Clozapine 50 mg Tablet, 100-count
🆔 Identity & classification
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🏷️ RxNorm drug class
This medicine belongs to the Atypical Antipsychotic class.
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🏭 Manufacturer & labeler
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🩺 Clinical
Clozapine is used to treat schizophrenia (a mental illness that affects how a person thinks, feels or behaves) in certain people. Clozapine is in a class of medications called atypical antipsychotics. It works by changing the activity of certain natural substances in the brain.
Read the full MedlinePlus article ↗- Clozapine is reserved for situations where other antipsychotics haven't provided enough relief. If you're taking it for schizophrenia, it means your care team determined that stand...
- Why am I on clozapine instead of a regular antipsychotic?
- This is genuinely one of the most important parts of being on clozapine. The medication can cause a dangerous drop in the white blood cells that fight infection — a condition calle...
- Why do I have to get blood tests so often?
Patient education
Supplement & herbal interactions
Some supplements/herbs that may interact with Clozapine — tap one for details:
Clozapine may be associated with lower levels of 1 nutrient — worth a chat with your pharmacist, not a cause for alarm.
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Ask a licensed pharmacist directly — free, answered by our team.
💊 What it looks like
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🧪 Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
💡 Tap an ingredient (hover on desktop) to see what it is and why it’s used.
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UNII EWQ57Q8I5X
Lactose monohydrate is a natural sugar derived from milk. It serves as a filler and binder in tablets and capsules, helping create the proper size, texture, and consistency of the medicine.
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UNII 70097M6I30
Magnesium stearate is a salt made from magnesium and stearic acid, a fatty substance. It's used in tablets and capsules as a lubricant and glidant to help ingredients flow smoothly during manufacturing and prevent sticking.
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UNII U725QWY32X
Povidone K30 is a synthetic polymer made from petroleum. It acts as a binder to hold tablet ingredients together and as a disintegrant to help the tablet break apart in the stomach so the medicine can be absorbed.
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Silicon dioxide is a naturally occurring mineral used as a glidant and anti-caking agent. It helps powder ingredients flow smoothly and prevents clumping during manufacturing and storage.
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UNII O8232NY3SJ
A plant-based carbohydrate derived from corn kernels. It acts as a filler to add bulk, a binder to hold ingredients together, and a disintegrant to help the tablet break apart in your stomach for absorption.
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UNII 7SEV7J4R1U
A powder made from a naturally occurring mineral. In medicines, talc works as a glidant and anti-caking agent, helping tablets and capsules flow smoothly during manufacturing and preventing clumping.
6 inactive ingredients listed in the exact product block matched to this NDC.
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ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.Inactive ingredient FAQ
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💲 Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per ea | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | $0.544 | $54.39 / 100 tablet |
| Medicaid paysCMS SDUD · 12 mo | $0.4842 | $48.42 / 100 tablet |
| Medicare drug plans payPart D · Q2 2026 | $0.3961 | $39.61 / 100 tablet |
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🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Clozapine 50 mg 00378-0972-01 | Mylan | 100 tablets | $0.544 | — | Availability likely | — |
| Clozapine 50 mg 00904-7406-61 | Major | 100 tablets | $0.544 | AB | Availability likely | — |
| Clozapine 50 mgthis 60687-0548-01 | American | 100 tablets | $0.544 | AB | Availability likely | — |
| Clozapine 50 mg 65862-0845-01 | Aurobindo | 100 tablets | $0.544 | — | Availability likely | — |
| Clozapine 50 mg 72603-0912-01 | NorthStar | 100 tablets | — | AB | FDA listed | — |
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⏳ Availability & generic status
This product is an FDA-approved generic. Other versions of the same drug are listed under Therapeutic equivalents, least expensive first.
