Clozapin: Fachinformation – Dosierung, Gegenanzeigen, Wechselwirkungen, Nebenwirkungen

Clozapine Tablets USP, 25 mg are pale yellow colored, round, flat faced, bevel edged uncoated tablets debossed with ‘C facilitated scoreline (functional) C’ on one side and ‘54’ on the other side.
Clozapine Tablets USP, 50 mg are pale yellow colored, round, flat faced, bevel edged uncoated tablets debossed with ‘C facilitated scoreline (functional) C’ on one side and ‘55’ on the other side.
Clozapine Tablets USP, 100 mg are pale yellow colored, round, flat faced, bevel edged uncoated tablets debossed with ‘C facilitated scoreline (functional) C’ on one side and ‘57’ on the other side.
Clozapine Tablets USP, 200 mg are pale yellow colored, oval shaped, uncoated tablets debossed with ‘C scoreline (functional) C’ on one side and ‘71’ on the other side.

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Severe Neutropenia [see Warnings and Precautions (5.1)]
• Orthostatic Hypotension, Bradycardia, and Syncope [see Warnings and Precautions (5.2)]
• Falls [see Warnings and Precautions (5.3)]
• Seizures [see Warnings and Precautions (5.4)]
• Myocarditis, Pericarditis, Cardiomyopathy, and Mitral Valve Incompetence [see Warnings and Precautions (5.5)]
• Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions (5.6)]
• Gastrointestinal Hypomotility with Severe Complications [See Warnings and Precautions (5.7)]
• Eosinophilia [see Warnings and Precautions (5.8)]
• QT Interval Prolongation [see Warnings and Precautions (5.9)]
• Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) [see Warnings and Precautions (5.10)]
• Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.11)]
• Hepatotoxicity [see Warnings and Precautions (5.12)]
• Fever [see Warnings and Precautions (5.13)]
• Pulmonary Embolism [see Warnings and Precautions (5.14)]
• Anticholinergic Toxicity [see Warnings and Precautions (5.15)]
• Interference with Cognitive and Motor Performance [see Warnings and Precautions (5.16)]
• Tardive Dyskinesia [see Warnings and Precautions (5.17)]
• Cerebrovascular Adverse Reactions [see Warnings and Precautions (5.18)]
• Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation [see Warnings and Precautions (5.19)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The most commonly reported adverse reactions (≥5%) across clozapine clinical trials were: CNS reactions, including sedation, dizziness/vertigo, headache, and tremor; cardiovascular reactions, including tachycardia, hypotension, and syncope; autonomic nervous system reactions, including hypersalivation, sweating, dry mouth, and visual disturbances; gastrointestinal reactions, including constipation and nausea; and fever. Table 9 summarizes the most commonly reported adverse reactions (≥5%) in clozapine-treated patients (compared to chlorpromazine-treated patients) in the pivotal, 6-week, controlled trial in treatment-resistant schizophrenia.

Table 9. Common Adverse Reactions (≥5%) in the 6-Week, Randomized, Chlorpromazine-controlled Trial in Treatment-Resistant Schizophrenia
Adverse Reaction | Clozapine (N=126) (%) | Chlorpromazine (N=142) (%)
Sedation | 21 | 13
Tachycardia | 17 | 11
Constipation | 16 | 12
Dizziness | 14 | 16
Hypotension | 13 | 38
Fever (hyperthermia) | 13 | 4
Hypersalivation | 13 | 1
Hypertension | 12 | 5
Headache | 10 | 10
Nausea/vomiting | 10 | 12
Dry mouth | 5 | 20

Table 10 summarizes the adverse reactions reported in clozapine-treated patients at a frequency of 2% or greater across all clozapine studies (excluding the 2-year InterSePT™ Study). These rates are not adjusted for duration of exposure.

Table 10. Adverse Reactions (≥2%) Reported in Clozapine-treated Patients (N=842) Across all Clozapine Studies (excluding the 2-year InterSePTTM Study)
Body System Adverse Reaction* | Clozapine N=842 Percentage of Patients
Central Nervous System |
Drowsiness/Sedation | 39
Dizziness/Vertigo | 19
Headache | 7
Tremor | 6
Syncope | 6
Disturbed Sleep/Nightmares | 4
Restlessness | 4
Hypokinesia/Akinesia | 4
Agitation | 4
Seizures (convulsions) | 3†
Rigidity | 3
Akathisia | 3
Confusion | 3
Fatigue | 2
Insomnia | 2
Cardiovascular |
Tachycardia | 25†
Hypotension | 9
Hypertension | 4
Gastrointestinal |
Constipation | 14
Nausea | 5
Abdominal Discomfort/Heartburn | 4
Nausea/Vomiting | 3
Vomiting | 3
Diarrhea | 2
Urogenital |
Urinary Abnormalities | 2
Autonomic Nervous System |
Salivation | 31
Sweating | 6
Dry Mouth | 6
Visual Disturbances | 5
Skin |
Rash | 2
Hemic/Lymphatic |
Leukopenia/Decreased WBC/Neutropenia | 3
Miscellaneous |
Fever | 5
Weight Gain | 4
†Rate based on population of approximately 1700 exposed during premarket clinical evaluation of clozapine.

