WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Severe Neutropenia
Background
CLOZARIL 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]
. 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
CLOZARIL 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 CLOZARIL 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.
CLOZARIL Treatment And Monitoring
In The General Patient Population (see Table 2)
Obtain a CBC, including the ANC
value, prior to initiating treatment with CLOZARIL 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 normal range
(Table 2) and are eligible to initiate treatment. Weekly ANC monitoring
is required for all patients during the first 6 months of treatment. If a
patient's ANC remains equal to or greater than 1500/μL for the first 6
months of treatment, monitoring frequency may be reduced to every 2 weeks for
the next 6 months. If the ANC remains equal to or greater than 1500/μL for
the second 6 months of continuous therapy, ANC monitoring frequency may be
reduced to once every 4 weeks thereafter.
Table 2: CLOZARIL Treatment Recommendations Based on
Absolute Neutrophil Count (ANC) Monitoring for the General Patient Population
ANC Level |
CLOZARIL Treatment Recommendations |
ANC Monitoring |
Normal range ( ≥ 1500/μL) |
- Initiate treatment
- If treatment interrupted:
- < 30 days, continue monitoring as before
- ≥ 30 days, monitor as if new patient
|
- Weekly from initiation to 6 months
- Every 2 weeks from 6 to 12 months
- Monthly after 12 months
|
- Discontinuation for reasons other than neutropenia
|
- See DOSAGE AND ADMINISTRATION
|
Mild Neutropenia (1000 to 1499/μL)* |
|
- Three times weekly until ANC ≥ 1500/μL
- Once ANC ≥ 1500/μL, return to patient’s last “Normal Range” ANC monitoring interval**
|
Moderate Neutropenia (500 to 999/μL)* |
- Recommend hematology consultation
- Interrupt treatment for suspected clozapine induced neutropenia
- Resume treatment once ANC ≥ 1000/μL
|
- Daily until ANC ≥ 1000/μL, then
- Three times weekly until ANC ≥ 1500/μL
- Once ANC ≥ 1500/μL, check ANC weekly for 4 weeks, then return to patient’s last “Normal Range” ANC monitoring interval**
|
Severe Neutropenia (less than 500/μL)* |
- Recommend hematology consultation
- Interrupt treatment for suspected clozapine-induced neutropenia
|
- Daily until ANC ≥ 1000/μL, then
- Three times weekly until ANC ≥ 1500/μL
- If patient rechallenged,
|
- Do not rechallenge unless prescriber determines benefits outweigh risks
|
- resume treatment as a new patient under “Normal Range” monitoring once ANC ≥ 1500/μL
|
* Confirm all initial reports
of ANC less than 1500/μL with a repeat ANC measurement within 24 hours
** If clinically appropriate |
CLOZARIL Treatment And Monitoring
In Patients With Benign Ethnic Neutropenia (see Table 3)
Benign ethnic neutropenia (BEN)
is a condition observed in certain ethnic groups whose average ANC values are
lower than “standard” laboratory ranges for neutrophils. It is most commonly
observed in individuals of African descent (approximate prevalence of 25-50%),
some Middle Eastern ethnic groups, and in other non-Caucasian ethnic groups
with darker skin. BEN is more common in men. Patients with BEN have normal
hematopoietic stem-cell number and myeloid maturation, are healthy, and do not
suffer from repeated or severe infections. They are not at increased risk for
developing CLOZARIL-induced neutropenia. Additional evaluation may be needed to
determine if baseline neutropenia is due to BEN. Consider hematology
consultation before initiating or during CLOZARIL treatment as necessary.
Patients with BEN require a
different ANC algorithm for CLOZARIL management due to their lower baseline ANC
levels. Table 3 provides guidelines for managing CLOZARIL treatment and ANC
monitoring in patients with BEN.