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🗺️ Medicaid utilization & spend
📊 Medicare Part D spend CMS · PART D · 2026 (Q1)
🔬 Reported adverse events (FAERS)
Top reported reactions
Age at onset
Reporter sex
Serious outcomes
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📦 Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Status |
|---|---|---|---|
| 60687-0548-01 You're viewing this | 100 BLISTER PACK in 1 BOX, UNIT-DOSE (60687-548-01) / 1 TABLET in 1 BLISTER PACK (60687-548-11) | 2020-07-07 | Active |
📄 Full prescribing information FDA SPL
🚨 Boxed Warning ▾
WARNING: SEVERE NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS, PERICARDITIS, AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Severe Neutropenia Clozapine treatment has caused severe neutropenia, defined as an absolute neutrophil count (ANC) less than 500 / μL. Severe neutropenia can lead to serious infection and death. Prior to initiating treatment with clozapine a baseline ANC must be at least 1500/μL for the general population; and must be at least 1000/μL for patients with documented Benign Ethnic Neutropenia (BEN).
During treatment, patients must have regular ANC monitoring. Advise patients to immediately report symptoms consistent with severe neutropenia or infection (e.g., fever, weakness, lethargy, or sore throat) [see Dosage and Administration (2.1) and Warnings and Precautions (5.1) ]. Because of the risk of severe neutropenia, clozapine is available only through a restricted program under a Risk Evaluation Mitigation Strategy (REMS) called the Clozapine REMS Program [see Warnings and Precautions (5.2) ].
Orthostatic Hypotension, Bradycardia, Syncope Orthostatic 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, with doses as low as 12.5 mg per day, or when restarting patients who have had even a brief interruption in treatment with clozapine.
Initiate treatment at 12.5 mg once or twice daily; titrate slowly; and use divided dosages to minimize risk. Use clozapine cautiously in patients with cardiovascular or cerebrovascular disease or conditions predisposing to hypotension (e.g., dehydration, use of antihypertensive medications) [see Dosage and Administration (2.2 , 2.5) , Warnings and Precautions (5.3) ]. Seizures Seizures have occurred with clozapine treatment.
The risk is dose-related. Initiate treatment at 12.5 mg, titrate gradually, and use divided dosing. Use caution when administering clozapine to patients with a history of seizures or other predisposing risk factors for seizure (CNS pathology, medications that lower the seizure threshold, alcohol abuse).
Caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others [see Dosage and Administration (2.2) , Warnings and Precautions (5.5) ]. Myocarditis, Pericarditis, Cardiomyopathy and Mitral Valve Incompetence Fatal myocarditis and cardiomyopathy have occurred with clozapine treatment. Discontinue clozapine and obtain a cardiac evaluation upon suspicion of these reactions.
Generally, patients with clozapine-related myocarditis or cardiomyopathy should not be rechallenged with clozapine. Consider the possibility of myocarditis, pericarditis, or cardiomyopathy if chest pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, hypotension, or ECG changes occur [see Warnings and Precautions (5.6) ] . Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
Clozapine is not approved for use in patients with dementia-related psychosis [see Warnings and Precautions (5.7 )]. WARNING: SEVERE NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS, PERICARDITIS, AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning . Severe Neutropenia: Clozapine can cause severe neutropenia, which can lead to serious and fatal infections.
Patients initiating and continuing treatment with clozapine must have a baseline blood absolute neutrophil count (ANC) measured before treatment initiation and regular ANC monitoring during treatment (2.1 , 5.1) . Clozapine is available only through a res…
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE Clozapine tablets are an atypical antipsychotic indicated for: Treatment-resistant schizophrenia. Efficacy was established in an active-controlled study. (1.1 , 14.1) Reducing suicidal behavior in patients with schizophrenia or schizoaffective disorder. Efficacy was established in an active-controlled study. (1.2 , 14.2)
1.1Treatment-Resistant Schizophrenia Clozapine tablets are indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, clozapine tablets should be used only in patients who have failed to respond adequately to standard antipsychotic treatment [see Warnings and Precautions (5.1 , 5.5 )]. The effectiveness of clozapine tablets in treatment-resistant schizophrenia was demonstrated in a 6-week, randomized, double-blind, active-controlled study comparing clozapine tablets and chlorpromazine in patients who had failed other antipsychotics [see Clinical Studies (14.1) ].
