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 reasonably be 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: CNS 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; 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

Table 2 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.

Table 2. Treatment-Emergent Adverse Experience Incidence Among Patients Taking Clozapine in Clinical Trials (excluding the InterSePT™ Study) (N = 842) (percentage of patients reporting)

Table 3 enumerates adverse events that occurred at a frequency of 10% for either treatment group in patients who took at least one dose of study medication during their participation in InterSePT, which was an adequate and well-controlled, two-year study evaluating the efficacy of clozapine relative to olanzapine in reducing the risk of emergent suicidal behavior in patients with schizophrenia or schizoaffective disorder. These rates are not adjusted for duration of exposure.

Table 3. Treatment-Emergent Adverse Experience Incidence^a Among Patients Taking Clozapine or Olanzapine in the InterSePT Study (percentage of patients reporting)

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. Table 2 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 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, polydypsia, 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 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

a href="/script/main/art.asp?articlekey=16730">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

Creatine phosphokinase elevation, hyperglycemia, hyperuricemia, hyponatremia, and weight loss

Drug Abuse And Dependence

Physical and psychological dependence have not been reported or observed in patients taking clozapine.

The risks of using FazaClo® (clozapine, USP) in combination with other drugs have not been systematically evaluated. Concurrent psychopharmaceuticals may affect plasma clozapine levels, thus, plasma concentrations of clozapine may fluctuate, and dosage adjustment may be required to avoid adverse effects or clinical failure.

Pharmacodynamic-Related Interactions

Although the exact mechanism of clozapine-induced agranulocytosis is unknown, the possibility that causative factors may interact synergistically with clozapine to increase the risk and/or severity of bone-marrow suppression warrants consideration. Therefore, FazaClo® (clozapine, USP) should not be used with other agents having a well-known potential to suppress bone-marrow function.

Given the primary CNS effects of clozapine, 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 3000 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 clozapine by itself. Although it has not been established that there is an interaction between clozapine and benzodiazepines or other psychotropics, caution is advised when clozapine is initiated in patients taking a benzodiazepine or any other psychotropic drug.

FazaClo® (clozapine, USP) 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 cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4. 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 of FazaClo® (clozapine, USP) with other drugs which 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, carbamazepine, and rifampin may decrease FazaClo® (clozapine, USP) plasma levels resulting in a decrease in effectiveness of a previously effective FazaClo® (clozapine, USP) 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, fluvoxamine, and erythromycin may increase plasma levels of FazaClo® (clozapine, USP), potentially resulting in adverse effects. Although concomitant use of FazaClo® (clozapine, USP) and carbamazepine is not recommended, it should be noted that discontinuation of concomitant carbamazepine administration may result in an increase in FazaClo® (clozapine, USP) 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 coadministration, mean trough concentrations of clozapine and its metabolites, N-desmethylclozapine and clozapine N-oxide, were elevated with fluvoxamine by about threefold 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 FazaClo® (clozapine, USP) is combined with these drugs, particularly with fluvoxamine. A reduced FazaClo® (clozapine, USP) 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 CYP2D6. Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, 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 P450 CYP2D6 may require lower doses than usually prescribed for either FazaClo® (clozapine, USP) or the other drug. Therefore, coadministration of FazaClo® (clozapine, USP) with other drugs that are metabolized by this isozyme, including antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (eg, propafenone, flecainide, and encainide), or that inhibit this enzyme (eg, quinidine) should be approached with caution.

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