Table 3: Patients with
Benign Ethnic Neutropenia (BEN); CLOZARIL Treatment Recommendations Based on
Absolute Neutrophil Count (ANC) Monitoring
ANC Level |
Treatment Recommendations |
ANC Monitoring |
Normal BEN Range (Established ANC baseline ≥ 1000/μL ) |
- Obtain at least two baseline ANC levels before initiating treatment
- If treatment interrupted
- < 30 days, continue monitoring as before
- ≥ 30 days, monitor as if new patient
|
- Weekly from initiation to 6 months
- Every 2 weeks from 6 to 12 months
- Monthly after 12 months
|
- Discontinuation of treatment for reasons other than neutropenia
|
- See DOSAGE AND ADMINISTRATION
|
BEN Neutropenia 500 to 999/μL* |
- Recommend hematology consultation
- Continue treatment
|
- Three times weekly until ANC ≥ 1000/μL or ≥ patient’s known baseline
- Once ANC ≥ 1000/μL or at patient’s known baseline, check ANC weekly for 4 weeks, then return to patient’s last “Normal BEN Range” ANC monitoring interval.**
|
BEN Severe Neutropenia less than 500/μL* |
- Recommend hematology consultation
- Interrupt treatment for suspected clozapine-induced neutropeniaDo not rechallenge unless prescriber determines benefits outweigh risks
|
- Daily until ANC ≥ 500/μL, then
- Three times weekly until ANC ≥ patient’s baseline
- If patient rechallenged, resume treatment as a new patient under “Normal Range” monitoring once ANC > 1000/^L or at patient’s baseline
|
* Confirm all initial reports
of ANC less than 1500/μL with a repeat ANC measurement within 24 hours
** If clinically appropriate |
General Guidelines for Management of All Patients with Fever or with Neutropenia
- Fever: Interrupt CLOZARIL as a
precautionary measure in any patient who develops fever, defined as a
temperature of 38.5°C [101.3°F] or greater,
and obtain an ANC level. Fever is often the first sign of neutropenic
infection.
- ANC less than 1000/μL: If fever occurs in any patient with an ANC less
than 1000/μL, initiate appropriate workup and treatment for infection and
refer to Tables 2 or 3 for management.
- Consider hematology
consultation.
- See Neuroleptic Malignant
Syndrome [NMS] and Fever under WARNINGS AND PRECAUTIONS and Instructions
for Patients, under PATIENT INFORMATION.
Rechallenge After an ANC Less
than 500/μL (severe neutropenia)
For some patients who
experience severe CLOZARIL-related neutropenia, the risk of serious psychiatric
illness from discontinuing CLOZARIL treatment may be greater than the risk of
rechallenge (e.g. patients with severe schizophrenic illness who have no
treatment options other than CLOZARIL). A hematology consultation may be useful
in deciding to rechallenge a patient. In general, however, do not
rechallenge patients who develop severe neutropenia with CLOZARIL or a
clozapine product.
If a patient will be rechallenged, the clinician should
consider thresholds provided in Tables 2 and 3, the patient's medical and
psychiatric history, a discussion with the patient and his/her caregiver about
the benefits and risks of CLOZARIL rechallenge, and the severity and
characteristics of the neutropenic episode.
Using CLOZARIL with Other Drugs Associated with
Neutropenia
It is unclear if concurrent use of other drugs known to
cause neutropenia increases the risk or severity of CLOZARIL-induced
neutropenia. There is no strong scientific rationale to avoid CLOZARIL
treatment in patients concurrently treated with these drugs. If CLOZARIL is
used concurrently with an agent known to cause neutropenia (e.g., some chemotherapeutic
agents), consider monitoring patients more closely than the treatment the
guidelines provided in Tables 2 and 3. Consult with the treating oncologist in
patients receiving concomitant chemotherapy.
Clozapine REMS Program
CLOZARIL is only available through a restricted program
under a REMS called the Clozapine REMS Program because of the risk of severe
neutropenia.
Notable requirements of the Clozapine REMS Program
include:
- Healthcare professionals who prescribe CLOZARIL must be
certified with the program by enrolling and completing training
- Patients who receive CLOZARIL must be enrolled in the
program and comply with the ANC testing and monitoring requirements
- Pharmacies dispensing CLOZARIL must be certified with the
program by enrolling and completing training and must only dispense to patients
who are eligible to receive CLOZARIL
Further information is available at www.clozapinerems.com
or 1-844-267-8678.
Orthostatic Hypotension, Bradycardia, And Syncope
Hypotension, bradycardia, syncope, and cardiac arrest
have occurred with clozapine treatment. The risk is highest during the initial
titration period, particularly with rapid dose-escalation. These reactions can
occur with the first dose, at doses as low as 12.5 mg. These reactions can be
fatal. The syndrome is consistent with neurally mediated reflex bradycardia
(NMRB).
