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Clozapine

Pronunciation

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

Warning(s)

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 has deemed that clozapine has in effect an approved REMS. (See .) 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 (). Also see Restricted Distribution Program under Dosage and Administration.

Warning(s)

  • 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.)

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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 REMS and also 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 urticaria1 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 process or development of agranulocytosis.1 Consider possibility of NMS in presence of high fever (see Neuroleptic Malignant Syndrome under Warnings).1

Sedation

Due to initial sedative effects, closely follow recommendation for gradual dosage escalation.1

Thromboembolic Effects

Risk of pulmonary embolism; consider possibility of pulmonary embolism in patients with DVT, acute dyspnea, chest pain, or other respiratory manifestations.1

Hepatic Effects

Caution advised in patients with hepatic disease; hepatitis reported in patients with normal and preexisting hepatic function abnormalities.1

Perform hepatic function tests immediately in patients who develop nausea, vomiting, and/or anorexia during therapy; if clinically important increases in hepatic function tests or symptoms of jaundice occur, discontinue drug.1

Phenylketonuria

Clozapine 25- or 100-mg orally disintegrating tablets contain aspartame, which is metabolized in the GI tract to provide about 1.74 or 6.96 mg of phenylalanine, respectively, per tablet.386 387 388 389 390 391

Anticholinergic Effects

Use with caution in individuals whose condition may be aggravated by anticholinergic effects (e.g., patients with prostatic hyperplasia, ileus, urinary retention, angle-closure [obstructive, narrow-angle] glaucoma).1 3 146 237

Varying degrees of impairment of intestinal peristalsis, ranging from constipation to intestinal obstruction, fecal impaction, and paralytic ileus, rarely fatal, reported.1 (See Contraindications under Cautions.) Treat constipation initially by maintaining adequate hydration and using bulk-forming laxatives; consult a gastroenterologist in more severe cases.1

Specific Populations

Pregnancy

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.

Category B.1

Lactation

May be distributed into milk in animals; not known whether distributed into human milk.1 Women receiving clozapine should not breast-feed.1

Pediatric Use

Safety and efficacy not established in children <16 years of age.1 5 319

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.1

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

Possible increased risk of death in geriatric patients with dementia-related psychosis.c d e Substantial (1.6-fold to 1.7-fold) increase in mortality rate reported in geriatric patients with dementia who received atypical antipsychotic agents (e.g., aripiprazole, olanzapine, quetiapine, risperidone) for treatment of behavioral disorders; 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 g (See Boxed Warning and see Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Cautions.)

Hepatic Impairment

Use with caution in patients with hepatic disease.1 (See Hepatic Effects under Cautions.)

Renal Impairment

Use with caution in patients with renal disease.1

Common Adverse Effects

Drowsiness/sedation, dizziness/vertigo, headache, tremor, salivation, sweating, dry mouth, visual disturbances, tachycardia, hypotension, syncope, constipation, nausea, fever.1

Interactions for Clozapine

Risk of concomitant use with other drugs not systematically evaluated, but clinical experience and/or theoretical considerations indicate certain potential drug interactions exist.1 3

Metabolized by many CYP isoenzymes, particularly CYP1A2, CYP2D6, and CYP3A4.1 320 May inhibit CYP2D6; may make normal CYP2D6 metabolizers resemble ‘‘poor metabolizers’’ with regard to concomitant therapy with other drugs metabolized by CYP2D6.1

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP1A2, CYP2D6, or CYP3A4: potential pharmacokinetic interaction (altered clozapine metabolism).1 Risk of metabolic interaction caused by an effect of an individual isoform minimized, but use concomitantly with caution; dosage adjustment of clozapine and/or other drug may be necessary.1 320

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2D6: potential pharmacokinetic interaction (decreased metabolism of substrate); reduced dosage of either clozapine or substrate may be required.1

Drugs Affecting Seizure Threshold

Possible increased risk of seizure; avoid concomitant use if possible.1 16 90 176 177 253 255 292 If concomitant use is required, exercise caution (e.g., use low initial clozapine dosages and slowly titrate upward) and consider possible need for anticonvulsant therapy.292

Protein-Bound Drugs

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

Psychotropic Agents

Orthostatic hypotension, rarely with profound collapse and respiratory and/or cardiac arrest, reported with clozapine alone or during concomitant use with other psychotropic agents.1 318 Caution advised if used concomitantly.1 318

Specific Drugs

Drug

Interaction

Comments

Alcohol

Additive CNS effects1

Avoid concomitant use1

Anesthetics, general

Additive CNS effects1

Administer with caution; consult anesthesiologist regarding clozapine continuation in patients undergoing surgery involving general anesthesia1

Antiarrhythmic agents: quinidine or type IC (e.g., encainide, flecainide, propafenone)

Possible increased plasma clozapine concentrations, potentially resulting in adverse effects1 320

Administer concomitantly with caution; dosage adjustment of either clozapine or antiarrhythmic agent may be necessary1

Anticholinergic agents

Additive anticholinergic effects1

Antidepressants, SSRIs (e.g., citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline)

Modest increases in plasma clozapine concentrations reported with concomitant use of certain SSRIs (i.e., fluoxetine, paroxetine, sertraline), but substantial increases in trough plasma clozapine concentrations reported with concomitant citaloprame f and fluvoxamine1 318

