Clozapine

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Clozapine Prescribing Information

Severe Neutropenia

Clozapine Orally Disintegrating Tablets (Clozapine ODT) has caused severe neutropenia which is associated with an increased risk of serious and potentially fatal infections. Prior to initiating Clozapine ODT treatment, obtain baseline ANC(s). Clozapine ODT initiation is not recommended in patients with a baseline ANC less than 1500/μL (less than 1000/μL for those with Benign Ethnic Neutropenia (also known as Duffy-null associated neutrophil count)). See recommendations for dosage modifications based on ANC levels during Clozapine ODT treatment

[see

2.3 Dosage Modifications Based on ANC Results

Table 1 provides recommended Clozapine ODT dosage modifications based on ANC results

[see Warnings and Precautions (5.1)].

For dosage modifications based on ANC results for patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count), see Table 2

[see Dosage and Administration (2.5)].

Table 1: Clozapine ODT Dosage Modifications Based on ANC Results and Frequency of ANC Testing
¹Confirm 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 ODT Treatment
ANC Within Normal Range (≥ 1500/μL)
No dosage modification; continue treatment	Day 1 to Month 6: Weekly Month 7 to Month 12: Every 2 weeks Month 13 and thereafter: Every month
	If Clozapine ODT treatment is reinitiated after a dosage interruption (e.g., patient had neutropenia which required dosage interruption and now has a normal ANC level) for: < 30 days, continue the previous ANC testing frequency ≥ 30 days, obtain ANC tests according to the frequency for patients who initiate treatment
Mild Neutropenia (ANC between 1000 to 1499/μL)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 ODT 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 (2.4)].

Table 2: Clozapine ODT Dosage Modifications Based on ANC Results and Frequency of ANC Testing in Patients with Benign Ethnic Neutropenia¹
¹Benign Ethnic Neutropenia (BEN) is also known as Duffy-null associated neutrophil count. ²Confirm 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 ODT Treatment in Patients with BEN
ANC Within the Normal Range for Patients with BEN (≥ 1000/μL )
No dosage modification; continue treatment	Day 1 to Month 6: Weekly Month 7 to Month 12: Every 2 weeks Month 13 and thereafter: Monthly
	If Clozapine ODT treatment is reinitiated after a dosage interruption (e.g., patient had neutropenia which required dosage interruption and now their ANC (≥ 1000/μL and ≥ the patient’s ANC baseline prior to treatment) for: < 30 days, continue previous ANC testing frequency ≥ 30 days, obtain ANC tests according to the frequency for patients with BEN who initiate treatment
Neutropenia in Patients with BEN (ANC level between 500 to 999/μL)²
Recommend hematology consultation No dosage modification; continue treatment	Three times weekly Once ANC ≥ 1000/μL and ≥ the patient’s ANC baseline, obtain ANC tests weekly for 4 weeks If ANC ≥1000/μL and ≥ the patient’s baseline after monitoring for 4 weeks, return to the patient’s last Normal ANC Range testing frequency for patients with BEN.
Severe Neutropenia in Patients with BEN (ANC level less than 500/μL)²
Discontinue treatment and recommend hematology consultation	Daily Once ANC ≥ 500/μL, obtain ANC three times weekly Once ANC ≥ 1000/μL and ≥ the patient’s baseline, if the benefits outweigh the risks of restarting treatment, resume treatment and obtain ANC tests according to the frequency for patients with BEN who initiate treatment

Consider a hematology consultation before initiating Clozapine ODT or during Clozapine ODT treatment

[see

5.1 Severe Neutropenia

Clozapine has caused severe neutropenia (absolute neutrophil count (ANC) less than 500/μL)

[see Adverse Reactions (6.1, 6.2)]

and is associated with an increased risk of serious and potentially fatal infections. Severe neutropenia occurred in a small percentage of clozapine-treated patients. The risk of severe neutropenia appears greatest during the first 18 weeks of Clozapine ODT treatment. The mechanism by which Clozapine ODT causes neutropenia is unknown. Neutropenia is not dose-dependent.

Consider a hematology consultation before initiating Clozapine ODT treatment or during treatment.

