Clozapine

Common Side Effects of Clozapine

You should tell your doctor if any of the following side effects become severe or don't go away:

• Dizziness
• Drowsiness
• Constipation
• Increased saliva
• Dry mouth
• Restlessness
• Weight gain
• Headache

Serious Side Effects of Clozapine

You should call your doctor immediately if you experience any of the symptoms listed in the Warning section or any of the following serious side effects:

• Seizures
• Shakiness
• Fainting
• Confusion
• Vision changes
• Difficulty urinating or loss of bladder control
• Severe muscle stiffness
• Sweating
• Changes in behavior
• Unusual bruising or bleeding
• Upset stomach
• Loss of appetite
• Yellowing of the skin or eyes
• Pain in the upper right part of the stomach
• Lack of energy
• Flu-like symptoms

CLOZARIL® (clozapine), an atypical antipsychotic drug, is a tricyclic dibenzodiazepine derivative, 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine. The structural formula is

CLOZARIL is available in pale yellow tablets of 25 mg and 100 mg for oral administration.

Active Ingredient: clozapine

Inactive Ingredients are colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch (corn), and talc.

Dosage Forms And Strengths

CLOZARIL (clozapine) is available as 25 mg and 100 mg round, pale-yellow, uncoated tablets with a facilitated score on one side.

Storage And Handling

CLOZARIL® (clozapine) is available as 25 mg and 100 mg round, pale-yellow, uncoated tablets with a facilitated score on one side.

Engraved with “CLOZARIL” once on the periphery of one side.

Engraved with a facilitated score and “25” once on the other side.

Bottle of 100...........................NDC 0078-0126-05
Bottle of 500...........................NDC 0078-0126-08
Unit dose packages of 100: 2 x 5 strips, 10 blisters per strip............................ NDC 0078-0126-06

Engraved with “CLOZARIL” once on the periphery of one side.

Engraved with a facilitated score and “100” once on the other side.

Bottle of 100...........................NDC 0078-0127-05
Bottle of 500...........................NDC 0078-0127-08
Unit dose packages of 100: 2 x 5 strips, 10 blisters per strip............................ NDC 0078-0127-06

Storage temperature should not exceed 30°C (86°F).

Keep out of reach of children.

Revised: Sep 2015

Clozapine is part of the drug class:

• Diazepines, oxazepines, thiazepines and oxepines

Clozapine is an antipsychotic medicine works by changing the actions of chemicals in the brain.

Clozapine is used to treat severe schizophrenia, or to reduce the risk of suicidal behavior in people with schizophrenia or similar disorders.

Clozapine is available only from a certified pharmacy under a special program.

Clozapine may also be used for purposes not listed in this medication guide.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose. If you miss taking clozapine for more than 2 days in a row, call your doctor before you start taking it again.

Usual Adult Dose for Schizophrenia:

Initial dose: 12.5 mg orally once or twice a day
Titration and Maintenance: May increase total daily dose in increments of 25 mg to 50 mg per day to a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of week 2. Subsequent dose increases can be in increments of up to 100 mg once or twice weekly.
Maximum dose: 900 mg per day

Comments:
-The absolute neutrophil count (ANC) must be 1500/microL or greater for the general population and at least 1000/microL for patients with documented Benign Ethnic Neutropenia (BEN) prior to initiating treatment; to continue therapy, the ANC must be monitored regularly.
-A low starting dose, gradual titration, and divided doses are necessary to minimize the risk of orthostatic hypotension, bradycardia, and syncope.
-When therapy is interrupted for 2 or more days, re-initiate with 12.5 mg once or twice a day; based on tolerability, a dose that is restarted may be increased to a previously therapeutic dose more quickly than it was for initial treatment.

Uses:
-For the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment.
-To reduce the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder, who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state.

In the U.S.