Table 11 summarizes the most commonly reported adverse reactions (≥10% of the clozapine or olanzapine group) in the InterSePT™ Study. This was an adequate and well-controlled, two-year study evaluating the efficacy of clozapine relative to olanzapine in reducing the risk of suicidal behavior in patients with schizophrenia or schizoaffective disorder. The rates are not adjusted for duration of exposure.

Table 11. Incidence of Adverse Reactions in Patients Treated with Clozapine or Olanzapine in the InterSePTTM Study (≥10% in the Clozapine or olanzapine group)
Adverse Reactions | Clozapine N=479 % Reporting | Olanzapine N=477 % Reporting
Salivary hypersecretion | 48 | 6
Somnolence | 46 | 25
Weight increased | 31 | 56
Dizziness (excluding vertigo) | 27 | 12
Constipation | 25 | 10
Insomnia | 20 | 33
Nausea | 17 | 10
Vomiting | 17 | 9
Dyspepsia | 14 | 8

Dystonia
Class effect : Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of clozapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Central Nervous System
Delirium, EEG abnormal, myoclonus, paresthesia, possible cataplexy, status epilepticus, obsessive compulsive symptoms, restless leg syndrome and post-discontinuation cholinergic rebound adverse reactions.

Cardiovascular System
Atrial or ventricular fibrillation, ventricular tachycardia, palpitations, QT interval prolongation, Torsades de Pointes, mitral valve incompetence associated with clozapine-related cardiomyopathy, myocardial infarction, cardiac arrest, myocarditis, pericarditis, and periorbital edema.

Endocrine System
Pseudopheochromocytoma
Gastrointestinal System
Acute pancreatitis, dysphagia, salivary gland swelling, colitis, megacolon, fecal incontinence, and intestinal ischemia, infarction, perforation, ulceration or necrosis.

Hepatobiliary System
Cholestasis, hepatitis, jaundice, hepatotoxicity, hepatic steatosis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, liver injury (hepatic, cholestatic, and mixed), and liver failure.

Immune System Disorders

Angioedema, leukocytoclastic vasculitis.
Urogenital System
Acute interstitial nephritis, nocturnal enuresis, priapism, renal failure, and retrograde ejaculation.
Skin and Subcutaneous Tissue Disorders
Hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, skin pigmentation disorder, and Stevens-Johnson Syndrome.
Musculoskeletal System and Connective Tissue Disorders

Myasthenic syndrome, rhabdomyolysis, and systemic lupus erythematosus.
Respiratory System
Aspiration, pleural effusion, pneumonia, lower respiratory tract infection, sleep apnea.

Hemic and Lymphatic System
Mild, moderate, or severe leukopenia, agranulocytosis, granulocytopenia, WBC decreased, deep-vein thrombosis, elevated hemoglobin/hematocrit, erythrocyte sedimentation rate (ESR) increased, sepsis, thrombocytosis, and thrombocytopenia.

Vision Disorders
Narrow-angle glaucoma.

Miscellaneous
Creatine phosphokinase elevation, hyperuricemia, hyponatremia, polyserositis, and weight loss.

5.1 Severe Neutropenia

Clozapine has caused severe neutropenia (absolute neutrophil count (ANC) less than 500/μL) [see Adverse Reactions (6.1, 6.2)] and is associated with an increased risk of serious and potentially fatal infections. Severe neutropenia occurred in a small percentage of clozapine-treated patients. The risk of severe neutropenia appears greatest during the first 18 weeks of clozapine treatment. The mechanism by which clozapine causes neutropenia is unknown. Neutropenia is not dose dependent.

Consider a hematology consultation before initiating clozapine treatment or during treatment.

ANC Monitoring and Dosage Modifications

Prior to initiating clozapine treatment, obtain a baseline ANC. Clozapine initiation is not recommended in patients with a baseline ANC less than 1500/μL. Throughout clozapine treatment, regularly monitor ANC. Table 1 provides recommendations for dosage modifications (dosage interruption and treatment discontinuation), based on ANC levels, during clozapine treatment and frequency of ANC monitoring [see Dosage and Administration (2.3)].

ANC Monitoring and Dosage Modification in Patients with Benign Ethnic Neutropenia

Patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count) generally have lower baseline neutrophil counts but they are not at higher risk for developing infections, and they are not at increased risk for developing clozapine-induced neutropenia.

