CLOZAPINE

1 INDICATIONS AND USAGE Clozapine tablets are an atypical antipsychotic indicated for: Treatment-resistant schizophrenia. Efficacy was established in an active-controlled study. ( 1.1 , 14.1 ) Reducing suicidal behavior in patients with schizophrenia or schizoaffective disorder. Efficacy was established in an active-controlled study. ( 1.2 , 14.2 ) 1.1 Treatment-Resistant Schizophrenia Clozapine tablets are 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, clozapine tablets should be used only in patients who have failed to respond adequately to standard antipsychotic treatment [see Warnings and Precautions ( 5.1 , 5.5 )] . The effectiveness of clozapine tablets in treatment-resistant schizophrenia was demonstrated in a 6-week, randomized, double-blind, active-controlled study comparing clozapine tablets and chlorpromazine in patients who had failed other antipsychotics [see Clinical Studies ( 14.1 )] . 1.2 Reduction in the Risk of Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder Clozapine tablets are 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 tablets in reducing the risk of recurrent suicidal behavior was demonstrated over a two-year treatment period in the InterSePT™ trial [see Clinical Studies ( 14.2 )] .

2 DOSAGE AND ADMINISTRATION Starting Dose: 12.5 mg once daily or twice daily. ( 2.2 ) Use cautious titration and divided dosage schedule. ( 2.2 , 5.3 ) Titration: increase the total daily dosage in increments of 25 mg to 50 mg per day, if well-tolerated. ( 2.2 ) Target dose: 300 mg to 450 mg per day, in divided doses, by the end of 2 weeks. ( 2.2 ) Subsequent increases: increase in increments of 100 mg or less, once or twice weekly. ( 2.2 ) Maximum daily dose: 900 mg. ( 2.2 ) 2.1 Required Laboratory Testing Prior to Initiation and During Therapy Prior to initiating treatment with clozapine tablets, a baseline ANC must be obtained. The baseline ANC must be at least 1500/µL for the general population, and at least 1000/µL for patients with documented Benign Ethnic Neutropenia (BEN). To continue treatment, the ANC must be monitored regularly [see Warnings and Precautions ( 5.1 )]. 2.2 Dosing Information The starting dose is 12.5 mg once daily or twice daily. The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to achieve a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks. Subsequently, the dose can be increased once weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. To minimize the risk of orthostatic hypotension, bradycardia, and syncope, it is necessary to use this low starting dose, gradual titration schedule, and divided dosages [see Warnings and Precautions ( 5.3 )] . Clozapine tablets can be taken with or without food [see Pharmacokinetics ( 12.3 )] . 2.3 Maintenance Treatment Generally, patients responding to clozapine tablets should continue maintenance treatment on their effective dose beyond the acute episode. 2.4 Discontinuation of Treatment Method of treatment discontinuation will vary depending on the patient’s last ANC: See Table 2 or 3 for appropriate ANC monitoring based on the level of neutropenia if abrupt treatment discontinuation is necessary because of moderate to severe neutropenia. Reduce the dose gradually over a period of 1 to 2 weeks if termination of clozapine tablets therapy is planned and there is no evidence of moderate to severe neutropenia. For abrupt clozapine discontinuation for a reason unrelated to neutropenia, continuation of the existing ANC monitoring is recommended for general population patients until their ANC is ≥1500/μL and for BEN patients until their ANC is ≥1000/μL or above their baseline. Additional ANC monitoring is required for any patient reporting onset of fever (temperature of 38.5°C or 101.3°F, or greater) during the 2 weeks after discontinuation [see Warnings and Precautions ( 5.1 )]. Monitor all patients carefully for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound such as profuse sweating, headache, nausea, vomiting, and diarrhea. 2.5 Re-Initiation of Treatment When restarting clozapine tablets in patients who have had even a brief interruption in treatment with clozapine tablets dosage must be reduced. This is necessary to minimize the risk of hypotension, bradycardia, and syncope [ see Warnings and Precautions (5.3) ] . If one day’s dosing has been missed, resume treatment at 40% to 50% of the established dose. If two days dosing have been missed, resume dose at approximately 25% of the established dosage. For longer interruptions, re-initiate at a dosage of 12.5 mg once daily or twice daily. If these dosages are well-tolerated, the dosage may be increased to the previous dosage more quickly than recommended for initial treatment. 2.6 Dosage Adjustments with Concomitant use of CYP1A2, CYP2D6, CYP3A4 Inhibitors or CYP1A2, CYP3A4 Inducers Dose adjustments may be necessary in patients with concomitant use of: strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin); moderate or weak CYP1A2 inhibitors (e.g., oral contraceptives, or caffeine); CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopra…