ANC Monitoring and Dosage Modifications

Prior to initiating Clozapine ODT treatment, obtain a baseline ANC. Clozapine ODT initiation is not recommended in patients with a baseline ANC less than 1500/μL. Throughout VERZACLOZ treatment, regularly monitor ANC. Table 1 provides recommendations for dosage modifications (dosage interruption and treatment discontinuation), based on ANC levels, during Clozapine ODT treatment and frequency of ANC monitoring

[see Dosage and Administration (2.4)]

ANC Monitoring and Dosage Modification in Patients with Benign Ethnic Neutropenia

Patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count) generally have lower baseline neutrophil counts but they are not at higher risk for developing infections, and they are not at increased risk for developing Clozapine ODT-induced neutropenia.

For patients with documented BEN, obtain at least two baseline ANC levels prior to Clozapine ODT initiation. Clozapine ODT initiation is not recommended in patients with BEN with an ANC less than 1000/μL. There are different ANC dosage modification recommendations in Clozapine ODT-treated patients with BEN due to their lower baseline ANC levels. Table 2 provides recommendations on dosage modifications (dosage interruption and treatment discontinuation), based on ANC monitoring, during Clozapine ODT treatment in patients with BEN and recommended frequency of ANC testing

[see Dosage and Administration (2.5)]

Management of Clozapine ODT

-Treated Patients Who Develop a Fever

For patients who develop a fever during Clozapine ODT treatment:

Interrupt Clozapine ODT 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 (2.5)]
.

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 ODT

in Patients Who Recovered from Severe Neutropenia

Generally, do not rechallenge patients with Clozapine ODT in those who experienced severe neutropenia. However, for some patients who had resolution of their Clozapine ODT-related severe neutropenia after stopping Clozapine ODT, the risk of schizophrenia exacerbation from not restarting Clozapine ODT treatment may be greater than the risk of neutropenia reoccurrence from restarting Clozapine ODT (e.g., patients who have no treatment options other than Clozapine ODT).

Concomitant Use of Clozapine ODT

with Other Drugs Known to Cause Neutropenia

If Clozapine ODT is used concomitantly with another drug known to cause neutropenia, consider more frequently ANC monitoring than the recommendations provided in Tables 1 and 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 ODT

. Initiate treatment at 12.5 mg once or twice daily; titrate slowly; and use divided dosages to minimize risk. Use

Clozapine ODT

cautiously in patients with cardiovascular or cerebrovascular disease or conditions predisposing to hypotension (e.g., dehydration, use of antihypertensive medications)

[see

2.3 Dosage Modifications Based on ANC Results

Table 1 provides recommended Clozapine ODT dosage modifications based on ANC results

[see Warnings and Precautions (5.1)].

For dosage modifications based on ANC results for patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count), see Table 2

[see Dosage and Administration (2.5)].

Table 1: Clozapine ODT Dosage Modifications Based on ANC Results and Frequency of ANC Testing
¹Confirm 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 ODT Treatment
ANC Within Normal Range (≥ 1500/μL)
No dosage modification; continue treatment	Day 1 to Month 6: Weekly Month 7 to Month 12: Every 2 weeks Month 13 and thereafter: Every month
	If Clozapine ODT treatment is reinitiated after a dosage interruption (e.g., patient had neutropenia which required dosage interruption and now has a normal ANC level) for: < 30 days, continue the previous ANC testing frequency ≥ 30 days, obtain ANC tests according to the frequency for patients who initiate treatment
Mild Neutropenia (ANC between 1000 to 1499/μL)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

, and

2.5 Discontinuation of Clozapine ODT Treatment

If discontinuing Clozapine ODT in patients with:

Moderate or severe neutropenia, see Table 1
[see Dosage and Administration (2.4)].
Normal or mild neutropenia, reduce the dosage gradually over a period of 1 to 2 weeks, and continue monitoring ANC levels until their ANC is ≥1500/μL.

If discontinuing Clozapine ODT in patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count) with:

Neutropenia, see Table 2
[see Dosage and Administration (2.5)].
ANC within their normal range of ANC reduce the dosage gradually over a period of 1 to 2 weeks.

When discontinuing Clozapine ODT, monitor patients for the symptoms related to psychotic recurrence and cholinergic rebound (e.g., profuse sweating, headache, nausea, vomiting, diarrhea).

5.2 Orthostatic Hypotension, Bradycardia, and Syncope

Hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment. The risk is highest during the initial titration period, particularly with rapid dose-escalation. These reactions can occur with the first dose, at doses as low as 12.5 mg. These reactions can be fatal. The syndrome is consistent with neurally mediated reflex bradycardia (NMRB).