1.2Reduction 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 ▾
2 DOSAGE AND ADMINISTRATION Starting Dose: 12.5 mg once daily or twice daily. (2.2) Use cautious titration and divided dosage schedule. (2.2 , 5.3) Titration: increase the total daily dosage in increments of 25 mg to 50 mg per day, if well-tolerated.
(2.2) Target dose: 300 mg to 450 mg per day, in divided doses, by the end of 2 weeks. (2.2) Subsequent increases: increase in increments of 100 mg or less, once or twice weekly. (2.2) Maximum daily dose: 900 mg (2.2)
2.1Required Laboratory Testing Prior to Initiation and During Therapy Prior to initiating treatment with clozapine tablets, a baseline ANC must be obtained. The baseline ANC must be at least 1500/μL for the general population, and at least 1000/μL for patients with documented Benign Ethnic Neutropenia (BEN). To continue treatment, the ANC must be monitored regularly [see Warnings and Precautions (5.1) ] .
2.2Dosing Information The starting dose is 12.5 mg once daily or twice daily. The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to achieve a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks. Subsequently, the dose can be increased once weekly or twice weekly, in increments of up to 100 mg.
The maximum dose is 900 mg per day. To minimize the risk of orthostatic hypotension, bradycardia, and syncope, it is necessary to use this low starting dose, gradual titration schedule, and divided dosages [see Warnings and Precautions (5.3) ] . Clozapine tablets can be taken with or without food [see Pharmacokinetics (12.3) ].
2.3Maintenance Treatment Generally, patients responding to clozapine tablets should continue maintenance treatment on their effective dose beyond the acute episode.
2.4Discontinuation of Treatment Method of treatment discontinuation will vary depending on the patient’s last ANC: See Tables 2 or 3 for appropriate ANC monitoring based on the level of neutropenia if abrupt treatment discontinuation is necessary because of moderate to severe neutropenia. Reduce the dose gradually over a period of 1 to 2 weeks if termination of clozapine therapy is planned and there is no evidence of moderate to severe neutropenia. For abrupt clozapine discontinuation for a reason unrelated to neutropenia, continuation of the existing ANC monitoring is recommended for general population patients until their ANC is ≥1500/μL and for BEN patients until their ANC is ≥1000/μL or above their baseline.
Additional ANC monitoring is required for any patient reporting onset of fever (temperature of 38.5°C or 101.3°F, or greater) during the 2 weeks after discontinuation [see Warnings and Precautions (5.1) ] . Monitor all patients carefully for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound such as profuse sweating, headache, nausea, vomiting, and diarrhea.
2.5Re-Initiation of Treatment When restarting clozapine tablets in patients who have had even a brief interruption in treatment with clozapine dosage must be reduced. This is necessary to minimize the risk of hypotension, bradycardia, and syncope [see Warnings and Precautions (5.3) ] . If one day’s dosing has been missed, resume treatment at 40% to 50% of the established dose.
If two days dosing have been missed, resume dose at approximately 25% of the established dosage. For longer interruptions, re-initiate at a dosage of 12.5 mg once daily or twice daily. If these dosages are well-tolerated, the dosage may be increased to the previous dosage more quickly than recommended for initial treatment.
2.6Dosage Adjustments with Concomitant use of CYP1A2, CYP2D6, CYP3A4 Inhibitors or CYP1A2, CYP3A4 Inducers Dose adjustments may be necessary in patients with concomitant use of: strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin); moderate or weak CYP1A2 inhibitors (e.g., oral contraceptives, or caffeine); CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bup…
💊 Dosage Forms and Strengths ▾
3 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 ▾
4 CONTRAINDICATIONS Clozapine tablets are contraindicated in patients with a history of serious hypersensitivity to clozapine (e.g., photosensitivity, vasculitis, erythema multiforme, or Stevens-Johnson Syndrome) or any other component of clozapine tablets [see Adverse Reactions (6.2) ] . Known serious hypersensitivity to clozapine or any other component of clozapine tablets. (4)
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS 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. (5.8) Eosinophilia : Assess for organ involvement (e.g., myocarditis, pancreatitis, hepatitis, colitis, nephritis).
