A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Clozaril Warnings, Precautions, Pregnancy, Nursing, Abuse - Clozapine
Clozaril Warnings, Precautions, Pregnancy, Nursing, Abuse - Clozapine
WARNINGS
General
BECAUSE OF THE SIGNIFICANT RISK OF AGRANULOCYTOSIS, A POTENTIALLY
LIFE-THREATENING ADVERSE EVENT (SEE FOLLOWING), CLOZARIL® (CLOZAPINE)
SHOULD BE RESERVED FOR USE IN (1) THE TREATMENT OF SEVERELY ILL PATIENTS WITH
SCHIZOPHRENIA WHO FAIL TO SHOW AN ACCEPTABLE RESPONSE TO ADEQUATE COURSES OF
STANDARD DRUG TREATMENT FOR SCHIZOPHRENIA, EITHER BECAUSE OF INSUFFICIENT EFFECTIVENESS
OR THE INABILITY TO ACHIEVE AN EFFECTIVE DOSE DUE TO INTOLERABLE ADVERSE EFFECTS
FROM THOSE DRUGS, OR (2) FOR REDUCING THE RISK OF RECURRENT SUICIDAL BEHAVIOR
IN PATIENTS WITH SCHIZOPHRENIA OR SCHIZOAFFECTIVE DISORDER WHO ARE JUDGED TO
BE AT RISK OF REEXPERIENCING SUICIDAL BEHAVIOR. CONSEQUENTLY, UNLESS THE PATIENT
IS AT RISK FOR RECURRENT SUICIDAL BEHAVIOR, BEFORE INITIATING TREATMENT WITH
CLOZARIL, IT IS STRONGLY RECOMMENDED THAT A PATIENT BE GIVEN AT LEAST 2 TRIALS,
EACH WITH A DIFFERENT STANDARD DRUG PRODUCT FOR SCHIZOPHRENIA, AT AN ADEQUATE
DOSE, AND FOR AN ADEQUATE DURATION.
PATIENTS WHO ARE BEING TREATED WITH CLOZARIL MUST HAVE A BASELINE
WHITE BLOOD CELL (WBC) AND DIFFERENTIAL COUNT BEFORE INITIATION OF TREATMENT,
AND A WBC COUNT EVERY WEEK FOR THE FIRST SIX MONTHS. THEREAFTER, IF ACCEPTABLE
WBC COUNTS (WBC ³ 3000/MM3, ANC ³
1500/MM3) HAVE BEEN MAINTAINED DURING THE FIRST 6 MONTHS OF CONTINUOUS
THERAPY, WBC COUNTS CAN BE MONITORED EVERY OTHER WEEK. WBC COUNTS MUST BE MONITORED
WEEKLY FOR AT LEAST 4 WEEKS AFTER THE DISCONTINUATION OF CLOZARIL.
CLOZARIL IS AVAILABLE ONLY THROUGH A DISTRIBUTION SYSTEM THAT
ENSURES MONITORING OF WBC COUNTS ACCORDING TO THE SCHEDULE DESCRIBED BELOW PRIOR
TO DELIVERY OF THE NEXT SUPPLY OF MEDICATION.
Agranulocytosis
Agranulocytosis, defined as an absolute neutrophil count (ANC)
of less than 500/mm3, has been estimated to occur in association
with CLOZARIL use at a cumulative incidence at 1 year of approximately 1.3%,
based on the occurrence of 15 U.S. cases out of 1,743 patients exposed to CLOZARIL
during its clinical testing prior to domestic marketing. All of these cases
occurred at a time when the need for close monitoring of WBC counts was already
recognized. This reaction could prove fatal if not detected early and therapy
interrupted. Of the 149 cases of agranulocytosis reported worldwide in association
with CLOZARIL use as of December 31, 1989, 32% were fatal. However, few of these
deaths occurred since 1977, at which time the knowledge of CLOZARIL induced
agranulocytosis became more widespread, and close monitoring of WBC counts more
widely practiced. Nevertheless, it is unknown at present what the case fatality
rate will be for CLOZARIL induced agranulocytosis, despite strict adherence
to the required frequency of monitoring. In the U.S., under a weekly WBC monitoring
system with CLOZARIL, there have been 585 cases of agranulocytosis as of August
21, 1997; 19 were fatal. During this period 150,409 patients received CLOZARIL.