• Clozaril
• FazaClo
• Versacloz

Available Dosage Forms:

• Tablet
• Tablet, Disintegrating
• Suspension

Therapeutic Class: Antipsychotic

Chemical Class: Dibenzodiazepine

Overdosage Experience

The most commonly reported signs and symptoms associated with Clozapine overdose are: sedation, delirium, coma, tachycardia, hypotension, respiratory depression or failure; and hypersalivation. There are reports of aspiration pneumonia, cardiac arrhythmias, and seizure. Fatal overdoses have been reported with Clozapine, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g.

Management of Overdosage

For the most up-to-date information on the management of Clozapine overdosage, contact a certified Regional Poison Control Center (1-800-222-1222). Telephone numbers of certified Regional Poison Control Centers are listed in the **Physicians’ Desk Reference®, a registered trademark of PDR Network. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. There are no specific antidotes for Clozapine.

In managing overdosage, consider the possibility of multiple-drug involvement.

Treatment-Resistant Schizophrenia

The efficacy of Clozapine in treatment-resistant schizophrenia was established in a multicenter, randomized, double-blind, active-controlled (chlorpromazine) study in patients with a DSM-III diagnosis of schizophrenia who had inadequate responses to at least 3 different antipsychotics (from at least 2 different chemical classes) during the preceding 5 years. The antipsychotic trials must have been judged adequate; the antipsychotic dosages must have been equivalent to or greater than 1000 mg per day of chlorpromazine for a period of at least 6 weeks, each without significant reduction of symptoms. There must have been no period of good functioning within the preceding 5 years. Patients must have had a baseline score of at least 45 on the investigator-rated Brief Psychiatric Rating Scale (BPRS). On the 18-item BPRS, 1 indicates the absence of symptoms, and 7 indicates severe symptoms; the maximum potential total BPRS score is 126. At baseline, the mean BPRS score was 61. In addition, patients must have had a score of at least 4 on at least two of the following four individual BPRS items: conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content. Patients must have had a Clinical Global Impressions–Severity Scale score of at least 4 (moderately ill).

In the prospective, lead-in phase of the trial, all patients (N=305) initially received single-blind treatment with haloperidol (the mean dose was 61 mg per day) for 6 weeks. More than 80% of patients completed the 6-week trial. Patients with an inadequate response to haloperidol (n=268) were randomized to double-blind treatment with Clozapine (N=126) or chlorpromazine (N=142). The maximum daily Clozapine dose was 900 mg; the mean daily dose was >600 mg. The maximum daily chlorpromazine dose was 1800 mg; the mean daily dose was >1200 mg.

The primary endpoint was treatment response, predefined as a decrease in BPRS score of at least 20% and either (1) a CGI-S score of ≤3 (mildly ill), or (2) a BPRS score of ≤35, at the end of 6 weeks of treatment. Approximately 88% of patients from the Clozapine and chlorpromazine groups completed the 6-week trial. At the end of 6 weeks, 30% of the Clozapine group responded to treatment, and 4% of the chlorpromazine group responded to treatment. The difference was statistically significant (p <0.001). The mean change in total BPRS score was -16 and -5 in the Clozapine and chlorpromazine group, respectively; the mean change in the 4 key BPRS item scores was -5 and -2 in the Clozapine and chlorpromazine group, respectively; and the mean change in CGI-S score was -1.2 and -0.4, in the Clozapine and chlorpromazine group, respectively. These changes in the Clozapine group were statistically significantly greater than in the chlorpromazine group (p<0.001 in each analysis).

Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder

The effectiveness of Clozapine in reducing the risk of recurrent suicidal behavior was assessed in the International Suicide Prevention Trial (InterSePT™, a trademark of Novartis Pharmaceuticals Corporation). This was a prospective, randomized, open-label, active-controlled, multicenter, international, parallel-group comparison of Clozapine versus olanzapine (*Zyprexa®, a registered trademark of Eli Lilly and Company) in 956 patients with schizophrenia or schizoaffective disorder (DSM-IV) who were judged to be at risk for recurrent suicidal behavior. Only about one-fourth of these patients (27%) were considered resistant to standard antipsychotic drug treatment. To enter the trial, patients must have met 1 of the following criteria:

• They had attempted suicide within the three years prior to their baseline evaluation.
• They had been hospitalized to prevent a suicide attempt within the three years prior to their baseline evaluation.
• They demonstrated moderate-to-severe suicidal ideation with a depressive component within one week prior to their baseline evaluation.
• They demonstrated moderate-to-severe suicidal ideation accompanied by command hallucinations to do self-harm within one week prior to their baseline evaluation.