Discontinue if these occur. (5.9) QT Interval Prolongation : Can be fatal. Consider additional risk factors for prolonged QT interval (disorders and drugs).
(5.10) Metabolic Changes : Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include: Hyperglycemia and Diabetes Mellitus: Monitor for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes.
(5.11) Dyslipidemia: Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics. (5.11) Weight Gain: Significant weight gain has occurred. Monitor weight gain.
(5.11) Neuroleptic Malignant Syndrome (NMS) : Immediately discontinue and monitor closely. Assess for co-morbid conditions. (5.12) Hepatotoxicity : Can be fatal.
Monitor for hepatotoxicity. Discontinue treatment if hepatitis or transaminase elevations combined with other symptoms occur (5.13) . Fever : Evaluate for infection and for neutropenia, NMS.
(5.14) Pulmonary Embolism (PE) : Consider PE if respiratory distress, chest pain, or deep-vein thrombosis occur. (5.15) Anticholinergic Toxicity : When possible, avoid use with other anticholinergic drugs and use with caution in patients with a current diagnosis or prior history of constipation, urinary retention, clinically significant prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions. (5.16 , 7.1) Interference with Cognitive and Motor Performance : Advise caution when operating machinery, including automobiles.
(5.17)
5.1Severe Neutropenia Background Clozapine can cause neutropenia (a low absolute neutrophil count (ANC)), defined as a reduction below pre-treatment normal levels of blood neutrophils. The ANC is usually available as a component of the complete blood count (CBC), including differential, and is more relevant to drug-induced neutropenia than is the white blood cell (WBC) count. The ANC may also be calculated using the following formula: ANC equals the Total WBC count multiplied by the total percentage of neutrophils obtained from the differential (neutrophil “segs” plus neutrophil “bands”).
Other granulocytes (basophils and eosinophils) contribute minimally to neutropenia and their measurement is not necessary [see Adverse Reactions (6.2) ] . Neutropenia may be mild, moderate, or severe (see Tables 2 and 3). To improve and standardize understanding, “severe neutropenia” replaces the previous terms severe leukopenia, severe granulocytopenia, or agranulocytosis.
Severe neutropenia, ANC less than ( < ) 500/μL, occurs in a small percentage of patients taking clozapine and is associated with an increase in the risk of serious and potentially fatal infections. Risk of neutropenia appears greatest during the first 18 weeks on treatment and then declines. The mechanism by which clozapine causes neutropenia is unknown and is not dose-dependent.
Two separate management algorithms are provided below, the first for patients in the general population, and the second for patients identified to have baseline neutropenia. Clozapine Treatment and Monitoring in the General Patient Population (see Table 2) Obtain a CBC, including the ANC value, prior to initiating treatment with clozapine to ensure the presence of a normal baseline neutrophil count (equal to or greater than 1500/μL) and to permit later comparisons. Patients in the general population with an ANC equal to or greater than (≥)1500/μL are considered within nor…
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Severe Neutropenia [see Warnings and Precautions (5.1) ] Orthostatic Hypotension, Bradycardia, and Syncope [see Warnings and Precautions (5.3) ] Falls [see Warnings and Precautions (5.4) ] Seizures [see Warnings and Precautions (5.5) ] Myocarditis, Pericarditis, Cardiomyopathy, and Mitral Valve Incompetence [see Warnings and Precautions (5.6) ] Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions (5.7) ] Gastrointestinal Hypomotility with Severe Complications [see Warnings and Precautions (5.8) ] Eosinophilia [see Warnings and Precautions (5.9) ] QT Interval Prolongation [see Warnings and Precautions (5.10) ] Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) [see Warnings and Precautions (5.11)] Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.12) ] Hepatotoxicity [see Warnings and Precautions (5.13) ] Fever [see Warnings and Precautions (5.14) ] Pulmonary Embolism [see Warnings and Precautions (5.15) ] Anticholinergic Toxicity [see Warnings and Precautions (5.16) ] Interference with Cognitive and Motor Performance [see Warnings and Precautions (5.17) ] Tardive Dyskinesia [see Warnings and Precautions (5.18) ] Cerebrovascular Adverse Reactions [see Warnings and Precautions (5.19) ] Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation [see Warnings and Precautions (5.20) ] Most common adverse reactions (≥5%) were: CNS reactions (sedation, dizziness/vertigo, headache, and tremor); cardiovascular reactions (tachycardia, hypotension, and syncope); autonomic nervous system reactions (hypersalivation, sweating, dry mouth, and visual disturbances); gastrointestinal reactions (constipation and nausea); and fever.