Treatment must begin at a maximum dose of 12.5 mg once
daily or twice daily. The total daily dose can be increased in increments of 25
mg to 50 mg per day, if well-tolerated, to a target dose of 300 mg to 450 mg
per day (administered in divided doses) by the end of 2 weeks. Subsequently,
the dose can be increased weekly or twice weekly, in increments of up to 100 mg.
The maximum dose is 900 mg per day. Use cautious titration and a divided dosage
schedule to minimize the risk of serious cardiovascular reactions [see
DOSAGE AND ADMINISTRATION]. Consider reducing the dose if hypotension
occurs. When restarting patients who have had even a brief interval off
CLOZARIL (i.e., 2 days or more since the last dose), re-initiate treatment at
12.5 mg once daily or twice daily [see DOSAGE AND ADMINISTRATION].
Use CLOZARIL cautiously in patients with cardiovascular disease
(history of myocardialinfarction 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
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 treatment
with a low dose (12.5 mg), titrate slowly, and use divided dosing.
Use caution when administering CLOZARIL 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 CLOZARIL 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 And Cardiomyopathy
Myocarditis and cardiomyopathy have occurred with the use
of CLOZARIL. These reactions can be fatal. Discontinue CLOZARIL and obtain a
cardiac evaluation upon suspicion of myocarditis or cardiomyopathy. Generally,
patients with a history of clozapine-associated myocarditis or cardiomyopathy
should not be rechallenged with CLOZARIL. However, if the benefit of CLOZARIL
treatment is judged to outweigh the potential risks of recurrent myocarditis or
cardiomyopathy, the clinician may consider rechallenge with CLOZARIL in consultation
with a cardiologist, after a complete cardiac evaluation, and under close
monitoring.
Consider the possibility of myocarditis or cardiomyopathy
in patients receiving CLOZARIL 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 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 and cardiomyopathy can occur at any period during
treatment with CLOZARIL. It is common for nonspecific flu-like symptoms such as
malaise, myalgia, pleuritic chest pain, and low-grade fevers to precede more
overt signs of heart failure. Typical laboratory findings include elevated
troponin I or T, elevated creatinine kinase-MB, peripheral eosinophilia, and
elevated C-reactive protein (CRP). Chest roentgenogram may demonstrate cardiac
silhouette enlargement, and cardiac imaging (echocardiogram, radionucleotide
studies, or cardiac catheterization) may reveal evidence of left ventricular
dysfunction.
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. CLOZARIL is not approved for the treatment of patients
with dementia-related psychosis [see BOXED WARNING].
Eosinophilia
Eosinophilia, defined as a blood eosinophil count of
greater than 700/μL, has occurred with CLOZARIL treatment. In clinical
trials, approximately 1% of patients developed eosinophilia. Clozapine-related
eosinophilia usually occurs during the first month of treatment. In some
patients, it has been associated with myocarditis, pancreatitis, hepatitis,
colitis, and nephritis. Such organ involvement could be consistent with a drug
reaction with eosinophilia and systemic symptoms syndrome (DRESS), also known
as drug induced hypersensitivity syndrome (DIHS). If eosinophilia develops
during CLOZARIL treatment, evaluate promptly for signs and symptoms of systemic
reactions, such as rash or other allergic symptoms, myocarditis, or other
organ-specific disease associated with eosinophilia. If CLOZARIL-related
systemic disease is suspected, discontinue CLOZARIL immediately.
If a cause of eosinophilia unrelated to CLOZARIL is
identified (e.g., asthma, allergies, collagen vascular disease, parasitic
infections, and specific neoplasms), treat the underlying cause and continue
CLOZARIL.
Clozapine-related eosinophilia has also occurred in the
absence of organ involvement and can resolve without intervention. There are
reports of successful rechallenge after discontinuation of clozapine, without
recurrence of eosinophilia. In the absence of organ involvement, continue
CLOZARIL under careful monitoring. If the total eosinophil count continues to
increase over several weeks in the absence of systemic disease, the decision to
interrupt CLOZARIL therapy and rechallenge after the eosinophil count decreases
should be based on the overall clinical assessment, in consultation with an
internist or hematologist.
