Clozapine
Tablet · Oral
Uses
Clozapine tablets are 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 tablets 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 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 , 5.4) ]. 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) ] .
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 to achieve a target dosage of 150 mg to 225 mg twice per day by the end of two weeks ( 2.2 ). Subsequently may increase the dosage 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 ( 2.2 ). See the dosage modifications based on ANC results and recommended frequency of ANC testing in the full prescribing information ( 2.3 , 2.4 ). See recommendations for discontinuing clozapine tablets treatment (2.5), restarting clozapine tablets 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. 2.1 Absolute Neutrophil Count Testing Prior to Clozapine Tablets Initiation Prior to initiating clozapine tablets treatment, obtain a baseline absolute neutrophil count (ANC). Clozapine tablets 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 tablets 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 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) ] . Clozapine tablets can be taken with or without food [see Clinical Pharmacology (12.3) ] . The recommended starting oral dosage of clozapine tablets 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 tablets oral dosage is 450 mg twice daily. 2.3 Dosage Modifications Based on ANC Results Table 1 provides recommended clozapine tablets 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 Tablets Dosage Modifications Based on ANC Results and Frequency of ANC Testing 1 Confirm all initial reports of ANC less than 1500/μL with a repeat ANC measurement within 24 hours Recommended Dosage Modification Recommended Frequency of ANC Testing During Clozapine Tablets 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 tablets 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) 1 No dosage modification; continue treatment Three times weekly Once ANC ≥ 1500/μL, recommend returning to the patient’s last Normal Range ANC testing frequency Moderate Neutropenia (ANC between 500 to 999/μL) 1 Interrupt treatment and recommend hematology consultation Resume treatment once ANC ≥1000/μL Daily Once ANC ≥ 1000/μL, three times weekly Once ANC ≥ 1500/μL, test weekly for 4 weeks. If ANC ≥ 1500/μL after monitoring weekly for 4 weeks, return to the patient’s last Normal Range ANC testing frequency Severe Neutropenia (ANC less than 500/μL) 1 Discontinue treatment and recommend hematology consultation Daily Once ANC ≥ 1000/μL, three times weekly Once ANC ≥ 1500/μL, if the benefits outweigh the risks of restarting treatment, resume treatment and obtain ANC tests according to the frequency for patients who initiate treatment 2.4 Dosage Modifications Based on ANC Results for Patients with Benign Ethnic Neutropenia Table 2 provides recommended clozapine tablets dosage modifications based on ANC results for patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count) [see Warnings and Precautions (5.1) ] . For dosage modifications based on ANC results for patients without BEN, see Table 1 [see Dosage and Administration (2.3) ]. Table 2. Clozapine Tablets Dosage Modifications Based on ANC Results and Frequency of ANC Testing in Patients with Benign Ethnic Neutropenia 1 1 Benign Ethnic Neutropenia (BEN) is also known as Duffy-null associated neutrophil count. 2 Confirm all initial reports of ANC less than 1500/μL with a repeat ANC measurement within 24 hours.