For patients with documented BEN, obtain at least two baseline ANC levels prior to clozapine initiation. Clozapine initiation is not recommended in patients with BEN with an ANC less than 1000/μL. There are different ANC dosage modification recommendations in clozapine-treated patients with BEN due to their lower baseline ANC levels. Table 2 provides recommendations on dosage modifications (dosage interruption and treatment discontinuation), based on ANC monitoring, during clozapine treatment in patients with BEN and recommended frequency of ANC testing [see Dosage and Administration (2.4)].

Management of Clozapine-Treated Patients Who Develop a Fever

For patients who develop a fever during clozapine treatment:

• Interrupt clozapine in those who develop a temperature of 101.3°F (38.5°C) or greater and obtain an ANC level.
• If the ANC is less than 1000/μL in patients without BEN, initiate appropriate workup and treatment for infection. Refer to Table 1 or Table 2 for dosage modifications based on ANC monitoring [see Dosage and Administration (2.3, 2.4)].

In patients with fever and a normal neutrophil count, see Warnings and Precautions (5.11) for neuroleptic malignant syndrome and Warnings and Precautions (5.13) for fever.

Restarting Clozapine in Patients Who Recovered from Severe Neutropenia

Generally, do not rechallenge patients with clozapine in those who experienced severe neutropenia. However, for some patients who had resolution of their clozapine-related severe neutropenia after stopping clozapine, the risk of schizophrenia exacerbation from not restarting clozapine treatment may be greater than the risk of neutropenia reoccurrence from restarting clozapine (e.g., patients who have no treatment options other than clozapine).

Concomitant Use of Clozapine with Other Drugs Known to Cause Neutropenia

If clozapine is used concomitantly with another drug known to cause neutropenia, consider more frequently ANC monitoring than the recommendations provided in Table 1 and Table 2.

5.2 Orthostatic Hypotension, Bradycardia, and Syncope

Hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment. The risk is highest during the initial titration period, particularly with rapid dose-escalation. These reactions can occur with the first dose, at doses as low as 12.5 mg. These reactions can be fatal. The syndrome is consistent with neurally mediated reflex bradycardia (NMRB).

Treatment must begin at a maximum dose of 12.5 mg once daily or twice daily. The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks. Subsequently, the dose can be increased weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. Use cautious titration and a divided dosage schedule to minimize the risk of serious cardiovascular reactions [see Dosage and Administration (2.2)]. Consider reducing the dose if hypotension occurs. When restarting clozapine in patients who have had even a brief interruption in treatment with clozapine, the dosage must be reduced. This is necessary to minimize the risk of hypotension, bradycardia, and syncope [see Dosage and Administration (2.6)].

Use clozapine cautiously in patients with cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (e.g., concomitant use of antihypertensives, dehydration and hypovolemia).

5.3 Falls

Clozapine may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.4 Seizures

Seizure has been estimated to occur in association with clozapine use at a cumulative incidence at one year of approximately 5%, based on the occurrence of one or more seizures in 61 of 1743 patients exposed to clozapine during its clinical testing prior to domestic marketing (i.e., a crude rate of 3.5%). The risk of seizure is dose-related. Initiate treatment with a low dose (12.5 mg), titrate slowly, and use divided dosing.
Use caution when administering clozapine to patients with a history of seizures or other predisposing risk factors for seizure (e.g., head trauma or other CNS pathology, use of medications that lower the seizure threshold, or alcohol abuse). Because of the substantial risk of seizure associated with clozapine use, caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others (e.g., driving an automobile, operating complex machinery, swimming, climbing).

5.5 Myocarditis, Pericarditis, Cardiomyopathy and Mitral Valve Incompetence

Myocarditis, pericarditis, and cardiomyopathy have occurred with the use of clozapine. These reactions can be fatal. Discontinue clozapine and obtain a cardiac evaluation upon suspicion of myocarditis, pericarditis, or cardiomyopathy. Generally, patients with a history of clozapine-associated myocarditis or cardiomyopathy should not be rechallenged with clozapine. However, if the benefit of clozapine treatment is judged to outweigh the potential risks of recurrence, the clinician may consider rechallenge with clozapine in consultation with a cardiologist.

Myocarditis and pericarditis most frequently present within the first 2 months of clozapine treatment. Symptoms of cardiomyopathy generally occur later than clozapine-associated myocarditis or pericarditis and usually after 8 weeks of treatment. However, myocarditis, pericarditis, and cardiomyopathy can occur at any period during treatment with clozapine. In patients who are diagnosed with cardiomyopathy while taking clozapine mitral valve incompetence has been reported.

5.6 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality in this population. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Clozapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning].