Clozapine ODT treatment must begin at a maximum dose of 12.5 mg once daily or twice daily. The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks. Subsequently, the dose can be increased weekly or twice weekly, in increments of up to 100 mg. The maximum Clozapine ODT dosage is 900 mg per day. Use cautious titration and a divided dosage schedule to minimize the risk of serious cardiovascular reactions

[see Dosage and Administration (2.3)]

. Consider reducing the dose if hypotension occurs. When restarting Clozapine ODT in patients who have had even a brief interruption in treatment with Clozapine ODT, the dosage must be reduced. This is necessary to minimize the risk of hypotension, bradycardia, and syncope

[see Dosage and Administration (2.6)]

Use Clozapine ODT cautiously in patients with cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (e.g., concomitant use of antihypertensives, dehydration and hypovolemia).

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 ODT

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

2.3 Dosage Modifications Based on ANC Results

Table 1 provides recommended Clozapine ODT dosage modifications based on ANC results

[see Warnings and Precautions (5.1)].

For dosage modifications based on ANC results for patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count), see Table 2

[see Dosage and Administration (2.5)].

Table 1: Clozapine ODT Dosage Modifications Based on ANC Results and Frequency of ANC Testing
¹Confirm 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 ODT Treatment
ANC Within Normal Range (≥ 1500/μL)
No dosage modification; continue treatment	Day 1 to Month 6: Weekly Month 7 to Month 12: Every 2 weeks Month 13 and thereafter: Every month
	If Clozapine ODT treatment is reinitiated after a dosage interruption (e.g., patient had neutropenia which required dosage interruption and now has a normal ANC level) for: < 30 days, continue the previous ANC testing frequency ≥ 30 days, obtain ANC tests according to the frequency for patients who initiate treatment
Mild Neutropenia (ANC between 1000 to 1499/μL)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

5.4 Seizures

Seizure has been estimated to occur in association with clozapine use at a cumulative incidence at one year of approximately 5%, based on the occurrence of one or more seizures in 61 of 1743 patients exposed to clozapine during its clinical testing prior to domestic marketing (i.e., a crude rate of 3.5%). The risk of seizure is dose-related. Initiate Clozapine ODT treatment with a low dose (12.5 mg), titrate slowly, and use divided dosing.

Use caution when administering Clozapine ODT to patients with a history of seizures or other predisposing risk factors for seizure (e.g., head trauma or other CNS pathology, use of medications that lower the seizure threshold, or alcohol abuse). Because of the substantial risk of seizure associated with Clozapine ODT use, caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others (e.g., driving an automobile, operating complex machinery, swimming, climbing).

Myocarditis, Pericarditis, Cardiomyopathy and Mitral Valve Incompetence

Fatal myocarditis and cardiomyopathy have occurred with clozapine treatment. Discontinue

Clozapine ODT

and obtain a cardiac evaluation upon suspicion of these reactions. Generally, patients with clozapine-related myocarditis or cardiomyopathy should not be rechallenged with

Clozapine ODT

. Consider the possibility of myocarditis, pericarditis, or cardiomyopathy if chest pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, hypotension, or ECG changes occur

[see

5.5 Myocarditis, Pericarditis, Cardiomyopathy and Mitral Valve Incompetence

Myocarditis, pericarditis, and cardiomyopathy have occurred with the use of clozapine. These reactions can be fatal. Discontinue Clozapine ODT and obtain a cardiac evaluation upon suspicion of myocarditis, pericarditis, or cardiomyopathy. Generally, patients with a history of clozapine-associated myocarditis, pericarditis or cardiomyopathy should not be rechallenged with Clozapine ODT. However, if the benefit of Clozapine ODT treatment is judged to outweigh the potential risks of recurrence, the clinician may consider rechallenge with Clozapine ODT in consultation with a cardiologist.

Consider the possibility of myocarditis or cardiomyopathy in patients receiving Clozapine ODT who present with chest pain, dyspnea, persistent tachycardia at rest, palpitations, fever, flu-like symptoms, hypotension, other signs or symptoms of heart failure, or electrocardiographic findings (low voltages, ST-T abnormalities, arrhythmias, right axis deviation, and poor R wave progression). Myocarditis and pericarditis most frequently presents within the first two months of clozapine treatment. Symptoms of cardiomyopathy generally occur later than clozapine-associated myocarditis and usually after 8 weeks of treatment. However, myocarditis, pericarditis, and cardiomyopathy can occur at any period during treatment with Clozapine ODT. In patients who are diagnosed with cardiomyopathy while taking clozapine mitral valve incompetence has been reported.

