ADVERSE REACTIONS
Associated with Discontinuation of Treatment
Sixteen percent of 1,080 patients who received CLOZARIL® (clozapine) in pre-marketing clinical trials discontinued treatment due to an adverse event, including both those that could be reasonably attributed to CLOZARIL 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 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 enumerates adverse events that occurred at a frequency of 1% or greater among CLOZARIL patients who participated in clinical trials. These rates are not adjusted for duration of exposure.
Treatment-Emergent Adverse Experience IncidenceAmong Patients Taking CLOZARIL® (clozapine) in Clinical Trials (excluding the InterSePT™ Study) (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 |
a Events reported by at least 1% of CLOZARIL patients are included.
b Rate based on population of approximately 1,700 exposed during pre-market clinical evaluation of CLOZARIL.
The following table enumerates adverse events that occurred at a frequency of 10% for either treatment group in patients who took at least 1 dose of study medication during their participation in InterSePT, which was an adequate and well-controlled 2-year study evaluating the efficacy of CLOZARIL relative to Zyprexa in reducing the risk of emergent suicidal behavior in patients with schizophrenia or schizoaffective disorder. These rates are not adjusted for duration of exposure.
Treatment-Emergent Adverse Experience Incidence1Among Patients Taking CLOZARIL® (clozapine) or Zyprexa® (olanzapine) in the InterSePT™ Study (Percentage of Patients Reporting)
| Clozaril ®
N=479
% Reporting | Zyprexa ®
N=477
% Reporting |
| Adverse Events |
|
|
| Salivary Hypersecretion | 48% | 6% |
| Somnolence | 46% | 25% |
| Weight Increased | 31% | 56% |
| Dizziness (Excluding Vertigo) | 27% | 12% |
| Constipation | 25% | 10% |
| Insomnia NEC | 20% | 33% |
| Nausea | 17% | 10% |
| Vomiting NOS | 17% | 9% |
| Dyspepsia | 14% | 8% |
1AEs are listed by frequency in CLOZARIL group, and included in the table are those for which the risk ratio of CLOZARIL
over Zyprexa or of Zyprexa over CLOZARIL was greater than 1.5.
NEC - not elsewhere classified
NOS - not otherwise specified
Other Events Observed During the Pre-marketing Evaluation of CLOZARIL® (clozapine)
This section reports additional, less frequent adverse events which occurred among the patients taking CLOZARIL in clinical trials. Various adverse events were reported as part of the total experience in these clinical studies; a causal relationship to CLOZARIL treatment cannot be determined in the absence of appropriate controls in some of the studies. The table above enumerates adverse events that occurred at a frequency of at least 1% of patients treated with CLOZARIL. 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 nosebleed.
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.
Post-marketing Clinical Experience
Post-marketing experience has shown an adverse experience profile similar to that presented above. Voluntary reports of adverse events temporally associated with CLOZARIL 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; possible mild cataplexy; and status epilepticus.
Cardiovascular System: atrial or ventricular fibrillation and periorbital edema.
Gastrointestinal System: acute pancreatitis; dysphagia; fecal impaction; intestinal obstruction/paralytic ileus; and salivary gland swelling.
Hepatobiliary System: cholestasis; hepatitis; jaundice.
Hepatic System: cholestasis.
Urogenital System: acute interstitial nephritis and priapism.
Integumentary (Skin): hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, and Stevens-Johnson Syndrome.
Metabolic and Nutritional Disorders: hypercholesterolemia (very rare); and hypertriglyceridemia (very rare).
Musculoskeletal System: myasthenic syndrome and rhabdomyolysis.
Respiratory System: aspiration and pleural effusion.
Hemic and Lymphatic System: deep vein thrombosis; elevated hemoglobin/hematocrit; ESR increased; pulmonary embolism; sepsis; thrombocytosis; and thrombocytopenia.
Vision Disorders: narrow angle glaucoma.
Miscellaneous: CPK elevation; hyperglycemia; hyperuricemia; hyponatremia; and weight loss.
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