(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical 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/Akinesi…
🔄 Drug Interactions ▾
7 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). (2.6 , 7.1) Concomitant use of Strong CYP3A4 Inducers is not recommended. (2.6 , 7.1) Discontinuation of CYP1A2 or CYP3A4 Inducers : Consider reducing clozapine dose when CYP1A2 inducers (e.g., tobacco smoke) or CYP3A4 inducers (e.g., carbamazepine) are discontinued.
(2.6 , 7.1) Anticholinergic drugs: Concomitant use may increase the risk for anticholinergic toxicity. (5.8 , 5.16 , 7.1)
7.1Potential 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 (2.6) , 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 (2.6) ]. 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 (2.6) ]. CYP1A2 and CYP3A4 Inducers Concomitant treatment with drugs that induce CYP1A2 or CYP3A4 can decrease the plasma concentration of clozapine, resulting in decreased effectiveness of clozapine.
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 (2.6) ] . 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 (2.6) ] .
Anticholinergic Drugs Concomitant treatment with clozapine and other drugs with anticholinergic activity (e.g., benztropine, cyclobenzaprine, diphenhydramine) can increase the risk for anticholinergic toxicity and severe gastrointestinal adverse reactions related to hypomotility. Avoid concomitant use of clozapine with anticholinergic drugs when possible [see Warnings and Precautions (5.8 , 5.16) ]. Drugs that Cause QT Interval Prolongation Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of clozapine.
Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, and pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see War…
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure (8.1) .
8.1Pregnancy 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.
8.2Lactation 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 n…
🤰 Pregnancy ▾
8.1Pregnancy 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 ▾
8.4Pediatric Use Safety and effectiveness in pediatric patients have not been established.
🧓 Geriatric Use ▾
8.5Geriatric 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 (5.3) ] . 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 (5.16) ] . 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 (5.18) ] .
🆘 Overdosage ▾
10 OVERDOSAGE
10.1Overdosage 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.
10.2Management 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).
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism 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.
12.2Pharmacodynamics Clozapine demonstrated binding affinity to the following receptors: histamine H 1 (K i 1.1 nM), adrenergic α 1A (K i 1.6 nM), serotonin 5-HT 6 (K i 4 nM), serotonin 5-HT 2A (K i 5.4 nM), muscarinic M 1 (K i 6.2 nM), serotonin 5-HT 7 (K i 6.3 nM), serotonin 5-HT 2C (K i 9.4 nM), dopamine D 4 (K i 24 nM), adrenergic α 2A (K i 90 nM), serotonin 5-HT 3 (K i 95 nM), serotonin 5-HT 1A (K i 120 nM), dopamine D 2 (K i 160 nM), dopamine D 1 (K i 270 nM), dopamine D 5 (K i 454 nM), and dopamine D 3 (K i 555 nM).
Clozapine causes little or no prolactin elevation. Clinical electroencephalogram (EEG) studies demonstrated that clozapine increases delta and theta activity and slows dominant alpha frequencies. Enhanced synchronization occurs.
Sharp wave activity and spike and wave complexes may also develop. Patients have reported an intensification of dream activity during clozapine therapy. REM sleep was found to be increased to 85% of the total sleep time.
