Following is some information about Clozaril, taken from the Physicians's Drug
Reference book. You must remember that this medication was originally
developed to treat people with Schizophrenia, hence the references to it.
Also there is some information regarding known drug interactions.
Brian Symonds   <[log in to unmask]>
 
 
ADVERSE REACTIONS
Associated with Discontinuation of Treatment. Sixteen percent of 1080
patients who received Clozaril (clozapine) in premarketing clinical trials
discontinued treatment due to an adverse event, including both those that
could be reasonably attributed to Clozaril (clozapine) treatment and those
that might more appropriately be considered intercurrent illness. The more
common events considered to be causes of discontinuation included: CNS,
primarily drowsiness/sedation, seizures, dizziness/syncope; cardiovascular,
primarily tachycardia, hypotension and ECG changes; gastrointestinal,
primarily nausea/vomiting; hematologic, primarily
leukopenia/granulocytopenia/agranulocytosis; and fever. None of the events
enumerated accounts for more than 1.7% of all discontinuations attributed to
adverse clinical events.
Commonly Observed Adverse events observed in association with the use of
Clozaril (clozapine) in clinical trials at an incidence of greater than 5%
were: central nervous system complaints, including drowsiness/sedation,
dizziness/vertigo, headache and tremor; autonomic nervous system complaints,
including salivation, sweating, dry mouth and visual disturbances;
cardiovascular findings, including tachycardia, hypotension and syncope; and
gastrointestinal complaints, including constipation and nausea; and fever.
Complaints of drowsiness/sedation tend to subside with continued therapy or
dose reduction. Salivation may be profuse, especially during sleep, but may
be diminished with dose reduction.
Incidence in Clinical Trials The following table (TABLE 1) enumerates adverse
events that occurred at a frequency of 1% or greater among Clozaril
(clozapine) patients who participated in clinical trials. These rates are not
adjusted for duration of exposure.
 
 
TABLE 1 - Clozapine, Adverse Reactions
Treatment-Emergent Adverse Experience Incidence Among Patients Taking
Clozaril (clozapine) in Clinical Trials
                             (N = 842)
                 (Percentage of Patients Reporting)
 ----------------------------------------------------------------------
Body System
 Adverse Event a                                                 Percent
 ----------------------------------------------------------------------
Central Nervous System
  Drowsiness/Sedation                                             39
  Dizziness/Vertigo                                               19
  Headache                                                         7
  Tremor                                                           6
  Syncope                                                          6
  Disturbed sleep/Nightmares                                       4
  Restlessness                                                     4
  Hypokinesia/Akinesia                                             4
  Agitation                                                        4
  Seizures (convulsions)                                           3b
  Rigidity                                                         3
  Akathisia                                                        3
  Confusion                                                        3
  Fatigue                                                          2
  Insomnia                                                         2
  Hyperkinesia                                                     1
  Weakness                                                         1
  Lethargy                                                         1
  Ataxia                                                           1
  Slurred speech                                                   1
  Depression                                                       1
  Epileptiform movements/Myoclonic jerks                           1
  Anxiety                                                          1
Cardiovascular
  Tachycardia                                                     25b
  Hypotension                                                      9
  Hypertension                                                     4
  Chest pain/Angina                                                1
  ECG change/Cardiac abnormality                                   1
Gastrointestinal
  Constipation                                                    14
  Nausea                                                           5
  Abdominal discomfort/Heartburn                                   4
  Nausea/Vomiting                                                  3
  Vomiting                                                         3
  Diarrhea                                                         2
  Liver test abnormality                                           1
  Anorexia                                                         1
Urogenital
  Urinary abnormalities                                            2
  Incontinence                                                     1
  Abnormal ejaculation                                             1
  Urinary urgency/frequency                                        1
  Urinary retention                                                1
Autonomic Nervous System
  Salivation                                                      31
  Sweating                                                         6
  Dry mouth                                                        6
  Visual disturbances                                              5
Integumentary (Skin)
  Rash                                                             2
Musculoskeletal
  Muscle weakness                                                  1
  Pain (back, neck, legs)                                          1
  Muscle spasm                                                     1
  Muscle pain, ache                                                1
Respiratory
  Throat discomfort                                                1
  Dyspnea, shortness of breath                                     1
  Nasal congestion                                                 1
Hemic/Lymphatic
  Leukopenia/Decreased WBC/Neutropenia                             3
  Agranulocytosis                                                  1b
  Eosinophilia                                                     1
Miscellaneous
  Fever                                                            5
  Weight gain                                                      4
  Tongue numb/sore                                                 1
 ----------------------------------------------------------------------
aEvents reported by at least 1% of Clozaril (clozapine) patients are
included.
bRate based on population of approximately 1700 exposed during
premarket clinical evaluation of Clozaril (clozapine).
 
