CLOZAPINE (Page 5 of 11)

5.12 Neuroleptic Malignant Syndrome

Antipsychotic drugs including clozapine tablets 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 tablets monotherapy and with concomitant CNS-active medications, including lithium.

5.13 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.

5.14 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)] .

5.15 Pulmonary Embolism

Pulmonary embolism and deep-vein thrombosis have occurred in patients treated with clozapine tablets. 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.

5.16 Anticholinergic Toxicity

Clozapine tablets has potent anticholinergic effects. Treatment with clozapine tablets 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 ( 5.8), Drug Interactions ( 7.1)] .

5.17 Interference with Cognitive and Motor Performance

Clozapine tablets 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 tablets does not affect them adversely. These reactions may be dose-related. Consider reducing the dose if they occur.

5.18 Tardive Dyskinesia

Tardive dyskinesia (TD) has occurred in patients treated with antipsychotic drugs, including clozapine tablets. 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 tablets 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 tablets despite the presence of the syndrome.

There is no known treatment for TD. However, the syndrome 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.

5.19 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 tablets or other antipsychotics or other patient populations. Clozapine tablets should be used with caution in patients with risk factors for cerebrovascular adverse reactions.

5.20 Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation of Clozapine Tablets

If abrupt discontinuation of clozapine tablets is necessary (because of severe neutropenia or another medical condition, for example) [see Dosage and Administration ( 2.4), 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.

6 ADVERSE REACTIONS

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 ( 5.3)]
  • Falls [ see Warnings and Precautions ( 5.4) ]
  • Seizures [see Warnings and Precautions ( 5.5)]
  • Myocarditis, Cardiomyopathy, and Mitral Valve Incompetence [see Warnings and Precautions ( 5.6)]
  • Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions ( 5.7)]
  • Gastrointestinal Hypomotility with Severe Complications [See Warnings and Precautions ( 5.8)]
  • Eosinophilia [see Warnings and Precautions ( 5.9)]
  • QT Interval Prolongation [see Warnings and Precautions ( 5.10)]
  • Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) [see Warnings and Precautions ( 5.11)]
  • Neuroleptic Malignant Syndrome [see Warnings and Precautions ( 5.12)]
  • Hepatotoxicity [ see Warnings and Precautions ( 5.13)]
  • Fever [see Warnings and Precautions ( 5.14)]
  • Pulmonary Embolism [see Warnings and Precautions ( 5.15)]
  • Anticholinergic Toxicity [see Warnings and Precautions ( 5.16)]
  • Interference with Cognitive and Motor Performance [see Warnings and Precautions ( 5.17)]
  • Tardive Dyskinesia [see Warnings and Precautions ( 5.18)]
  • Cerebrovascular Adverse Reactions [see Warnings and Precautions ( 5.19)]
  • Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation [see Warnings and Precautions ( 5.20)]

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