Dosage forms and strengths
Clozapine Tablets USP, 25 mg are pale yellow colored, round, flat faced, bevel edged uncoated tablets debossed with ‘C facilitated scoreline (functional) C’ on one side and ‘54’ on the other side. Clozapine Tablets USP, 50 mg are pale yellow colored, round, flat faced, bevel edged uncoated tablets debossed with ‘C facilitated scoreline (functional) C’ on one side and ‘55’ on the other side. Clozapine Tablets USP, 100 mg are pale yellow colored, round, flat faced, bevel edged uncoated tablets debossed with ‘C facilitated scoreline (functional) C’ on one side and ‘57’ on the other side. Clozapine Tablets USP, 200 mg are pale yellow colored, oval shaped, uncoated tablets debossed with ‘C scoreline (functional) C’ on one side and ‘71’ on the other side. 25 mg, 50 mg, 100 mg and 200 mg tablets with score on one side (3)
Contraindications
Clozapine tablets are 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 tablets [see Adverse Reactions (6.2) ] . Known hypersensitivity to clozapine or any other component of clozapine tablets. ( 4 )
Warnings and precautions
Severe neutropenia: See Boxed Warning ( 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: 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 occur. ( 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 treatment. The mechanism by which clozapine causes neutropenia is unknown. Neutropenia is not dose dependent. Consider a hematology consultation before initiating clozapine treatment or during treatment. ANC Monitoring and Dosage Modifications Prior to initiating clozapine treatment, obtain a baseline ANC. Clozapine initiation is not recommended in patients with a baseline ANC less than 1500/μL. Throughout clozapine treatment, regularly monitor ANC. Table 1 provides recommendations for dosage modifications (dosage interruption and treatment discontinuation), based on ANC levels, during clozapine treatment and frequency of ANC monitoring [see Dosage and Administration (2.3) ]. 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-induced neutropenia. For patients with documented BEN, obtain at least two baseline ANC levels prior to clozapine initiation. Clozapine initiation is not recommended in patients with BEN with an ANC less than 1000/μL. There are different ANC dosage modification recommendations in clozapine-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 clozapine treatment in patients with BEN and recommended frequency of ANC testing [see Dosage and Administration (2.4) ]. Management of Clozapine-Treated Patients Who Develop a Fever For patients who develop a fever during clozapine treatment: Interrupt clozapine 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 or Table 2 for dosage modifications based on ANC monitoring [see Dosage and Administration (2.3 , 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 Clozapine in Patients Who Recovered from Severe Neutropenia Generally, do not rechallenge patients with clozapine in those who experienced severe neutropenia. However, for some patients who had resolution of their clozapine-related severe neutropenia after stopping clozapine, the risk of schizophrenia exacerbation from not restarting clozapine treatment may be greater than the risk of neutropenia reoccurrence from restarting clozapine (e.g., patients who have no treatment options other than clozapine). Concomitant Use of Clozapine with Other Drugs Known to Cause Neutropenia If clozapine 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.
Side effects
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 Northstar Rx LLC at 1-800-206-7821 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 TM Study) Body System Adverse Reaction* Clozapine 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 † 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 TM 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.
Drug interactions
Concomitant use of Strong CYP1A2 Inhibitors : Reduce clozapine 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 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 Clozapine Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6. Use caution when administering clozapine concomitantly with drugs that are inducers or inhibitors of these enzymes. CYP1A2 Inhibitors Concomitant use of clozapine and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. Reduce the clozapine dose to one-third of the original dose when clozapine is coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin). The clozapine 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 is coadministered with these inhibitors. Consider reducing the clozapine dosage if necessary [see Dosage and Administration (2.7) ]. CYP2D6 and CYP3A4 Inhibitors Concomitant treatment with clozapine 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 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. 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 dose if used concomitantly with inducers of these enzymes. However, concomitant use of clozapine and strong CYP3A4 inducers is not recommended [see Dosage and Administration (2.7) ] . Consider reducing the clozapine 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 clozapine 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 Clozapine to Affect Other Drugs Concomitant use of clozapine with other drugs metabolized by CYP2D6 can increase levels of these CYP2D6 substrates. Use caution when coadministering clozapine 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).
Use in specific populations
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 clozapine, 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, 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, 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 clozapine, 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. 8.2 Lactation Risk Summary Clozapine is present in human milk. There is one case report 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 clozapine and any potential adverse effects on the breastfed child from clozapine or from the underlying maternal condition. Clinical Considerations Infants exposed to clozapine 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 clozapine to determine whether those over 65 years of age differ from younger subjects in their response to clozapine. 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 clozapine 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 (2.8) , Clinical Pharmacology (12.3) ].
Pregnancy
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including clozapine, 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, 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, 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 clozapine, 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
8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.
Geriatric use
8.5 Geriatric Use There have not been sufficient numbers of geriatric patients in clinical studies utilizing clozapine to determine whether those over 65 years of age differ from younger subjects in their response to clozapine. 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 clozapine 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) ] .
Overdosage
10.1 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. 10.2 Management of Overdosage There is no available specific antidote to an overdose of clozapine. 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).
Description
Clozapine, an atypical antipsychotic drug, is a tricyclic dibenzodiazepine derivative, 8-chloro-11-(4-methyl-1-piperazinyl)-5 H -dibenzo [ b,e ] [1,4] diazepine. The structural formula is: Clozapine USP is available in pale yellow colored tablets of 25 mg, 50 mg, 100 mg, and 200 mg for oral administration. Active Ingredient: clozapine Inactive Ingredients are colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, povidone, and talc. Chemical Structure
Mechanism of action
12.1 Mechanism of Action 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. Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic and other dopaminergic and serotonergic receptors.