 
Other Events Observed During the Premarketing Evaluation of Clozaril
(clozapine) This section reports additional, less frequent adverse events
which occurred among the patients taking Clozaril (clozapine) in clinical
trials. Various adverse events were reported as part of the total experience
in these clinical studies; a causal relationship to Clozaril (clozapine)
treatment cannot be determined in the absence of appropriate controls in some
of the studies. The table (TABLE 1) above enumerates adverse events that
occurred at a frequency of at least 1% of patients treated with Clozaril
(clozapine). The list below includes all additional adverse experiences
reported as being temporally associated with the use of the drug which
occurred at a frequency less than 1% enumerated by organ system.
Central Nervous System: loss of speech, amentia, tics, poor coordination,
delusions/hallucinations, involuntary movement, stuttering, dysarthria,
amnesia/memory loss, histrionic movements, libido increase or decrease,
paranoia, shakiness, Parkinsonism, and irritability.
Cardiovascular System: edema, palpitations, phlebitis/thrombophlebitis,
cyanosis, premature ventricular contraction, bradycardia, and nose bleed.
Gastrointestinal System: abdominal distention, gastroenteritis, rectal
bleeding, nervous stomach, abnormal stools, hematemesis, gastric ulcer,
bitter taste, and eructation.
Urogenital System: dysmenorrhea, impotence, breast pain/discomfort, and
vaginal itch/infection.
Autonomic Nervous System: numbness, polydipsia, hot flashes, dry throat, and
mydriasis.
Integumentary (Skin): pruritus, pallor, eczema, erythema, bruise, dermatitis,
petechiae, and urticaria.
Musculoskeletal System: twitching and joint pain.
Respiratory System: coughing, pneumonia/pneumonia-like symptoms, rhinorrhea,
hyperventilation, wheezing, bronchitis, laryngitis, and sneezing.
Hemic and Lymphatic System: anemia and leukocytosis.
Miscellaneous: chills/chills with fever, malaise, appetite increase, ear
disorder, hypothermia, eyelid disorder, bloodshot eyes, and nystagmus.
Postmarketing Clinical Experience Postmarketing experience has shown an
adverse experience profile similar to that presented above. Voluntary reports
of adverse events temporally associated with Clozaril (clozapine) not
mentioned above that have been received since market introduction and that
may have no causal relationship with the drug include the following:
Central Nervous System: delirium; EEG abnormal; exacerbation of psychosis;
myoclonus; overdose; paresthesia; and status epilepticus.
Cardiovascular System: atrial or ventricular fibrillation and periorbital
edema.
Gastrointestinal System: acute pancreatitis; dysphagia; fecal impaction;
hepatitis; intestinal obstruction/paralytic ileus; jaundice; and salivary
gland swelling.
Urogenital System: priapism.
Integumentary (Skin): hypersensitivity reactions: photosensitivity,
vasculitis, erythema multiforme, and Stevens-Johnson Syndrome.
Respiratory System: aspiration and pleural effusion.
Hemic and Lymphatic System: deep vein thrombosis; elevated
hemoglobin/hematocrit; ESR increased; pulmonary embolism; sepsis;
thrombocytosis; and thrombocytopenia.
Miscellaneous: CPK elevation; hyperglycemia; hyperuricemia; hyponatremia; and
weight loss.
 
DRUG ABUSE AND DEPENDENCE
Physical and psychological dependence have not been reported or observed in
patients taking Clozaril (clozapine).
 
OVERDOSAGE
Human Experience The most commonly reported signs and symptoms associated
with Clozaril (clozapine) overdose are: altered states of consciousness,
including drowsiness, delirium and coma; tachycardia; hypotension;
respiratory depression or failure; hypersalivation. Aspiration pneumonia and
cardiac arrhythmias have also been reported. Seizures have occurred in a
minority of reported cases. Fatal overdoses have been reported with Clozaril
(clozapine), generally at doses above 2500 mgs. There have also been reports
of patients recovering from overdoses well in excess of 4 gms.
Management of Overdose Establish and maintain an airway; ensure adequate
oxygenation and ventilation. Activated charcoal, which may be used with
sorbitol, may be as or more effective than emesis or lavage, and should be
considered in treating overdosage. Cardiac and vital signs monitoring is
recommended along with general symptomatic and supportive measures.
Additional surveillance should be continued for several days because of the
risk of delayed effects. Avoid epinephrine and derivatives when treating
hypotension, and quinidine and procainamide when treating cardiac arrhythmia.
There are no specific antidotes for Clozaril (clozapine). Forced diuresis,
dialysis, hemoperfusion and exchange transfusion are unlikely to be of
benefit.
In managing overdosage, the physician should consider the possibility of
multiple drug involvement.
Up-to-date information about the treatment of overdose can often be obtained
from a certified Regional Poison Control Center. Telephone numbers of
certified Poison Control Centers are listed in the Physicians GenRx.
 