A hematologic risk analysis was conducted based upon the available information
in the Clozaril® National Registry (CNR) for U.S. patients. Based
upon a cut-off date of April 30, 1995, the incidence rates of agranulocytosis
based upon a weekly monitoring schedule, rose steeply during the first two months
of therapy, peaking in the third month. Among CLOZARIL patients who continued
the drug beyond the third month, the weekly incidence of agranulocytosis fell
to a substantial degree, so that by the sixth month the weekly incidence of
agranulocytosis was reduced to 3 per 1,000 person-years. After six months, the
weekly incidence of agranulocytosis declines still further, however, never reaches
zero. It should be noted that any type of reduction in the frequency of monitoring
WBC counts may result in an increased incidence of agranulocytosis.
Because of the substantial risk for developing agranulocytosis
in association with CLOZARIL use, which may persist over an extended period
of time, patients must have a blood sample drawn for a WBC count before initiation
of treatment with CLOZARIL, and must have subsequent WBC counts done at least
weekly for the first 6 months of continuous treatment. If WBC counts remain
acceptable (WBC ³ 3000/mm3, ANC ³
1500/mm3) during this period, WBC counts may be monitored every other
week thereafter. After the discontinuation of CLOZARIL, weekly WBC counts should
be continued for an additional 4 weeks.
If a patient is on CLOZARIL therapy for less than 6 months
with no abnormal blood events and there is a break on therapy which is less
than or equal to 1 month, then patients can continue where they left off with
weekly WBC testing for 6 months. When this 6-month period has been completed,
the frequency of WBC count monitoring can be reduced to every other week. If
a patient is on CLOZARIL therapy for less than 6 months with no abnormal blood
events and there is a break on therapy which is greater than 1 month, then patients
should be tested weekly for an additional 6-month period before biweekly testing
is initiated. If a patient is on CLOZARIL therapy for less than 6 months and
experiences an abnormal blood event as described below but remains a rechallengeable
patient (patients cannot be reinitiated on CLOZARIL therapy if WBC counts fall
below 2000/mm3 or the ANC falls below 1000/mm3 during
CLOZARIL therapy), the patient must restart the 6-month period of weekly WBC
monitoring at Day 0.
If a patient is on CLOZARIL therapy for 6 months or longer
with no abnormal blood events and there is a break on therapy which is 1 year
or less, then the patient can continue WBC count monitoring every other week
if CLOZARIL therapy is reinitiated. If a patient is on CLOZARIL therapy for
6 months or longer with no abnormal blood events and there is a break on therapy
which is greater than 1 year, then, if CLOZARIL therapy is reinitiated, the
patient must have WBC counts monitored weekly for an additional 6 months. If
a patient is on CLOZARIL therapy for 6 months or longer and subsequently has
an abnormal blood event, but remains a rechallengeable patient, then the patient
must restart weekly WBC count monitoring until an additional 6 months of CLOZARIL
therapy has been received. The distribution of CLOZARIL is contingent upon performance
of the required blood tests.
Treatment should not be initiated if the WBC count is less
than 3500/mm3, or if the patient has a history of a myeloproliferative
disorder, or previous CLOZARIL induced agranulocytosis or granulocytopenia.
Patients should be advised to report immediately the appearance of lethargy,
weakness, fever, sore throat or any other signs of infection. If, after the
initial treatment, the total WBC count has dropped below 3500/mm3
or it has dropped by a substantial amount from baseline, even if the count is
above 3500/mm3, or if immature forms are present, a repeat WBC count
and a differential count should be done. A substantial drop is defined as a
single drop of 3,000 or more in the WBC count or a cumulative drop of 3,000
or more within 3 weeks. If subsequent WBC counts and the differential count
reveal a total WBC count between 3000 and 3500/mm3 and an ANC above
1500/mm3, twice weekly WBC counts and differential counts should
be performed.