5.7 Gastrointestinal Hypomotility with Severe Complications

Severe gastrointestinal adverse reactions have occurred with the use of clozapine, primarily due to its potent anticholinergic effects and resulting gastrointestinal hypomotility. In post marketing experience, reported effects range from constipation to paralytic ileus. Increased frequency of constipation and delayed diagnosis and treatment increased the risk of severe complications of gastrointestinal hypomotility, which can result in fecal impaction, megacolon, and intestinal obstruction, ischemia, infarction, perforation, ulceration, or necrosis [see Adverse Reaction (6.2)]. These reactions have resulted in hospitalization, surgery, and death. The risk of severe adverse reactions is further increased with anticholinergic medications (and other medications that decrease gastrointestinal peristalsis); therefore, concomitant use should be avoided when possible [see Warnings and Precautions (5.15), Drug Interactions (7.1)].

Prior to initiating clozapine, screen for constipation and treat as necessary. Subjective symptoms of constipation may not accurately reflect the degree of gastrointestinal hypomotility in clozapine treated patients. Therefore, reassess bowel function frequently with careful attention to any changes in the frequency or character of bowel movements, as well as signs and symptoms of complications of hypomotility (e.g., nausea, vomiting, abdominal distension, abdominal pain). If constipation or gastrointestinal hypomotility are identified, monitor closely and treat promptly with appropriate laxatives, as necessary, to prevent severe complications. Consider prophylactic laxatives in high risk patients.

5.8 Eosinophilia

Eosinophilia, defined as a blood eosinophil count of greater than 700/µL, has occurred with clozapine treatment. In clinical trials, approximately 1% of patients developed eosinophilia. Clozapine-related eosinophilia usually occurs during the first month of treatment. In some patients, it has been associated with myocarditis, pancreatitis, hepatitis, colitis, and nephritis. Such organ involvement could be consistent with a drug reaction with eosinophilia and systemic symptoms syndrome (DRESS), also known as drug induced hypersensitivity syndrome (DIHS). If eosinophilia develops during clozapine treatment, evaluate promptly for signs and symptoms of systemic reactions, such as rash or other allergic symptoms, myocarditis, or other organ-specific disease associated with eosinophilia. If clozapine-related systemic disease is suspected, discontinue clozapine immediately.
If a cause of eosinophilia unrelated to clozapine is identified (e.g., asthma, allergies, collagen vascular disease, parasitic infections, and specific neoplasms), treat the underlying cause and continue clozapine.
Clozapine-related eosinophilia has also occurred in the absence of organ involvement and can resolve without intervention. There are reports of successful rechallenge after discontinuation of clozapine, without recurrence of eosinophilia. In the absence of organ involvement, continue clozapine under careful monitoring. If the total eosinophil count continues to increase over several weeks in the absence of systemic disease, the decision to interrupt clozapine therapy and rechallenge after the eosinophil count decreases should be based on the overall clinical assessment, in consultation with an internist or hematologist.

5.9 QT Interval Prolongation

QT prolongation, Torsade de Pointes and other life-threatening ventricular arrhythmias, cardiac arrest, and sudden death have occurred with clozapine treatment. When prescribing clozapine, consider the presence of additional risk factors for QT prolongation and serious cardiovascular reactions. Conditions that increase these risks include the following: history of QT prolongation, long QT syndrome, family history of long QT syndrome or sudden cardiac death, significant cardiac arrhythmia, recent myocardial infarction, uncompensated heart failure, treatment with other medications that cause QT prolongation, treatment with medications that inhibit the metabolism of clozapine, and electrolyte abnormalities.
Prior to initiating treatment with clozapine, perform a careful physical examination, medical history, and concomitant medication history. Consider obtaining a baseline ECG and serum chemistry panel. Correct electrolyte abnormalities. Discontinue clozapine if the QTc interval exceeds 500 msec. If patients experience symptoms consistent with Torsades de Pointes, or other arrhythmias (e.g., syncope, presyncope, dizziness, or palpitations), obtain a cardiac evaluation and discontinue clozapine.
Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of clozapine. Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmic medications (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). Clozapine is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. Concomitant treatment with inhibitors of these enzymes can increase the concentration of clozapine [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
Hypokalemia and hypomagnesemia increase the risk of QT prolongation. Hypokalemia can result from diuretic therapy, diarrhea, and other causes. Use caution when treating patients at risk for significant electrolyte disturbance, particularly hypokalemia. Obtain baseline measurements of serum potassium and magnesium levels, and periodically monitor electrolytes. Correct electrolyte abnormalities before initiating treatment with clozapine.

5.10 Metabolic Changes

Atypical antipsychotic drugs, including clozapine have been associated with metabolic changes that can increase cardiovascular and cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While atypical antipsychotic drugs may produce some metabolic changes, each drug in the class has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including clozapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent, hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on clozapine should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.

