Agranulocytosis: Because of a significant risk of agranulocytosis, a potentially life-threatening adverse event, clozapine should be reserved for use in 1) the treatment of severely ill patients with schizophrenia who fail to show an acceptable response to adequate courses of standard antipsychotic drug treatment, or 2) for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at risk of re-experiencing suicidal behavior. Patients being treated with clozapine must have a baseline white blood cell (WBC) count and absolute neutrophil count (ANC) before initiation of treatment as well as regular WBC counts and ANCs during treatment and for at least four weeks after discontinuation of treatment.
Seizures: Seizures have been associated with the use of clozapine. Dose appears to be an important predictor of seizure, with a greater likelihood at higher clozapine doses. Caution should be used when administering clozapine to patients having a history of seizures or other predisposing factors. Patients should be advised not to engage in any activity where sudden loss of consciousness could cause serious risk to themselves or others.
Myocarditis: Analyses of postmarketing safety databases suggest that clozapine is associated with an increased risk of fatal myocarditis, especially during, but not limited to, the first month of therapy. In patients in whom myocarditis is suspected, clozapine treatment should be promptly discontinued.
Other Adverse Cardiovascular and Respiratory Effects: Orthostatic hypotension, with or without syncope, can occur with clozapine treatment. Rarely, collapse can be profound and be accompanied by respiratory and/or cardiac arrest. Orthostatic hypotension is more likely to occur during initial titration in association with rapid dose escalation. In patients who have had even a brief interval off clozapine, i.e., two or more days since the last dose, treatment should be started with 12.5 mg once or twice a day. Since collapse, respiratory arrest and cardiac arrest during initial treatment has occurred in patients who were being administered benzodiazepines or other psychotropic drugs, caution is advised when clozapine is initiated in patients taking a benzodiazepine or any other psychotropic drug.
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 seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in the 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. 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.
Agranulocytosis, defined as an ANC <500/mm3, has been estimated to occur in association with clozapine use at a cumulative incidence at 1 year of approximately 1.3%. All these cases occurred at a time when the need for close monitoring of WBC counts was already recognized. Agranulocytosis can be fatal if not detected early and therapy interrupted.
It is advised to avoid clozapine or use it cautiously in patients with a previous history of agranulocytosis induced by other drugs.
Risk Factors: Patients who have developed agranulocytosis during clozapine therapy are at increased risk of subsequent episodes of agranulocytosis. Except for bone marrow suppression during initial clozapine therapy, there are no other established risk factors for the development of agranulocytosis in association with clozapine use. Agranulocytosis associated with other antipsychotic drugs has been reported to occur with a greater frequency in women, the elderly and in patients who are cachectic or have a serious underlying medical illness; such patients may also be at particular risk with clozapine, although this has not been definitely shown.
WBC Count and ANC Monitoring Schedule: WBC counts and differential blood counts must be done within 10 days prior to initiating clozapine treatment to ensure that only patients with normal WBC counts and ANC will receive clozapine. The current recommendations for WBC count and ANC monitoring based on the stage of therapy and the results from WBC and ANC monitoring are provided in Table 1. (See Table 1.)
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Nonrechallengeable Patients: Bone marrow aspiration should be considered to determine granulopoietic status and patients should not be rechallenged with clozapine if the total WBC count falls below 2,000/mm3 or the ANC falls below 1,000/mm3.
Protective isolation with close observation may be indicated if granulopoiesis is determined to be deficient. Should evidence of infection develop, the patient should have appropriate cultures done and an appropriate antibiotic regimen instituted.
Treatment of Rechallengeable Patients: Patients may be rechallenged with clozapine if their WBC count does not fall below 2,000/mm3 and the ANC does not fall below 1,000/mm3. Patients who have an initial episode of moderate leukopenia (3,000/mm3>WBC≥2,000/mm3) have up to a 12-fold increased risk of having a subsequent episode of agranulocytosis when rechallenged compared to the full cohort of patients treated with clozapine. Although clozapine therapy may be resumed if no symptoms of infection develop, and when the WBC count rises above 3,500/mm3 and the ANC rises above 2,000/mm3, prescribers are strongly advised to consider whether the benefit of continuing clozapine treatment outweighs the increased risk of agranulocytosis.
There is an increased risk of having a subsequent episode of granulopoietic suppression up to a year after recovery from the initial episode. Therefore, patients must undergo weekly WBC count and ANC monitoring for 1 year following recovery from an episode of moderate leukopenia and/or moderate granulocytopenia regardless of when the episode develops. If acceptable WBC counts and ANC (WBC≥3,500/mm3 and ANC≥2,000/mm3) have been maintained during the year of weekly monitoring, WBC counts can be monitored every two weeks for the next six months. If acceptable WBC counts and ANC (WBC≥3,500/mm3 and ANC≥2,000/mm3) continue to be maintained during the six months of every two week monitoring, WBC counts can be monitored every four weeks, thereafter.
Interruptions of Therapy: If clozapine therapy is reinitiated after interruption of therapy, WBC counts and ANC should be monitored after reinitiating therapy based on the duration of previous therapy, length of interruption of therapy, and previous WBC counts and ANC in the patient according to the schedule in Table 2. (See Table 2.)
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Eosinophilia and Thrombocytopenia: Eosinophilia has been reported in 1% of patients who received clozapine. If a differential count reveals a total eosinophil count above 4,000/mm3, clozapine therapy should be interrupted until the eosinophil count falls below 3,000/mm3. In the event of thrombocytopenia, discontinuation of clozapine therapy is recommended if the platelet count falls below 50,000/mm3.