QT Interval Prolongation
QT prolongation, Torsade de Pointes and other
life-threatening ventricular arrhythmias, cardiac arrest, and sudden death have
occurred with CLOZARIL treatment. When prescribing CLOZARIL, consider the
presence of additional risk factors for QT prolongation and serious
cardiovascular reactions. Conditions that increase these risks include the following:
history of QT prolongation, long QT syndrome, family history of long QT
syndrome or sudden cardiac death, significant cardiac arrhythmia, recent
myocardial infarction, uncompensated heart failure, treatment with other
medications that cause QT prolongation, treatment with medications that inhibit
the metabolism of clozapine, and electrolyte abnormalities.
Prior to initiating treatment with CLOZARIL, perform a
careful physical examination, medical history, and concomitant medication
history. Consider obtaining a baseline ECG and serum chemistry panel. Correct
electrolyte abnormalities. Discontinue CLOZARIL if the QTc interval exceeds 500
msec. If patients experience symptoms consistent with Torsades de Pointes or
other arrhythmias, (e.g., syncope, presyncope, dizziness, or palpitations),
obtain a cardiac evaluation and discontinue CLOZARIL.
Use caution when administering concomitant medications
that prolong the QT interval or inhibit the metabolism of CLOZARIL. Drugs that
cause QT prolongation include: specific antipsychotics (e.g., ziprasidone,
iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, pimozide),
specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin,
sparfloxacin), Class 1A antiarrhythmic medications (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). Clozapine is
primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. Concomitant
treatment with inhibitors of these enzymes can increase the concentration of
CLOZARIL [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].
Hypokalemia and hypomagnesemia increase the risk of QT
prolongation. Hypokalemia can result from diuretic therapy, diarrhea, and other
causes. Use caution when treating patients at risk for significant electrolyte
disturbance, particularly hypokalemia. Obtain baseline measurements of serum
potassium and magnesium levels, and periodically monitor electrolytes. Correct
electrolyte abnormalities before initiating treatment with CLOZARIL.
Metabolic Changes
Atypical antipsychotic drugs, including CLOZARIL have
been associated with metabolic changes that can increase cardiovascular and
cerebrovascular risk. These metabolic changes include hyperglycemia,
dyslipidemia, and body weight gain. While atypical antipsychotic drugs may
produce some metabolic changes, each drug in the class has its own specific
risk profile.
Hyperglycemia And Diabetes Mellitus
Hyperglycemia, in some cases extreme and associated with
ketoacidosis or hyperosmolar coma or death, has been reported in patients
treated with atypical antipsychotics including CLOZARIL. Assessment of the
relationship between atypical antipsychotic use and glucose abnormalities is
complicated by the possibility of an increased background risk of diabetes
mellitus in patients with schizophrenia and the increasing incidence of
diabetes mellitus in the general population. Given these confounders, the
relationship between atypical antipsychotic use and hyperglycemia-related
adverse reactions is not completely understood. However, epidemiological
studies suggest an increased risk of treatment-emergent, hyperglycemia-related
adverse reactions in patients treated with the atypical antipsychotics. Precise
risk estimates for hyperglycemia-related adverse reactions in patients treated
with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes
mellitus who are started on CLOZARIL should be monitored regularly for
worsening of glucose control. Patients with risk factors for diabetes mellitus
(e.g., obesity, family history of diabetes) who are starting treatment with atypical
antipsychotics should undergo fasting blood glucose testing at the beginning of
treatment and periodically during treatment. Any patient treated with atypical
antipsychotics should be monitored for symptoms of hyperglycemia including
polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms
of hyperglycemia during treatment with atypical antipsychotics should undergo
fasting blood glucose testing. In some cases, hyperglycemia has resolved when
the atypical antipsychotic was discontinued; however, some patients required
continuation of anti-diabetic treatment despite discontinuation of the suspect
drug.
In a pooled data analysis of 8 studies in adult subjects
with schizophrenia, the mean changes in fasting glucose concentration in the
CLOZARIL and chlorpromazine groups were +11 mg/dL and +4 mg/dL respectively. A
higher proportion of the CLOZARIL group demonstrated categorical increases from
baseline in fasting glucose concentrations, compared to the chlorpromazine
group (Table 4). The CLOZARIL doses were 100-900 mg per day (mean modal dose:
512 mg per day). The maximum chlorpromazine dose was 1800 mg per day (mean
modal dose: 1029 mg per day). The median duration of exposure was 42 days for
CLOZARIL and chlorpromazine.
