Clozapine

VERSACLOZ 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, VERSACLOZ 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 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 (5.1 , 5.4) ] . 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 (14.1) ] .

1.2 Reduction in the Risk of Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorders 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 (14.2) ] .

VERSACLOZ is available as a free-flowing yellow oral suspension. Each mL contains 50 mg of clozapine. Oral suspension: 50 mg per mL ( 3 ).

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

Severe neutropenia: See Boxed Warning (5.1) Gastrointestinal Hypomotility with Severe Complications: Severe gastrointestinal adverse reactions have occurred with the use of VERSACLOZ. 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: 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 ( 5.10 ). Dyslipidemia: Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics ( 5.10 ). Weight Gain: Significant weight gain has occurred. Monitor weight gain ( 5.10 ). 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 VERSACLOZ 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 VERSACLOZ-treated patients. The risk of severe neutropenia appears greatest during the first 18 weeks of VERSACLOZ treatment. The mechanism by which VERSACLOZ causes neutropenia is unknown. Neutropenia is not dose dependent. Consider a hematology consultation before initiating VERSACLOZ treatment or during treatment. ANC Monitoring and Dosage Modifications Prior to initiating VERSACLOZ treatment, obtain a baseline ANC. VERSACLOZ initiation is not recommended in patients with a baseline ANC less than 1500/μL. Throughout VERSACLOZ treatment, regularly monitor ANC. Table 1 provides recommendations for dosage modifications (dosage interruption and treatment discontinuation), based on ANC levels, during VERSACLOZ 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 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 VERSACLOZ-induced neutropenia. For patients with documented BEN, obtain at least two baseline ANC levels prior to VERSACLOZ initiation. VERSACLOZ initiation is not recommended in patients with BEN with an ANC less than 1000/μL. There are different ANC dosage modification recommendations in VERSACLOZ-treated patients with BEN due to their lower baseline ANC levels. Table 2 provides recommendations on dosage modifications (dosage interruption and treatment discontinuation), based on ANC monitoring, during VERSACLOZ treatment in patients with BEN and recommended frequency of ANC testing [see Dosage and Administration (2.5)] . Management of VERSACLOZ-Treated Patients Who Develop a Fever For patients who develop a fever during VERSACLOZ treatment: Interrupt VERSACLOZ in those who develop a temperature of 101.3 °F (38.5 °C) or greater and obtain an ANC level. If the ANC is less than 1000/μL in patients without BEN, initiate appropriate workup and treatment for infection. Refer to Table 1 for dosage modifications based on ANC monitoring [see Dosage and Administration (2.4)] . In patients with fever and a normal neutrophil count, see Warnings and Precautions (5.11) for neuroleptic malignant syndrome and Warnings and Precautions (5.13) for fever. Restarting VERSACLOZ in Patients Who Recovered from Severe Neutropenia Generally, do not rechallenge patients with VERSACLOZ in those who experienced severe neutropenia. However, for some patients who had resolution of their VERSACLOZ-related severe neutropenia after stopping VERSACLOZ, the risk of schizophrenia exacerbation from not restarting VERSACLOZ treatment may be greater than the risk of neutropenia reoccurrence from restarting VERSACLOZ (e.g., patients who have no treatment options other than VERSACLOZ). Concomitant Use of VERSACLOZ with Other Drugs Known to Cause Neutropenia If VERSACLOZ is used concomitantly with another drug known to cause neutropenia, consider more frequently ANC monitoring than the recommendations provided in Table 1 and Table 2.

5.2 Orthostatic Hypotension, Bradycardia, and Syncope Hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment. The risk is highest during the initial titration period, particularly with rapid dose-escalation. These reactions can occur with the first dose, at doses as low as 12.5 mg. These reactions can be fatal. The syndrome is consistent with neurally mediated reflex bradycardia (NMRB). Treatment must begin at a maximum dose of 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 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 weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. Use cautious titration and a divided dosage schedule to minimize the risk of serious cardiovascular reactions [see Dosage and Administration (2.2) ] . Consider reducing the dose if hypotension occurs. When restarting VERSACLOZ in patients who have had even a brief interruption in treatment with VERSACLOZ, the dosage must be reduced. This is necessary to minimize the risk of hypotension, bradycardia, and syncope [see Dosage and Administration (2.6) ]. Use VERSACLOZ cautiously in patients with cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (e.g., concomitant use of antihypertensives, dehydration and hypovolemia).

5.3 Falls VERSACLOZ may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic treatment.

5.4 Seizures Seizure has been estimated to occur in association with clozapine use at a cumulative incidence at one year of approximately 5%, based on the occurrence of one or more seizures in 61 of 1743 patients exposed to clozapine during its clinical testing prior to domestic marketing (i.e., a crude rate of 3.5%). The risk of seizure is dose-related. […]