How supplied
16.1 How Supplied Clozapine Tablets USP, 25 mg are pale yellow colored, round, flat faced, bevel edged uncoated tablets debossed with ‘C facilitated scoreline (functional) C’ on one side and ‘54’ on the other side. Bottles of 100 NDC 72603-911-01 Clozapine Tablets USP, 50 mg are pale yellow colored, round, flat faced, bevel edged uncoated tablets debossed with ‘C facilitated scoreline (functional) C’ on one side and ‘55’ on the other side. Bottles of 100 NDC 72603-912-01 Clozapine Tablets USP, 100 mg are pale yellow colored, round, flat faced, bevel edged uncoated tablets debossed with ‘C facilitated scoreline (functional) C’ on one side and ‘57’ on the other side. Bottles of 100 NDC 72603-913-01 Bottles of 500 NDC 72603-913-02 Clozapine Tablets USP, 200 mg are pale yellow colored, oval shaped, uncoated tablets debossed with ‘C scoreline (functional) C’ on one side and ‘71’ on the other side. Bottles of 100 NDC 72603-914-01 16.2 Storage and Handling Store clozapine tablets, USP at room temperature between 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Keep out of reach of children.
Patient information
Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Discuss the following issues with patients and caregivers: Severe Neutropenia: Instruct patients (and caregivers) [see Warnings and Precautions (5.1) ]: - About the risk of developing severe neutropenia and infection with clozapine tablets treatment. - Instruct patients to immediately report to their health care provider any symptom or sign of during clozapine tablets treatment. - About the importance of having frequent ANC testing. Orthostatic Hypotension, Bradycardia, and Syncope : Inform patients and caregivers about the risk of orthostatic hypotension and syncope, especially during the period of initial dose titration. Instruct them to strictly follow the clinician’s instructions for dosage and administration [see Dosage and Administration (2.2 , 2.6) ]. Advise patients to consult their clinician immediately if they feel faint, lose consciousness or have signs or symptoms suggestive of bradycardia or arrhythmia [ Warnings and Precautions (5.2) ]. Seizures: Inform patients and caregivers about the significant risk of seizure during clozapine treatment. Caution them about driving and any other potentially hazardous activity while taking clozapine tablets [see Warnings and Precautions (5.4) ]. Gastrointestinal Hypomotility with Severe Complications: Educate patients and caregivers on the risks, prevention and treatment of clozapine-induced constipation, including medications to avoid when possible (e.g., drugs with anticholinergic activity). Encourage appropriate hydration, physical activity, and fiber intake and emphasize that prompt attention and treatment to the development of constipation or other gastrointestinal symptoms is critical in preventing severe complications. Advise patients and caregivers to contact their health care provider if they experience symptoms of constipation (e.g., difficulty passing stools, incomplete passage of stool, decreased bowel movement frequency) or other symptoms associated with gastrointestinal hypomotility (e.g., nausea, abdominal distension or pain, vomiting) [see Warnings and Precautions (5.7) , Drug Interactions (7.1) ]. QT Interval Prolongation: Advise patients to consult their clinician immediately if they feel faint, lose consciousness or have signs or symptoms suggestive of arrhythmia. Instruct patients to not take clozapine tablets with other drugs that cause QT interval prolongation. Instruct patients to inform their clinicians that they are taking clozapine tablets before any new drug [see Warnings and Precautions (5.9) , Drug Interactions (7.1) ]. Metabolic Changes (hyperglycemia and diabetes mellitus, dyslipidemia, weight gain) : Educate patients and caregivers