Table 4: Categorical Changes in Fasting Glucose Level
in Studies in Adult Subjects with Schizophrenia
Laboratory Parameter |
Category Change (at least once) from baseline |
Treatment Arm |
N |
n (%) |
Fasting Glucose |
Normal ( < 100 mg/dL) to High ( ≥ 126 mg/dL) |
CLOZARIL |
198 |
53 (27) |
Chlorpromazine |
135 |
14 (10) |
Borderline (100 to 125 mg/dL) to High ( ≥ 126 mg/dL) |
CLOZARIL |
57 |
24 (42) |
Chlorpromazine |
43 |
12 (28) |
Dyslipidemia
Undesirable alterations in
lipids have occurred in patients treated with atypical antipsychotics,
including CLOZARIL. Clinical monitoring, including baseline and periodic
follow-up lipid evaluations in patients using CLOZARIL, is recommended.
In a pooled data analysis of 10
studies in adult subjects with schizophrenia, CLOZARIL treatment was associated
with increases in serum total cholesterol. No data were collected on LDL and
HDL cholesterol. The mean increase in total cholesterol was 13 mg/dL in the
CLOZARIL group and 15 mg/dL in the chlorpromazine group. In a pooled data
analysis of 2 studies in adult subjects with schizophrenia, CLOZARIL treatment
was associated with increases in fasting serum triglyceride. The mean increase
in fasting triglyceride was 71 mg/dL (54%) in the CLOZARIL group and 39 mg/dL
(35%) in the chlorpromazine group (Table 5). In addition, CLOZARIL treatment
was associated with categorical increases in serum total cholesterol and
triglyceride, as illustrated in Table 6.The proportion of patients with
categorical increases in total cholesterol or fasting triglyceride increased
with the duration of exposure. The median duration of CLOZARIL and
chlorpromazine exposure was 45 days and 38 days, respectively. The CLOZARIL
dose range was 100 mg to 900 mg daily; the maximum chlorpromazine dose was 1800
mg daily.
Table 5: Mean Changes in Total Cholesterol and Triglyceride
Concentration in Studies in Adult Subjects with Schizophrenia
Treatment Arm |
Baseline total cholesterol concentration (mg/dL) |
Change from baseline mg/dL (%) |
CLOZARIL (N=334) |
184 |
+13 (7) |
Chlorpromazine (N=185) |
182 |
+15 (8) |
|
Baseline triglyceride concentration (mg/dL) |
Change from baseline mg/dL (%) |
CLOZARIL (N=6) |
130 |
+71 (54) |
Chlorpromazine (N=7) |
110 |
+39 (35) |
Table 6: Categorical Changes
in Lipid Concentrations in Studies in Adult Subjects with Schizophrenia
Laboratory Parameter |
Category Change (at least once) from baseline |
Treatment Arm |
N |
n (%) |
Total Cholesterol (random or fasting) |
Increase by ≥ 40 mg/dL |
CLOZARIL |
334 |
111 (33) |
Chlorpromazine |
185 |
46 (25) |
Normal ( < 200 mg/dL) to High ( ≥ 240 mg/dL) |
CLOZARIL |
222 |
18 (8) |
Chlorpromazine |
132 |
3 (2) |
|
|
|
Borderline (200 - 239 mg/dL) to High ( ≥ 240 mg/dL) |
CLOZARIL |
79 |
30 (38) |
Chlorpromazine |
34 |
14 (41) |
Triglycerides (fasting) |
Increase by ≥ 50 mg/dL |
CLOZARIL |
6 |
3 (50) |
Chlorpromazine |
7 |
3 (43) |
Normal ( < 150 mg/dL) to High ( ≥ 200 mg/dL) |
CLOZARIL |
4 |
0 (0) |
Chlorpromazine |
6 |
2 (33) |
Borderline ( ≥ 150 mg/dL and < 200 mg/dL) to High ( ≥ 200 mg/dL) |
CLOZARIL |
1 |
1 (100) |
Chlorpromazine |
1 |
0 (0) |
Weight Gain
Weight gain has occurred with the use of antipsychotics,
including CLOZARIL. Monitor weight during treatment with CLOZARIL. Table 7
summarizes the data on weight gain by the duration of exposure pooled from 11
studies with CLOZARIL and active comparators. The median duration of exposure
was 609, 728, and 42 days, in the CLOZARIL, olanzapine, and chlorpromazine
group, respectively.