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 ODT is

not approved for use in patients with dementia-related psychosis

[see

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. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality in this population. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Clozapine ODT is not approved for the treatment of patients with dementia-related psychosis

[see Boxed Warning]

Clozapine orally disintegrating tablets (Clozapine ODT) is an atypical antipsychotic indicated for:

Treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, Clozapine ODT should be used only in patients who have failed to respond adequately to standard antipsychotic treatment (
1.1 Treatment-resistant Schizophrenia
Clozapine Orally Disintegrating Tablets (Clozapine ODT) are indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with their use, Clozapine ODT should be used only in patients who have failed to respond adequately to standard antipsychotic treatment
[see Warnings and Precautions (5.1, 5.4)].

The effectiveness of Clozapine ODT in treatment-resistant schizophrenia was demonstrated in a 6-week, randomized, double-blind, active-controlled study comparing Clozapine ODT and chlorpromazine in patients who had failed other antipsychotics
[see Clinical Studies (14.1)].

)
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 Reduction in the Risk of Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder
Clozapine ODT is indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state. Suicidal behavior refers to actions by a patient that put him/herself at risk for death.

The effectiveness of Clozapine ODT in reducing the risk of recurrent suicidal behavior was demonstrated over a two-year treatment period in the InterSePT™ trial
[see Clinical Studies (14.2)]
.

)

Recommended starting oral dosage is 12.5 mg once daily or twice daily. (
2.2 Recommended Dosage and Administration
Recommended Dosage

To reduce the risk of orthostatic hypotension, bradycardia, and syncope, the recommended starting dosage is much lower than the target dosage
[see Warnings and Precautions (5.3)].
The recommended starting oral dosage of Clozapine ODT is 12.5 mg once or twice daily. If well-tolerated, increase the total daily dose in increments of 25 mg to 50 mg per day to achieve a target dosage of 150 mg to 225 mg twice per day by the end of two weeks. Subsequently, may increase the dosage in increments of up to 100 mg once weekly or twice weekly. The maximum recommended Clozapine ODT oral dosage is 450 mg twice daily.

Administration Instructions

Clozapine ODT can be taken with or without food, may be allowed to disintegrate or chewed, and may be taken with or without water
[see Clinical Pharmacology (12.3)].
Just prior to use, peel the foil from the blister and gently remove the orally disintegrating tablet (ODT). Do not push the ODT through the foil, because this could damage the ODT. After removing Clozapine ODT from the blister pack or bottle, immediately place in the mouth.

)
If well-tolerated, increase the total daily dosage in increments of 25 mg to 50 mg per day at target dosage of 150 mg to 225 mg twice per day by the end of two weeks (
2.2 Recommended Dosage and Administration
Recommended Dosage

To reduce the risk of orthostatic hypotension, bradycardia, and syncope, the recommended starting dosage is much lower than the target dosage
[see Warnings and Precautions (5.3)].
The recommended starting oral dosage of Clozapine ODT is 12.5 mg once or twice daily. If well-tolerated, increase the total daily dose in increments of 25 mg to 50 mg per day to achieve a target dosage of 150 mg to 225 mg twice per day by the end of two weeks. Subsequently, may increase the dosage in increments of up to 100 mg once weekly or twice weekly. The maximum recommended Clozapine ODT oral dosage is 450 mg twice daily.

Administration Instructions

Clozapine ODT can be taken with or without food, may be allowed to disintegrate or chewed, and may be taken with or without water
[see Clinical Pharmacology (12.3)].
Just prior to use, peel the foil from the blister and gently remove the orally disintegrating tablet (ODT). Do not push the ODT through the foil, because this could damage the ODT. After removing Clozapine ODT from the blister pack or bottle, immediately place in the mouth.

)
Subsequently may increase the dosage in increments up to 100 mg, once or twice weekly. (
2.2 Recommended Dosage and Administration
Recommended Dosage

To reduce the risk of orthostatic hypotension, bradycardia, and syncope, the recommended starting dosage is much lower than the target dosage
[see Warnings and Precautions (5.3)].
The recommended starting oral dosage of Clozapine ODT is 12.5 mg once or twice daily. If well-tolerated, increase the total daily dose in increments of 25 mg to 50 mg per day to achieve a target dosage of 150 mg to 225 mg twice per day by the end of two weeks. Subsequently, may increase the dosage in increments of up to 100 mg once weekly or twice weekly. The maximum recommended Clozapine ODT oral dosage is 450 mg twice daily.

