ADVERSE REACTIONS
Associated with Discontinuation of Treatment
Sixteen percent of 1080 patients who received clozapine in premarketing clinical trials discontinued treatment due to an adverse event, including both those that could be reasonably attributed to 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 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 enumerates adverse events that occurred at a frequency of 1% or greater among clozapine patients who participated in clinical trials. These rates are not adjusted for duration of exposure.
Treatment-Emergent Adverse Experience Incidence Among Patients Taking Clozapine in Clinical Trials (excluding the InterSePT™ Study) (N = 842) (Percentage of Patients Reporting) Body System
Adverse EventsEvents reported by at least 1% of clozapine patients are included. | 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) | 3Rate based on population of approximately 1700 exposed during premarket clinical evaluation of clozapine. |
| 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 | 25 |
| 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 | 1 |
| Eosinophilia | 1 |
| Miscellaneous | |
| Fever | 5 |
| Weight gain | 4 |
| Tongue numb/sore | 1 |
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 clozapine 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 IncidenceAEs are listed frequency in clozapine group, and included in the table are those for which the risk ratio of clozapine over Zyprex or of Zyprea over clozapine was greater than 1.5. Among Patients Taking clozapine or Zyprexa® (olanzapine) in the InterSePT™ Study (Percentage of Patients Reporting) | Clozapine
N=479%
Reporting | Zyprexa®
N=477%
Reporting |
|---|
| Adverse Events | | |
|---|
| NEC - not elsewhere classified |
| NOS - not otherwise specified |
| Salivary hypersecretion | 48% | 6% |
| Somnolence | 46% | 25% |
| Weight increased | 31% | 56% |
| Dizziness (excluding vertigo) | 27% | 12% |
| Constipation | 25% | 10% |
| Insomnia NEC | 20% | 33% |
| Nausea 1 | 17% | 10% |
| Vomiting NOS | 17% | 9% |
| Dyspepsia | 14% | 8% |
Other Events Observed During the Premarketing Evaluation of Clozapine
This section reports additional, less frequent adverse events which occurred among the patients taking clozapine in clinical trials. Various adverse events were reported as part of the total experience in these clinical studies; a causal relationship to clozapine 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 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 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 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; 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; and 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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