Table 7: Mean Change in Body Weight (kg) by duration
of exposure from studies in adult subjects with schizophrenia
Metabolic parameter |
Exposure duration |
CLOZARIL
(N = 669) |
Olanzapine
(N = 442) |
Chlorpromazine
(N = 155) |
n |
Mean |
N |
Mean |
n |
Mean |
Weight change from baseline |
2 weeks (Day 11 - 17) |
6 |
+0.9 |
3 |
+0.7 |
2 |
-0.5 |
4 weeks (Day 21 - 35) |
23 |
+0.7 |
8 |
+0.8 |
17 |
+0.6 |
8 weeks (Day 49 - 63) |
12 |
+ 1.9 |
13 |
+ 1.8 |
16 |
+0.9 |
12 weeks (Day 70 - 98) |
17 |
+2.8 |
5 |
+3.1 |
0 |
0 |
24 weeks (154 - 182) |
42 |
- 0.6 |
12 |
+5.7 |
0 |
0 |
48 weeks (Day 322 - 350) |
3 |
+3.7 |
3 |
+13.7 |
0 |
0 |
Table 8 summarizes pooled data
from 11 studies in adult subjects with schizophrenia demonstrating weight gain
≤ 7% of body weight relative to baseline. The median duration of exposure
was 609, 728, and 42 days, in the CLOZARIL, olanzapine, and chlorpromazine
group, respectively.
Table 8: Proportion of adult
subjects in schizophrenia studies with weight gain ≤ 7% relative to
baseline body weight
Weight change |
CLOZARIL |
Olanzapine |
Chlorpromazine |
N |
669 |
442 |
155 |
≥ 7% (inclusive) |
236 (35%) |
203 (46%) |
13 (8%) |
Neuroleptic Malignant Syndrome
Antipsychotic drugs including
CLOZARIL can cause a potentially fatal symptom complex referred to as
Neuroleptic Malignant Syndrome (NMS). Clinical manifestations of NMS include
hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability
(irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac
dysrhythmias). Associated findings can include elevated creatine phosphokinase
(CPK), myoglobinuria, rhabdomyolysis, and acute renal failure.
The diagnostic evaluation of patients with this syndrome
is complicated. It is important to consider the presence of other serious
medical conditions (e.g., severe neutropenia, infection, heat stroke, primary
CNS pathology, central anticholinergic toxicity, extrapyramidal symptoms, and
drug fever).
The management of NMS should include (1) immediate
discontinuation of antipsychotic drugs and other drugs not essential to
concurrent therapy, (2) intensive symptomatic treatment and medical monitoring,
and (3) treatment of comorbid medical conditions. There is no general agreement
about specific pharmacological treatments for NMS.
If a patient requires antipsychotic drug treatment after
recovery from NMS, the potential reintroduction of drug therapy should be
carefully considered. NMS can recur. Monitor closely if restarting treatment
with antipsychotics.
NMS has occurred with CLOZARIL monotherapy and with
concomitant CNS-active medications, including lithium.
Fever
During clozapine therapy, patients have experienced
transient, clozapine-related fever. The peak incidence is within the first 3
weeks of treatment. While this fever is generally benign and self-limited, it
may necessitate discontinuing treatment. The fever can be associated with an
increase or decrease in WBC count. Carefully evaluate patients with fever to
rule out severe neutropenia or infection. Consider the possibility of NMS [see WARNINGS AND PRECAUTIONS].
Pulmonary Embolism
Pulmonary embolism and deep-vein thrombosis have occurred
in patients treated with CLOZARIL. Consider the possibility of pulmonary
embolism in patients who present with deep-vein thrombosis, acute dyspnea,
chest pain, or with other respiratory signs and symptoms. Whether pulmonary
embolus and deep vein thrombosis can be attributed to clozapine or some
characteristic(s) of patients is not clear.
