Side Effects of Clozaril (clozapine)

Clozaril (clozapine) is an antipsychotic medication prescribed to manage psychotic disorders such as schizophrenia. 

Clozaril works by blocking receptors in the brain for several neurotransmitters (chemicals that nerves use to communicate with each other), including dopamine type 4 receptors, serotonin type 2 receptors, norepinephrine receptors, acetylcholine receptors, and histamine receptors. Unlike traditional antipsychotic agents, Clozaril only weakly blocks dopamine type 2 receptors.

Common side effects of Clozaril include

• drowsiness,
• dizziness, and
• dizziness on standing.

Serious side effects of Clozaril include

• seizures.

Drug interactions of Clozaril include risperidone, which may cause an increase in the amount of Clozaril in the blood. This could lead to an increased risk of side effects from Clozaril. 

There are no adequate studies of Clozaril in pregnant women. Clozaril can be used in pregnancy if the physician feels it is necessary. 

Animal studies suggest that Clozaril is secreted in breast milk. Women taking Clozaril should not breastfeed.

The most common side effect of clozapine is drowsiness.

Dizziness is another side effect of clozapine. Dizziness may occur in 1 of 5 persons taking clozapine. In some cases this may be due to orthostatic hypotension, a marked decrease in blood pressure that occurs when going from a lying or sitting position to a standing position.

The drop in blood pressure may lead to loss of consciousness or even cardiac and respiratory arrest. This reaction is more common during the first few weeks of therapy while the dose is increasing, when drug is stopped briefly, or when patients are taking benzodiazepines such as diazepam (Valium) or other anti-psychotic drugs.

Seizures have occurred in approximately 1 of every 20 to 30 persons receiving clozapine. Patients receiving higher doses seem to be at higher risk.

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

• Severe Neutropenia
• Orthostatic Hypotension, Bradycardia, and Syncope
• Seizures
• Myocarditis and Cardiomyopathy
• Increased Mortality in Elderly Patients with Dementia-Related Psychosis
• Eosinophilia
• QT Interval Prolongation
• Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain)
• Neuroleptic Malignant Syndrome
• Fever
• Pulmonary Embolism
• Anticholinergic Toxicity
• Interference with Cognitive and Motor Performance
• Tardive Dyskinesia
• Cerebrovascular Adverse Reactions
• Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation

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 Clozaril 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 Clozaril-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

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

Table 10: Adverse Reactions ( ≤ 2%) Reported in Clozaril-treated Patients (N=842) across all Clozaril Studies (excluding the 2-year InterSePT™ Study)

Table 11 summarizes the most commonly reported adverse reactions ( ≤ 10% of the Clozaril or olanzapine group) in the InterSePT Study. This was an adequate and well-controlled, two-year study evaluating the efficacy of Clozaril 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 Clozaril or Olanzapine in the InterSePT™ Study ( ≤ 10% in the Clozaril or olanzapine group)

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.

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, and
• post-discontinuation cholinergic rebound adverse reactions.

Cardiovascular System

• Atrial or ventricular fibrillation,
•  ventricular tachycardia,
• QT interval prolongation,
• Torsades de Pointes,
• myocardial infarction,
•  cardiac arrest, and
• periorbital edema.

Endocrine System

• Pseudopheochromocytoma.

Gastrointestinal System

• Acute pancreatitis,
• dysphagia,
• salivary gland swelling.

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.

Hemic and Lymphatic System

• Mild, moderate, or severeleukopenia,
• 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, and
• weight loss.

Potential For Other Drugs To Affect Clozaril

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

CYP1A2 Inhibitors

• Concomitant use of Clozaril and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions.
• Reduce the Clozaril dose to one third of the original dose when Clozaril is coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin).
• The Clozaril dose should be increased to the original dose when coadministration of strong CYP1A2 inhibitors is discontinued.
• Moderate or weak CYP1A2 inhibitors include oral contraceptives and caffeine.
• Monitor patients closely when Clozaril is coadministered with these inhibitors.
• Consider reducing the Clozaril dosage if necessary.

CYP2D6 And CYP3A4 Inhibitors

• Concomitant treatment with Clozaril 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.
• Use caution and monitor patients closely when using such inhibitors.
• Consider reducing the Clozaril dose.

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 Clozaril. 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 Clozaril dose if used concomitantly with inducers of these enzymes.
• However, concomitant use of Clozaril and strong CYP3A4 inducers is not recommended.
• Consider reducing the Clozaril dosage when discontinuing coadministered enzyme inducers; because discontinuation of inducers can result in increased clozapine plasma levels and an increased risk of adverse reactions.

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).

Potential For Clozaril To Affect Other Drugs

• Concomitant use of Clozaril with other drugs metabolized by CYP2D6 can increase levels of these CYP2D6 substrates.
• Use caution when coadministering Clozaril 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).