"Feb. 22, 2011 -- The FDA has issued a safety announcement notifying health care professionals that it has updated the pregnancy section of drug labels for the entire class of antipsychotic medications.
Antipsychotic drugs are used to "...
The following adverse reactions are discussed in more detail in other sections of the labeling:
- Severe Neutropenia [see WARNINGS AND PRECAUTIONS].
- Orthostatic Hypotension, Bradycardia, and Syncope [see WARNINGS AND PRECAUTIONS].
- Seizures [see WARNINGS AND PRECAUTIONS].
- Myocarditis and Cardiomyopathy [see WARNINGS AND PRECAUTIONS].
- Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see WARNINGS AND PRECAUTIONS].
- Eosinophilia [see WARNINGS AND PRECAUTIONS].
- QT Interval Prolongation [see WARNINGS AND PRECAUTIONS].
- Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) [see WARNINGS AND PRECAUTIONS].
- Neuroleptic Malignant Syndrome [see WARNINGS AND PRECAUTIONS].
- Fever [see WARNINGS AND PRECAUTIONS].
- Pulmonary Embolism [see WARNINGS AND PRECAUTIONS].
- Anticholinergic Toxicity [see WARNINGS AND PRECAUTIONS].
- Interference with Cognitive and Motor Performance [see WARNINGS AND PRECAUTIONS].
- Tardive Dyskinesia [see WARNINGS AND PRECAUTIONS].
- Patients with Phenylketonuria [see WARNINGS AND PRECAUTIONS].
- Cerebrovascular Adverse Reactions [see WARNINGS AND PRECAUTIONS].
- Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation [see WARNINGS AND PRECAUTIONS].
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, Chlorpromazinecontrolled Trial in Treatment-Resistant
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 InterSePT™ Study)
Percentage of Patients
|Central Nervous System|
|Autonomic Nervous System|
|† 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 InterSePT™ Study ( ≥ 10% in the
clozapine or olanzapine group)
N=479 % Reporting
N=477 % Reporting
|Dizziness (excluding vertigo)||27%||12%|
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.
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
Immune System Disorders
Angioedema, leukocytoclastic vasculitis.
Skin and Subcutaneous Tissue Disorders
Musculoskeletal System and Connective Tissue Disorders
Myasthenic syndrome, rhabdomyolysis, and systemic lupus erythematosus.
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.
Read the Fazaclo (clozapine) Side Effects Center for a complete guide to possible side effects
Potential For Other Drugs To Affect FAZACLO
Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6. Use caution when administering FAZACLO concomitantly with drugs that are inducers or inhibitors of these enzymes.
Concomitant use of FAZACLO and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. Reduce the FAZACLO dose to one third of the original dose when FAZACLO is coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin). The FAZACLO dose should be increased to the original dose when coadministration of strong CYP1A2 inhibitors is discontinued [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].
Moderate or weak CYP1A2 inhibitors include oral contraceptives and caffeine. Monitor patients closely when FAZACLO is coadministered with these inhibitors. Consider reducing the FAZACLO dosage if necessary [see DOSAGE AND ADMINISTRATION].
CYP2D6 and CYP3A4 Inhibitors
Concomitant treatment with FAZACLO 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]. Use caution and monitor patients closely when using such inhibitors. Consider reducing the FAZACLO dose [see DOSAGE AND ADMINISTRATION].
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 FAZACLO. 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 FAZACLO dose if used concomitantly with inducers of these enzymes. However, concomitant use of FAZACLO and strong CYP3A4 inducers is not recommended [see DOSAGE AND ADMINISTRATION].
Consider reducing the FAZACLO 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].
Drugs that Cause QT Interval Prolongation
Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of FAZACLO. 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].
Potential For FAZACLO To Affect Other Drugs
Concomitant use of FAZACLO with other drugs metabolized by CYP2D6 can increase levels of these CYP2D6 substrates. Use caution when coadministering FAZACLO 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).This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 10/1/2015
Additional Fazaclo Information
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