If the total WBC count falls below 3000/mm3 or the
ANC below 1500/mm3, CLOZARIL therapy should be interrupted, WBC count
and differential should be performed daily, and patients should be carefully
monitored for flu-like symptoms or other symptoms suggestive of infection. CLOZARIL
therapy may be resumed if no symptoms of infection develop, and if the total
WBC count returns to levels above 3000/mm3 and the ANC returns to
levels above 1500/mm3. However, in this event, twice-weekly WBC counts
and differential counts should continue until total WBC counts return to levels
above 3500/mm3.
If the total WBC count falls below 2000/mm3 or the
ANC falls below 1000/mm3, bone marrow aspiration should be considered
to ascertain granulopoietic status. Protective isolation with close observation
may be indicated if granulopoiesis is determined to be deficient. Should evidence
of infection develop, the patient should have appropriate cultures performed
and an appropriate antibiotic regimen instituted.
Patients whose total WBC counts fall below 2000/mm3,
or ANCs below 1000/mm3 during CLOZARIL therapy should have daily
WBC count and differential. These patients should not be rechallenged with CLOZARIL.
Patients discontinued from CLOZARIL therapy due to significant WBC suppression
have been found to develop agranulocytosis upon rechallenge, often with a shorter
latency on re-exposure. To reduce the chances of rechallenge occurring in patients
who have experienced significant bone marrow suppression during CLOZARIL therapy,
a single, national master file will be maintained confidentially.
Except for evidence of significant bone marrow suppression
during initial CLOZARIL therapy, there are no established risk factors, based
on world-wide experience, for the development of agranulocytosis in association
with CLOZARIL use. However, a disproportionate number of the U.S. cases of agranulocytosis
occurred in patients of Jewish background compared to the overall proportion
of such patients exposed during domestic development of CLOZARIL. Most of the
U.S. cases occurred within 4-10 weeks of exposure, but neither dose nor duration
is a reliable predictor of this problem. No patient characteristics have been
clearly linked to the development of agranulocytosis in association with CLOZARIL
use, but agranulocytosis associated with other antipsychotic drugs has been
reported to occur with a greater frequency in women, the elderly and in patients
who are cachectic or have serious underlying medical illness; such patients
may also be at particular risk with CLOZARIL.
To reduce the risk of agranulocytosis developing undetected,
CLOZARIL is available only through a distribution system that ensures monitoring
of WBC counts according to the schedule described above prior to delivery of
the next supply of medication.
Eosinophilia
In clinical trials, 1% of patients developed eosinophilia,
which, in rare cases, can be substantial. If a differential count reveals a
total eosinophil count above 4000/mm3, CLOZARIL therapy should be
interrupted until the eosinophil count falls below 3000/mm3.
Seizures
Seizure has been estimated to occur in association with CLOZARIL
use at a cumulative incidence at one year of approximately 5%, based on the
occurrence of one or more seizures in 61 of 1,743 patients exposed to CLOZARIL
during its clinical testing prior to domestic marketing (i.e., a crude rate
of 3.5%). Dose appears to be an important predictor of seizure, with a greater
likelihood of seizure at the higher CLOZARIL doses used.
Caution should be used in administering CLOZARIL to patients
having a history of seizures or other predisposing factors. Because of the substantial
risk of seizure associated with CLOZARIL use, patients should be advised not
to engage in any activity where sudden loss of consciousness could cause serious
risk to themselves or others, e.g., the operation of complex machinery, driving
an automobile, swimming, climbing, etc.
Myocarditis
Post-marketing surveillance data from four countries that employ
hematological monitoring of clozapine-treated patients revealed: 30 reports
of myocarditis with 17 fatalities in 205,493 U.S. patients (August 2001); 7
reports of myocarditis with 1 fatality in 15,600 Canadian patients (April 2001);
30 reports of myocarditis with 8 fatalities in 24,108 U.K. patients (August
2001); 15 reports of myocarditis with 5 fatalities in 8,000 Australian patients
(March 1999). These reports represent an incidence of 5.0, 16.3, 43.2, and 96.6
cases/100,000 patient-years, respectively. The number of fatalities represent
an incidence of 2.8, 2.3, 11.5, and 32.2 cases/100,000 patient-years, respectively.