Dosing regimens for each treatment group were determined by individual investigators and were individualized by patient. Dosing was flexible, with a dose range of 200–900 mg/day for Clozapine and 5–20 mg/day for olanzapine. For the 956 patients who received Clozapine or olanzapine in this study, there was extensive use of concomitant psychotropics: 84% with antipsychotics, 65% with anxiolytics, 53% with antidepressants, and 28% with mood stabilizers. There was significantly greater use of concomitant psychotropic medications among the patients in the olanzapine group.

The primary efficacy measure was time to (1) a significant suicide attempt, including a completed suicide; (2) hospitalization due to imminent suicide risk, including increased level of surveillance for suicidality for patients already hospitalized; or (3) worsening of suicidality severity as demonstrated by “much worsening” or “very much worsening” from baseline in the Clinical Global Impression of Severity of Suicidality as assessed by the Blinded Psychiatrist (CGI-SS-BP) scale. A determination of whether or not a reported event met criterion 1 or 2 above was made by the Suicide Monitoring Board (SMB), a group of experts blinded to patient data.

A total of 980 patients were randomized to the study and 956 received study medication. Sixty-two percent of the patients were diagnosed with schizophrenia, and the remainder (38%) were diagnosed with schizoaffective disorder. Only about one-fourth of the total patient population (27%) was identified as “treatment-resistant” at baseline. There were more males than females in the study (61% of all patients were male). The mean age of patients entering the study was 37 years of age (range 18–69). Most patients were Caucasian (71%), 15% were Black, 1% were Asian, and 13% were classified as being of “other” races.

Patients treated with Clozapine had a statistically significant longer delay in the time to recurrent suicidal behavior in comparison with olanzapine. This result should be interpreted only as evidence of the effectiveness of Clozapine in delaying time to recurrent suicidal behavior and not a demonstration of the superior efficacy of Clozapine over olanzapine.

The probability of experiencing (1) a significant suicide attempt, including a completed suicide, or (2) hospitalization because of imminent suicide risk, including increased level of surveillance for suicidality for patients already hospitalized, was lower for Clozapine patients than for olanzapine patients at Week 104: Clozapine 24% versus olanzapine 32%; 95% CI of the difference: 2%, 14% (Figure 1).

Figure 1. Cumulative Probability of a Significant Suicide Attempt or Hospitalization to Prevent Suicide in Patients with Schizophrenia or Schizoaffective Disorder at High Risk of Suicidality

Discuss the following issues with patients and caregivers:

• Severe Neutropenia:
  • Instruct patients (and caregivers) beginning treatment with Clozapine tablets about the risk of developing severe neutropenia and infection.
  • Instruct patients to immediately report to their physician any symptom or sign of infection (e.g., flu-like illness; fever; lethargy; general weakness or malaise; mucus membrane ulceration; skin, pharyngeal, vaginal, urinary, or pulmonary infection; or extreme weakness or lethargy) occurring at any time during Clozapine therapy, to aid in evaluation for neutropenia and to institute prompt and appropriate management. [see Warnings and Precautions (5.1), (5.11), and (5.13)].
  • Inform patients and caregivers Clozapine is available only through a restricted program called the Clozapine REMS Program designed to ensure the required blood monitoring, in order to reduce the risk of developing severe neutropenia. Advise patients and caregivers of the importance of having blood tested as follows:
    • Weekly blood tests are required for the first 6 months.
    • An ANC is required every 2 weeks for the next 6 months if an acceptable ANC is maintained during the first 6 months of continuous therapy,
    • An ANC is required once every 4 weeks thereafter if an acceptable ANC is maintained during the second 6 months of continuous therapy.
  • Clozapine is available only from certified pharmacies participating in the program. Provide patients (and caregivers) with website information and the telephone number on how to obtain the product (www.Clozapinerems.com or 1-844-267-8678) [see Warnings and Precautions (5.2)].
• Orthostatic Hypotension, Bradycardia, and Syncope: Inform patients and caregivers about the risk of orthostatic hypotension and syncope, especially during the period of initial dose titration. Instruct them to strictly follow the clinician’s instructions for dosage and administration. Advise patients to consult their clinician immediately if they feel faint, lose consciousness or have signs or symptoms suggestive of bradycardia or arrhythmia [see Dosage and Administration (2.2) and Warnings and Precautions (5.3)].
• Seizures: Inform patients and caregivers about the significant risk of seizure during Clozapine treatment. Caution them about driving and any other potentially hazardous activity while taking Clozapine [see Warnings and Precautions (5.5)].
• QT Interval Prolongation: Advise patients to consult their clinician immediately if they feel faint, lose consciousness or have signs or symptoms suggestive of arrhythmia. Instruct patients to not take Clozapine with other drugs that cause QT interval prolongation. Instruct patients to inform their clinicians that they are taking Clozapine before any new drug [see Warnings and Precautions (5.9) and Drug Interactions (7.1)].
• Metabolic Changes (hyperglycemia and diabetes mellitus, dyslipidemia, weight gain): Educate patients and caregivers about the risk of metabolic changes and the need for specific monitoring. The risks include hyperglycemia and diabetes mellitus, dyslipidemia, weight gain, and cardiovascular reactions. Educate patients and caregivers about the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus (e.g., polydipsia, polyuria, polyphagia, and weakness). Monitor all patients for these symptoms. Patients who are diagnosed with diabetes or have risk factors for diabetes (obesity, family history of diabetes) should have their fasting blood glucose monitored before beginning treatment and periodically during treatment. Patients who develop symptoms of hyperglycemia should have assessments of fasting glucose. Clinical monitoring of weight is recommended [see Warnings and Precautions (5.10)].
• Interference with Cognitive and Motor Performance: Because Clozapine may have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Clozapine therapy does not affect them adversely [see Warnings and Precautions (5.16)].
• Missed Doses and Re-initiating Treatment: Inform patients and caregivers that if the patient misses taking Clozapine for more than 2 days, they should not restart their medication at the same dosage but should contact their physician for dosing instructions [see Dosage and Administration (2.5) and Warnings and Precautions (5.1, 5.3)].
• Pregnancy: Patients and caregivers should notify the clinician if the patient becomes pregnant or intends to become pregnant during therapy [see Use in Specific Populations (8.1)].
• Nursing: Advise patients and caregivers that the patient should not breastfeed an infant if they are taking Clozapine [see Use in Specific Populations (8.3)].
• Concomitant Medication: Advise patients to inform their healthcare provider if they are taking, or plan to take, any prescription or over-the-counter drugs; there is a potential for significant drug-drug interactions [see Dosage and Administration (Table 1].

*Zyprexa® (olanzapine) is a registered trademark of Eli Lilly and Company.

**Trademark of Thomson Healthcare, Inc.

Distributed by:

Sandoz Inc.

Princeton, NJ 08540

2017B0012

February 2017

Clozapine concentrations may be increased.

There are no dosage adjustments provided in the manufacturer's labeling; however, labeling suggests that dose reductions may be necessary with significant impairment but does not provide specific dosing recommendations. Alternatively, an initial dose of 12.5 mg once daily has been recommended for patients with mild to moderate impairment (Clozaril Canadian product labeling 2016).

Administer without regard to food. Total daily dose may be divided into uneven doses with larger dose administered at bedtime.

Orally disintegrating tablet: Remove from foil blister by peeling apart (do not push tablet through the foil). Remove immediately prior to use. Place tablet in mouth and chew or allow to dissolve; swallow with saliva. If dosing requires splitting tablet, throw unused portion away.

