Clozaril Side Effects & Drug Interactions Associated with Discontinuation of Treatment




Clozaril


Side Effects & Drug Interactions
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 Incidence
Among Patients Taking CLOZARIL® (clozapine) in Clinical Trials
(excluding the InterSePT™ Study) (N = 842)
(Percentage of Patients Reporting)














































































































































































































Body System
Adverse Eventa
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 Incidence1
Among 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.


Drug Abuse And Dependence


Physical and psychological dependence have not been reported or observed in patients taking CLOZARIL® (clozapine).



DRUG INTERACTIONS




The risks of using CLOZARIL in combination with other drugs have not been systematically evaluated.


Pharmacodynamic-Related Interactions


The mechanism of CLOZARIL-induced agranulocytosis is unknown; nonetheless, the possibility that causative factors may interact synergistically to increase the risk and/or severity of bone marrow suppression warrants consideration. Therefore, CLOZARIL should not be used with other agents having a well-known potential to suppress bone marrow function.


Given the primary CNS effects of CLOZARIL, caution is advised in using it concomitantly with other CNS-active drugs or alcohol.


Orthostatic hypotension in patients taking clozapine can, in rare cases (approximately 1 case per 3,000 patients), be accompanied by profound collapse and respiratory and/or cardiac arrest. 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.


CLOZARIL may potentiate the hypotensive effects of antihypertensive drugs and the anticholinergic effects of atropine-type drugs. The administration of epinephrine should be avoided in the treatment of drug-induced hypotension because of a possible reverse epinephrine effect.


Pharmacokinetic-Related Interactions


Clozapine is a substrate for many CYP450 isozymes, in particular 1A2, 2D6, and 3A4. The risk of metabolic interactions caused by an effect on an individual isoform is therefore minimized. Nevertheless, caution should be used in patients receiving concomitant treatment with other drugs that are either inhibitors or inducers of these enzymes.


Concomitant administration of drugs known to induce cytochrome P450 enzymes may decrease the plasma levels of clozapine. Phenytoin, nicotine, and rifampin may decrease CLOZARIL plasma levels, resulting in a decrease in effectiveness of a previously effective CLOZARIL dose.


Concomitant administration of drugs known to inhibit the activity of cytochrome P450 isozymes may increase the plasma levels of clozapine. Cimetidine, caffeine, citalopram, ciprofloxacin, and erythromycin may increase plasma levels of CLOZARIL, potentially resulting in adverse effects. Although concomitant use of CLOZARIL and carbamazepine is not recommended, it should be noted that discontinuation of concomitant carbamazepine administration may result in an increase in CLOZARIL plasma levels.


In a study of schizophrenic patients who received clozapine under steady-state conditions, fluvoxamine or paroxetine was added in 16 and 14 patients, respectively. After 14 days of co-administration, mean trough concentrations of clozapine and its metabolites, N- desmethylclozapine and clozapine N-oxide, were elevated with fluvoxamine by about three- fold compared to baseline concentrations. Paroxetine produced only minor changes in the levels of clozapine and its metabolites. However, other published reports describe modest elevations (less than two-fold) of clozapine and metabolite concentrations when clozapine was taken with paroxetine, fluoxetine, and sertraline. Therefore, such combined treatment should be approached with caution and patients should be monitored closely when CLOZARIL is combined with these drugs, particularly with fluvoxamine. A reduced CLOZARIL dose should be considered.


A subset (3%-10%) of the population has reduced activity of certain drug metabolizing enzymes such as the cytochrome P450 isozyme P450 2D6. Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, the tricyclic antidepressants, and clozapine. These individuals may develop higher than expected plasma concentrations of clozapine when given usual doses. In addition, certain drugs that are metabolized by this isozyme, including many antidepressants (clozapine, selective serotonin reuptake inhibitors, and others), may inhibit the activity of this isozyme, and thus may make normal metabolizers resemble poor metabolizers with regard to concomitant therapy with other drugs metabolized by this enzyme system, leading to drug interaction.


Concomitant use of clozapine with other drugs metabolized by cytochrome P450 2D6 may require lower doses than usually prescribed for either clozapine or the other drug. Therefore, co-administration of clozapine with other drugs that are metabolized by this isozyme, including antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution.


Brand Name: Clozaril
Generic Name: Clozapine


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