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 and 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 TruPharma, LLC, at 1-877-541-5504 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 Tachycardia Constipation Dizziness Hypotension Fever (hyperthermia) Hypersalivation Hypertension Headache Nausea/vomiting Dry mouth 21 17 16 14 13 13 13 12 10 10 5 13 11 12 16 38 4 1 5 10 12 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 Dizziness/Vertigo Headache Tremor Syncope Disturbed Sleep/Nightmares Restlessness Hypokinesia/Akinesia Agitation Seizures (convulsions) Rigidity Akathisia Confusion Fatigue Insomnia 39 19 7 6 6 4 4 4 4 3† 3 3 3 2 2 Cardiovascular Tachycardia Hypotension Hypertension 25† 9 4 Gastrointestinal Constipation Nausea Abdominal Discomfort/Heartburn Nausea/Vomiting Vomiting Diarrhea 14 5 4 3 3 2 Urogenital Urinary Abnormalities 2 Autonomic Nervous System Salivation Sweating Dry Mouth Visual Disturbances 31 6 6 5 Skin Rash 2 Hemic/Lymphatic Leukopenia/Decreased WBC/Neutropenia 3 Miscellaneous Fever Weight Gain 5 4 † Rate based on population of approximately 1700 exposed during premarket clinical evaluation of clozapine. 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) Adverse Reactions Clozapine 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, 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, 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. […]

Concomitant use of Strong CYP1A2 Inhibitors : Reduce VERSACLOZ dose to one third when coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, enoxacin) ( 2.8 , 7.1 ). Concomitant use of Strong CYP3A4 Inducers is not recommended ( 2.8 , 7.1 ). Discontinuation of CYP1A2 or CYP3A4 Inducers : Consider reducing VERSACLOZ dose when CYP1A2 (e.g., tobacco smoke) or CYP3A4 inducers (e.g., carbamazepine) are discontinued ( 2.8 , 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 VERSACLOZ Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6. Use caution when administering VERSACLOZ concomitantly with drugs that are inducers or inhibitors of these enzymes. CYP1A2 Inhibitors Concomitant use of VERSACLOZ and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. Reduce the VERSACLOZ dose to one third of the original dose when VERSACLOZ is coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin). The VERSACLOZ dose should be increased to the original dose when coadministration of strong CYP1A2 inhibitors is discontinued [see Dosage and Administration (2.8) , Clinical Pharmacology (12.3) ]. Moderate or weak CYP1A2 inhibitors include oral contraceptives and caffeine. Monitor patients closely when VERSACLOZ is coadministered with these inhibitors. Consider reducing the VERSACLOZ dosage if necessary [see Dosage and Administration (2.8) ] . CYP2D6 and CYP3A4 Inhibitors Concomitant treatment with VERSACLOZ 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 VERSACLOZ dose [see Dosage and Administration (2.8) ] . 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 VERSACLOZ. 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 VERSACLOZ dose if used concomitantly with inducers of these enzymes. However, concomitant use of VERSACLOZ and strong CYP3A4 inducers is not recommended [see Dosage and Administration (2.8) ]. Consider reducing the VERSACLOZ 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 (2.8) ]. 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 VERSACLOZ 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 VERSACLOZ. 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 VERSACLOZ to Affect Other Drugs Concomitant use of VERSACLOZ with other drugs metabolized by CYP2D6 can increase levels of these CYP2D6 substrates. Use caution when coadministering VERSACLOZ 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: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure ( 8.1 ).

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including VERSACLOZ, during pregnancy. Health care providers are encouraged to advise patients to register by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visiting http://womensmental health.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs, including VERSACLOZ, 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 VERSACLOZ, 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/m 2 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 VERSACLOZ, 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 Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics do not report a clear association with antipsychotics and major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. 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.

8.2 Lactation Risk Summary Clozapine is present in human milk. There are reports of sedation and a report of agranulocytosis in an infant exposed to clozapine through human milk ( see Clinical Considerations ). There is no information on the effects of clozapine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VERSACLOZ and any potential adverse effects on the breastfed-child from VERSACLOZ or from the underlying maternal condition. Clinical Considerations Infants exposed to VERSACLOZ should be monitored for excess sedation and neutropenia.

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

8.5 Geriatric Use There have not been sufficient numbers of geriatric patients in clinical studies utilizing VERSACLOZ to determine whether those over 65 years of age differ from younger subjects in their response to VERSACLOZ. Orthostatic hypotension and tachycardia can occur with clozapine treatment [see Boxed Warning and Warnings and Precautions (5. 2 ) ]. Elderly patients, particularly those with compromised cardiovascular functioning, may be more susceptible to these effects. Elderly patients may be particularly susceptible to the anticholinergic effects of clozapine, such as urinary retention and constipation [see Warnings and Precautions (5.15) ]. Carefully select VERSACLOZ doses in elderly patients, taking into consideration their greater frequency of decreased hepatic, renal, or cardiac function, as well as other concomitant disease and other drug therapy. Clinical experience suggests that the prevalence of tardive dyskinesia appears to be highest among the elderly; especially elderly women [see Warnings and Precautions (5.17) ].

8.6 Patients with Renal or Hepatic Impairment Dose reduction may be necessary in patients with significant impairment of renal or hepatic function. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted [see Dosage and Administration (2.9) , Clinical Pharmacology (12.3) ]. 8.7 CYP2D6 Poor Metabolizers Dose reduction may be necessary in patients who are CYP2D6 poor metabolizers. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted [see Dosage and Administration (2.8) , Clinical Pharmacology (12.3) ].

The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors. VERSACLOZ also acts as an antagonist at adrenergic, cholinergic, histaminergic and other dopaminergic and serotonergic receptors.