Suspension: Shake bottle prior to use. Using syringe adaptor and oral syringe provided withdrawal dose from bottle. Administer immediately after preparation using the oral syringe provided.

Some products may contain phenylalanine.

Clozapine treatment has caused severe neutropenia, defined as an absolute neutrophil count (ANC) less than 500/mcL. Severe neutropenia can lead to serious infection and death. Prior to initiating treatment, a baseline ANC must be at least 1,500/mcL for the general population and must be at least 1,000/mcL for patients with documented Benign Ethnic Neutropenia. During treatment, patients must have regular ANC monitoring. Advise patients to immediately report symptoms consistent with severe neutropenia or infection (eg, fever, weakness, lethargy, sore throat).

Because of the risk of severe neutropenia, clozapine is available only through a restricted program under a Risk Evaluation Mitigation Strategy (REMS) called the Clozapine REMS Program.

Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have occurred with treatment. The risk is highest during the initial titration period, particularly with rapid dose escalation. These reactions can occur with the first dose, with dosages as low as 12.5 mg/day. Initiate treatment at 12.5 mg once or twice daily, titrate slowly, and use divided dosages. Use cautiously in patients with cardiovascular or cerebrovascular disease or conditions predisposing to hypotension (eg, dehydration, use of antihypertensive medications).

Seizures have occurred with treatment. The risk is dose-related. Initiate treatment at 12.5 mg, titrate gradually, and use divided dosing. Use caution when administering to patients with a history of seizures or other predisposing risk factors for seizure (CNS pathology, medications that lower the seizure threshold, alcohol abuse). Caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others.

Fatal myocarditis and cardiomyopathy have occurred with treatment. Discontinue clozapine and obtain a cardiac evaluation upon suspicion of these reactions. Generally, patients with clozapine-related myocarditis or cardiomyopathy should not be rechallenged with clozapine. Consider the possibility of myocarditis or cardiomyopathy if chest pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, hypotension, or electrocardiogram (ECG) changes occur.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Clozapine is not approved for use in patients with dementia-related psychosis.

Applies to clozapine: oral suspension, oral tablet, oral tablet disintegrating

General

The most commonly reported side effects included salivary hypersecretion, somnolence, and weight gain.[Ref]

Gastrointestinal

Very common (10% or more): Salivary hypersecretion/hypersalivation (up to 48%), salivation (up to 31%), constipation (up to 25%), nausea (up to 17%), vomiting (up to 17%), dyspepsia (up to 14%)
Common (1% to 10%): Abdominal discomfort/dyspepsia/heartburn, diarrhea, dry mouth
Rare (0.01% to 0.1%): Acute pancreatitis, Dysphagia, ileus impaction, pancreatitis
Very rare (less than 0.01%): Fecal impaction/intestinal obstruction/paralytic ileus, parotid gland enlargement
Frequency not reported: Colitis, swallowing difficulty, tongue protrusion
Postmarketing reports: Intestinal infarction/ischemia/fatal intestinal infarction/ischemia, megacolon/fatal megacolon, salivary gland swelling[Ref]

Nervous system

Very common (10% or more): Somnolence (up to 46%), drowsiness/sedation (up to 39%), dizziness (up to 27%), vertigo (up to 19%), headache (up to 10%)
Common (1% to 10%): Akathisia, akinesia, convulsions/myoclonic jerks/seizures, dysarthria, extrapyramidal symptoms, hypokinesia, syncope, tremor
Uncommon (0.1% to 1%): Neuroleptic malignant syndrome
Very rare (less than 0.01%): Tardive dyskinesia
Frequency not reported: Dystonia
Postmarketing reports: Abnormal EEG, cholinergic syndrome, clozapine-induced seizures, EEG changes, motor instability, myasthenic syndrome, myoclonus, paresthesia, pleurothotonus, possible cataplexy, post-discontinuation cholinergic rebound adverse reactions, sensory instability, status epilepticus[Ref]

The cumulative incidence of seizure at 1 year is approximately 5% based on pre-marketing testing. The risk is dose-related.