about the risk of metabolic changes and the need for specific monitoring. The risks include hyperglycemia and diabetes mellitus, dyslipidemia, weight gain, and cardiovascular reactions. Educate patients and caregivers about the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus (e.g., polydipsia, polyuria, polyphagia, and weakness). Monitor all patients for these symptoms. Patients who are diagnosed with diabetes or have risk factors for diabetes (obesity, family history of diabetes) should have their fasting blood glucose monitored before beginning treatment and periodically during treatment. Patients who develop symptoms of hyperglycemia should have assessments of fasting glucose. Clinical monitoring of weight is recommended [see Warnings and Precautions (5.10) ] . Interference with Cognitive and Motor Performance: Because clozapine tablets may have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that clozapine therapy does not affect them adversely [see Warnings and Precautions (5.16) ] . Missed Doses and Re-initiating Treatment: Inform patients and caregivers that if the patient misses taking clozapine tablets for 1 day or more, they should not restart their medication at the same dosage but should contact their physician for dosing instructions [see Dosage and Administration (2.6) , Warnings and Precautions (5.1 , 5.2) ]. Pregnancy: Advise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with clozapine. Advise patients that clozapine tablets may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to clozapine tablets during pregnancy [see Use in Specific Populations (8.1) ]. Lactation: Advise breastfeeding women using clozapine to monitor infants for excess sedation and to seek medical care if they notice this sign. Inform breastfeeding women using clozapine that their healthcare provider will monitor infants for neutropenia [see Use in Specific Populations (8.2) ]. Concomitant Medication: Advise patients to inform their healthcare provider if they are taking, or plan to take, any prescription or over-the-counter drugs; there is a potential for significant drug-drug interactions [see Dosage and Administration (2.7) , Drug Interactions (7.1) ] . Manufactured for: Northstar Rx LLC Memphis, TN 38141. Manufactured by: Aurobindo Pharma Limited Unit-VII (SEZ) Mahabubnagar (Dt)-509302 India. M.L.No.: 22/MN/AP/2009/F/R Issued: 04/2026 *Zyprexa ® (olanzapine) is a registered trademark of Eli Lilly and Company.
Label text from the FDA structured product label by NorthStar Rx LLC (revised May 11, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Clozapine in 45 products
Clozapine NDC products (45)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 16729-142 | Clozapine 100 mg/1 Tablet | Accord Healthcare Inc. | ANDA |
| 16729-141 | Clozapine 25 mg/1 Tablet | Accord Healthcare Inc. | ANDA |
| 60687-548 | Clozapine 50 mg/1 Tablet | American Health Packaging | ANDA |
| 60687-426 | Clozapine 200 mg/1 Tablet | American Health Packaging | ANDA |
| 60687-415 | Clozapine 100 mg/1 Tablet | American Health Packaging | ANDA |
| 60687-404 | Clozapine 25 mg/1 Tablet | American Health Packaging | ANDA |
| 59651-264 | Clozapine 200 mg/1 Tablet, Orally Disintegrating | Aurobindo Pharma Limited | ANDA |
| 59651-263 | Clozapine 150 mg/1 Tablet, Orally Disintegrating | Aurobindo Pharma Limited | ANDA |
| 59651-262 | Clozapine 100 mg/1 Tablet, Orally Disintegrating | Aurobindo Pharma Limited | ANDA |
| 59651-261 | Clozapine 25 mg/1 Tablet, Orally Disintegrating | Aurobindo Pharma Limited | ANDA |
| 59651-260 | Clozapine 12.5 mg/1 Tablet, Orally Disintegrating | Aurobindo Pharma Limited | ANDA |
| 65862-844 | Clozapine 25 mg/1 Tablet | Aurobindo Pharma Limited | ANDA |
| 65862-845 | Clozapine 50 mg/1 Tablet | Aurobindo Pharma Limited | ANDA |
| 65862-846 | Clozapine 100 mg/1 Tablet | Aurobindo Pharma Limited | ANDA |