Administration Instructions

Clozapine ODT can be taken with or without food, may be allowed to disintegrate or chewed, and may be taken with or without water
[see Clinical Pharmacology (12.3)].
Just prior to use, peel the foil from the blister and gently remove the orally disintegrating tablet (ODT). Do not push the ODT through the foil, because this could damage the ODT. After removing Clozapine ODT from the blister pack or bottle, immediately place in the mouth.

)
Maximum daily dosage is 450 mg twice daily. (
2.2 Recommended Dosage and Administration
Recommended Dosage

To reduce the risk of orthostatic hypotension, bradycardia, and syncope, the recommended starting dosage is much lower than the target dosage
[see Warnings and Precautions (5.3)].
The recommended starting oral dosage of Clozapine ODT is 12.5 mg once or twice daily. If well-tolerated, increase the total daily dose in increments of 25 mg to 50 mg per day to achieve a target dosage of 150 mg to 225 mg twice per day by the end of two weeks. Subsequently, may increase the dosage in increments of up to 100 mg once weekly or twice weekly. The maximum recommended Clozapine ODT oral dosage is 450 mg twice daily.

Administration Instructions

Clozapine ODT can be taken with or without food, may be allowed to disintegrate or chewed, and may be taken with or without water
[see Clinical Pharmacology (12.3)].
Just prior to use, peel the foil from the blister and gently remove the orally disintegrating tablet (ODT). Do not push the ODT through the foil, because this could damage the ODT. After removing Clozapine ODT from the blister pack or bottle, immediately place in the mouth.

)
Administer with or without food. Clozapine ODT may be allowed to disintegrate or chewed, and may be taken with or without water. See additional administration instructions in full prescribing information (
2.2 Recommended Dosage and Administration
Recommended Dosage

To reduce the risk of orthostatic hypotension, bradycardia, and syncope, the recommended starting dosage is much lower than the target dosage
[see Warnings and Precautions (5.3)].
The recommended starting oral dosage of Clozapine ODT is 12.5 mg once or twice daily. If well-tolerated, increase the total daily dose in increments of 25 mg to 50 mg per day to achieve a target dosage of 150 mg to 225 mg twice per day by the end of two weeks. Subsequently, may increase the dosage in increments of up to 100 mg once weekly or twice weekly. The maximum recommended Clozapine ODT oral dosage is 450 mg twice daily.

Administration Instructions

Clozapine ODT can be taken with or without food, may be allowed to disintegrate or chewed, and may be taken with or without water
[see Clinical Pharmacology (12.3)].
Just prior to use, peel the foil from the blister and gently remove the orally disintegrating tablet (ODT). Do not push the ODT through the foil, because this could damage the ODT. After removing Clozapine ODT from the blister pack or bottle, immediately place in the mouth.

).

See dosage modification based on ANC results (

2.3 Dosage Modifications Based on ANC Results

Table 1 provides recommended Clozapine ODT dosage modifications based on ANC results

[see Warnings and Precautions (5.1)].

For dosage modifications based on ANC results for patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count), see Table 2

[see Dosage and Administration (2.5)].

Table 1: Clozapine ODT Dosage Modifications Based on ANC Results and Frequency of ANC Testing
¹Confirm 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 ODT Treatment
ANC Within Normal Range (≥ 1500/μL)
No dosage modification; continue treatment	Day 1 to Month 6: Weekly Month 7 to Month 12: Every 2 weeks Month 13 and thereafter: Every month
	If Clozapine ODT treatment is reinitiated after a dosage interruption (e.g., patient had neutropenia which required dosage interruption and now has a normal ANC level) for: < 30 days, continue the previous ANC testing frequency ≥ 30 days, obtain ANC tests according to the frequency for patients who initiate treatment
Mild Neutropenia (ANC between 1000 to 1499/μL)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 ODT 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 (2.4)].