In these patients, the onset of REM sleep occurred almost immediately after falling asleep.
12.3Pharmacokinetics Absorption In humans, clozapine tablets (25 mg and 100 mg) are equally bioavailable relative to a clozapine solution. Following oral administration of clozapine 100 mg twice daily, the average steady-state peak plasma concentration was 319 ng/mL (range: 102 to 771 ng/mL), occurring at the average of 2.5 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at steady state was 122 ng/mL (range: 41 to 343 ng/mL), after 100 mg twice daily dosing.
Food does not appear to affect the systemic bioavailability of clozapine. Thus, clozapine may be administered with or without food. Distribution Clozapine is approximately 97% bound to serum proteins.
The interaction between clozapine and other highly protein-bound drugs has not been fully evaluated but may be important [see Drug Interactions (7) ]. Metabolism and Excretion Clozapine is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces. Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4.
Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. The demethylated, hydroxylated, and N -oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite (norclozapine) to have only limited activity, while the hydroxylated and N -oxide derivatives were inactive.
The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4 to 12 hours), compared to a mean elimination half-life of 12 hours (range: 4 to 66 hours), after achieving steady state with 100 mg twice daily dosing. A comparison of single-dose and multiple-dose administration of clozapine demonstrated that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics.
However, at steady state, approximately dose-proportional changes with respect to AUC (area under the curve), peak, and minimum clozapine plasma concentrations were observed after administration of 37.5, 75, and 150 mg twice daily. Drug-Drug Interaction Studies Fluvoxamine A pharmacokinetic study was conducted in 16 schizophrenic patients who received clozapine under steady-state conditions. After coadministration of fluvoxamine for 14 days, mean trough concentrations of clozapine and its metaboli…
🧬 Mechanism of Action ▾
12.1Mechanism 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 / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1How 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. Unit dose packages of 100 (10 x 10) NDC 60687-404-01 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. Unit dose packages of 100 (10 x 10) NDC 60687-548-01 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.
Unit dose packages of 100 (10 x 10) NDC 60687-415-01 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. Unit dose packages of 100 (10 x 10) NDC 60687-426-01
16.2Storage and Handling Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Keep out of reach of children. FOR YOUR PROTECTION: Do not use if blister is torn or broken.
📋 Description ▾
11 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
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Discuss the following issues with patients and caregivers: • Severe Neutropenia: Instruct patients (and caregivers) beginning treatment with clozapine about the risk of developing severe neutropenia and infection. Instruct patients to immediately report to their physician any symptom or sign of infection (e.g., flu-like illness; fever; lethargy; general weakness or malaise; mucus membrane ulceration; skin, pharyngeal, vaginal, urinary, or pulmonary infection; or extreme weakness or lethargy) occurring at any time during clozapine therapy, to aid in evaluation for neutropenia and to institute prompt and appropriate management. [see Warnings and Precautions (5.1 , 5.12 , 5.14) ] .
Inform patients and caregivers clozapine is available only through a restricted program called the Clozapine REMS Program designed to ensure the required blood monitoring, in order to reduce the risk of developing severe neutropenia. Advise patients and caregivers of the importance of having blood tested as follows: Weekly blood tests are required for the first 6 months. An ANC is required every 2 weeks for the next 6 months if an acceptable ANC is maintained during the first 6 months of continuous therapy, An ANC is required once every 4 weeks thereafter if an acceptable ANC is maintained during the second 6 months of continuous therapy.
Clozapine is available only from certified pharmacies participating in the program. Provide patients (and caregivers) with website information and the telephone number on how to obtain the product ( www.clozapinerems.com or 1-844-267-8678) [see Warnings and Precautions (5.2) ] • 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 Administraton (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 [see Warnings and Precautions (5.3) ]. • 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 [see Warnings and Precautions (5.5) ]. • 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 (5.8) , 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 with other drugs that cause QT interval prolongation. Instruct patients to inform their clinicians that they are taking clozapine before any new drug [see Warnings and Precautions (5.10) , 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, dyslipidemi…