Clozaril Drug Information

• 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 ( 5.2 )]
• Falls [see Warnings and Precautions ( 5.3 )]
• Seizures [see Warnings and Precautions ( 5.4 )]
• Myocarditis, Pericarditis, Cardiomyopathy, and Mitral Valve Incompetence [see Warnings and Precautions ( 5.5 )]
• Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions ( 5.6 )]
• Gastrointestinal Hypomotility with Severe Complications [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 )] Most common adverse reactions (≥5%) were: CNS reactions (sedation, dizziness/vertigo, headache, and tremor); cardiovascular reactions (tachycardia, hypotension, and syncope); autonomic nervous system reactions (hypersalivation, sweating, dry mouth, and visual disturbances); gastrointestinal reactions (constipation and nausea); and fever. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact HLS Therapeutics (USA), Inc. at (844) 457-8721 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 Adverse Reaction CLOZARIL (N=126) (%) Chlorpromazine (N=142) (%) Sedation 21 13 Tachycardia 17 11 Constipation 16 12 Dizziness 14 16 Hypotension 13 38 Fever (hyperthermia) 13 4 Hypersalivation 13 1 Hypertension 12 5 Headache 10 10 Nausea/vomiting 10 12 Dry mouth 5 20 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) †Rate based on population of approximately 1700 exposed during premarket clinical evaluation of CLOZARIL. Body System Adverse Reaction * CLOZARIL N=842 Percentage of Patients Central Nervous System Drowsiness/Sedation 39 Dizziness/Vertigo 19 Headache 7 Tremor 6 Syncope 6 Disturbed Sleep/Nightmares 4 Restlessness 4 Hypokinesia/Akinesia 4 Agitation 4 Seizures (convulsions) 3† Rigidity 3 Akathisia 3 Confusion 3 Fatigue 2 Insomnia 2 Cardiovascular Tachycardia 25† Hypotension 9 Hypertension 4 Gastrointestinal Constipation 14 Nausea 5 Abdominal Discomfort/Heartburn 4 Nausea/Vomiting 3 Vomiting 3 Diarrhea 2 Urogenital Urinary Abnormalities 2 Autonomic Nervous System Salivation 31 Sweating 6 Dry Mouth 6 Visual Disturbances 5 Skin Rash 2 Hemic/Lymphatic Leukopenia/Decreased WBC/Neutropenia 3 Miscellaneous Fever 5 Weight Gain 4 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) Adverse Reactions CLOZARIL N=479 % Reporting Olanzapine N=477 % Reporting Salivary hypersecretion 48 6 Somnolence 46 25 Weight increased 31 56 Dizziness (excluding vertigo) 27 12 Constipation 25 10 Insomnia 20 33 Nausea 17 10 Vomiting 17 9 Dyspepsia 14 8 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. 6.2 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, restless leg syndrome 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, myocarditis, pericarditis and periorbital edema. Endocrine System Pseudopheochromocytoma Gastrointestinal System Acute pancreatitis, dysphagia, salivary gland swelling, colitis, megacolon, fecal incontinence, and intestinal ischemia, infarction, perforation, ulceration or necrosis. 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, polyserositis, and weight loss.

• Concomitant use of Strong CYP1A2 Inhibitors: Reduce CLOZARIL dose to one-third when coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, enoxacin). ( 2.7 , 7.1 )
• Concomitant use of Strong CYP3A4 Inducers is not recommended. ( 2.7 , 7.1 )
• Discontinuation of CYP1A2 or CYP3A4 Inducers: Consider reducing CLOZARIL dose when CYP1A2 inducers (e.g., tobacco smoke) or CYP3A4 inducers (e.g., carbamazepine) are discontinued. ( 2.7 , 7.1 )
• Anticholinergic drugs: Concomitant use may increase the risk for anticholinergic toxicity. ( 5.7 , 5.15 , 7.1 ) 7.1 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 [see Dosage and Administration ( 2.7 ), Clinical Pharmacology ( 12.3 )] . 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 [see Dosage and Administration ( 2.7 )] . 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 [see Clinical Pharmacology ( 12.3 )] . Use caution and monitor patients closely when using such inhibitors. Consider reducing the CLOZARIL dose [see Dosage and Administration ( 2.7 )] . 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 [see Dosage and Administration ( 2.7 )] . 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 [see Dosage and Administration ( 2.7 )] . Anticholinergic Drugs Concomitant treatment with clozapine and other drugs with anticholinergic activity (e.g., benztropine, cyclobenzaprine, diphenhydramine) can increase the risk for anticholinergic toxicity and severe gastrointestinal adverse reactions related to hypomotility. Avoid concomitant use of CLOZARIL with anticholinergic drugs when possible [see Warnings and Precautions ( 5.7 , 5.15 )] . 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) [see Warnings and Precautions ( 5.9 )] . 7.2 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).

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including CLOZARIL, during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for Atypical Antipsychotics at1-866-961-2388 or visiting http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs, including CLOZARIL, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery ( see Clinical Considerations ). Available data from published epidemiologic studies over decades of use with clozapine during pregnancy have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes ( see Data ). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including CLOZARIL, during pregnancy ( see Clinical Considerations ). In animal reproduction studies, no adverse developmental effects were observed when clozapine was administered orally to pregnant rats or rabbits during the period of organogenesis, or to pregnant rats during pregnancy and lactation, at doses up to approximately 0.4 and 0.9 times the maximum recommended human dose (MRHD) of 900 mg/day, for rats and rabbits respectively, based on mg/m2 body surface area ( see Data ). The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth.

It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal adverse reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who have been exposed to antipsychotic drugs, including CLOZARIL, during the third trimester of pregnancy. These symptoms have varied in severity.

Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Animal Data In embryofetal developmental studies, clozapine had no effects on maternal parameters, litter sizes, or fetal parameters when administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 0.4 and 0.9 times, respectively, the MRHD of 900 mg/day on a mg/m 2 body surface area basis.

In peri/postnatal developmental studies, pregnant female rats were administered clozapine over the last third of pregnancy and until day 21 postpartum. Observations were made on fetuses at birth and during the postnatal period; the offspring were allowed to reach sexual maturity and mated. Clozapine caused a decrease in maternal body weight but had no effects on litter size or body weights of either F1 or F2 generations at doses up to 0.4 times the MRHD of 900 mg/day on a mg/m 2 body surface area basis.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

is contraindicated in patients with a history of hypersensitivity to clozapine (e.g., photosensitivity, vasculitis, erythema multiforme, or Stevens-Johnson syndrome) or any other component of CLOZARIL. Known hypersensitivity to clozapine or any other component of CLOZARIL.

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

There is no available specific antidote to an overdose of CLOZARIL. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures.

Consider the possibility of multiple-drug involvement. Contact a Certified Poison Control Center for the most up to date information on the management of overdosage (1-800-222-1222).