5 WARNINGS AND PRECAUTIONS Gastrointestinal Hypomotility with Severe Complications : Severe gastrointestinal adverse reactions have occurred with the use of clozapine tablets. If constipation is identified, close monitoring and prompt treatment is advised. ( 5.8 ) Eosinophilia: Assess for organ involvement (e.g., myocarditis, pancreatitis, hepatitis, colitis, nephritis). Discontinue if these occur. ( 5.9 ) QT Interval Prolongation: Can be fatal. Consider additional risk factors for prolonged QT interval (disorders and drugs). ( 5.10 ) Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/ cerebrovascular risk. These metabolic changes include: Hyperglycemia and Diabetes Mellitus: Monitor for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes. ( 5.11 ) Dyslipidemia: Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics. ( 5.11 ) Weight Gain: Significant weight gain has occurred. Monitor weight gain. ( 5.11 ) Neuroleptic Malignant Syndrome (NMS): Immediately discontinue and monitor closely. Assess for co-morbid conditions. ( 5.12 ) Hepatotoxicity : Can be fatal. Monitor for hepatotoxicity. Discontinue treatment if hepatitis or transaminase elevations combined with other symptoms occur ( 5.13 ). Fever: Evaluate for infection and for neutropenia, NMS. ( 5.14 ) Pulmonary Embolism (PE): Consider PE if respiratory distress, chest pain, or deep-vein thrombosis occur. ( 5.15 ) Anticholinergic Toxicity: When possible, avoid use with other anticholinergic drugs and use with caution in patients with a current diagnosis or prior history of constipation, urinary retention, clinically significant prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions. ( 5.16 , 7.1 ) Interference with Cognitive and Motor Performance: Advise caution when operating machinery, including automobiles. ( 5.17 ) 5.1 Severe Neutropenia Background Clozapine tablets can cause neutropenia (a low absolute neutrophil count (ANC)), defined as a reduction below pre-treatment normal levels of blood neutrophils. The ANC is usually available as a component of the complete blood count (CBC), including differential, and is more relevant to drug-induced neutropenia than is the white blood cell (WBC) count. The ANC may also be calculated using the following formula: ANC equals the Total WBC count multiplied by the total percentage of neutrophils obtained from the differential (neutrophil “segs” plus neutrophil “bands”) . Other granulocytes (basophils and eosinophils) contribute minimally to neutropenia and their measurement is not necessary [see Adverse Reactions ( 6.2 )] . Neutropenia may be mild, moderate, or severe (see Table 2 and 3 ). To improve and standardize understanding, “severe neutropenia” replaces the previous terms severe leukopenia, severe granulocytopenia, or agranulocytosis. Severe neutropenia, ANC less than (<) 500/μL, occurs in a small percentage of patients taking clozapine tablets and are associated with an increase in the risk of serious and potentially fatal infections. Risk of neutropenia appears greatest during the first 18 weeks on treatment and then declines. The mechanism by which clozapine tablets cause neutropenia is unknown and is not dose-dependent. Two separate management algorithms are provided below, the first for patients in the general population, and the second for patients identified to have baseline neutropenia. Clozapine Tablets Treatment and Monitoring in the General Patient Population (see Table 2 ) Obtain a CBC, including the ANC value, prior to initiating treatment with clozapine tablets to ensure the presence of a normal baseline neutrophil count (equal to or greater than 1500/μL) and to permit later comparisons. Patients in the general population with an …

4 CONTRAINDICATIONS Clozapine tablets are 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 clozapine tablets [see Adverse Reactions ( 6.2 )] . Known serious hypersensitivity to clozapine or any other component of clozapine tablets. (4)