DOSAGE AND ADMINISTRATION
In order to minimize the risk of agranulocytosis, Clozaril (clozapine) is
available only through a distribution system that ensures weekly WBC testing
prior to delivery of the next week's supply of medication. Upon initiation of
Clozaril (clozapine) therapy, up to a 1 week supply of additional Clozaril
(clozapine) tablets may be provided to the patient to be held for emergencies
(e.g., weather, holidays).
Initial Treatment It is recommended that treatment with Clozaril (clozapine)
begin with one-half of a 25 mg (12.5 mg) once or twice daily and then be
continued with daily dosage increments of 25-50 mg/day, if well-tolerated, to
achieve a target dose of 300-450 mg/day by the end of 2 weeks. Subsequent
dosage increments should be made no more than once or twice-weekly, in
increments not to exceed 100 mg. Cautious titration and a divided dosage
schedule are necessary to minimize the risks of hypotension, seizure, and
sedation.
In the multicenter study that provides primary support for the effectiveness
of Clozaril (clozapine) in patients resistant to standard antipsychotic drug
treatment, patients were titrated during the first 2 weeks up to a maximum
dose of 500 mg/day, on a t.i.d. basis, and were then dosed in a total daily
dose range of 100-900 mg/day, on a t.i.d. basis thereafter, with clinical
response and adverse effects as guides to correct dosing.
Therapeutic Dose Adjustment Daily dosing should continue on a divided basis
as an effective and tolerable dose level is sought. While many patients may
respond adequately at doses between 300-600 mg/day, it may be necessary to
raise the dose to the 600-900 mg/day range to obtain an acceptable response.
[Note: In the multicenter study providing the primary support for the
superiority of Clozaril (clozapine) in treatment resistant patients, the mean
and median Clozaril (clozapine) doses were both approximately 600 mg/day.]
Because of the possibility of increased adverse reactions at higher doses,
particularly seizures, patients should ordinarily be given adequate time to
respond to a given dose level before escalation to a higher dose is
contemplated.
Dosing should not exceed 900 mg/day.
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.
Maintenance Treatment While the maintenance effectiveness of Clozaril
(clozapine) in schizophrenia is still under study, the effectiveness of
maintenance treatment is well established for many other antipsychotic drugs.
It is recommended that responding patients be continued on Clozaril
(clozapine), but at the lowest level needed to maintain remission. Because of
the significant risk associated with the use of Clozaril (clozapine),
patients should be periodically reassessed to determine the need for
maintenance treatment.
Discontinuation of Treatment In the event of planned termination of Clozaril
(clozapine) therapy, gradual reduction in dose is recommended over a 1-2 week
period. However, should a patient's medical condition require abrupt
discontinuation (e.g., leukopenia), the patient should be carefully observed
for the recurrence of psychotic symptoms.
Re-initiation of Treatment in Patients Previously Discontinued When
restarting patients who have had even a brief interval off Clozaril
(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 Warnings). If that dose is well tolerated, it may be
feasible to titrate patients back to a therapeutic dose more quickly than is
recommended for initial treatment. However, any patient who has previously
experienced respiratory or cardiac arrest with initial dosing, but was then
able to be successfully titrated to a therapeutic dose, should be re-titrated
with extreme caution after even 24 hours of discontinuation.
Certain additional precautions seem prudent when re-initiating treatment. The
mechanisms underlying Clozaril (clozapine)-induced adverse reactions are
unknown. It is conceivable, however, that re-exposure of a patient might
enhance the risk of an untoward event's occurrence and increase its severity.
Such phenomena, for example, occur when immune mediated mechanisms are
responsible. Consequently, during the re-initiation of treatment, additional
caution is advised. Patients discontinued for WBC counts below 2000/mm 3 or
an ANC below 1000/mm 3 must not be restarted on Clozaril (clozapine). (See
WARNINGS)
Store and Dispense Storage temperature should not exceed 86F (30C). Drug
dispensing should not ordinarily exceed a weekly supply. Dispensing should be
contingent upon the results of a WBC count.
 
HOW SUPPLIED
Clozaril (clozapine) is available only through a distribution system that
ensures weekly WBC testing prior to delivery of the next week's supply of
medication.
Clozaril (clozapine) Tablets 25 mg Round, pale yellow, scored, uncoated
tablets, engraved with "CLOZARIL" (on the periphery) on one side, and "25" on
the scored side.
Bottle of 100 (NDC 0078-0126-05).
SandoPak(R) unit-dose packages of 100: 2 x 5 strips, 10 blisters per strip
(NDC 0078-0126-06).
100 mg Round, pale yellow, compressed tablets, engraved with "CLOZARIL" (on
the periphery) on one side, and "100" on the other side.
Bottle of 100 (NDC 0078-0127-05).
SandoPak unit-dose packages of 100: 2 x 5 strips, 10 blisters per strip (NDC
0078-0127-06).
(Sandoz Pharmaceuticals Corporation, 3/94, 30518901) (94/03).
 