Table 2: Clozapine ODT Dosage Modifications Based on ANC Results and Frequency of ANC Testing in Patients with Benign Ethnic Neutropenia¹
¹Benign Ethnic Neutropenia (BEN) is also known as Duffy-null associated neutrophil count. ²Confirm 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 ODT Treatment in Patients with BEN
ANC Within the Normal Range for Patients with BEN (≥ 1000/μL )
No dosage modification; continue treatment	Day 1 to Month 6: Weekly Month 7 to Month 12: Every 2 weeks Month 13 and thereafter: Monthly
	If Clozapine ODT treatment is reinitiated after a dosage interruption (e.g., patient had neutropenia which required dosage interruption and now their ANC (≥ 1000/μL and ≥ the patient’s ANC baseline prior to treatment) for: < 30 days, continue previous ANC testing frequency ≥ 30 days, obtain ANC tests according to the frequency for patients with BEN who initiate treatment
Neutropenia in Patients with BEN (ANC level between 500 to 999/μL)²
Recommend hematology consultation No dosage modification; continue treatment	Three times weekly Once ANC ≥ 1000/μL and ≥ the patient’s ANC baseline, obtain ANC tests weekly for 4 weeks If ANC ≥1000/μL and ≥ the patient’s baseline after monitoring for 4 weeks, return to the patient’s last Normal ANC Range testing frequency for patients with BEN.
Severe Neutropenia in Patients with BEN (ANC level less than 500/μL)²
Discontinue treatment and recommend hematology consultation	Daily Once ANC ≥ 500/μL, obtain ANC three times weekly Once ANC ≥ 1000/μL and ≥ the patient’s baseline, if the benefits outweigh the risks of restarting treatment, resume treatment and obtain ANC tests according to the frequency for patients with BEN who initiate treatment

)

See recommendations for discontinuing Clozapine ODT treatment (

2.5 Discontinuation of Clozapine ODT Treatment

If discontinuing Clozapine ODT in patients with:

Moderate or severe neutropenia, see Table 1
[see Dosage and Administration (2.4)].
Normal or mild neutropenia, reduce the dosage gradually over a period of 1 to 2 weeks, and continue monitoring ANC levels until their ANC is ≥1500/μL.

If discontinuing Clozapine ODT in patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count) with:

Neutropenia, see Table 2
[see Dosage and Administration (2.5)].
ANC within their normal range of ANC reduce the dosage gradually over a period of 1 to 2 weeks.

When discontinuing Clozapine ODT, monitor patients for the symptoms related to psychotic recurrence and cholinergic rebound (e.g., profuse sweating, headache, nausea, vomiting, diarrhea).

), restarting Clozapine ODT after interrupting dosing (

2.6 Restarting Clozapine ODT Treatment After Interrupting Clozapine ODT

When restarting Clozapine ODT in patients who have interrupted Clozapine ODT treatment, use a lower dosage to minimize the risk of hypotension, bradycardia, and syncope

[see Warnings and Precautions (5.3)].

If one day’s dosage is missed, resume Clozapine ODT treatment at 40% to 50% of the previous dosage.
If two days of dosing is missed, resume Clozapine ODT treatment at approximately 25% of the previous dosage.
For longer interruptions, restart Clozapine ODT treatment with a dosage of 12.5 mg once or twice daily. If this dosage is well-tolerated, may increase the dosage to the previous dosage more quickly than recommended than for initial Clozapine ODT treatment.

), dosage modifications for drug interactions (

2.7 Dosage Modifications for Drug Interactions

See Table 3 for recommended dosage modifications to reduce the risk of Clozapine ODT-associated adverse reactions or reduce the risk of lower effectiveness

[see Drug Interactions (7)]

Table 3: Clozapine ODT Dosage Modifications for Drug Interactions
Strong CYP1A2 Inhibitors	Administer one third of the Clozapine ODT dosage.
Moderate or Weak CYP1A2 Inhibitors	Consider reducing the Clozapine ODT dosage if necessary.
CYP2D6 or CYP3A4 Inhibitors	Consider reducing the Clozapine ODT dosage if necessary.
Strong CYP3A4 Inducers	Concomitant use is not recommended. However, if concomitant use is necessary, it may be necessary to increase the Clozapine ODT dosage. Monitor for decreased effectiveness.
Moderate or weak CYP1A2 or CYP3A4 Inducers	Consider increasing the Clozapine ODT dosage if necessary.

), dosage recommendations in patients with renal or hepatic impairment and CYP2D6 poor metabolizers (

2.8 Dosage Recommendations in Patients with Renal or Hepatic Impairment, or CYP2D6 Poor Metabolizers

It may be necessary to reduce the Clozapine ODT dosage in patients with significant renal impairment or hepatic impairment, or in CYP2D6 poor metabolizers

[see Use in Specific Populations (8.6, 8.7)].