In a pooled data analysis of 8 studies in adult subjects with schizophrenia, the mean changes in fasting glucose concentration in the clozapine and chlorpromazine groups were +11 mg/dL and +4 mg/dL respectively. A higher proportion of the clozapine group demonstrated categorical increases from baseline in fasting glucose concentrations, compared to the chlorpromazine group (Table 4). The clozapine doses were 100 to 900 mg per day (mean modal dose: 512 mg per day). The maximum chlorpromazine dose was 1800 mg per day (mean modal dose: 1029 mg per day). The median duration of exposure was 42 days for clozapine and chlorpromazine.

Table 4. Categorical Changes in Fasting Glucose Level in Studies in Adult Subjects with Schizophrenia
Laboratory Parameter | Category Change (at least once) from baseline | Treatment Arm | N | n (%)
Fasting Glucose | Normal (<100 mg/dL) to High (≥126 mg/dL) | Clozapine | 198 | 53 (27)
Chlorpromazine | 135 | 14 (10)
Borderline (100 to 125 mg/dL) to High (≥126 mg/dL) | Clozapine | 57 | 24 (42)
Chlorpromazine | 43 | 12 (28)

Dyslipidemia

Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics, including clozapine. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using clozapine, is recommended.

In a pooled data analysis of 10 studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in serum total cholesterol. No data were collected on LDL and HDL cholesterol. The mean increase in total cholesterol was 13 mg/dL in the clozapine group and 15 mg/dL in the chlorpromazine group. In a pooled data analysis of 2 studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in fasting serum triglyceride. The mean increase in fasting triglyceride was 71 mg/dL (54%) in the clozapine group and 39 mg/dL (35%) in the chlorpromazine group (Table 5). In addition, clozapine treatment was associated with categorical increases in serum total cholesterol and triglyceride, as illustrated in Table 6. The proportion of patients with categorical increases in total cholesterol or fasting triglyceride increased with the duration of exposure. The median duration of clozapine and chlorpromazine exposure was 45 days and 38 days, respectively. The clozapine dose range was 100 mg to 900 mg daily; the maximum chlorpromazine dose was 1800 mg daily.

Table 5. Mean Changes in Total Cholesterol and Triglyceride Concentration in Studies in Adult Subjects with Schizophrenia
Treatment Arm | Baseline total cholesterol concentration (mg/dL) | Change from baseline mg/dL (%)
Clozapine (N=334) | 184 | +13 (7)
Chlorpromazine (N=185) | 182 | +15 (8)
| Baseline triglyceride concentration (mg/dL) | Change from baseline mg/dL (%)
Clozapine (N=6) | 130 | +71 (54)
Chlorpromazine (N=7) | 110 | +39 (35)

Table 6. Categorical Changes in Lipid Concentrations in Studies in Adult Subjects with Schizophrenia
Laboratory Parameter | Category Change (at least once) from baseline | Treatment Arm | N | n (%)
Total Cholesterol (random or fasting) | Increase by ≥40 mg/dL | Clozapine | 334 | 111 (33)
Chlorpromazine | 185 | 46 (25)
Normal (<200 mg/dL) to High (≥240 mg/dL) | Clozapine | 222 | 18 (8)
Chlorpromazine | 132 | 3 (2)
Borderline (200 to 239 mg/dL) to High (≥240 mg/dL) | Clozapine | 79 | 30 (38)
Chlorpromazine | 34 | 14 (41)
Triglycerides (fasting) | Increase by ≥50 mg/dL | Clozapine | 6 | 3 (50)
Chlorpromazine | 7 | 3 (43)
Normal (<150 mg/dL) to High (≥200 mg/dL) | Clozapine | 4 | 0 (0)
Chlorpromazine | 6 | 2 (33)
Borderline (≥150 mg/dL and <200 mg/dL) to High (≥200 mg/dL) | Clozapine | 1 | 1 (100)
Chlorpromazine | 1 | 0 (0)

Weight Gain

Weight gain has occurred with the use of antipsychotics, including clozapine. Monitor weight during treatment with clozapine. Table 7 summarizes the data on weight gain by the duration of exposure pooled from 11 studies with clozapine and active comparators. The median duration of exposure was 609, 728, and 42 days, in the clozapine, olanzapine, and chlorpromazine group, respectively.