HOW SUPPLIED - EQUIVALENTS NOT AVAILABLE
Tablet, Uncoated - Oral - 25 mg
100's  $132.00  CLOZARIL, Sandoz Pharm        00078-0126-05*
100's  $132.00  CLOZARIL, U.D., Sandoz Pharm  00078-0126-06
 
Tablet, Uncoated - Oral - 100 mg
100's  $342.00  CLOZARIL, Sandoz Pharm        00078-0127-05*
100's  $342.00  CLOZARIL, U.D., Sandoz Pharm  00078-0127-06
 
From The Medical Letter
ANTIDEPRESSANTS -- Depression commonly accompanies Parkinson's disease and
must be treated, if present, for the patient to benefit adequately from
antiparkinson drugs. A tricyclic antidepressant or trazodone (Desyrel) is
usually the drug of choice. Experience with fluoxetine (Prozac), other
selective serotonin reuptake inhibitors, or bupropion (Wellbutrin) is more
limited; worsening of Parkinson's symptoms has been reported with fluoxetine
(EN Steur, Neurology, 43:211, Jan 1993). MAO-A inhibitors should not be used
because they can cause marked swings in blood pressure in patients taking
levodopa.
 
CLOZAPINE -- Several reports indicate that psychosis associated with levodopa
or dopamine agonists responds to low doses of clozapine (Clozaril - Medical
Letter, 35:16, 1993), an antipsychotic drug with hematological toxicity but
few extrapyramidal effects (SI Wolk and CJ Douglas, J Clin Psychiatry,
53:373, 1992).
 
Drug Interactions
Clozapine:
Clozaril with anti depressants
Effect: Possible antidepressant toxicity with nortriptyline (possibly
decreased metabolism) [1173]
Comments: Single case report (1994); monitor clinical status and adjust
antidepressat dosage if needed.
 
Clozapine:
Clozaril with H2 blockers
Effect: Clozapine toxicity with cimetidine (possibly decreased
metabolism)[913]
Comments: Single case report (1991); did not occur with ranitidine.
 
Clozapine:
Clozaril with benzodiazepines
Effect: Respiratory arrest (mechanism not established)[966]
Comments: Has been reported more frequently with clozapine alone than with
combination; monitor respiratory status.
 
Clozapine:
Clozaril with Carbamazepine
Effect: 1)Neuroleptic malignant syndrome (mechanism not established)[797]
2)Agranulocytosis with pancytopenia (possibly synergism)[797] 3)Possibly
decreased clozapine effect (possibly increased metabolism)[797]
Comments: 1)Single case report (1988) in patient who received clozapine
shortly after lithium was stopped; syndrome has been reported with clozapine
or lithium alone 2)Single case report (1991); avoid concurrent use 3)Two case
reports (1993).
 
Clozapine:
Clozarilwith Erythromycins
Erythromycins:
A/T/S, AK-Mycin, Akne-mycin, Dowmycin E, E-Base, E-Mycin, E.E.S., E.T.S.,
Ery-Sol, Ery-Tab, ERYC, Erycette, Eryderm, Erygel, Erymax, Erypar, Erythro,
Erythrocin, Erythrocot, Ilosone, Ilotycin, My-E, PCE Dispertab, Pediamycin,
Robimycin, RP-Mycin, Spectro-Erythromycin, Staticin, Wintrocin, Wyamycin
Effect: Possible clozapine toxicity (decreased metabolism)[1182]
Comments: Based on single case report of seizures (1994) and theoretical
considerations (erythromycin inhibits enzyme that metabolizes clozapine,
CYP1A2).
 
Clozapine:
Clozaril with Lithium
Lithium:
Cibalith-S, Eskalith, Lithane, Lithizine, Lithobid, Lithonate, Lithotabs
Effect: CNS toxicity (mechanism not established)[1034]
Comments: Monitor clinical status and maintain lithium concentration below
0.5 mEq/L.
 
Clozapine:
Clozaril with Phenytoin
Phenytoin:
Dihycon, Dilantin, Diphen, Diphentoin, Diphenylan, Dyatoin, Ekko, Phenytex
Effect: Decreased clozapine effect (increased metabolism)[930]
Comments: Two cases (1991).
 
Clozapine:
Clozaril with Selective serotonin reuptake inhibitors (SSRIs)
Selective serotonin reuptake inhibitors (SSRIs):
fluoxetine - Prozac
fluvoxamine - Luvox
paroxetine - Paxil
sertraline - Zoloft
Effect: Possible clozapine toxicity with fluoxetine or fluvoxamine (decreased
metabollism)[1131]
Comments: Monitor clozapine concentration.