7 DRUG INTERACTIONS Concomitant use of Strong CYP1A2 Inhibitors : Reduce clozapine tablets dose to one-third when coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, enoxacin). ( 2.6 , 7.1 ) Concomitant use of Strong CYP3A4 Inducers is not recommended. ( 2.6 , 7.1 ) Discontinuation of CYP1A2 or CYP3A4 Inducers: Consider reducing clozapine tablets dose when CYP1A2 inducers (e.g., tobacco smoke) or CYP3A4 inducers (e.g., carbamazepine) are discontinued. ( 2.6 , 7.1 ) Anticholinergic drugs: Concomitant use may increase the risk for anticholinergic toxicity. ( 5.8 , 5.16 , 7.1 ) 7.1 Potential for Other Drugs to Affect Clozapine Tablets Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6. Use caution when administering clozapine tablets concomitantly with drugs that are inducers or inhibitors of these enzymes. CYP1A2 Inhibitors Concomitant use of clozapine tablets and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. Reduce the clozapine tablets dose to one-third of the original dose when clozapine tablets are coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin). The clozapine tablets dose should be increased to the original dose when coadministration of strong CYP1A2 inhibitors is discontinued [see Dosage and Administration ( 2.6 ), Clinical Pharmacology ( 12.3 )] . Moderate or weak CYP1A2 inhibitors include oral contraceptives and caffeine. Monitor patients closely when clozapine tablets are coadministered with these inhibitors. Consider reducing the clozapine tablets dosage if necessary [see Dosage and Administration ( 2.6 )] . CYP2D6 and CYP3A4 Inhibitors Concomitant treatment with clozapine tablets 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 clozapine tablets dose [see Dosage and Administration ( 2.6 )] . 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 clozapine tablets. 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 clozapine tablets dose if used concomitantly with inducers of these enzymes. However, concomitant use of clozapine tablets and strong CYP3A4 inducers is not recommended [see Dosage and Administration ( 2.6 )] . Consider reducing the clozapine tablets 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 ( 2.6 )] . 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 clozapine tablets with anticholinergic drugs when possible [see Warnings and Precautions ( 5.8, 5.16 )]. 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…

8.1 Pregnancy Pregnancy Category B Risk Summary There are no adequate or well-controlled studies of clozapine in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 0.4 and 0.9 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on a mg/m 2 body surface area basis. The studies revealed no evidence of impaired fertility or harm to the fetus due to clozapine. Because animal reproduction studies are not always predictive of human response, clozapine tablets should be used during pregnancy only if clearly needed. Clinical Considerations Consider the risk of exacerbation of psychosis when discontinuing or changing treatment with antipsychotic medications during pregnancy and postpartum. Consider early screening for gestational diabetes for patients treated with antipsychotic medications [see Warnings and Precautions ( 5.11 )] . Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Monitor neonates for symptoms of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding difficulties. The severity of complications can vary from self-limited symptoms to some neonates requiring intensive care unit support and prolonged hospitalization. Animal Data In embryo fetal 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.

8.3 Nursing Mothers Clozapine tablets is present in human milk. Because of the potential for serious adverse reactions in nursing infants from clozapine tablets, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

6 ADVERSE REACTIONS 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 )] Gastrointestinal Hypomotility with Severe Complications [See Warnings and Precautions ( 5.8 )] Eosinophilia [see Warnings and Precautions ( 5.9 )] QT Interval Prolongation [see Warnings and Precautions ( 5.10 )] Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) [see Warnings and Precautions ( 5.11 )] Neuroleptic Malignant Syndrome [see Warnings and Precautions ( 5.12 )] Hepatotoxicity [ see Warnings and Precautions ( 5.13 )] Fever [see Warnings and Precautions ( 5.14 )] Pulmonary Embolism [see Warnings and Precautions ( 5.15 )] Anticholinergic Toxicity [see Warnings and Precautions ( 5.16 )] Interference with Cognitive and Motor Performance [see Warnings and Precautions ( 5.17 )] Tardive Dyskinesia [see Warnings and Precautions ( 5.18 )] Cerebrovascular Adverse Reactions [see Warnings and Precautions ( 5.19 )] Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation [see Warnings and Precautions ( 5.20 )] 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 Sun Pharmaceutical Industries, Inc. at 1-800-406-7984 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 clozapine tablets 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 tablets-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 Clozapine Tablets (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 clozapine tablets-treated patients at a frequency of 2% or greater across all clozapine tablets studies (excluding the 2-year InterSePT™ Study). These rates are not adjusted for duration of exposure. Table 10. Adverse Reactions (≥2%) Reported in Clozapine Tablets-treated Patients (N=842) Across all Clozapine Tablets Studies (excluding the 2-year InterSePT™ Study) Body System Clozapine Tablets N = 842 Percentage of Patients Adverse Reaction* Central Nervous System 39 Drowsiness/Sedation 19 Dizziness/Vertigo 7 Hea…