Table 7. Mean Change in Body Weight (kg) by Duration of Exposure from Studies in Adult Subjects with Schizophrenia
Metabolic parameter | Exposure duration | C lozapine (N=669) | Olanzapine (N=442) | Chlorpromazine (N=155)
n | Mean | n | Mean | n | Mean
Weight change from baseline | 2 weeks (Day 11 to 17) | 6 | +0.9 | 3 | +0.7 | 2 | -0.5
4 weeks (Day 21 to 35) | 23 | +0.7 | 8 | +0.8 | 17 | +0.6
8 weeks (Day 49 to 63) | 12 | +1.9 | 13 | +1.8 | 16 | +0.9
12 weeks (Day 70 to 98) | 17 | +2.8 | 5 | +3.1 | 0 | 0
24 weeks (Day 154 to 182) | 42 | -0.6 | 12 | +5.7 | 0 | 0
48 weeks (Day 322 to 350) | 3 | +3.7 | 3 | +13.7 | 0 | 0

Table 8 summarizes pooled data from 11 studies in adult subjects with schizophrenia demonstrating weight gain ≥7% of body weight relative to baseline. The median duration of exposure was 609, 728, and 42 days, in the clozapine, olanzapine, and chlorpromazine group, respectively.

Table 8. Proportion of Adult Subjects in Schizophrenia Studies with Weight Gain ≥7% Relative to Baseline Body Weight
Weight change | Clozapine | Olanzapine | Chlorpromazine
N | 669 | 442 | 155
≥7% (inclusive) | 236 (35%) | 203 (46%) | 13 (8%)

5.11 Neuroleptic Malignant Syndrome

Antipsychotic drugs including clozapine can cause a potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS). Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Associated findings can include elevated creatine phosphokinase (CPK), myoglobinuria, rhabdomyolysis, and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. It is important to consider the presence of other serious medical conditions (e.g., severe neutropenia, infection, heat stroke, primary CNS pathology, central anticholinergic toxicity, extrapyramidal symptoms, and drug fever).
The management of NMS should include (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, (2) intensive symptomatic treatment and medical monitoring, and (3) treatment of comorbid medical conditions. There is no general agreement about specific pharmacological treatments for NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. NMS can recur. Monitor closely if restarting treatment with antipsychotics.
NMS has occurred with clozapine monotherapy and with concomitant CNS-active medications, including lithium.

5.12 Hepatotoxicity

Severe, life threatening, and in some cases fatal hepatotoxicity including hepatic failure, hepatic necrosis, and hepatitis have been reported in post marketing studies in patients treated with clozapine [see Adverse Reactions (6.2)]. Monitor for the appearance of signs and symptoms of hepatotoxicity such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, coagulopathy, and hepatic encephalopathy. Perform serum tests for liver injury and consider permanently discontinuing treatment if hepatitis or transaminase elevations combined with other systemic symptoms are due to clozapine.

5.13 Fever

During clozapine therapy, patients have experienced transient, clozapine-related fever. The peak incidence is within the first 3 weeks of treatment. While this fever is generally benign and self-limited, it may necessitate discontinuing treatment. The fever can be associated with an increase or decrease in WBC count. Carefully evaluate patients with fever to rule out severe neutropenia or infection. Consider the possibility of NMS [see Warnings and Precautions (5.11)].

5.14 Pulmonary Embolism

Pulmonary embolism and deep-vein thrombosis have occurred in patients treated with clozapine. Consider the possibility of pulmonary embolism in patients who present with deep-vein thrombosis, acute dyspnea, chest pain, or with other respiratory signs and symptoms. Whether pulmonary embolus and deep-vein thrombosis can be attributed to clozapine or some characteristic(s) of patients is not clear.

5.15 Anticholinergic Toxicity

Clozapine has potent anticholinergic effects. Treatment with clozapine can result in CNS and peripheral anticholinergic toxicity, especially at higher dosages, or in overdose situations [see Overdosage (10)]. Use with caution in patients with a current diagnosis or prior history of constipation, urinary retention, clinically significant prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions. When possible, avoid concomitant use, with other anticholinergic medications because the risk for anticholinergic toxicity or severe gastrointestinal adverse reactions is increased [see Warnings and Precautions (5.7), Drug Interactions (7.1)].

5.16 Interference with Cognitive and Motor Performance

Clozapine can cause sedation and impairment of cognitive and motor performance. Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that clozapine does not affect them adversely. These reactions may be dose-related. Consider reducing the dose if they occur.

5.17 Tardive Dyskinesia

Tardive dyskinesia (TD) has occurred in patients treated with antipsychotic drugs, including clozapine. The syndrome consists of potentially irreversible, involuntary, dyskinetic movements. The risk of TD and the likelihood that it will become irreversible are believed to increase with greater durations of treatment and higher total cumulative doses. However, the syndrome can develop after relatively brief treatment periods at low doses. Prescribe clozapine in a manner that is most likely to minimize the risk of developing TD. Use the lowest effective dose and the shortest duration necessary to control symptoms. Periodically assess the need for continued treatment. Consider discontinuing treatment if TD occurs. However, some patients may require treatment with clozapine despite the presence of the syndrome.
TD may remit partially or completely if treatment is discontinued. Antipsychotic treatment, itself, may suppress (or partially suppress) the signs and symptoms, and it has the potential to mask the underlying process. The effect of symptom suppression on the long-term course of TD is unknown.