) in the full prescribing information.

Tablets rapidly disintegrate after placement in the mouth and may be chewed if desired. No water is needed (

2.3 Dosage Modifications Based on ANC Results

Table 1 provides recommended Clozapine ODT dosage modifications based on ANC results

[see Warnings and Precautions (5.1)].

For dosage modifications based on ANC results for patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count), see Table 2

[see Dosage and Administration (2.5)].

Table 1: Clozapine ODT Dosage Modifications Based on ANC Results and Frequency of ANC Testing
¹Confirm 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 ODT Treatment
ANC Within Normal Range (≥ 1500/μL)
No dosage modification; continue treatment	Day 1 to Month 6: Weekly Month 7 to Month 12: Every 2 weeks Month 13 and thereafter: Every month
	If Clozapine ODT treatment is reinitiated after a dosage interruption (e.g., patient had neutropenia which required dosage interruption and now has a normal ANC level) for: < 30 days, continue the previous ANC testing frequency ≥ 30 days, obtain ANC tests according to the frequency for patients who initiate treatment
Mild Neutropenia (ANC between 1000 to 1499/μL)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

Clozapine Orally Disintegrating Tablets are available as:

12.5 mg:

yellow to pale yellow color, round shaped tablet, flat faced bevelled edge debossed with “CLO” on one side and “12.5” on the other side.

25 mg:

yellow to pale yellow color, round shaped tablet, flat faced bevelled edge debossed with “CLO” on one side and “25” on the other side.

100 mg:

yellow to pale yellow color, round shaped tablet, flat faced bevelled edge debossed with “CLO” on one side and “100” on the other side.

150 mg:

yellow to pale yellow color, round shaped tablet, flat faced bevelled edge debossed with “CLO” on one side and “150” on the other side.

200 mg:

yellow to pale yellow color, round shaped tablet, flat faced bevelled edge debossed with “CLO” on one side and “200” on the other side.

Lactaton

: Infants exposed to Clozapine ODT through breast milk should be monitored for excess sedation and neutropenia (

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 ODT and any potential adverse effects on the breastfed child from Clozapine ODT or from the underlying maternal condition.

Clinical Considerations

Infants exposed to Clozapine ODT should be monitored for excess sedation and neutropenia.

)

Clozapine ODT is 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 ODT

[see

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of clozapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Central Nervous System

Delirium, EEG abnormal, myoclonus, paresthesia, possible cataplexy, status epilepticus, obsessive compulsive symptoms, and post-discontinuation cholinergic rebound adverse reactions.

Cardiovascular

System

Atrial or ventricular fibrillation, ventricular tachycardia, QT interval prolongation, Torsades de Pointes, myocardial infarction, cardiac arrest, pericarditis, and periorbital edema.

Endocrine System

Pseudopheochromocytoma.

Gastrointestinal System

Acute pancreatitis, dysphagia, salivary gland swelling, megacolon, fecal incontinence, and intestinal ischemia, infarction, perforation, ulceration or necrosis.

Hepatobiliary System

Cholestasis, hepatitis, jaundice, hepatotoxicity, hepatic steatosis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, liver injury (hepatic, cholestatic, and mixed), and liver failure.

Immune System Disorders

Angioedema, leukocytoclastic vasculitis.

Urogenital System

Acute interstitial nephritis, nocturnal enuresis, priapism, and renal failure.

Skin and Subcutaneous Tissue Disorders

Hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, skin pigmentation disorder, and Stevens-Johnson syndrome.

Musculoskeletal System and Connective Tissue Disorders

Myasthenic syndrome, rhabdomyolysis, and systemic lupus erythematosus.

Respiratory System

Aspiration, pleural effusion, pneumonia, lower respiratory tract infection.

Hemic and Lymphatic System

Mild, moderate, or severe leukopenia, agranulocytosis, granulocytopenia, WBC decreased, deep-vein thrombosis, elevated hemoglobin/hematocrit, erythrocyte sedimentation rate (ESR) increased, sepsis, thrombocytosis, and thrombocytopenia.

Vision Disorders

Narrow-angle glaucoma.

Miscellaneous

Creatine phosphokinase elevation, hyperuricemia, hyponatremia, and weight loss.

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