The overall incidence rate of myocarditis in patients with
schizophrenia treated with antipsychotic agents is unknown. However, for the
established market economies (WHO), the incidence of myocarditis is 0.3 cases/100,000
patient-years and the fatality rate is 0.2 cases/100,000 patient-years. Therefore,
the rate of myocarditis in clozapine-treated patients appears to be 17-322 times
greater than the general population and is associated with an increased risk
of fatal myocarditis that is 14-161 times greater than the general population.
The total reports of myocarditis for these four countries was
82 of which 51 (62%) occurred within the first month of clozapine treatment,
25 (31%) occurred after the first month of therapy and 6 (7%) were unknown.
The median duration of treatment was 3 weeks. Of 5 patients rechallenged with
clozapine, 3 had a recurrence of myocarditis. Of the 82 reports, 31 (38%) were
fatal and 25 patients who died had evidence of myocarditis at autopsy. These
data also suggest that the incidence of fatal myocarditis may be highest during
the first month of therapy.
Therefore, the possibility of myocarditis should be considered
in patients receiving CLOZARIL who present with unexplained fatigue, dyspnea,
tachypnea, fever, chest pain, palpitations, other signs or symptoms of heart
failure, or electrocardiographic findings such as ST-T wave abnormalities or
arrhythmias. It is not known whether eosinophilia is a reliable predictor of
myocarditis. Tachycardia, which has been associated with CLOZARIL treatment,
has also been noted as a presenting sign in patients with myocarditis. Therefore,
tachycardia during the first month of therapy warrants close monitoring for
other signs of myocarditis.
Prompt discontinuation of CLOZARIL treatment is warranted upon
suspicion of myocarditis. Patients with clozapine-related myocarditis should
not be rechallenged with CLOZARIL.
Other Adverse Cardiovascular and Respiratory Effects
Orthostatic hypotension with or without syncope can occur
with CLOZARIL treatment and may represent a continuing risk in some patients.
Rarely (approximately 1 case per 3,000 patients), collapse can be profound and
be accompanied by respiratory and/or cardiac arrest. Orthostatic hypotension
is more likely to occur during initial titration in association with rapid dose
escalation and may even occur on first dose. In one report, initial doses as
low as 12.5 mg were associated with collapse and respiratory arrest. When restarting
patients who have had even a brief interval off CLOZARIL , i.e., 2 days or more
since the last dose, it is recommended that treatment be reinitiated with one-half
of a 25 mg tablet (12.5 mg) once or twice daily. (See DOSAGE
AND ADMINISTRATION)
Some of the cases of collapse/respiratory arrest/cardiac arrest
during initial treatment occurred in patients who were being administered benzodiazepines;
similar events have been reported in patients taking other psychotropic drugs
or even CLOZARIL by itself. Although it has not been established that there
is an interaction between CLOZARIL and benzodiazepines or other psychotropics,
caution is advised when clozapine is initiated in patients taking a benzodiazepine
or any other psychotropic drug.
Tachycardia, which may be sustained, has also been observed
in approximately 25% of patients taking CLOZARIL, with patients having an average
increase in pulse rate of 10-15 bpm. The sustained tachycardia is not simply
a reflex response to hypotension, and is present in all positions monitored.
Either tachycardia or hypotension may pose a serious risk for an individual
with compromised cardiovascular function.
A minority of CLOZARIL treated patients experience ECG repolarization
changes similar to those seen with other antipsychotic drugs, including S-T
segment depression and flattening or inversion of T waves, which all normalize
after discontinuation of CLOZARIL. The clinical significance of these changes
is unclear. However, in clinical trials with CLOZARIL, several patients experienced
significant cardiac events, including ischemic changes, myocardial infarction,
arrhythmias and sudden death. In addition there have been post-marketing reports
of congestive heart failure, pericarditis, and pericardial effusions. Causality
assessment was difficult in many of these cases because of serious preexisting
cardiac disease and plausible alternative causes. Rare instances of sudden death
have been reported in psychiatric patients, with or without associated antipsychotic
drug treatment, and the relationship of these events to antipsychotic drug use
is unknown.
CLOZARIL should be used with caution in patients with known
cardiovascular and/or pulmonary disease, and the recommendation for gradual
titration of dose should be carefully observed.
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 events is not completely understood. However,
epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related
adverse events in patients treated with the atypical antipsychotics. Precise
risk estimates for hyperglycemia-related adverse events in patients treated
with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus
who are started on atypical antipsychotics 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 atypicalantipsychotics
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.
Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as
Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic
drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered
mental status and evidence of autonomic instability (irregular pulse or blood
pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).
The diagnostic evaluation of patients with this syndrome is
complicated. In arriving at a diagnosis, it is important to identify cases where
the clinical presentation includes both serious medical illness (e.g., pneumonia,
systemic infection, etc.) and untreated or inadequately treated extrapyramidal
signs and symptoms (EPS). Other important considerations in the differential
diagnosis include central anticholinergic toxicity, heat stroke, drug fever
and primary central nervous system (CNS) pathology.
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 any concomitant serious medical problems for which specific treatments are
available. There is no general agreement about specific pharmacological treatment
regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery
from NMS, the potential reintroduction of drug therapy should be carefully considered.
The patient should be carefully monitored, since recurrences of NMS have been
reported.
There have been several reported cases of NMS in patients receiving
CLOZARIL alone or in combination with lithium or other CNS-active agents.
Tardive Dyskinesia
A syndrome consisting of potentially irreversible, involuntary,
dyskinetic movements may develop in patients treated with antipsychotic drugs.
Although the prevalence of the syndrome appears to be highest among the elderly,
especially elderly women, it is impossible to rely upon prevalence estimates
to predict, at the inception of treatment, which patients are likely to develop
the syndrome.
There are several reasons for predicting that CLOZARIL may
be different from other antipsychotic drugs in its potential for inducing tardive
dyskinesia, including the preclinical finding that it has a relatively weak
dopamine-blocking effect and the clinical finding of a virtual absence of certain
acute extrapyramidal symptoms, e.g., dystonia. A few cases of tardive dyskinesia
have been reported in patients on CLOZARIL who had been previously treated with
other antipsychotic agents, so that a causal relationship cannot be established.
There have been no reports of tardive dyskinesia directly attributable
to CLOZARIL alone. Nevertheless, it cannot be concluded, without more extended
experience, that CLOZARIL is incapable of inducing this syndrome.
Both the risk of developing the syndrome and the likelihood
that it will become irreversible are believed to increase as the duration of
treatment and the total cumulative dose of antipsychotic drugs administered
to the patient increase. However, the syndrome can develop, although much less
commonly, after relatively brief treatment periods at low doses. There is no
known treatment for established cases of tardive dyskinesia, although the syndrome
may remit, partially or completely, if antipsychotic drug treatment is withdrawn.
Antipsychotic drug treatment, itself, however, may suppress (or partially suppress)
the signs and symptoms of the syndrome and thereby may possibly mask the underlying
process. The effect that symptom suppression has upon the long-term course of
the syndrome is unknown.
Given these considerations, CLOZARIL should be prescribed in
a manner that is most likely to minimize the occurrence of tardive dyskinesia.
As with any antipsychotic drug, chronic CLOZARIL use should be reserved for
patients who appear to be obtaining substantial benefit from the drug. In such
patients, the smallest dose and the shortest duration of treatment should be
sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient
on CLOZARIL, drug discontinuation should be considered. However, some patients
may require treatment with CLOZARIL despite the presence of the syndrome.
PRECAUTIONS
General
Because of the significant risk of agranulocytosis and seizure,
both of which present a continuing risk over time, the extended treatment of
patients failing to show an acceptable level of clinical response should ordinarily
be avoided. In addition, the need for continuing treatment in patients exhibiting
beneficial clinical responses should be periodically reevaluated. Although it
is not known whether the risk would be increased, it is prudent either to avoid
CLOZARIL® (clozapine) or use it cautiously in patients with a
previous history of agranulocytosis induced by other drugs.
Cardiomyopathy
Cases of cardiomyopathy have been reported in patients treated
with clozapine. The reporting rate for cardiomyopathy in clozapine-treated patients
in the U.S. (8.9 per 100,000 person-years) was similar to an estimate of the
cardiomyopathy incidence in the U.S. general population derived from the 1999
National Hospital Discharge Survey data (9.7 per 100,000 person-years). Approximately
80% of clozapine-treated patients in whom cardiomyopathy was reported were less
than 50 years of age; the duration of treatment with clozapine prior to cardiomyopathy
diagnosis varied, but was >6 months in 65% of the reports. Dilated cardiomyopathy
was most frequently reported, although a large percentage of reports did not
specify the type of cardiomyopathy. Signs and symptoms suggestive of cardiomyopathy,
particularly exertional dyspnea, fatigue, orthopnea, paroxysmal nocturnal dyspnea,
and peripheral edema should alert the clinician to perform further investigations.
If the diagnosis of cardiomyopathy is confirmed, the prescriber should discontinue
clozapine unless the benefit to the patient clearly outweighs the risk.
Fever
During CLOZARIL therapy, patients may experience transient
temperature elevations above 100.4_F (38_C), with the peak incidence within
the first 3 weeks of treatment. While this fever is generally benign and self
limiting, it may necessitate discontinuing patients from treatment. On occasion,
there may be an associated increase or decrease in WBC count. Patients with
fever should be carefully evaluated to rule out the possibility of an underlying
infectious process or the development of agranulocytosis. In the presence of
high fever, the possibility of Neuroleptic Malignant Syndrome (NMS) must be
considered. There have been several reports of NMS in patients receiving CLOZARIL,
usually in combination with lithium or other CNS-active drugs. [See Neuroleptic
Malignant Syndrome (NMS), under WARNINGS]
Pulmonary Embolism
The possibility of pulmonary embolism should be considered
in patients receiving CLOZARIL who present with deep vein thrombosis, acute
dyspnea, chest pain or with other respiratory signs and symptoms. As of December
31, 1993 there were 18 cases of fatal pulmonary embolism in association with
CLOZARIL therapy in users 10-54 years of age. Based upon the extent of use observed
in the Clozaril National Registry, the mortality rate associated with pulmonary
embolus was 1 death per 3,450 person-years of use. This rate was about 27.5
times higher than that in the general population of a similar age and gender
(95% Confidence Interval; 17.1, 42.2). Deep vein thrombosis has also been observed
in association with CLOZARIL therapy. Whether pulmonary embolus can be attributed
to CLOZARIL or some characteristic(s) of its users is not clear, but the occurrence
of deep vein thrombosis or respiratory symptomatology should suggest its presence.
Hyperglycemia
Severe hyperglycemia, sometimes leading to ketoacidosis, has
been reported during CLOZARIL treatment in patients with no prior history of
hyperglycemia. While a causal relationship to CLOZARIL use has not been definitively
established, glucose levels normalized in most patients after discontinuation
of CLOZARIL, and a rechallenge in one patient produced a recurrence of hyperglycemia.
The effect of CLOZARIL on glucose metabolism in patients with diabetes mellitus
has not been studied. The possibility of impaired glucose tolerance should be
considered in patients receiving CLOZARIL who develop symptoms of hyperglycemia,
such as polydipsia, polyuria, polyphagia, and weakness. In patients with significant
treatment-emergent hyperglycemia, the discontinuation of CLOZARIL should be
considered.
Hepatitis
Caution is advised in patients using CLOZARIL who have concurrent
hepatic disease. Hepatitis has been reported in both patients with normal and
preexisting liver function abnormalities. In patients who develop nausea, vomiting,
and/or anorexia during CLOZARIL treatment, liver function tests should be performed
immediately. If the elevation of these values is clinically relevant or if symptoms
of jaundice occur, treatment with CLOZARIL should be discontinued.
Anticholinergic Toxicity
Eye: CLOZARIL has potent anticholinergic effects
and care should be exercised in using this drug in the presence of narrow angle
glaucoma.
Gastrointestinal: CLOZARIL use has been associated
with varying degrees of impairment of intestinal peristalsis, ranging from constipation
to intestinal obstruction, fecal impaction and paralytic ileus (see ADVERSE
REACTIONS). On rare occasions, these cases have been 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.
Prostate: CLOZARIL has potent anticholinergic
effects and care should be exercised in using this drug in the presence of prostatic
enlargement.
Interference with Cognitive and Motor Performance
Because of initial sedation, CLOZARIL may impair mental and/or
physical abilities, especially during the first few days of therapy. The recommendations
for gradual dose escalation should be carefully adhered to, and patients cautioned
about activities requiring alertness.
Use in Patients with Concomitant Illness
Clinical experience with CLOZARIL in patients with concomitant
systemic diseases is limited. Nevertheless, caution is advisable in using CLOZARIL
in patients with renal or cardiac disease.
Use in Patients Undergoing General Anesthesia
Caution is advised in patients being administered general anesthesia
because of the CNS effects of CLOZARIL. Check with the anesthesiologist regarding
continuation of CLOZARIL therapy in a patient scheduled for surgery.
INFORMATION FOR PATIENTS
Physicians are advised to discuss the following issues with
patients for whom they prescribe CLOZARIL:
– Patients who are to receive CLOZARIL should be warned
about the significant risk of developing agranulocytosis. They should be informed
that weekly blood tests are required for the first 6 months, if acceptable WBC
counts (WBC ³ 3000/mm3, ANC ³
1500/mm3) have been maintained during the first 6 months of continuous
therapy, then WBC counts can be monitored every other week in order to monitor
for the occurrence of agranulocytosis, and that CLOZARIL tablets will be made
available only through a special program designed to ensure the required blood
monitoring. Patients should be advised to report immediately the appearance
of lethargy, weakness, fever, sore throat, malaise, mucous membrane ulceration
or other possible signs of infection.
Particular attention should be paid to any flu-like complaints
or other symptoms that might suggest infection.
– Patients should be informed of the significant risk of
seizure during CLOZARIL treatment, and they should be advised to avoid driving
and any other potentially hazardous activity while taking CLOZARIL.
– Patients should be advised of the risk of orthostatic
hypotension, especially during the period of initial dose titration.
– Patients should be informed that if they stop 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.
– Patients should notify their physician if they are taking,
or plan to take, any prescription or over-the-counter drugs or alcohol.
– Patients should notify their physician if they become
pregnant or intend to become pregnant during therapy.
– Patients should not breast-feed an infant if they are
taking CLOZARIL.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No carcinogenic potential was demonstrated in long-term studies
in mice and rats at doses approximately 7 times the typical human dose on a
mg/kg basis. Fertility in male and female rats was not adversely affected by
clozapine. Clozapine did not produce genotoxic or mutagenic effects when assayed
in appropriate bacterial and mammalian tests.
Pregnancy Category B
Reproduction studies have been performed in rats and rabbits
at doses of approximately 2-4 times the human dose and have revealed no evidence
of impaired fertility or harm to the fetus due to clozapine. There are, however,
no adequate and well-controlled studies in pregnant women. Because animal reproduction
studies are not always predictive of human response, and in view of the desirability
of keeping the administration of all drugs to a minimum during pregnancy, this
drug should be used only if clearly needed.
Nursing Mothers
Animal studies suggest that clozapine may be excreted in breast
milk and have an effect on the nursing infant. Therefore, women receiving CLOZARIL
should not breast-feed.
Pediatric Use
Safety and effectiveness in pediatric patients have not been
established.
Geriatric Use
Clinical studies of clozapine did not include sufficient numbers
of subjects age 65 and over to determine whether they respond differently from
younger subjects.
Orthostatic hypotension can occur with CLOZARIL treatment and
tachycardia, which may be sustained, has been observed in about 25% of patients
taking CLOZARIL (see BOXED WARNING, Other Adverse
Cardiovascular and Respiratory Effects). Elderly patients, particularly those
with compromised cardiovascular functioning, may be more susceptible to these
effects.
Also, elderly patients may be particularly susceptible to the
anticholinergic effects of CLOZARIL, such as urinary retention and constipation.
(See PRECAUTIONS, Anticholinergic Toxicity)
Dose selection for an elderly patient should be cautious, reflecting
the greater frequency of decreased hepatic, renal, or cardiac function, and
of concomitant disease or other drug therapy. Other reported clinical experience
does suggest that the prevalence of tardive dyskinesia appears to be highest
among the elderly, especially elderly women. (See WARNINGS,
Tardive Dyskinesia)
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