Extrapyramidal symptoms that occur appear to be milder and less frequent than other antipsychotic drugs. There have been no reports of tardive dyskinesia directly attributable to clozapine; however, the syndrome has been reported in a few patients who were treated with other antipsychotics prior to receiving clozapine. A causal relationship can neither be established nor excluded.

Cholinergic syndrome occurred after abrupt withdrawal.[Ref]

Metabolic

Diabetes mellitus occurred in patients without a history of hyperglycemia or diabetes mellitus.

Pooled data from 8 studies in patients with schizophrenia found the mean change in fasting blood glucose in clozapine treated patients was +11 mg/dL; pooled data from 10 studies revealed clozapine treatment was associated a mean increase of 13 mg/dl in total cholesterol; pooled data from 11 studies showed a weight gain of 7% or greater relative to baseline body weight occurred in 35% of patients with a mean weight gain of 3.7 kg.[Ref]

Very common (10% or more): Increased weight/weight gain (up to 31%)
Common (1% to 10%): Anorexia
Rare (0.01% to 0.1%): Aggravated diabetes, diabetes mellitus, hyperosmolar coma, impaired glucose tolerance, ketoacidosis, severe hyperglycemia
Very rare (less than 0.01%): Hypercholesterolemia, hypertriglyceridemia
Frequency not reported: Pseudopheochromocytoma
Postmarketing reports: Hypernatremia, hyperuricemia, obesity, weight loss[Ref]

Cardiovascular

Very common (10% or more): Tachycardia (up to 25%), hypotension (up to 13%), hypertension (up to 12%)
Common (1% to 10%): ECG changes, postural hypotension
Rare (0.01% to 0.1%): Arrhythmias, circulatory collapse, myocarditis, pericardial effusion, pericarditis, thromboembolism, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia
Very rare (less than 0.01%): Cardiac arrest, cardiomyopathy/clozapine-related cardiomyopathy, QT prolongation, skin reactions, Torsade de pointes
Frequency not reported: Angina pectoris/chest pain, myocardial infarction/fatal myocardial infarction, pigmentation disorder, venous thromboembolism
Postmarketing reports: Atrial fibrillation, deep vein thrombosis, mitral valve incompetence, palpitations[Ref]

Isolated cases of cardiac arrhythmias, pericarditis/pericardial effusion, and myocarditis have been reported. Postmarketing, very rare events of ventricular tachycardia, cardiac arrest, and QT prolongation which may be associated with Torsades de pointes have been observed, although there is no conclusive causal relationship to use of this drug.[Ref]

Psychiatric

Very common (10% or more): Insomnia (up to 20%)
Common (1% to 10%): Agitation, confusion, disturbed sleep/nightmares, restlessness
Uncommon (0.1% to 1%): Dysphemia
Rare (0.01% to 0.1%): Delirium, dream activity intensification
Very rare (less than 0.01%): Obsessive compulsive disorder/symptoms
Frequency not reported: Neonatal drug withdrawal syndrome[Ref]

Other

Very common (10% or more): Fever/hyperthermia (up to 13%)
Common (1% to 10%): Benign hyperthermia, fatigue, temperature regulation disturbance
Very rare (less than 0.01%): Sudden unexplained death
Postmarketing reports: Falls, polyserositis, sepsis[Ref]

Hematologic

Common (1% to 10%): Decreased white blood cells, eosinophilia, leukocytosis, leukopenia, neutropenia
Uncommon (0.1% to 1%): Agranulocytosis
Rare (0.01% to 0.1%): Anemia
Very rare (less than 0.01%): Thrombocythemia, thrombocytopenia
Postmarketing reports: Elevated hematocrit, elevated hemoglobin, granulocytopenia, increased erythrocyte sedimentation rate, mild leukopenia, moderate leukopenia, severe leukopenia, thrombocytosis[Ref]

During pre-marketing testing, the cumulative incidence of agranulocytosis at one year was reported to be 1.3%. Based on Clozaril National Registry (US patients) data collected up to April 1995, a hematologic risk analysis found the incidence of agranulocytosis rises steeply during the first 2 months, peaks at approximately the third month, and decreases at 6 months of therapy; after 6 months, the incidence decreases further, however, it never reaches zero. Individuals with an initial episode of moderate leukopenia (WBC of at least 2000/mm3 and less than 3000/mm3) are at an increased risk of having a subsequent episode of agranulocytosis.

