Clozaril

• Novartis Pharmaceuticals Corporation

Clozaril can cause a serious blood condition. Your doctor will order certain lab tests before you start your treatment, during your treatment, and for at least 4 weeks after your treatment. Your doctor will order the lab tests once a week at first and may order the tests less often as your treatment continues. If you experience any of the following symptoms, call your doctor immediately: extreme tiredness; weakness; fever, sore throat, chills, or other signs of flu or infection; or sores in your mouth or throat.

A program has been set up to be sure that people do not take Clozaril without the necessary monitoring. You, your doctor, and your pharmacist must be registered with the program, and your pharmacist will not dispense your medication unless he or she has received the results of your blood tests. Ask your doctor for more information about this program and how you will receive your medication.

Clozaril may cause seizures. Tell your doctor if you have or have ever had seizures. Do not drive a car, operate machinery, swim, or climb while taking Clozaril, because if you suddenly lose consciousness, you could harm yourself or others.

Clozaril may cause myocarditis (swelling of the heart muscle that may be dangerous). If you experience any of the following symptoms, call your doctor immediately: extreme tiredness; difficulty breathing or fast breathing; fever; chest pain; or fast, irregular, or pounding heartbeat.

Clozaril may cause dizziness, lightheadedness, or fainting when you stand up, especially when you first start taking it or when your dose is increased. Tell your doctor if you are taking medications for anxiety such as diazepam (Valium), sleeping pills, or other medications for schizophrenia. Your doctor will probably start you on a low dose of clozapine and gradually increase your dose to give your body time to adjust to the medication and decrease the chance that you will experience this side effect. Talk to your doctor if you do not take Clozaril for 2 days or longer. Your doctor will probably tell you to restart your treatment with a low dose of Clozaril.

Use in Older Adults:

Studies have shown that older adults with dementia (a brain disorder that affects the ability to remember, think clearly, communicate, and perform daily activities and that may cause changes in mood and personality) who take antipsychotics (medications for mental illness) such as Clozaril have an increased chance of death during treatment.

Clozaril is not approved by the Food and Drug Administration (FDA) for the treatment of behavior problems in older adults with dementia. Talk to the doctor who prescribed clozapine if you, a family member, or someone you care for has dementia and is taking this medication.

Clozapine is an antipsychotic medication. It works by changing the actions of chemicals in the brain.

Clozapine is used to treat severe schizophrenia. Clozapine is also used to reduce the risk of suicidal behavior in people with schizophrenia or similar disorders. Clozapine is usually given after other medications have been tried without successful treatment of symptoms.

Clozapine may also be used for purposes not listed in this medication guide.

Clozapine may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert. Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Avoid drinking alcohol. It can increase some of the side effects of clozapine.

• Schizoaffective Disorder
• Schizophrenia

Call your doctor right away if you have: chest pain, trouble breathing, fluttering in your chest, signs of infection (weakness, fever, sore throat, cold or flu symptoms), or if you feel like you might pass out.

Clozapine can cause severe dizziness, slow heartbeats, fainting, or seizures. Do not take more of this medicine than recommended.

Clozapine is not approved for use in psychotic conditions related to dementia. Clozapine may increase the risk of death in older adults with dementia-related conditions.

Clozapine is available only from a certified pharmacy under a special program.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Blurred vision
• confusion
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• fainting
• fast, pounding, or irregular heartbeat or pulse
• fever
• shakiness in the legs, arms, hands, or feet
• sleepiness or unusual drowsiness
• sweating
• trembling or shaking of the hands or feet
• unusual tiredness or weakness

• Anxiety
• black, tarry stools
• chest pain
• chills
• convulsions
• cough or hoarseness
• decrease in the frequency of urination
• decrease in urine volume
• difficult or labored breathing
• difficulty in passing urine (dribbling)
• discouragement
• dry mouth
• feeling sad or empty
• fever with or without chills
• frequent strong or increased urge to urinate
• general feeling of tiredness or weakness
• headache
• hyperventilation
• irritability
• lack of appetite
• loss of bladder control
• loss of interest or pleasure
• lower back or side pain
• muscle spasm or jerking of the arms or legs
• painful or difficult urination
• pounding in the ears
• restlessness or need to keep moving
• severe or continuing headache
• shakiness and unsteady walk
• slurred speech
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• sudden jerky movements of the body
• sudden loss of consciousness
• swollen glands
• throat discomfort
• tightness in the chest
• trouble concentrating
• trouble sleeping
• unsteadiness, trembling, or other problems with muscle control or coordination

• Absence of or decrease in movement
• change in appetite
• dark urine
• decreased sexual ability
• difficult or fast breathing or sudden shortness of breath
• increased sweating
• increased thirst
• increased urination
• lip smacking or puckering
• muscle stiffness (severe)
• nausea
• puffing of the cheeks
• rapid or worm-like movements of the tongue
• swelling or pain in the leg
• uncontrolled chewing movements
• uncontrolled movements of the arms and legs
• unusual bleeding or bruising
• unusually pale skin
• vomiting
• weakness
• yellow eyes or skin