| 65862-847 | Clozapine 200 mg/1 Tablet | Aurobindo Pharma Limited | ANDA |
| 55154-3568 | Clozapine 100 mg/1 Tablet | Cardinal Health 107, LLC | ANDA |
| 0904-7089 | Clozapine 25 mg/1 Tablet | Major Pharmaceuticals | ANDA |
| 0904-7406 | Clozapine 50 mg/1 Tablet | Major Pharmaceuticals | ANDA |
| 0904-7088 | Clozapine 200 mg/1 Tablet | Major Pharmaceuticals | ANDA |
| 0904-7087 | Clozapine 100 mg/1 Tablet | Major Pharmaceuticals | ANDA |
| 51079-922 | Clozapine 100 mg/1 Tablet | Mylan Institutional Inc. | ANDA |
| 51079-921 | Clozapine 25 mg/1 Tablet | Mylan Institutional Inc. | ANDA |
| 51079-288 | Clozapine 100 mg/1 Tablet, Orally Disintegrating | Mylan Institutional Inc. | ANDA |
| 51079-749 | Clozapine 200 mg/1 Tablet | Mylan Institutional Inc. | ANDA |
| 0378-0972 | Clozapine 50 mg/1 Tablet | Mylan Pharmaceuticals Inc. | ANDA |
| 0378-0825 | Clozapine 25 mg/1 Tablet | Mylan Pharmaceuticals Inc. | ANDA |
| 0378-3817 | Clozapine 200 mg/1 Tablet, Orally Disintegrating | Mylan Pharmaceuticals Inc. | ANDA |
| 0378-3816 | Clozapine 150 mg/1 Tablet, Orally Disintegrating | Mylan Pharmaceuticals Inc. | ANDA |
| 0378-3815 | Clozapine 100 mg/1 Tablet, Orally Disintegrating | Mylan Pharmaceuticals Inc. | ANDA |
| 0378-3813 | Clozapine 25 mg/1 Tablet, Orally Disintegrating | Mylan Pharmaceuticals Inc. | ANDA |
| 0378-0973 | Clozapine 200 mg/1 Tablet | Mylan Pharmaceuticals Inc. | ANDA |
| 0378-0860 | Clozapine 100 mg/1 Tablet | Mylan Pharmaceuticals Inc. | ANDA |
| 72603-911 | Clozapine 25 mg/1 Tablet | NorthStar Rx LLC | ANDA |
| 72603-912 | Clozapine 50 mg/1 Tablet | NorthStar Rx LLC | ANDA |
| 72603-913 | Clozapine 100 mg/1 Tablet | NorthStar Rx LLC | ANDA |
| 72603-914 | Clozapine 200 mg/1 Tablet | NorthStar Rx LLC | ANDA |
| 48433-025 | Clozapine 200 mg/1 Tablet | Safecor Health LLC | ANDA |
| 48433-024 | Clozapine 100 mg/1 Tablet | Safecor Health LLC | ANDA |
| 48433-023 | Clozapine 25 mg/1 Tablet | Safecor Health LLC | ANDA |
| 48433-022 | Clozapine 100 mg/1 Tablet, Orally Disintegrating | Safecor Health, LLC | ANDA |
| 0093-5376 | Clozapine 150 mg/1 Tablet, Orally Disintegrating | Teva Pharmaceuticals USA, Inc. | ANDA |
| 0093-5419 | Clozapine 100 mg/1 Tablet, Orally Disintegrating | Teva Pharmaceuticals USA, Inc. | ANDA |
| 0093-5417 | Clozapine 25 mg/1 Tablet, Orally Disintegrating | Teva Pharmaceuticals USA, Inc. | ANDA |
| 0093-5416 | Clozapine 12.5 mg/1 Tablet, Orally Disintegrating | Teva Pharmaceuticals USA, Inc. | ANDA |
| 0093-5377 | Clozapine 200 mg/1 Tablet, Orally Disintegrating | Teva Pharmaceuticals USA, Inc. | ANDA |
Clozapine recalls
- D-1370-2020 Jul 1, 2020 · Class II · Terminated
Presence of foreign tablet: Consumer complaint of Clozapine Tablets 50mg being present in 500 count bottles of Clozapine Tablets USP 100mg. - D-0001-2019 Oct 10, 2018 · Class II · Terminated
Failed Disintegration Specifications: Out-of-specification disintegration test result obtained during routine stability testing.
Frequently asked questions
What is Clozapine used for?
Clozapine tablets are 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 tablets should be used only in patients who have failed to respond adequately to standard antipsychotic treatment. ( 1.1…
What are the side effects of Clozapine?
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… See the full label for the complete list.
Who makes Clozapine?
Clozapine is listed by 11 labelers in the FDA NDC directory, including Accord Healthcare Inc., American Health Packaging, Aurobindo Pharma Limited, Cardinal Health 107, LLC.
Has Clozapine been recalled?
The FDA enforcement database lists 2 recalls for Clozapine, most recently D-1370-2020 (class ii): Presence of foreign tablet: Consumer complaint of Clozapine Tablets 50mg being present in 500 count bottles of Clozapine Tablets USP 100mg.