Clozapine

1 INDICATIONS AND USAGE Clozapine orally disintegrating tablets (Clozapine ODT) is an atypical antipsychotic indicated for: 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 ODT should be used only in patients who have failed to respond adequately to standard antipsychotic treatment ( 1.1 ) 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 ( 1.2 ) 1.1 Treatment-resistant Schizophrenia Clozapine Orally Disintegrating Tablets (Clozapine ODT) 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 their use, Clozapine ODT should be used only in patients who have failed to respond adequately to standard antipsychotic treatment [see Warnings and Precautions (5.1 , 5.4) ]. The effectiveness of Clozapine ODT in treatment-resistant schizophrenia was demonstrated in a 6-week, randomized, double-blind, active-controlled study comparing Clozapine ODT 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 ODT 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 ODT 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 Recommended starting oral dosage is 12.5 mg once daily or twice daily. ( 2.2 ) If well-tolerated, increase the total daily dosage in increments of 25 mg to 50 mg per day at target dosage of 150 mg to 225 mg twice per day by the end of two weeks. ( 2.2 ) Subsequently may increase the doage in increments up to 100 mg, once or twice weekly. ( 2.2 ) Maximum daily dosage is 450 mg twice daily. ( 2.2 ) Administer with or without food. Clozapine ODT may be allowed to disintegrate or chewed, and may be taken with or without water. See additional administration instructions in the full prescribing information. ( 2.2 ) See dosage modification based on ANC results. ( 2.3 , 2.4 ) See recommendations for discontinuing Clozapine ODT treatment ( 2.5 ), restarting Clozapine ODT after interrupting dosing (2.6), dosage modifications for drug interactions ( 2.7 ), dosage recommendations in patients with renal or hepatic impairment and CYP2D6 poor metabolizers ( 2.8 ) in the full prescribing information. Tablets rapidly disintegrate after placement in the mouth and may be chewed if desired. No water is needed. ( 2.2 ) 2.1 Absolute Neutrophil Count Testing Prior to Clozapine ODT Initiation Prior to initiating Clozapine ODT treatment, obtain a baseline absolute neutrophil count (ANC). Clozapine ODT initiation is not recommended in patients with an ANC less than 1500/µL [see Warnings and Precautions (5.1) ] . For patients with documented Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count)), obtain at least two baseline ANC levels. Clozapine ODT initiation is not recommended in patients with BEN with an ANC less than 1000/µL [see Warnings and Precautions (5.1) ] . For dosage modifications based on ANC results, see Dosage and Administration (2.3 , 2.4) . 2.2 Recommended Dosage and Administration Recommended Dosage To reduce the risk of orthostatic hypotension, bradycardia, and syncope, the recommended starting dosage is much lower than the target dosage [see Warnings and Precautions (5.2) ] . The recommended starting oral dosage of Clozapine ODT is 12.5 mg once or twice daily. If well-tolerated, increase the total daily dose in increments of 25 mg to 50 mg per day to achieve a target dosage of 150 mg to 225 mg twice per day by the end of two weeks. Subsequently, may increase the dosage in increments of up to 100 mg once weekly or twice weekly. The maximum recommended Clozapine ODT oral dosage is 450 mg twice daily. Administration Instructions Clozapine ODT can be taken with or without food, may be allowed to disintegrate or chewed, and may be taken with or without water [see Clinical Pharmacology (12.3) ] . After removing Clozapine ODT from the bottle, immediately place in the mouth. 2.3 Dosage Modifications Based on ANC Results Table 1 provides recommended Clozapine ODT dosage modifications based on ANC results [see Warnings and Precautions (5.1) ] . For dosage modifications based on ANC results for patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count), see Table 2 [see Dosage and Administration (2.4) ] . Table 1: Clozapine ODT Dosage Modifications Based on ANC Results and Frequency of ANC Testing Recommended Dosage Modification Recommended Frequency of ANC Testing During Clozapine ODT Treatment ANC Within Normal Range (≥ 1500/µL) No dosage modification; continue treatment Day 1 to Month 6: Weekly Month 7 to Month 12: Every 2 weeks Month 13 and thereafter: Every month If Clozapine ODT treatment is reinitiated after a dosage interruption (e.g., patient had neutropenia which required dosage interruption and now has a normal ANC level) for: < 30 days, continue the previous ANC testing frequency ≥ 30 days, obtain ANC tests according to the frequency for patients who initiate treatment Mild Neutropenia (ANC between 1000 to 1499/µL) Confirm all initial reports of ANC less than 1500/µL with a repeat ANC measurement within 24 hours No dosage modifica…