Anticholinergic Toxicity
CLOZARIL has potent anticholinergic effects. Treatment
with CLOZARIL can result in CNS and peripheral anticholinergic toxicity. Use
with caution in the presence of narrow-angle glaucoma, concomitant
anticholinergic medications, prostatic hypertrophy, or other conditions in
which anticholinergic effects can lead to significant adverse reactions.
Treatment with CLOZARIL can result in gastrointestinal
adverse reactions, including constipation, intestinal obstruction, fecal
impaction, and paralytic ileus. Such reactions can be fatal. Constipation
should be initially treated by ensuring adequate hydration and use of ancillary
therapy such as bulk laxatives. Consultation with a gastroenterologist is
advisable in more serious cases.
Interference With Cognitive And Motor Performance
CLOZARIL can cause sedation and impairment of cognitive
and motor performance. Caution patients about operating hazardous machinery,
including automobiles, until they are reasonably certain that CLOZARIL does not
affect them adversely. These reactions may be dose-related. Consider reducing
the dose if they occur.
Tardive Dyskinesia
Tardive dyskinesia (TD) has occurred in patients treated
with antipsychotic drugs, including CLOZARIL. The syndrome consists of
potentially irreversible, involuntary, dyskinetic movements. The risk of TD and
the likelihood that it will become irreversible are believed to increase with
greater durations of treatment and higher total cumulative doses. However, the
syndrome can develop after relatively brief treatment periods at low doses.
Prescribe CLOZARIL in a manner that is most likely to minimize the risk of
developing TD. Use the lowest effective dose and the shortest duration
necessary to control symptoms. Periodically assess the need for continued
treatment. Consider discontinuing treatment if TD occurs. However, some
patients may require treatment with CLOZARIL despite the presence of the
syndrome.
There is no known treatment for TD. However, the syndrome
may remit partially or completely if treatment is discontinued. Antipsychotic
treatment, itself, may suppress (or partially suppress) the signs and symptoms,
and it has the potential to mask the underlying process. The effect of symptom
suppression on the long-term course of TD is unknown.
Cerebrovascular Adverse Reactions
In controlled trials, elderly patients with
dementia-related psychosis treated with some atypical antipsychotics had an
increased risk (compared to placebo) of cerebrovascular adverse reactions
(e.g., stroke, transient ischemic attack), including fatalities. The mechanism
for this increased risk is not known. An increased risk cannot be excluded for
CLOZARIL or other antipsychotics or other patient populations. CLOZARIL should
be used with caution in patients with risk factors for cerebrovascular adverse
reactions.
Recurrence Of Psychosis And Cholinergic Rebound After Abrupt
Discontinuation Of CLOZARIL
If abrupt discontinuation of CLOZARIL is necessary
(because of severe neutropenia or another medical condition, for example) [see
DOSAGE AND ADMINISTRATION, WARNINGS AND
PRECAUTIONS], monitor carefully for the recurrence of psychotic
symptoms and adverse reactions related to cholinergic rebound, such as profuse
sweating, headache, nausea, vomiting and diarrhea.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenesis
No carcinogenic potential was demonstrated in long-term
studies in mice and rats at doses up to 0.3 times and 0.4 times, respectively,
the maximum recommended human dose (MRHD) of 900 mg/day on a mg/m² body
surface area basis.
Mutagenesis
Clozapine was not genotoxic when tested in the following
gene mutation and chromosomal aberration tests: the bacterial Ames test, the in
vitro mammalian V79 in Chinese hamster cells, the in vitro unscheduled DNA
synthesis in rat hepatocytes or the in vivo micronucleus assay in mice.
Impairment Of Fertility
Clozapine had no effect on any parameters of fertility,
pregnancy, fetal weight or postnatal development when administered orally to
male rats 70 days before mating and to female rats for 14 days before mating at
doses up to 0.4 times the MRHD of 900 mg/day on a mg/m² body surface
area basis.
Patient Counseling Information
See FDA-approved patient
labeling (PATIENT INFORMATION and Instructions for Use).
Discuss the following issues
with patients and caregivers:
- Severe Neutropenia:
- Instruct patients (and
caregivers) beginning treatment with CLOZARIL 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 CLOZARIL therapy, to aid in evaluation for neutropenia and to
institute prompt and appropriate management. [see WARNINGS AND PRECAUTIONS].
- Inform patients and caregivers
CLOZARIL 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.
- CLOZARIL 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.