• Abdominal or stomach pain
• bloating
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• clay-colored stools
• confusion as to time, place, or person
• constipation
• diarrhea
• epileptic seizure that will not stop
• feeling that others are watching you or controlling your behavior
• feeling that others can hear your thoughts
• feeling, seeing, or hearing things that are not there
• holding false beliefs that cannot be changed by fact
• inability to move the eyes
• increased blinking or spasms of the eyelid
• indigestion
• itching or skin rash
• joint pain
• light-colored stools
• muscle twitching
• pains in the stomach, side, or abdomen, possibly radiating to the back
• rhythmic movement of the muscles
• severe mood or mental changes
• sticking out of the tongue
• swelling around the eyes
• swelling of the body or feet and ankles
• trouble with speaking
• unpleasant breath odor
• unusual behavior
• unusual excitement, nervousness, or restlessness
• unusual facial expressions
• unusual weight gain
• upper right abdominal or stomach pain
• vomiting of blood

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• belching
• feeling of constant movement of self or surroundings
• heartburn
• relaxed and calm sensation of spinning
• sleepiness

• Blurred or loss of vision
• change or problem with discharge of semen
• disturbed color perception
• double vision
• halos around lights
• inability to sit still
• increase in body movements
• muscle ache or pain
• muscle weakness
• night blindness
• nightmares
• overbright appearance of lights
• pain in the back, neck, or legs
• pain in the chest below the breastbone
• severe muscle stiffness
• sore tongue
• stuffy nose
• tunnel vision
• unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness

• Blistering, peeling, or loosening of the skin
• hives
• increased sensitivity of the skin to sunlight
• painful or prolonged erection of the penis
• red skin lesions, often with a purple center
• red, irritated eyes
• reddening of the skin, especially around the ears
• severe stomach pain
• severe sunburn
• sores, welting, or blisters
• swelling of the eyes, face, or inside of the nose
• swelling of the salivary glands

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• 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 Clozaril.

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 Clozaril with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Hypersensitivity

Clozaril is contraindicated in patients with a history of serious hypersensitivity to clozapine (e.g., photosensitivity, vasculitis, erythema multiforme, or Stevens-Johnson Syndrome) or any other component of Clozaril [see Adverse Reactions (6.2)].

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)].
• Eosinophilia [see Warnings and Precautions (5.8)].
• QT Interval Prolongation [see Warnings and Precautions (5.9)].
• Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) [see Warnings and Precautions (5.10)].
• Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.11)].
• Hepatotoxicity [see Warnings and Precautions (5.12)].
• Fever [see Warnings and Precautions (5.13)].
• Pulmonary Embolism [see Warnings and Precautions (5.14)].
• Anticholinergic Toxicity [see Warnings and Precautions (5.15)].
• Interference with Cognitive and Motor Performance [see Warnings and Precautions (5.16)].
• Tardive Dyskinesia [see Warnings and Precautions (5.17)].
• Cerebrovascular Adverse Reactions [see Warnings and Precautions (5.18)].
• Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation [see Warnings and Precautions (5.19)].

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 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 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.

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, palpitations, QT interval prolongation, Torsades de Pointes, mitral valve incompetence associated with clozapine-related cardiomyopathy, myocardial infarction, cardiac arrest, and periorbital edema.

Endocrine System

Pseudopheochromocytoma

Gastrointestinal System

Acute pancreatitis, dysphagia, salivary gland swelling, colitis.

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, sleep apnea.

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.

Overdosage Experience

The most commonly reported signs and symptoms associated with clozapine overdose are: sedation, delirium, coma, tachycardia, hypotension, respiratory depression or failure; and hypersalivation. There are reports of aspiration pneumonia, cardiac arrhythmias, and seizure. Fatal overdoses have been reported with clozapine, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g.

Management of Overdosage

For the most up-to-date information on the management of Clozaril overdosage, contact a certified Regional Poison Control Center (1-800-222-1222). Telephone numbers of certified Regional Poison Control Centers are listed in the **Physicians’ Desk Reference®, a registered trademark of PDR Network. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. There are no specific antidotes for Clozaril.

In managing overdosage, consider the possibility of multiple-drug involvement.

Call your doctor right away if you have: chest pain, trouble breathing, fluttering in your chest, signs of infection (weakness, fever, sore throat, cold or flu symptoms), or if you feel like you might pass out.

Clozaril can cause severe dizziness, slow heartbeats, fainting, or seizures. Do not take more of this medicine than recommended.

Clozaril is not approved for use in psychotic conditions related to dementia. Clozapine may increase the risk of death in older adults with dementia-related conditions.

Clozaril is available only from a certified pharmacy under a special program.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose. If you miss taking Clozaril for more than 2 days in a row, call your doctor before you start taking it again.