In the UK, agranulocytosis occurred within the first 18 weeks in approximately 70% of patients who developed the condition.

In clinical trials, eosinophil counts of greater than 700/mm3 occurred in approximately 1% of patients. Eosinophilia has been co-reported with some cases of myocarditis (approximately 14%) and pericarditis/pericardial effusion, although it is unknown whether eosinophilia is a reliable predictor of carditis.[Ref]

Genitourinary

Common (1% to 10%): Urinary abnormalities, urinary incontinence, urinary retention
Very rare (less than 0.01%): Dysmenorrhea, ejaculation change, impotence, priapism
Postmarketing reports: Nocturnal enuresis, retrograde ejaculation[Ref]

Dermatologic

Common (1% to 10%): Rash, sweating/sweating disturbance
Frequency not reported: Leukocytoclastic vasculitis
Postmarketing reports: Erythema multiforme, photosensitivity, skin pigmentation disorder, Stevens-Johnson syndrome[Ref]

Ocular

Common (1% to 10%): Blurred vision, visual disturbances
Postmarketing reports: Narrow angle glaucoma, periorbital edema[Ref]

Hepatic

Common (1% to 10%): Elevated liver enzymes
Rare (0.01% to 0.1%): Cholestasis, cholestatic jaundice, hepatitis
Very rare (less than 0.01%): Fulminant hepatic necrosis
Postmarketing reports: Cholestatic injury, hepatic cirrhosis, hepatic fibrosis, hepatic injury, hepatic necrosis, hepatic steatosis, hepatotoxicity, jaundice, liver failure, liver transplant, mixed injury[Ref]

Musculoskeletal

Common (1% to 10%): Rigidity
Rare (0.01% to 0.1%): Creatine phosphokinase elevation
Frequency not reported: Muscle pain, muscle spasms, muscle weakness, neck muscle spasm, systemic lupus erythematosus
Postmarketing reports: Rhabdomyolysis[Ref]

Respiratory

Aspiration of ingested food usually occurred in patients with dysphagia or in acute overdose.[Ref]

Rare (0.01% to 0.1%): Aspiration of ingested food, lower respiratory tract infection/fatal lower respiratory tract infection, pneumonia, pulmonary embolism, respiratory arrest, respiratory depression, respiratory depression/arrest with/without circulatory collapse
Very rare (less than 0.01%): Allergic asthma
Frequency not reported: Difficulty breathing, nasal congestion, throat tightness
Postmarketing reports: Pleural effusion, sleep apnea/sleep apnea syndrome[Ref]

Renal

Very rare (less than 0.01%): Acute interstitial nephritis/interstitial nephritis
Postmarketing reports: Renal failure[Ref]

Hypersensitivity

Frequency not reported: Angioedema
Postmarketing reports: hypersensitivity reactions[Ref]

Endocrine

Postmarketing reports: Pseudopheochromocytoma[Ref]

Some side effects of clozapine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Use with caution; dose reduction may be necessary in patients with significant renal impairment

There is limited data regarding use of this drug during breastfeeding. Because sedation and adverse hematologic effects have been reported, other agents are preferred. In 4 breastfed infants, 1 experienced sedation and 1 agranulocytosis; specific details of these cases are not available.

Use should be avoided; discontinue drug or discontinue nursing taking into consideration importance of drug to mother. Excreted into human milk: Yes Comments: If breastfeeding is undertaken, closely monitor breastfed infant for excessive sedation and periodically monitor WBC.