- 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.
Advise patients to consult their clinician immediately if they feel faint, lose
consciousness or have signs or symptoms suggestive of bradycardia or arrhythmia
[see DOSAGE AND ADMINISTRATION and WARNINGS
AND PRECAUTIONS].
- Seizures: Inform patients and caregivers about the
significant risk of seizure during CLOZARIL treatment. Caution them about
driving and any other potentially hazardous activity while taking CLOZARIL [see WARNINGS AND PRECAUTIONS].
- 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
CLOZARIL with other drugs that cause QT interval prolongation. Instruct
patients to inform their clinicians that they are taking CLOZARIL before any
new drug [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
- 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].
- Interference with Cognitive and Motor Performance: Because CLOZARIL 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 CLOZARIL therapy does not
affect them adversely [see WARNINGS AND PRECAUTIONS].
- Missed Doses and Re-initiating Treatment: Inform
patients and caregivers that if the patient misses taking CLOZARIL for more
than 2 days, they should not restart their medication at the same dosage but
should contact their physician for dosing instructions [see DOSAGE AND
ADMINISTRATION and WARNINGS AND PRECAUTIONS].
- Pregnancy: Patients and caregivers
should notify the clinician if the patient becomes pregnant or intends to
become pregnant during therapy. [see Use in Specific Populations]
- Nursing: Advice patients and
caregivers that the patient should not breast feed an infant if they are taking
CLOZARIL. [see Use in Specific Populations]
- Concomitant Medication: Advise patients to inform their health care 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
ADMINISTRATIONS, DRUG INTERACTIONS, and Table 1].
Use In Specific Populations
Pregnancy
Pregnancy Category B
Risk Summary
There are no adequate or well-controlled studies of
clozapine in pregnant women.
Reproduction studies have been performed in rats and
rabbits at doses up to 0.4 and 0.9 times, respectively, the maximum recommended
human dose (MRHD) of 900 mg/day on a mg/m² body surface area basis.
The studies revealed no evidence of impaired fertility or harm to the fetus due
to clozapine. Because animal reproduction studies are not always predictive of
human response, CLOZARIL should be used during pregnancy only if clearly
needed.
Clinical Considerations
Consider the risk of exacerbation of psychosis when
discontinuing or changing treatment with antipsychotic medications during
pregnancy and postpartum. Consider early screening for gestational diabetes for
patients treated with antipsychotic medications [see WARNINGS AND PRECAUTIONS]. Neonates exposed to antipsychotic
drugs during the third trimester of pregnancy are at risk for extrapyramidal
and/or withdrawal symptoms following delivery. Monitor neonates for symptoms of
agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and
feeding difficulties. The severity of complications can vary from self-limited
symptoms to some neonates requiring intensive care unit support and prolonged
hospitalization.
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/m² 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 F1or F2 generations at doses up to 0.4
times the MRHD of 900 mg/day on a mg/m² body surface area basis.
Nursing Mothers
CLOZARIL is present in human milk. Because of the
potential for serious adverse reactions in nursing infants from CLOZARIL, a
decision should be made whether to discontinue nursing or to discontinue the
drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not
been established.
Geriatric Use
There have not been sufficient numbers of geriatric
patients in clinical studies utilizing CLOZARIL to determine whether those over
65 years of age differ from younger subjects in their response to CLOZARIL.
Orthostatic hypotension and tachycardia can occur with
CLOZARIL treatment [see BOXED WARNING and WARNINGS
AND PRECAUTIONS]. 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 CLOZARIL, such as urinary retention and constipation
[see WARNINGS AND PRECAUTIONS].
Carefully select CLOZARIL 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].
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, CLINICAL
PHARMACOLOGY].
CYP2D6 Poor Metabolizers
Dose reduction may be necessary in patients who are
CYP2D6 poor metabolizers. Clozapine concentrations may be increased in these
patients, because clozapine is almost completely metabolized and then excreted [see
DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].
Hospice Patients
For hospice patients (i.e., terminally ill patients with
an estimated life expectancy of six months or less), the prescriber may reduce
the ANC monitoring frequency to once every 6 months, after a discussion with
the patient and his/her caregiver. Individual treatment decisions should weigh
the importance of monitoring ANC in the context of the need to control
psychiatric symptoms and the patient's terminal illness.