5.18 Cerebrovascular Adverse Reactions

In controlled trials, elderly patients with dementia-related psychosis treated with some atypical antipsychotics had an increased risk (compared to placebo) of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities. The mechanism for this increased risk is not known. An increased risk cannot be excluded for clozapine or other antipsychotics or other patient populations. Clozapine should be used with caution in patients with risk factors for cerebrovascular adverse reactions.

5.19 Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation of Clozapine

If abrupt discontinuation of clozapine is necessary (because of severe neutropenia or another medical condition, for example) [see Dosage and Administration (2.5), Warnings and Precautions (5.1)], monitor carefully for the recurrence of psychotic symptoms and adverse reactions related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting and diarrhea.

7.1 Potential for Other Drugs to Affect Clozapine

Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6. Use caution when administering clozapine concomitantly with drugs that are inducers or inhibitors of these enzymes.

CYP1A2 Inhibitors

Concomitant use of clozapine and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. Reduce the clozapine dose to one-third of the original dose when clozapine is coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin). The clozapine dose should be increased to the original dose when coadministration of strong CYP1A2 inhibitors is discontinued [see Dosage and Administration (2.7), Clinical Pharmacology (12.3)].

Moderate or weak CYP1A2 inhibitors include oral contraceptives and caffeine. Monitor patients closely when clozapine is coadministered with these inhibitors. Consider reducing the clozapine dosage if necessary [see Dosage and Administration (2.7)].

CYP2D6 and CYP3A4 Inhibitors

Concomitant treatment with clozapine and CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline) can increase clozapine levels and lead to adverse reactions [see Clinical Pharmacology (12.3)]. Use caution and monitor patients closely when using such inhibitors. Consider reducing the clozapine dose [see Dosage and Administration (2.7)].

CYP1A2 and CYP3A4 Inducers

Concomitant treatment with drugs that induce CYP1A2 or CYP3A4 can decrease the plasma concentration of clozapine, resulting in decreased effectiveness of clozapine. Tobacco smoke is a moderate inducer of CYP1A2. Strong CYP3A4 inducers include carbamazepine, phenytoin, St. John’s wort, and rifampin. It may be necessary to increase the clozapine dose if used concomitantly with inducers of these enzymes. However, concomitant use of clozapine and strong CYP3A4 inducers is not recommended [see Dosage and Administration (2.7)].

Consider reducing the clozapine dosage when discontinuing coadministered enzyme inducers; because discontinuation of inducers can result in increased clozapine plasma levels and an increased risk of adverse reactions [see Dosage and Administration (2.7)].

Anticholinergic Drugs
Concomitant treatment with clozapine and other drugs with anticholinergic activity (e.g., benztropine, cyclobenzaprine, diphenhydramine) can increase the risk for anticholinergic toxicity and severe gastrointestinal adverse reactions related to hypomotility. Avoid concomitant use of clozapine with anticholinergic drugs when possible [see Warnings and Precautions (5.7, 5.15)].

Drugs that Cause QT Interval Prolongation

Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of clozapine. Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, and pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see Warnings and Precautions (5.9)].

7.2 Potential for Clozapine to Affect Other Drugs

Concomitant use of clozapine with other drugs metabolized by CYP2D6 can increase levels of these CYP2D6 substrates. Use caution when coadministering clozapine with other drugs that are metabolized by CYP2D6. It may be necessary to use lower doses of such drugs than usually prescribed. Such drugs include specific antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide).

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including clozapine, during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for Atypical Antipsychotics at1-866-961-2388 or visiting http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Risk Summary
Neonates exposed to antipsychotic drugs, including clozapine, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). Available data from published epidemiologic studies over decades of use with clozapine during pregnancy have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including clozapine, during pregnancy (see Clinical Considerations).
In animal reproduction studies, no adverse developmental effects were observed when clozapine was administered orally to pregnant rats or rabbits during the period of organogenesis, or to pregnant rats during pregnancy and lactation, at doses up to approximately 0.4 and 0.9 times the maximum recommended human dose (MRHD) of 900 mg/day, for rats and rabbits respectively, based on mg/m² body surface area (see Data).
The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk
There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.
Fetal/Neonatal adverse reactions
Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who have been exposed to antipsychotic drugs, including clozapine, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.
Data
Animal Data
In embryofetal developmental studies, clozapine had no effects on maternal parameters, litter sizes, or fetal parameters when administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 0.4 and 0.9 times, respectively, the MRHD of 900 mg/day on a mg/m² body surface area basis.
In peri/postnatal developmental studies, pregnant female rats were administered clozapine over the last third of pregnancy and until day 21 postpartum. Observations were made on fetuses at birth and during the postnatal period; the offspring were allowed to reach sexual maturity and mated. Clozapine caused a decrease in maternal body weight but had no effects on litter size or body weights of either F1 or F2 generations at doses up to 0.4 times the MRHD of 900 mg/day on a mg/m² body surface area basis.

