Clozapine Oral Suspension

Treatment-Resistant Schizophrenia

VERSACLOZ is indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, VERSACLOZ should be used only in patients who have failed to respond adequately to standard antipsychotic treatment [see WARNINGS AND PRECAUTIONS].

The effectiveness of clozapine in treatment-resistant schizophrenia was demonstrated in a 6-week, randomized, double-blind, active-controlled study comparing clozapine and chlorpromazine in patients who had failed other antipsychotics [see Clinical Studies].

Reduction In The Risk Of Recurrent Suicidal Behavior In Schizophrenia Or Schizoaffective Disorder

VERSACLOZ is indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state. Suicidal behavior refers to actions by a patient that put him/herself at risk for death.

The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was demonstrated over a two-year treatment period in the InterSePT™ trial [see Clinical Studies].

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].
• Falls [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].
• Hepatotoxicity [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].
• 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 Schizophrenia

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)

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)

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, and renal failure.

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 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, and weight loss.

Included as part of the PRECAUTIONS section.

• It is used to treat schizophrenia.
• It is used to treat problems with how one acts.
• It may be given to you for other reasons. Talk with the doctor.

• If you have an allergy to clozapine or any other part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have a low white blood cell count.
• If you have bone marrow disease.
• If you have any of these health problems: Low potassium or magnesium levels.
• If you have ever had a low white blood cell count when taking a drug before.
• If you are taking any drugs that can stop your bone marrow from making some of the cells that your body needs. There are many drugs that can do this. Ask your doctor or pharmacist if you are not sure.
• If you are not able to get blood tests as you have been told by your doctor.
• If you are breast-feeding. Do not breast-feed while you take clozapine oral suspension.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take clozapine oral suspension with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Avoid driving and doing other tasks or actions that call for you to be alert until you see how clozapine oral suspension affects you.
• To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.
• High blood sugar or diabetes, high cholesterol, and weight gain have happened with drugs like this one. These changes may raise the chance of heart and brain blood vessel disease. Talk with the doctor.
• If you have high blood sugar (diabetes), you will need to watch your blood sugar closely. Tell your doctor if you get signs of high blood sugar like confusion, feeling sleepy, more thirst, more hungry, passing urine more often, flushing, fast breathing, or breath that smells like fruit.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• An unsafe heartbeat that is not normal (long QT on ECG) has happened with this medicine. Chest pain, heart attack, and sudden deaths have also rarely happened in people taking clozapine oral suspension. Talk with the doctor.
• You will need to have heart function tests while taking this medicine. Talk with the doctor.
• Blood clots have happened with clozapine oral suspension. Tell your doctor if you have ever had a blood clot. Talk with your doctor.
• Talk with your doctor before you drink alcohol or use other drugs and natural products that slow your actions.
• Be careful in hot weather or while being active. Drink lots of fluids to stop fluid loss.
• Dizziness, sleepiness, and feeling less stable may happen with this medicine. These may lead to falling. Broken bones or other health problems can happen from falling. Talk with the doctor.
• Very bad and sometimes deadly liver problems have happened with clozapine oral suspension. Call your doctor right away if you have signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Older adults with dementia taking drugs like this one have had a higher number of strokes. Sometimes these strokes have been deadly. This drug is not approved to treat mental problems caused by dementia. Talk with your doctor.
• If you are 60 or older, use this medicine with care. You could have more side effects.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using clozapine oral suspension while you are pregnant.
• Taking this medicine in the third trimester of pregnancy may lead to muscle movements that cannot be controlled and withdrawal in the newborn. Talk with the doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Dizziness.
• Feeling sleepy.
• Hard stools (constipation).
• Dry mouth.
• Upset stomach or throwing up.
• Weight gain.
• Not able to sleep.
• Drooling.
• Headache.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

• Store at room temperature. Do not refrigerate or freeze.
• Store in a dry place. Do not store in a bathroom.
• Protect from light.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Throw away any part not used 100 days after opening the first time.