5 WARNINGS AND PRECAUTIONS Severe neutropenia: See ( 5.1 ) Gastrointestinal Hypomotility with Severe Complications: Severe gastrointestinal adverse reactions have occurred with the use of clozapine. If constipation is identified, close monitoring and prompt treatment is advised. ( 5.7 ) Eosinophilia: Assess for organ involvement (e.g., myocarditis, pancreatitis, hepatitis, colitis, nephritis). Discontinue if these occur. ( 5.8 ) QT Interval Prolongation: Can be fatal. Consider additional risk factors for prolonged QT interval (disorders and drugs). ( 5.9 ) Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include ( 5.10 ): 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. Dyslipidemia: Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics. Weight Gain: Significant weight gain has occurred. Monitor weight gain. Neuroleptic Malignant Syndrome (NMS): Immediately discontinue and monitor closely. Assess for co-morbid conditions. ( 5.11 ) Hepatotoxicity: Can be fatal. Monitor for hepatotoxicity. Discontinue treatment if hepatitis or transaminase elevations combined with other symptoms occur. ( 5.12 ) Fever: Evaluate for infection and for neutropenia, NMS. ( 5.13 ) Pulmonary Embolism (PE): Consider PE if respiratory distress, chest pain, or deep vein thrombosis occurs. ( 5.14 ) 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. ( 5.15 , 7.1 ) Interference with Cognitive and Motor Performance: Advise caution when operating machinery, including automobiles. ( 5.16 ) 5.1 Severe Neutropenia Clozapine has caused severe neutropenia (absolute neutrophil count (ANC) less than 500/µL) [see Adverse Reactions (6.1 , 6.2) ] and is associated with an increased risk of serious and potentially fatal infections. Severe neutropenia occurred in a small percentage of clozapine-treated patients. The risk of severe neutropenia appears greatest during the first 18 weeks of Clozapine ODT treatment. The mechanism by which Clozapine ODT causes neutropenia is unknown. Neutropenia is not dose-dependent. Consider a hematology consultation before initiating Clozapine ODT treatment or during treatment. ANC Monitoring and Dosage Modifications Prior to initiating Clozapine ODT treatment, obtain a baseline ANC. Clozapine ODT initiation is not recommended in patients with a baseline ANC less than 1500/µL. Throughout Clozapine ODT treatment, regularly monitor ANC. Table 1 provides recommendations for dosage modifications (dosage interruption and treatment discontinuation), based on ANC levels, during Clozapine ODT treatment and frequency of ANC monitoring [see Dosage and Administration (2.4) ] . ANC Monitoring and Dosage Modification in Patients with Benign Ethnic Neutropenia Patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count) generally have lower baseline neutrophil counts but they are not at higher risk for developing infections, and they are not at increased risk for developing Clozapine ODT-induced neutropenia. For patients with documented BEN, obtain at least two baseline ANC levels prior to Clozapine ODT initiation. Clozapine ODT initiation is not recommended in patients with BEN with an ANC less than 1000/µL. There are different ANC dosage modification recommendations in Clozapine ODT-treated patients with BEN due to their lower baseline ANC levels. Table 2 provides recommendations on dosage modifications (dosage i…

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

7 DRUG INTERACTIONS Concomitant use of Strong CYP1A2 Inhibitors : Reduce Clozapine ODT 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 Clozapine ODT dose when CYP1A2 (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 Clozapine ODT Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6. Use caution when administering Clozapine ODT concomitantly with drugs that are inducers or inhibitors of these enzymes. CYP1A2 Inhibitors Concomitant use of Clozapine ODT and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. Reduce the Clozapine ODT dose to one-third of the original dose when Clozapine ODT is coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin). The Clozapine ODT 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 Clozapine ODT is coadministered with these inhibitors. Consider reducing the Clozapine ODT dosage if necessary [see Dosage and Administration (2.7) ] . CYP2D6 and CYP3A4 Inhibitors Concomitant treatment with Clozapine ODT 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 ODT 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 Clozapine ODT. 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 ODT dose if used concomitantly with inducers of these enzymes. However, concomitant use of Clozapine ODT and strong CYP3A4 inducers is not recommended [see Dosage and Administration (2.7) ] . Consider reducing the Clozapine ODT 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 ODT 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 ODT 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, halof…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including Clozapine ODT, 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 Clozapine ODT, 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 Clozapine ODT, 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 Clozapine ODT, 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.

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 (5.2) ] 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) ] Patients with Phenylketonuria [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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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 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, Chlorpromazine-Controlled Trial in Treatment-Resistant Schizophrenia Adverse Reaction Clozapine (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-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) Body System Adverse Reaction Clozapine N = 842 Percentage of Patients Central Nervous System Drowsiness/Sedation 39 Dizziness/Vertigo 19 Headache 7 Tremo…