastern European Jewish heritage; ^{1 2 12 139 230 237} most cases occurred within 4–16 weeks of drug exposure, but neither dose nor duration of therapy reliably predicts agranulocytosis.^{1 2}

Agranulocytosis associated with other antipsychotic agents reportedly occurs more frequently in women, geriatric patients, and patients who are cachectic or have serious underlying medical conditions (e.g., immunocompromised, HIV infection);²⁹² possible increased risk with clozapine use in such patients.^{1 292}

Determine baseline WBC count and ANC before initiation of therapy.^{e f g} Do not initiate therapy if baseline WBC count is <3500/mm³, baseline ANC is <2000/mm³, or patient has history of myeloproliferative disorder or previous clozapine-induced agranulocytosis or granulocytopenia.^{e f g}

For first 6 months, monitor WBC counts and ANC every week; after 6 months of continuous therapy, if acceptable counts (i.e., WBC ≥3500/mm³ and ANC ≥2000/mm³) have been maintained, may monitor every other week.^{e f g} After a further 6 months, if acceptable counts continue to be maintained, may reduce monitoring to every 4 weeks for the remainder of therapy.^{e f g} After discontinuance, monitor weekly for at least 4 weeks from the day of discontinuance (regardless of reason for discontinuance) or until WBC ≥3500/mm³ and ANC ≥2000/mm³.^{e f g} Dispensing of clozapine is contingent upon compliance with these required WBC and ANC tests.^{e f g} (See Restricted Distribution under Dosage and Administration.)

If decreases in WBC count or ANC observed, the patient should be managed according to the following recommendations.^{e f g}

Agranulocytosis develops upon rechallenge, often with a shorter latency.¹ Patients who have experienced substantial bone marrow suppression during therapy are listed in a national master file.¹ (See Restricted Distribution under Dosage and Administration.)

Carefully monitor for flu-like symptoms or other manifestations of infection; institute appropriate anti-infective therapy if necessary.^{e f g}

Table 1. Frequency of Monitoring Based on Stage of Therapy or Results from WBC and ANC Monitoring

Situation	Hematological Values	Frequency of WBC and ANC Monitoring
Initiation of therapy and first 6 months of therapy	WBC ≥3500/mm3 ANC ≥2000/mm3 Do not initiate in patients with a history of myeloproliferative disorder or clozapine-induced agranulocytosis or granulocytopenia	Weeklye f g
During second 6 months of therapy	All results for WBC ≥3500/mm3 and ANC ≥2000/mm3	Every 2 weekse f g
After 12 months of therapy	All results for WBC ≥3500/mm3 and ANC ≥2000/mm3	Every 4 weeks thereaftere f g
Immature forms present	Not applicable	Repeat WBC and ANCe f g
Discontinuance of therapy	Not applicable	Weekly for at least 4 weeks from day of discontinuance or until WBC ≥3500/mm3 and ANC ≥2000/mm3e f g
Substantial decrease in WBC or ANC	Single decrease or cumulative decrease within 3 weeks of WBC ≥3000/mm3 or ANC ≥1500/mm3	Repeat WBC and ANC.e f g Carefully monitor for manifestations of infection**e f g If repeat values for WBC ≥3000/mm3 and ≤3500/mm3 and ANC <2000/mm3, monitor twice weeklye f g
Mild leukopenia/mild granulocytopenia	WBC ≥3000/mm3 but <3500/mm3 and/or ANC ≥1500/mm3 but <2000/mm3	Monitor twice weekly until WBC >3500/mm3 and ANC >2000/mm3, then resume previous monitoring frequency.e f g Carefully monitor for manifestations of infection**e f g
Moderate leukopenia/moderate granulocytopenia	WBC ≥2000/mm3 but <3000/mm3 and/or ANC ≥1000/mm3 but <1500/mm3	Interrupt therapy and carefully monitor for manifestations of infection**e f g Monitor daily until WBC >3000/mm3 and ANC >1500/mm3, then monitor twice weekly until WBC >3500/mm3 and ANC >2000/mm3.e f g May rechallenge when WBC >3500/mm3 and ANC >2000/mm3e f g If rechallenged, monitor weekly for 1 year before returning to the usual monitoring schedule of every 2 weeks for 6 months then every 4 weeks indefinitelye f g
Severe leukopenia/severe granulocytopenia	WBC <2000/mm3 and/or ANC <1000/mm3	Discontinue therapy and do not rechallenge patient.*e f g Carefully monitor for manifestations of infection**e f g Monitor until normal and for at least 4 weeks from day of discontinuance as follows: daily until WBC >3000/mm3 and ANC >1500/mm3, twice weekly until WBC >3500/mm3 and ANC >2000/mm3, then weekly after WBC >3500/mm3e f g Consider bone marrow aspiration to determine granulopoietic status; if granulopoiesis is deficient, protective isolation with close observation may be indicated. If infection develops, perform cultures and institute appropriate anti-infective therapye f g
Agranulocytosis	ANC ≤500/mm3	Discontinue therapy and do not rechallenge patient.e f g Carefully monitor for manifestations of infectione f g Monitor until normal and for at least 4 weeks from day of discontinuance as follows: daily until WBC >3000/mm3 and ANC >1500/mm3, twice weekly until WBC >3500/mm3 and ANC >2000/mm3, then weekly after WBC >3500/mm3e f g Consider bone marrow aspiration to determine granulopoietic status; if granulopoiesis is deficient, protective isolation with close observation may be indicated. If infection develops, perform cultures and institute appropriate anti-infective therapy.e f g

