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
AUDIENCE: Psychiatry, Pharmacy, Hematology
ISSUE: FDA is making changes to the requirements for monitoring, prescribing, dispensing, and receiving the schizophrenia medicine clozapine, to address continuing safety concerns and current knowledge about a serious blood condition called severe neutropenia. Severe neutropenia is a dangerously low number of neutrophils, white blood cells that help fight infections. Severe neutropenia can be life-threatening.
There are two parts to the changes in the requirements for treating patients with clozapine. First, FDA clarified and enhanced the prescribing information for clozapine that explains how to monitor patients for neutropenia and manage clozapine treatment. Second, FDA approved a new, shared risk evaluation and mitigation strategy (REMS) called the Clozapine REMS Program. The revised prescribing information and the Clozapine REMS Program will improve monitoring and management of patients with severe neutropenia. The shared REMS is also expected to reduce the burden and possible confusion related to having separate registries for individual clozapine medicines. The requirements to monitor, prescribe, dispense, and receive all clozapine medicines are now incorporated into the Clozapine REMS Program.
BACKGROUND: Clozapine is an antipsychotic medicine used to treat schizophrenia in patients whose symptoms are not controlled with standard antipsychotic treatment. It is also used to treat recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder.
RECOMMENDATION: Patients who are currently treated with clozapine will be automatically transferred to the Clozapine REMS Program. In order to prescribe and dispense clozapine, prescribers and pharmacies will be required to be certified in the Clozapine REMS Program according to a specific transition schedule starting October 12, 2015 (see Additional Information for Prescribers, Additional Information for Pharmacies, and Additional Information for Patients and Caregivers sections of the Drug Safety Communication at: for more details).
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 .
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.
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.)
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.)
- 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
- 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.
Uses for Clozapine
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.)
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
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
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.)
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
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
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
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
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
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
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
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
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
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
Maximum 900 mg daily.1
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
Uncontrolled seizure disorder.1
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
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
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
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.)
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.)
Frequency of WBC and ANC Monitoring
Initiation of therapy and first 6 months of therapy
Do not initiate in patients with a history of myeloproliferative disorder or clozapine-induced agranulocytosis or granulocytopenia
During second 6 months of therapy
All results for WBC ≥3500/mm3 and ANC ≥2000/mm3
After 12 months of therapy
All results for WBC ≥3500/mm3 and ANC ≥2000/mm3
Immature forms present
Discontinuance of therapy
Substantial decrease in WBC or ANC
Single decrease or cumulative decrease within 3 weeks of WBC ≥3000/mm3 or ANC ≥1500/mm3
Mild leukopenia/mild granulocytopenia
WBC ≥3000/mm3 but <3500/mm3 and/or ANC ≥1500/mm3 but <2000/mm3
Moderate leukopenia/moderate granulocytopenia
WBC ≥2000/mm3 but <3000/mm3 and/or ANC ≥1000/mm3 but <1500/mm3
Severe leukopenia/severe granulocytopenia
WBC <2000/mm3 and/or ANC <1000/mm3
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
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
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
Previous therapy duration <6 months, with no abnormal blood event and interruption in therapy >1 month
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)
Previous therapy duration 6–12 months, with no abnormal blood event and interruption in therapy≥3 days but ≤1 month
Previous therapy duration 6–12 months, with no abnormal blood event and interruption in therapy >1 month
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)
Previous therapy duration >12 months, with no abnormal blood event and interruption in therapy≥3 days but ≤1 month
Previous therapy duration >12 months, with no abnormal blood event and interruption in therapy >1 month
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)
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
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
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
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
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
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
Due to initial sedative effects, closely follow recommendation for gradual dosage escalation.1
Risk of pulmonary embolism; consider possibility of pulmonary embolism in patients with DVT, acute dyspnea, chest pain, or other respiratory manifestations.1
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
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
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
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.
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.)
Use with caution in patients with hepatic disease.1 (See Hepatic Effects under Cautions.)
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
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
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
Additive CNS effects1
Avoid concomitant use1
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)
Administer concomitantly with caution; dosage adjustment of either clozapine or antiarrhythmic agent may be necessary1
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
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
CNS depressants (e.g., opiate analgesics, sedative/hypnotics)
Additive or potentiated CNS effects1
Exercise caution to avoid excessive sedation1
Possible reversal of epinephrine’s vasopressor effects and subsequent further decrease in blood pressure1
Avoid epinephrine administration in treatment of clozapine-induced hypotension1
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
Additive or potentiated hypotensive effects1
Nicotine (e.g., smoking)
Use concomitantly with caution1
If used concomitantly, monitor carefully for reemergence of psychotic manifestations; adjust clozapine dosage accordingly285
Possible decreased plasma clozapine concentrations, potentially resulting in decreased efficacy of previously effective clozapine dosage1
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
Plasma Protein Binding
In patients with poor metabolizer phenotypes of CYP2D6, increased plasma clozapine concentrations are possible at usual dosages.1
Orally disintegrating Tablets
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
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 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.)
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 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
Mylan, Teva, UDL
Clozaril (with povidone; scored)
Mylan, Teva, UDL
Clozaril (with povidone; scored)
Tablets, orally disintegrating
FazaClo (with aspartame; scored)
FazaClo (with aspartame; scored)
AHFS DI Essentials. © Copyright, 2004-2016, Selected Revisions September 16, 2015. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
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