Caution advised; monitor closely and consider reduction in clozapine dosage if used concomitantly1 318

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 therapy1 166 188 237 281 296 318

Caution when clozapine is initiated in patients receiving benzodiazepines1

Caffeine

Possible increased plasma clozapine concentrations, potentially resulting in adverse effects1 320

Carbamazepine

Decreased plasma clozapine concentrations1 320

NMS reported rarely with concomitant use1 147 148 237 255

Concomitant use not recommended1 ; if used concomitantly, consider that discontinuance of carbamazepine may result in increased plasma clozapine concentrations1

Cimetidine

Possible increased plasma clozapine concentrations, potentially resulting in adverse effects1 320

Ciprofloxacin

Possible increased plasma clozapine concentrations, potentially resulting in adverse effectse f

CNS depressants (e.g., opiate analgesics, sedative/hypnotics)

Additive or potentiated CNS effects1

Exercise caution to avoid excessive sedation1

Epinephrine

Possible reversal of epinephrine’s vasopressor effects and subsequent further decrease in blood pressure1

Avoid epinephrine administration in treatment of clozapine-induced hypotension1

Erythromycin

Possible increased plasma clozapine concentrations, potentially resulting in adverse effects1 320

Haloperidol

At least 1 death reported with concomitant use of oral haloperidol and IM clozapine (not commercially available in US)166

Causal relationship not established.166

Hypotensive agents

Additive or potentiated hypotensive effects1

Lithium

Possible increased risk of seizures;292 330 NMS reported rarely with concomitant use147 148 237 255

Myelosuppressive agents

Possible increased risk and/or severity of bone marrow suppression1 3 255 303

Concomitant use contraindicated1 3 5 12 90 141 177 237 255 303

Nicotine (e.g., smoking)

Possible decreased plasma clozapine concentrations, potentially resulting in decreased efficacy of previously effective clozapine dosage1 40 45 108 237

Phenothiazines

Possible increased plasma clozapine concentrations, potentially resulting in adverse effects1 320

Use concomitantly with caution1

Phenytoin

Possible substantially decreased plasma clozapine concentrations, potentially resulting in decreased efficacy of previously effective clozapine dosage1 285

If used concomitantly, monitor carefully for reemergence of psychotic manifestations; adjust clozapine dosage accordingly285

Rifampin

Possible decreased plasma clozapine concentrations, potentially resulting in decreased efficacy of previously effective clozapine dosage1

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 3 46

Relative oral bioavailability of commercially available tablets (25- and 100-mg) is equivalent.1 3 5 Conventional and orally disintegrating tablets387 of clozapine have been shown to be bioequivalent.1 3 5 387

Onset

Pharmacologic effects (e.g., sedation)189 reportedly are apparent within 15 minutes and become clinically important within 1–6 hours.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 or orally disintegrating tablets.1 3 5 218 219 387

Plasma Concentrations

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

Special Populations

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; not known whether crosses placenta or is distributed into milk in humans.1 2 292

Plasma Protein Binding

Approximately 97%.1 3 5

Elimination

Metabolism

Almost completely metabolized in the liver;2 3 desmethyl metabolite has only limited activity, while hydroxylated andn-oxide metabolites 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 3 67

Half-life

8 hours (range: 4–12 hours) after single oral dose and 12 hours (range: 4–66 hours) at steady state.1 3 5 11 38 67 179

Special Populations

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

Stability

Storage

Oral

Conventional Tablets

Store in tight, light-resistant containers at <30°C.1 3 a

Orally disintegrating Tablets

Store in original sealed blister at 25°C (may be exposed to 15–30°C).387 Protect from moisture.387

Actions

  • Exact mechanism of antipsychotic action not fully elucidated;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

  • 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

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.

  • Risk of agranulocytosis.1 Advise patient of drug availability only through special program designed to ensure required blood monitoring and importance of adhering to monitoring schedule.1

  • Importance of immediately informing clinician if lethargy, weakness, fever, sore throat, malaise, mucous membrane ulceration, flu-like symptoms, or other signs of infection occur.1

  • Risk of sedation and impairment of mental and/or physical abilities, especially during initial dosage titration; avoid activities requiring alertness until gain experience with the drug’s effects.1

  • Risk of seizure; avoid driving and other potentially hazardous activity during therapy.1

  • Risk of orthostatic hypotension, particularly during initial dosage titration.1

  • If therapy interrupted for ≥2 days, contact clinician for dosage instructions.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 clinician of existing or contemplated alcohol use.1

  • Importance of informing patients with phenylketonuria that clozapine 25- and 100-mg orally disintegrating tablets contain aspartame.386 387 388 389 390 391

  • 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 (See Cautions.)

Preparations

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

Clozapine is available only through distribution systems that ensure periodic testing of leukocyte and absolute neutrophil counts as a condition of provision of the patient’s next supply of drug. The individual manufacturer should be contacted for additional information on current mechanisms for obtaining the drug.e f g

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

Clozapine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

25 mg*

Clozapine Tablets

Mylan, Teva, UDL

Clozaril (with povidone; scored)

Novartis

100 mg*

Clozapine Tablets

Mylan, Teva, UDL

Clozaril (with povidone; scored)

Novartis

Tablets, orally disintegrating

25 mg

FazaClo (with aspartame; scored)

Alamo

100 mg

FazaClo (with aspartame; scored)

Alamo

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 14, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

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