If clozapine therapy is reinitiated after interruption, monitor WBC counts and ANC after reinitiating therapy based on duration of previous therapy, length of interruption of therapy, and previous WBC counts and ANC in the patient according to this schedule:^{e f g}

Transition to reduce frequency of monitoring only permitted if all WBC counts ≥3500/mm³ and ANC values ≥2000/mm³.^{e f g}

Table 2. WBC and ANC Monitoring for Clozapine Reinitiation

Previous therapy duration <6 months, with no abnormal blood event (WBC ≥3500/mm3 and ANC ≥2000/mm3) and interruption in therapy ≥3 days but ≤1 month	Continue with weekly WBC and ANC monitoring where left off in schedule; do not restart 6-month period.e f g When 6-month period complete, may decrease monitoring frequency to every other weeke f g
Previous therapy duration <6 months, with no abnormal blood event and interruption in therapy >1 month	Monitor WBC and ANC weekly for additional 6 months before decreasing to biweekly testinge f g
Previous therapy duration <6 months, with abnormal blood event (WBC <3500/mm3 or ANC <2000/mm3) but rechallengeable (i.e., WBC ≥2000/mm3 and ANC ≥1000/mm3 during previous therapy)	See Table 1e f g
Previous therapy duration 6–12 months, with no abnormal blood event and interruption in therapy≥3 days but ≤1 month	Monitor WBC and ANC weekly for 6 weeks, then resume monitoring every other week for an additional 6 monthse f g
Previous therapy duration 6–12 months, with no abnormal blood event and interruption in therapy >1 month	Monitor WBC and ANC weekly for 6 months, then resume monitoring every other week for an additional 6 monthse f g
Previous therapy duration 6–12 months, with abnormal blood event (WBC <3500/mm3 or ANC <2000/mm3) but rechallengeable (i.e., WBC ≥2000/mm3 and ANC ≥1000/mm3 during previous therapy)	See Table 1e f g
Previous therapy duration >12 months, with no abnormal blood event and interruption in therapy≥3 days but ≤1 month	Monitor WBC and ANC weekly for 6 weeks, then resume monitoring every 4 weekse f g
Previous therapy duration >12 months, with no abnormal blood event and interruption in therapy >1 month	Monitor WBC and ANC weekly for 6 months, then resume monitoring every other week for an additional 6 months, then resume monitoring every 4 weekse f g
Previous therapy duration >12 months, with abnormal blood event (WBC <3500/mm3 or ANC <2000/mm3) but rechallengeable (i.e., WBC ≥2000/mm3 and ANC ≥1000/mm3 during previous therapy)	See Table 1e f g

Eosinophilia

Possible eosinophilia, substantial in rare cases.¹ If total eosinophil count >4000/mm³, interrupt therapy until eosinophil count <3000/mm³.¹

Seizures

Contraindicated in patients with uncontrolled seizure disorders.¹

Risk of seizure, 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., abnormal EEG without history of epilepsy, preexisting CNS pathology, history of electroconvulsive therapy [ECT], or perinatal or birth difficulties, family history of seizure or febrile convulsion).^{1 2 5 151 244 292}

Avoid activity where sudden loss of consciousness could cause serious risk to patient or others (e.g., operating heavy machinery, driving automobile, swimming, climbing).^{1 2 3}

Myocarditis

Increased risk of fatal myocarditis, particularly during, but not limited to, first month of therapy; consider possibility in patients with unexplained fatigue, dyspnea, tachypnea, fever, chest pain, palpitations, manifestations of heart failure, or ECG findings (e.g., ST-T wave abnormalities, arrhythmias).¹ Not known whether eosinophilia is reliable predictor of myocarditis.¹

Discontinue promptly if myocarditis suspected; do not rechallenge patients with clozapine-related myocarditis.^{1 324}

Tachycardia may represent a presenting sign in patients with myocarditis; closely monitor patients with tachycardia during first month of therapy for other signs of myocarditis.¹

Other Cardiovascular and Respiratory Effects

Use with caution in patients with cardiovascular and/or pulmonary disease due to risk of tachycardia, hypotension, collapse, and cardiac and/or respiratory arrest; carefully observe gradual dosage titration recommendations.¹

Orthostatic hypotension, with or without syncope, possible; more likely to occur during initial titration in association with rapid dosage escalation or even with first dose, but may represent continuing risk in some patients.¹

Tachycardia, sometimes sustained, possible; not simply reflex response to hypotension and is present in all positions monitored.

Possible ECG repolarization changes, including S-T segment depression and flattening or inversion of T waves, which normalize after discontinuance.¹

Substantial cardiac events (i.e., CHF, pericarditis, pericardial effusions, ischemic changes, MI, arrhythmias, sudden death) reported.¹ Sudden death reported rarely in psychiatric patients, with or without antipsychotic drug therapy; relationship to antipsychotic agent unknown.¹

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, reported.¹

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary dyskinetic movements may occur in patients receiving antipsychotic agents.¹ Consider discontinuance of clozapine.¹

Hyperglycemia and Diabetes Mellitus

Severe hyperglycemia, sometimes associated with ketoacidosis, hyperosmolar coma, or death, reported in patients receiving atypical antipsychotic agents,^{331 332 333} including clozapine,^{1 318 a b} Closely monitor patients with preexisting diabetes mellitus for worsening of glycemic control and perform fasting blood glucose tests at baseline and periodically for patients with risk factors for diabetes (e.g., obesity, family history of diabetes).^{331 332 a b} If manifestations of hyperglycemia occur, test for diabetes mellitus.^{331 332 a b} Consider discontinuance in patients who develop severe hyperglycemia.^{1 a b}

Sensitivity Reactions

Dermatologic Reactions

Rash,^{1 5 7 286} pruritus,^{1 253} eczema,¹ erythema,¹ bruising,¹ dermatitis,¹ petechiae,¹ urticaria^{1 286} reported.

Hypersensitivity Reactions

Hypersensitivity reactions, including photosensitivity,^{1 318} vasculitis,^{1 318} erythema multiforme,^{1 318} and Stevens-Johnson syndrome,^{1 318} reported; causal relationship not established.^{1 318}

General Precautions

Cardiomyopathy

Cardiomyopathy reported, principally in patients <50 years of age and with duration of therapy >6 months.¹ Caution advised if used in patients with cardiovascular disease; carefully observe gradual dosage titration recommendations.¹

Consider possibility in patients with manifestations suggestive of cardiomyopathy, particularly exertional dyspnea, fatigue, orthopnea, paroxysmal nocturnal dyspnea, or peripheral edema.¹ If cardiomyopathy confirmed, discontinue clozapine unless benefit clearly outweighs risk.¹

Fever

Possible transient temperature elevations >38°C, with peak incidence within first 3 months of therapy; usually benign and self-limiting, but may necessitate discontinuance.¹ Evaluate for possible underlying infectious pro