Myocarditis, pericarditis/pericardial effusion and cardiomyopathy (see Warnings): Pericarditis/pericardial effusion and cardiomyopathy have also been reported in association with clozapine use; these reports also include fatalities. Myocarditis or cardiomyopathy should be suspected in patients who experience persistent tachycardia at rest, particularly in the first two months of treatment, and/or palpitations, arrhythmias, chest pain, and other signs and symptoms of heart failure (e.g., unexplained fatigue, dyspnea, tachypnea), or symptoms that mimic myocardial infarction. Other symptoms which may be present include flu-like symptoms. If myocarditis or cardiomyopathy is suspected, clozapine treatment should be promptly discontinued and the patient immediately referred to a cardiologist. Patients with clozapine-related myocarditis should not be rechallenged with clozapine.
Seizures (see Warnings).
Other Adverse Cardiovascular and Respiratory Effects (see Warnings): Tachycardia, which may persist throughout therapy in some cases, has been reported in 25% of patients receiving clozapine, with patients having an average increase in pulse rate of 10 to 15 bpm. The sustained tachycardia is not simply a reflex response to hypotension, and is present in all positions monitored. Either tachycardia or hypotension may pose a serious risk for an individual with compromised cardiovascular function. Some clozapine-treated patients experience ECG repolarization changes similar to those seen with other antipsychotic drugs, including ST segment depression and flattening or inversion of T waves, which all normalize after discontinuation of clozapine. However, in clinical trials, several patients experienced significant cardiac events including ischemic changes, myocardial infarction, arrhythmias and sudden death. In addition, there have been post-marketing reports of congestive heart failure, pericarditis and pericardial effusions. Clozapine should be used with caution in patients with known cardiovascular and/or pulmonary disease, and the recommendation for gradual titration of dose should be carefully observed.
Hyperglycemia and Diabetes Mellitus: There have been reports of severe hyperglycemia, sometimes associated with ketoacidosis, hyperosmolar coma or death, in patients receiving certain atypical antipsychotic agents including clozapine. Patients with preexisting diabetes mellitus in whom therapy with an atypical antipsychotic is initiated should be closely monitored for worsening of glucose control; those with risk factors for diabetes (e.g., obesity, family history of diabetes) should undergo fasting blood glucose testing upon therapy initiation and periodically throughout treatment. Any patient who develops manifestations of hyperglycemia (e.g., polydipsia, polyphagia, polyuria, weakness) during treatment with an atypical antipsychotic should undergo fasting blood glucose testing.
Neuroleptic Malignant Syndrome (NMS): There have been reports of NMS, a potentially fatal symptom complex, in association with antipsychotic drugs. Clinical manifestations include hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmias).
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. Careful monitoring of patients is necessary since recurrences of NMS have been reported.
Tardive Dyskinesia: Patients treated with antipsychotic drugs may develop tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements. The prevalence of the syndrome appears to be highest among the elderly, particularly elderly women. There have been a few cases of tardive dyskinesia in patients on clozapine therapy who had been previously treated with other antipsychotic agents, so that a causal relationship cannot be established. There have been no reports of tardive dyskinesia directly attributable to clozapine alone. Nevertheless, it cannot be concluded that clozapine is incapable of inducing this syndrome.
Fever: Patients may experience transient temperature elevations above 38°C (100.4°F), with peak incidence within the first three weeks of treatment with clozapine. While this fever is generally benign and self-limiting, it may necessitate discontinuing patients from treatment; there may be an associated increase or decrease in WBC count.
Pulmonary Embolism: There have been reports of fatal pulmonary embolism in association with clozapine therapy. The possibility of pulmonary embolism should be considered in patients presenting with deep-vein thrombosis, acute dyspnea, chest pain, or other respiratory signs and symptoms.
Hepatic disease: Liver function tests should be done in patients in whom symptoms of possible liver dysfunction (e.g., nausea, vomiting and/or anorexia) develop during clozapine therapy. Treatment with clozapine must be discontinued if the elevation of the values is clinically relevant [more than three times the upper limit of normal (ULN)] or if the symptoms of jaundice occur. It may be resumed only when the results of liver function tests are normal. Liver function should be closely monitored after re-introduction of the drug.
Anticholinergic Effects: Careful supervision should be done in patients with prostatic enlargement and narrow-angle glaucoma since clozapine exerts anticholinergic activity which may produce undesirable effects throughout the body. Clozapine has been associated with varying degrees of impairment of intestinal peristalsis, ranging from constipation to intestinal obstruction, fecal impaction and paralytic ileus. On rare occasions, these cases have been fatal. Constipation should be initially treated by ensuring adequate hydration, and use of ancillary therapy such as bulk laxatives. Consultation with a gastroenterologist is advisable in more serious cases.
Cerebrovascular adverse events: An increased risk of cerebrovascular adverse events has been reported in patients with dementia treated with some atypical antipsychotics. Clozapine should be used with caution in patients with dementia or risk factors for stroke.
Use in patients with concomitant illness: Caution is advised in using clozapine in patients with renal or cardiac disease.
Use in patients undergoing general anesthesia: Clozapine should be used with caution in patients undergoing general anesthesia because of the CNS effects of the drug. The anesthesiologist should be consulted regarding continuation of clozapine therapy in a patient scheduled for surgery.
Interference with cognitive and motor performance: Clozapine may impair mental and/or physical abilities, particularly during the first few days of therapy, because of initial sedation. Gradual dose escalation is recommended and should be carefully followed. Patients should be cautioned about activities requiring alertness such as driving or operating machinery.
Use in Children: The safety and effectiveness in pediatric patients have not been established.
Use in Elderly: Clozapine can cause orthostatic hypotension and tachycardia, which may be sustained. Elderly patients, particularly those with compromised cardiovascular functioning, may be more susceptible to these effects.
Elderly patients may also be particularly susceptible to the anticholinergic effects of clozapine such as urinary retention and constipation.
Dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.