8.2 Lactation

Risk Summary
Clozapine is present in human milk. There is one case report of sedation and a report of agranulocytosis in an infant exposed to clozapine through human milk (see Clinical Considerations). There is no information on the effects of clozapine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for clozapine and any potential adverse effects on the breastfed child from clozapine or from the underlying maternal condition.
Clinical Considerations
Infants exposed to clozapine should be monitored for excess sedation and neutropenia.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

There have not been sufficient numbers of geriatric patients in clinical studies utilizing clozapine to determine whether those over 65 years of age differ from younger subjects in their response to clozapine.
Orthostatic hypotension and tachycardia can occur with clozapine treatment [see Boxed Warning and Warnings and Precautions (5.2)]. Elderly patients, particularly those with compromised cardiovascular functioning, may be more susceptible to these effects.
Elderly patients may be particularly susceptible to the anticholinergic effects of clozapine, such as urinary retention and constipation [see Warnings and Precautions (5.15)].
Carefully select clozapine doses in elderly patients, taking into consideration their greater frequency of decreased hepatic, renal, or cardiac function, as well as other concomitant disease and other drug therapy. Clinical experience suggests that the prevalence of tardive dyskinesia appears to be highest among the elderly; especially elderly women [see Warnings and Precautions (5.17) ].

8.6 Patients with Renal or Hepatic Impairment

Dose reduction may be necessary in patients with significant impairment of renal or hepatic function. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted [see Dosage and Administration (2.8), Clinical Pharmacology (12.3)].

8.7 CYP2D6 Poor Metabolizers

Dose reduction may be necessary in patients who are CYP2D6 poor metabolizers. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted [see Dosage and Administration (2.8), Clinical Pharmacology (12.3)].

10.1 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.

10.2 Management of Overdosage

There is no available specific antidote to an overdose of clozapine. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. Consider the possibility of multiple-drug involvement.

Contact a Certified Poison Control Center for the most up to date information on the management of overdosage (1-800-222-1222).

12.1 Mechanism of Action

The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D₂) and the serotonin type 2A (5-HT2A) receptors. Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic and other dopaminergic and serotonergic receptors.

12.2 Pharmacodynamics

Clozapine demonstrated binding affinity to the following receptors: histamine H₁ (Ki 1.1 nM), adrenergic α1A (Ki 1.6 nM), serotonin 5-HT₆ (Ki 4 nM), serotonin 5-HT2A (Ki 5.4 nM), muscarinic M₁ (Ki 6.2 nM), serotonin 5-HT₇ (Ki 6.3 nM), serotonin 5-HT2C (Ki 9.4 nM), dopamine D₄ (Ki 24 nM), adrenergic α2A (Ki 90 nM), serotonin 5-HT₃ (Ki 95 nM), serotonin 5-HT1A (Ki 120 nM), dopamine D₂ (Ki 160 nM), dopamine D₁ (Ki 270 nM), dopamine D₅ (Ki 454 nM), and dopamine D₃ (Ki 555 nM).
Clozapine causes little or no prolactin elevation.
Clinical electroencephalogram (EEG) studies demonstrated that clozapine increases delta and theta activity and slows dominant alpha frequencies. Enhanced synchronization occurs. Sharp wave activity and spike and wave complexes may also develop. Patients have reported an intensification of dream activity during clozapine therapy. REM sleep was found to be increased to 85% of the total sleep time. In these patients, the onset of REM sleep occurred almost immediately after falling asleep.

12.3 Pharmacokinetics

Absorption
In humans, clozapine tablets (25 mg and 100 mg) are equally bioavailable relative to a clozapine solution. Following oral administration of clozapine 100 mg twice daily, the average steady-state peak plasma concentration was 319 ng/mL (range: 102 to 771 ng/mL), occurring at the average of 2.5 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at steady state was 122 ng/mL (range: 41 to 343 ng/mL), after 100 mg twice daily dosing. Food does not appear to affect the systemic bioavailability of clozapine. Thus, clozapine may be administered with or without food.
Distribution
Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine and other highly protein-bound drugs has not been fully evaluated but may be important [see Drug Interactions (7)].
Metabolism and Excretion
Clozapine is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces. Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4. Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. The demethylated, hydroxylated, and N-oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite (norclozapine) to have only limited activity, while the hydroxylated and N-oxide derivatives were inactive. The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: