CLOZAPINE
DESCRIPTION:
LOZAPIN (clozapine), an atypical antipsychotic drug, is a tricyclic
dibenzodiazepine derivative, 8-chloro-11-(4- methyl-1-piperazinyl)-5H-dibenzo
(B,E) (1,4) diazepine.
LOZAPIN (clozapine) is available in pale yellow tablets of 25 mg and 100 mg
for oral administration.
25 MG AND 100 MG TABLETS
ACTIVE INGREDIENT: clozapine is a yellow, crystalline powder, very slightly
soluble in water.
INACTIVE INGREDIENTS: colloidal silicon dioxide, NF; lactose, NF; magnesium
stearate, NF; povidone, USP; starch, NF; and talc, USP.
ACTIONS/CLINICAL PHARMACOLOGY:
PHARMACODYNAMICS
LOZAPIN (clozapine) is classified as an 'atypical' antipsychotic drug
because its profile of binding to dopamine receptors and its effects on various
dopamine mediated behaviors differ from those exhibited by more typical
antipsychotic drug products. In particular, although LOZAPIN (clozapine)
does interfere with the binding of dopamine at D1, D2, D3 and D5 receptors, and
has a high affinity for the D4 receptor, it does not induce catalepsy nor
inhibit apomorphine-induced stereotypy. This evidence, consistent with the view
that LOZAPIN (clozapine) is preferentially more active at limbic than at
striatal dopamine receptors, may explain the relative freedom of LOZAPIN
(clozapine) from extrapyramidal side effects.
LOZAPIN (clozapine) also acts as an antagonist at adrenergic, cholinergic,
histaminergic and serotonergic receptors.
ABSORPTION, DISTRIBUTION, METABOLISM AND EXCRETION
In man, LOZAPIN (clozapine) tablets (25 mg and 100 mg) are equally
bioavailable relative to a clozapine solution. Following a dosage of 100 mg
b.i.d., the average steady state peak plasma concentration was 319 ng/mL (range:
102-771 ng/mL), occurring at the average of 2.5 hours (range: 1-6 hours) after
dosing. The average minimum concentration at steady state was 122 ng/mL (range:
41-343 ng/mL), after 100 mg b.i.d. dosing. Food does not appear to affect the
systemic bioavailability of LOZAPIN (clozapine). Thus, LOZAPIN
(clozapine) may be administered with or without food.
Clozapine is approximately 97% bound to serum proteins. The interaction between
LOZAPIN (clozapine) and other highly protein-bound drugs has not been fully
evaluated but may be important. (SEE PRECAUTIONS)
Clozapine is almost completely metabolized prior to excretion and only trace
amounts of unchanged drug are detected in the urine and feces. Approximately 50%
of the administered dose is excreted in the urine and 30% in the feces. The
demethylated, hydroxylated and N-oxide derivatives are components in both urine
and feces. Pharmacological testing has shown the desmethyl metabolite to have
only limited activity, while the hydroxylated and N-oxide derivatives were
inactive.
The mean elimination half-life of clozapine after a single 75 mg dose was 8
hours (range: 4-12 hours), compared to a mean elimination half-life, after
achieving steady state with 100 mg b.i.d. dosing, of 12 hours (range: 4-66
hours). A comparison of single-dose and multiple-dose administration of
clozapine showed that the elimination half-life increased significantly after
multiple dosing relative to that after single-dose administration, suggesting
the possibility of concentration dependent pharmacokinetics. However, at steady
state, linearly dose-proportional changes with respect to AUC (area under the
curve), peak and minimum clozapine plasma concentrations were observed after
administration of 37.5 mg, 75 mg, and 150 mg b.i.d.
HUMAN PHARMACOLOGY
In contrast to more typical antipsychotic drugs, LOZAPIN (clozapine) therapy
produces little or no prolactin elevation.
As is true of more typical antipsychotic drugs, clinical EEG studies have shown
that LOZAPIN (clozapine) increases delta and theta activity and slows
dominant alpha frequencies. Enhanced synchronization occurs, and sharp wave
activity and spike and wave complexes may also develop. Patients, on rare
occasions, may report an intensification of dream activity during LOZAPIN
(clozapine) therapy. REM sleep was found to be increased to 85% of the total
sleep time. In these patients, the onset of REM sleep occurred almost
immediately after falling asleep.
INDICATIONS AND USAGE:
LOZAPIN (clozapine) is indicated for the management of severely ill
schizophrenic patients who fail to respond adequately to standard antipsychotic
drug treatment. Because of the significant risk of agranulocytosis and seizure
associated with its use, LOZAPIN (clozapine) should be used only in patients
who have failed to respond adequately to treatment with appropriate courses of
standard antipsychotic drugs, either because of insufficient effectiveness or
the inability to achieve an effective dose due to intolerable adverse effects
from those drugs. (SEE WARNINGS)
The effectiveness of LOZAPIN (clozapine) in a treatment resistant
schizophrenic population was demonstrated in a 6-week study comparing
LOZAPIN (clozapine) and chlorpromazine. Patients meeting DSM-III criteria
for schizophrenia and having a mean BPRS total score of 61 were demonstrated to
be treatment resistant by history and by open, prospective treatment with
haloperidol before entering into the double- blind phase of the study. The
superiority of LOZAPIN (clozapine) to chlorpromazine was documented in
statistical analyses employing both categorical and continuous measures of
treatment effect.
Because of the significant risk of agranulocytosis and seizure, events which
both 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 re-evaluated.
CONTRAINDICATIONS:
LOZAPIN (clozapine) is contraindicated in patients with a previous
hypersensitivity to clozapine or any other component of this drug, in patients
with myeloproliferative disorders, uncontrolled epilepsy, or a history of
LOZAPIN (clozapine) induced agranulocytosis or severe granulocytopenia. As
with more typical antipsychotic drugs, LOZAPIN (clozapine) is
contraindicated in severe central nervous system depression or comatose states
from any cause.
LOZAPIN (clozapine) should not be used simultaneously with other agents
having a well- known potential to cause agranulocytosis or otherwise suppress
bone marrow function. The mechanism of LOZAPIN (clozapine) induced
agranulocytosis is unknown; nonetheless, it is possible that causative factors
may interact synergistically to increase the risk and/or severity of bone marrow
suppression.
WARNINGS:
GENERAL
BECAUSE OF THE SIGNIFICANT RISK OF AGRANULOCYTOSIS, A POTENTIALLY LIFE-
THREATENING ADVERSE EVENT (SEE FOLLOWING), LOZAPIN (CLOZAPINE) SHOULD BE
RESERVED FOR USE IN THE TREATMENT OF SEVERELY ILL SCHIZOPHRENIC PATIENTS WHO
FAIL TO SHOW AN ACCEPTABLE RESPONSE TO ADEQUATE COURSES OF STANDARD
ANTIPSYCHOTIC DRUG TREATMENT, EITHER BECAUSE OF INSUFFICIENT EFFECTIVENESS OR
THE INABILITY TO ACHIEVE AN EFFECTIVE DOSE DUE TO INTOLERABLE ADVERSE EFFECTS
FROM THOSE DRUGS. CONSEQUENTLY, BEFORE INITIATING TREATMENT WITH LOZAPIN
(CLOZAPINE), IT IS STRONGLY RECOMMENDED THAT A PATIENT BE GIVEN AT LEAST 2
TRIALS, EACH WITH A DIFFERENT STANDARD ANTIPSYCHOTIC DRUG PRODUCT, AT AN
ADEQUATE DOSE, AND FOR AN ADEQUATE DURATION.
PATIENTS WHO ARE BEING TREATED WITH LOZAPIN (CLOZAPINE) 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 GREATER THAN OR EQUAL TO 3,000/MM(CUBED), ANC
(>/=)1500/MM(CUBED) 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 LOZAPIN
(CLOZAPINE).
LOZAPIN (CLOZAPINE) 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/MM(CUBED), HAS BEEN ESTIMATED TO OCCUR *
* IN ASSOCIATION WITH LOZAPIN (CLOZAPINE) *
* USE AT A CUMULATIVE INCIDENCE AT 1 YEAR OF *
* APPROXIMATELY 1.3%, BASED ON THE OCCURRENCE *
* OF 15 US CASES OUT OF 1743 PATIENTS EXPOSED *
* TO LOZAPIN (CLOZAPINE) 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 LOZAPIN (CLOZAPINE) *
* USE AS OF DECEMBER 31, 1989, 32% WERE *
* FATAL. HOWEVER, FEW OF THESE DEATHS *
* OCCURRED SINCE 1977, AT WHICH TIME THE *
* KNOWLEDGE OF LOZAPIN (CLOZAPINE) *
* 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 LOZAPIN *
* (CLOZAPINE) INDUCED AGRANULOCYTOSIS, *
* DESPITE STRICT ADHERENCE TO THE REQUIRED *
* FREQUENCY OF MONITORING. IN THE U.S., UNDER *
* A WEEKLY WBC MONITORING SYSTEM WITH *
* LOZAPIN (CLOZAPINE), THERE HAVE BEEN *
* 585 CASES OF AGRANULOCYTOSIS AS OF AUGUST *
* 21, 1997; 19 WERE FATAL. DURING THIS PERIOD *
* 150, 409 PATIENTS RECEIVED LOZAPIN *
* (CLOZAPINE). A HEMATOLOGIC RISK ANALYSIS *
* WAS CONDUCTED BASED UPON THE AVAILABLE *
* INFORMATION IN THE LOZAPIN 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 *
* LOZAPIN (CLOZAPINE) 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 1000 *
* 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 INCREASE INCIDENCE OF *
* AGRANULOCYTOSIS. *
* BECAUSE OF THE SUBSTANTIAL RISK FOR *
* DEVELOPING AGRANULOCYTOSIS IN ASSOCIATION *
* WITH LOZAPIN (CLOZAPINE) 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 LOZAPIN (CLOZAPINE), AND MUST HAVE *
* SUBSEQUENT WBC COUNTS DONE AT LEAST WEEKLY *
* FOR THE FIRST 6 MONTHS OF CONTINUOUS *
* TREATMENT. IF WBC COUNTS REMAIN ACCEPTABLE *
* (WBC GREATER THAN OR EQUAL TO *
* 3000/MM(CUBED), ANC (>/=)1500/MM(CUBED)) *
* DURING THIS PERIOD, WBC COUNTS MAY BE *
* MONITORED EVERY OTHER WEEK THEREAFTER. *
* AFTER DISCONTINUATION OF LOZAPIN *
* (CLOZAPINE), WEEKLY WBC COUNTS SHOULD BE *
* CONTINUED FOR AN ADDITIONAL 4 WEEKS. *
* IF A PATIENT IS ON LOZAPIN (CLOZAPINE) *
* 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 LOZAPIN *
* (CLOZAPINE) 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 LOZAPIN (CLOZAPINE) *
* 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 LOZAPIN (CLOZAPINE) *
* THERAPY IF WBC COUNTS FALL BELOW *
* 2000/MM(CUBED) OR THE ANC FALLS BELOW *
* 1000/MM(CUBED) DURING LOZAPIN *
* (CLOZAPINE) THERAPY), THE PATIENT MUST RE- *
* START THE 6 MONTH PERIOD OF WEEKLY WBC *
* MONITORING AT DAY 0. *
* IF A PATIENT IS ON LOZAPIN (CLOZAPINE) *
* 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 LOZAPIN *
* (CLOZAPINE) THERAPY IS REINITIATED. IF A *
* PATIENT IS ON LOZAPIN (CLOZAPINE) *
* 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 LOZAPIN (CLOZAPINE) THERAPY IS *
* REINITIATED, THE PATIENT MUST HAVE WBC *
* COUNTS MONITORED WEEKLY FOR AN ADDITIONAL 6 *
* MONTHS. IF A PATIENT ON LOZAPIN *
* (CLOZAPINE) THERAPY FOR 6 MONTHS OR LONGER *
* AND SUBSEQUENTLY HAS AN ABNORMAL BLOOD *
* EVENT, BUT REMAINS A RECHALLENGEABLE *
* PATIENT, THEN THE PATIENT MUST RE-START *
* WEEKLY WBC COUNT MONITORING UNTIL AN *
* ADDITIONAL 6 MONTHS OF LOZAPIN *
* (CLOZAPINE) THERAPY HAS BEEN RECEIVED. THE *
* DISTRIBUTION OF LOZAPIN (CLOZAPINE) IS *
* CONTINGENT UPON PERFORMANCE OF THE REQUIRED *
* BLOOD TESTS. *
* TREATMENT SHOULD NOT BE INITIATED IF THE *
* WBC COUNT IS LESS THAN 3500/MM(CUBED), OR *
* IF THE PATIENT HAS A HISTORY OF A *
* MYELOPROLIFERATIVE DISORDER, OR PREVIOUS *
* LOZAPIN (CLOZAPINE) 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 *
* INITIATION OF TREATMENT, THE TOTAL WBC *
* COUNT HAS DROPPED BELOW 3500/MM(CUBED) OR *
* IT HAS DROPPED BY A SUBSTANTIAL AMOUNT FROM *
* BASELINE, EVEN IF THE COUNT IS ABOVE *
* 3500/MM(CUBED) 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/MM(CUBED) AND AN ANC *
* ABOVE 1500/MM(CUBED), TWICE WEEKLY WBC *
* COUNTS AND DIFFERENTIAL COUNTS SHOULD BE *
* PERFORMED. *
* IF THE TOTAL WBC COUNT FALLS BELOW *
* 3000/MM(CUBED) OR THE ANC BELOW *
* 1500/MM(CUBED), LOZAPIN (CLOZAPINE) *
* 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. LOZAPIN *
* (CLOZAPINE) THERAPY MAY BE RESUMED IF NO *
* SYMPTOMS OF INFECTION DEVELOP, AND IF THE *
* TOTAL WBC COUNT RETURNS TO LEVELS ABOVE *
* 3000/MM(CUBED) AND THE ANC RETURNS TO *
* LEVELS ABOVE 1500/MM(CUBED). HOWEVER, IN *
* THIS EVENT, TWICE-WEEKLY WBC COUNTS AND *
* DIFFERENTIAL COUNTS SHOULD CONTINUE UNTIL *
* TOTAL WBC COUNTS RETURN TO LEVELS ABOVE *
* 3500/MM(CUBED). *
* IF THE TOTAL WBC COUNT FALLS BELOW *
* 2000/MM(CUBED) OR THE ANC FALLS BELOW *
* 1000/MM(CUBED), 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/MM(CUBED), OR ANCS BELOW *
* 1000/MM(CUBED) DURING LOZAPIN *
* (CLOZAPINE) THERAPY SHOULD HAVE DAILY WBC *
* COUNT AND DIFFERENTIAL. THESE PATIENTS *
* SHOULD NOT BE RE-CHALLENGED WITH *
* LOZAPIN (CLOZAPINE). PATIENTS *
* DISCONTINUED FROM LOZAPIN (CLOZAPINE) *
* 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 LOZAPIN *
* (CLOZAPINE) THERAPY, A SINGLE, NATIONAL *
* MASTER FILE WILL BE MAINTAINED *
* CONFIDENTIALLY. *
* EXCEPT FOR EVIDENCE OF SIGNIFICANT BONE *
* MARROW SUPPRESSION DURING INITIAL *
* LOZAPIN (CLOZAPINE) THERAPY, THERE ARE *
* NO ESTABLISHED RISK FACTORS, BASED ON *
* WORLD-WIDE EXPERIENCE, FOR THE DEVELOPMENT *
* OF AGRANULOCYTOSIS IN ASSOCIATION WITH *
* LOZAPIN (CLOZAPINE) USE. HOWEVER, A *
* DISPROPORTIONATE NUMBER OF THE US CASES OF *
* AGRANULOCYTOSIS OCCURRED IN PATIENTS OF *
* JEWISH BACKGROUND COMPARED TO THE OVERALL *
* PROPORTION OF SUCH PATIENTS EXPOSED DURING *
* DOMESTIC DEVELOPMENT OF LOZAPIN *
* (CLOZAPINE). MOST OF THE US 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 *
* LOZAPIN (CLOZAPINE) 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 LOZAPIN *
* (CLOZAPINE). *
* TO REDUCE THE RISK OF AGRANULOCYTOSIS *
* DEVELOPING UNDETECTED, LOZAPIN *
* (CLOZAPINE) 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. *
* *
*************************************************
Click here for illustration(s).
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 4,000/mm(cubed), LOZAPIN (clozapine) therapy should be interrupted
until the eosinophil count falls below 3,000/mm(cubed).
*************************************************
* *
* SEIZURES *
* SEIZURE HAS BEEN ESTIMATED TO OCCUR IN *
* ASSOCIATION WITH LOZAPIN (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 LOZAPIN *
* (CLOZAPINE) DURING ITS CLINICAL TESTING *
* PRIOR TO DOMESTIC MARKETING (I.E., CRUDE *
* RATE OF 3.5%). DOSE APPEARS TO BE AN *
* IMPORTANT PREDICTOR OF SEIZURE, WITH A *
* GREATER LIKELIHOOD OF SEIZURE AT THE HIGHER *
* LOZAPIN (CLOZAPINE) DOSES USED. *
* CAUTION SHOULD BE USED IN ADMINISTERING *
* LOZAPIN (CLOZAPINE) TO PATIENTS HAVING *
* A HISTORY OF SEIZURES OR OTHER PREDISPOSING *
* FACTORS. BECAUSE OF THE SUBSTANTIAL RISK OF *
* SEIZURE ASSOCIATED WITH LOZAPIN *
* (CLOZAPINE) 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. *
* *
*************************************************
ADVERSE CARDIOVASCULAR AND RESPIRATORY EFFECTS
*************************************************
* *
* ORTHOSTATIC HYPOTENSION WITH OR WITHOUT *
* SYNCOPE CAN OCCUR WITH LOZAPIN *
* (CLOZAPINE) 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 LOZAPIN (CLOZAPINE), 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 *
* LOZAPIN (CLOZAPINE) BY ITSELF. ALTHOUGH *
* IT HAS NOT BEEN ESTABLISHED THAT THERE IS *
* AN INTERACTION BETWEEN LOZAPIN *
* (CLOZAPINE) 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 LOZAPIN (clozapine), 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 LOZAPIN (clozapine) 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 LOZAPIN (clozapine). The clinical
significance of these changes is unclear. However, in clinical trials with
LOZAPIN (clozapine), several patients experienced significant cardiac
events, including ischemic changes, myocardial infarction, arrhythmias and
sudden death. In addition there have been postmarketing reports of congestive
heart failure, myocarditis, with or without eosinophilia, and
pericarditis/pericardial effusions in association with LOZAPIN (clozapine)
use. 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.
LOZAPIN (clozapine) 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.
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 LOZAPIN
(clozapine) 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 LOZAPIN (clozapine) 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 LOZAPIN (clozapine) 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 LOZAPIN (clozapine) alone. Nevertheless,
it cannot be concluded, without more extended experience, that LOZAPIN
(clozapine) 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, LOZAPIN (clozapine) should be prescribed in a
manner that is most likely to minimize the occurrence of tardive dyskinesia. As
with any antipsychotic drug, chronic LOZAPIN (clozapine) 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 LOZAPIN
(clozapine), drug discontinuation should be considered. However, some patients
may require treatment with LOZAPIN (clozapine) 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 re-evaluated. Although it is not
known whether the risk would be increased, it is prudent either to avoid
LOZAPIN (clozapine) or use it cautiously in patients with a previous history
of agranulocytosis induced by other drugs.
FEVER
During LOZAPIN (clozapine) therapy, patients may experience transient
temperature elevations above 100.4 deg F (38 deg 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
LOZAPIN (clozapine), 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
LOZAPIN (clozapine) 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 LOZAPIN
(clozapine) therapy in users 10-54 years of age. Based upon the extent of use
observed in the Lozapin National Registry, the mortality rate associated with
pulmonary embolus was 1 death per 3450 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 LOZAPIN (clozapine) therapy. Whether pulmonary
embolus can be attributed to LOZAPIN (clozapine) 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 LOZAPIN (clozapine) treatment in patients with no prior history of
hyperglycemia. While a causal relationship to LOZAPIN (clozapine) use has
not been definitively established, glucose levels normalized in most patients
after discontinuation of LOZAPIN (clozapine), and a rechallenge in one
patient produced a recurrence of hyperglycemia. The effect of LOZAPIN
(clozapine) on glucose metabolism in patients with diabetes mellitus has not
been studied. The possibility of impaired glucose tolerance should be considered
in patients receiving LOZAPIN (clozapine) who develop symptoms of
hyperglycemia, such as polydipsia, polyuria, polyphagia, and weakness. In
patients with significant treatment-emergent hyperglycemia, the discontinuation
of LOZAPIN (clozapine) should be considered.
HEPATITIS
Caution is advised in patients using LOZAPIN (clozapine) who have concurrent
hepatic disease. Hepatitis has been reported in both patients with normal and
pre-existing liver function abnormalities. In patients who develop nausea,
vomiting, and/or anorexia during LOZAPIN (clozapine) 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
LOZAPIN (clozapine) should be discontinued.
ANTICHOLINERGIC TOXICITY
LOZAPIN (clozapine) has very potent anticholinergic effects and great care
should be exercised in using this drug in the presence of prostatic enlargement
or narrow angle glaucoma. In addition, LOZAPIN (clozapine) 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.
INTERFERENCE WITH COGNITIVE AND MOTOR PERFORMANCE
Because of initial sedation, LOZAPIN (clozapine) 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 LOZAPIN (clozapine) in patients with concomitant
systemic diseases is limited. Nevertheless, caution is advisable in using
LOZAPIN (clozapine) 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 LOZAPIN (clozapine). Check with the anesthesiologist
regarding continuation of LOZAPIN (clozapine) therapy in a patient scheduled
for surgery.
INFORMATION FOR PATIENTS
Physicians are advised to discuss the following issues with patients for whom
they prescribe LOZAPIN (clozapine):
--Patients who are to receive LOZAPIN (clozapine) 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 greater than or equal to 3000/mm(cubed), ANC (>/=) 1500/mm(cubed) 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 LOZAPIN (clozapine) 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
LOZAPIN (clozapine) treatment, and they should be advised to avoid driving
and any other potentially hazardous activity while taking LOZAPIN
(clozapine).
--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 LOZAPIN (clozapine)
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 LOZAPIN
(clozapine).