clozapine ( CLOZARIL®)

 

 

CLOZARIL® (clozapine), an atypical antipsychotic drug, is a tricyclic dibenzodiazepine derivative, 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine.

 
Clozapine has been shown to be the most effective drug in treating schizophrenia but due to its potential to cause many severe side effects, it is relegated to third-line use. Clozapine is only used in patients after other anti-psychotics have failed. Safer use of clozapine requires weekly blood monitoring for around five months followed by four weekly testing thereafter.
 
Contraindications

Clozapine is contraindicated in individuals with uncontrolled epilepsy, myeloproliferative disease, or agranulocytosis with prior clozapine treatment.

Interactions

Fluvoxamine inhibits the metabolism of clozapine leading to significantly increased blood levels of clozapine.

Adverse effects

The use of clozapine is associated with a fair number of side effects, many minor though some serious and potentially fatal: the more common include constipation, drooling, muscle stiffness, sedation, tremors, orthostasis, hyperglycemia, and weight gain. The risks of extrapyramidal symptoms such as tardive dyskinesia are much less with clozapine when compared to the typical antipsychotics; this may be due to clozapine's anticholinergic effects. Extrapyramidal symptoms may subside somewhat after a person switches from another antipsychotic to clozapine.

 

 

Black box warnings

  1. AGRANULOCYTOSIS
    BECAUSE OF A SIGNIFICANT RISK OF AGRANULOCYTOSIS, A POTENTIALLY LIFE-THREATENING ADVERSE EVENT, CLOZARIL® (CLOZAPINE) SHOULD BE RESERVED FOR USE IN (1) THE TREATMENT OF SEVERELY ILL PATIENTS WITH SCHIZOPHRENIA WHO FAIL TO SHOW AN ACCEPTABLE RESPONSE TO ADEQUATE COURSES OF STANDARD ANTIPSYCHOTIC DRUG TREATMENT, OR (2) FOR REDUCING THE RISK OF RECURRENT SUICIDAL BEHAVIOR IN PATIENTS WITH SCHIZOPHRENIA OR SCHIZOAFFECTIVE DISORDER WHO ARE JUDGED TO BE AT RISK OF REEXPERIENCING SUICIDAL BEHAVIOR.

    PATIENTS BEING TREATED WITH CLOZAPINE MUST HAVE A BASELINE WHITE BLOOD CELL (WBC) COUNT AND ABSOLUTE NEUTROPHIL COUNT (ANC) BEFORE INITIATION OF TREATMENT AS WELL AS REGULAR WBC COUNTS AND ANCs DURING TREATMENT AND FOR AT LEAST 4 WEEKS AFTER DISCONTINUATION OF TREATMENT (SEE
    WARNINGS).

    CLOZAPINE IS AVAILABLE ONLY THROUGH A DISTRIBUTION SYSTEM THAT ENSURES MONITORING OF WBC COUNT AND ANC ACCORDING TO THE SCHEDULE DESCRIBED BELOW PRIOR TO DELIVERY OF THE NEXT SUPPLY OF MEDICATION (SEE
    WARNINGS).

  2. SEIZURES
    SEIZURES HAVE BEEN ASSOCIATED WITH THE USE OF CLOZAPINE. DOSE APPEARS TO BE AN IMPORTANT PREDICTOR OF SEIZURE, WITH A GREATER LIKELIHOOD AT HIGHER CLOZAPINE DOSES. CAUTION SHOULD BE USED WHEN ADMINISTERING CLOZAPINE TO PATIENTS HAVING A HISTORY OF SEIZURES OR OTHER PREDISPOSING FACTORS. PATIENTS SHOULD BE ADVISED NOT TO ENGAGE IN ANY ACTIVITY WHERE SUDDEN LOSS OF CONSCIOUSNESS COULD CAUSE SERIOUS RISK TO THEMSELVES OR OTHERS. (SEE WARNINGS.)

  3. MYOCARDITIS
    ANALYSES OF POSTMARKETING SAFETY DATABASES SUGGEST THAT CLOZAPINE IS ASSOCIATED WITH AN INCREASED RISK OF FATAL MYOCARDITIS, ESPECIALLY DURING, BUT NOT LIMITED TO, THE FIRST MONTH OF THERAPY. IN PATIENTS IN WHOM MYOCARDITIS IS SUSPECTED, CLOZAPINE TREATMENT SHOULD BE PROMPTLY DISCONTINUED. (SEE WARNINGS.)

  4. OTHER ADVERSE CARDIOVASCULAR AND RESPIRATORY EFFECTS
    ORTHOSTATIC HYPOTENSION, WITH OR WITHOUT SYNCOPE, CAN OCCUR WITH CLOZAPINE TREATMENT. RARELY, COLLAPSE CAN BE PROFOUND AND BE ACCOMPANIED BY RESPIRATORY AND/OR CARDIAC ARREST. ORTHOSTATIC HYPOTENSION IS MORE LIKELY TO OCCUR DURING INITIAL TITRATION IN ASSOCIATION WITH RAPID DOSE ESCALATION. IN PATIENTS WHO HAVE HAD EVEN A BRIEF INTERVAL OFF CLOZAPINE, i.e., 2 OR MORE DAYS SINCE THE LAST DOSE, TREATMENT SHOULD BE STARTED WITH 12.5 mg ONCE OR TWICE DAILY. (SEE WARNINGS and DOSAGE AND ADMINISTRATION.)

    SINCE COLLAPSE, RESPIRATORY ARREST AND CARDIAC ARREST DURING INITIAL TREATMENT HAS OCCURRED IN PATIENTS WHO WERE BEING ADMINISTERED BENZODIAZEPINES OR OTHER PSYCHOTROPIC DRUGS, CAUTION IS ADVISED WHEN CLOZAPINE IS INITIATED IN PATIENTS TAKING A BENZODIAZEPINE OR ANY OTHER PSYCHOTROPIC DRUG. (SEE WARNINGS.)

  5. INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
    ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS TREATED WITH ATYPICAL ANTIPSYCHOTIC DRUGS ARE AT AN INCREASED RISK OF DEATH COMPARED TO PLACEBO. ANALYSES OF SEVENTEEN PLACEBO-CONTROLLED TRIALS (MODAL DURATION OF 10 WEEKS) IN THESE PATIENTS REVEALED A RISK OF DEATH IN THE DRUG-TREATED PATIENTS OF BETWEEN 1.6 TO 1.7 TIMES THAT SEEN IN PLACEBO-TREATED PATIENTS. OVER THE COURSE OF A TYPICAL 10-WEEK CONTROLLED TRIAL, THE RATE OF DEATH IN DRUG-TREATED PATIENTS WAS ABOUT 4.5%, COMPARED TO A RATE OF ABOUT 2.6% IN THE PLACEBO GROUP. ALTHOUGH THE CAUSES OF DEATH WERE VARIED, MOST OF THE DEATHS APPEARED TO BE EITHER CARDIOVASCULAR (e.g., HEART FAILURE, SUDDEN DEATH) OR INFECTIOUS (e.g., PNEUMONIA) IN NATURE. CLOZARIL® (CLOZAPINE) IS NOT APPROVED FOR THE TREATMENT OF PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS.

DRUG DESCRIPTION

CLOZARIL® (clozapine), an atypical antipsychotic drug, is a tricyclic dibenzodiazepine derivative, 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine.

 

INDICATIONS

Treatment-Resistant Schizophrenia

CLOZARIL® (clozapine) is indicated for the management of severely ill schizophrenic patients who fail to respond adequately to standard drug treatment for schizophrenia. Because of the significant risk of agranulocytosis and seizure associated with its use, CLOZARIL should be used only in patients who have failed to respond adequately to treatment with appropriate courses of standard drug treatments for schizophrenia, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs. (See WARNINGS.)

The effectiveness of CLOZARIL in a treatment-resistant schizophrenic population was demonstrated in a 6-week study comparing CLOZARIL and chlorpromazine. Patients meeting DSM-III criteria for schizophrenia and having a mean BPRS total score of 61 were demonstrated to be treatment resistant by history and by open, prospective treatment with haloperidol before entering into the double-blind phase of the study. The superiority of CLOZARIL to chlorpromazine was documented in statistical analyses employing both categorical and continuous measures of treatment effect.

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. In addition, the need for continuing treatment in patients exhibiting beneficial clinical responses should be periodically reevaluated.

Reduction in the Risk of Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorders

CLOZARIL is indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for reexperiencing suicidal behavior, based on history and recent clinical state. Suicidal behavior refers to actions by a patient that puts him/herself at risk for death.

The effectiveness of CLOZARIL in reducing the risk of recurrent suicidal behavior was demonstrated over a 2-year treatment period in the InterSePT Trial (see Clinical Trial Data under CLINICAL PHARMACOLOGY). Therefore, CLOZARIL treatment to reduce the risk of suicidal behavior should be continued for at least 2 years (see DOSAGE AND ADMINISTRATION).

The prescriber should be aware that a majority of patients in both treatment groups in InterSePT received other treatments as well to reduce suicide risk, such as antidepressants and other medications, hospitalization, and/or psychotherapy. The contributions of these additional measures are unknown.

DOSAGE AND ADMINISTRATION

Treatment-Resistant Schizophrenia

Upon initiation of CLOZARIL® (clozapine) therapy, up to a 1-week supply of additional CLOZARIL 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 begin with one-half of a 25-mg tablet (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 in patients resistant to standard drug treatment for schizophrenia, 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 in treatment-resistant patients, the mean and median CLOZARIL 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. CLOZARIL can cause EEG changes, including the occurrence of spike and wave complexes. It lowers the seizure threshold in a dose-dependent manner and may induce myoclonic jerks or generalized seizures. These symptoms may be likely to occur with rapid dose increase and in patients with preexisting epilepsy. In this case, the dose should be reduced and, if necessary, anticonvulsant treatment initiated.

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 in schizophrenia is still under study, the effectiveness of maintenance treatment is well established for many other drugs used to treat schizophrenia. It is recommended that responding patients be continued on CLOZARIL, but at the lowest level needed to maintain remission. Because of the significant risk associated with the use of CLOZARIL, patients should be periodically reassessed to determine the need for maintenance treatment.

Discontinuation of Treatment

In the event of planned termination of CLOZARIL 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 and symptoms related to cholinergic rebound such as headache, nausea, vomiting, and diarrhea.

Reinitiation of Treatment in Patients Previously Discontinued

When restarting patients who have had even a brief interval off CLOZARIL, 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 retitrated with extreme caution after even 24 hours of discontinuation.

Certain additional precautions seem prudent when reinitiating treatment. The mechanisms underlying CLOZARIL-induced adverse reactions are unknown. It is conceivable, however, that reexposure 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 reinitiation of treatment, additional caution is advised. Patients discontinued for WBC counts below 2000/mm³ or an ANC below 1000/mm³ must not be restarted on CLOZARIL. (See WARNINGS.)

Reducing the Risk of Recurrent Suicidal Behavior in Patients with Schizophrenia or Schizoaffective Disorder

The dosage and administration recommendations outlined above regarding the use of CLOZARIL in patients with treatment-resistant schizophrenia should also be followed when treating patients with schizophrenia or schizoaffective disorder at risk for recurrent suicidal behavior.

The InterSePT study demonstrated the efficacy of CLOZARIL in treatment of patients with schizophrenia or schizoaffective disorder at risk for recurrent suicidal behavior where the mean daily dose was about 300 mg (range 12.5 to 900 mg).

Patients previously treated with other antipsychotics were cross-titrated to CLOZARIL over a one-month interval; the dose of the previous antipsychotic was gradually decreased simultaneous with a gradual increase in CLOZARIL dose over the first month of the study. Patients on depot antipsychotic medication began CLOZARIL after one full dosing interval since the last injection.

Recommendations to Reduce the Risk of Recurrent Suicidal Behavior in Patients Who Otherwise Previously Responded to Treatment of Schizophrenia or Schizoaffective Disorder with Another Antipsychotic Medication:

The results of the InterSePT study demonstrated that, for a 2-year treatment period, the probability of a suicide attempt or a hospitalization due to imminent suicide risk is stable at approximately 24% after one year of treatment with CLOZARIL (Figure 1, Clinical Trial Data Section). A course of treatment with CLOZARIL of at least 2 years is therefore recommended in order to maintain the reduction of risk for suicidal behavior. After 2 years, it is recommended that the patient's risk of suicidal behavior be assessed. If the physician's assessment indicates that a significant risk for suicidal behavior is still present, treatment with CLOZARIL should be continued. Thereafter, the decision to continue treatment with CLOZARIL should be revisited at regular intervals, based on thorough assessments of the patient's risk for suicidal behavior during treatment. If the physician determines that the patient is no longer at risk for suicidal behavior, treatment with CLOZARIL may be discontinued (see recommendations above regarding discontinuation of treatment) and treatment of the underlying disorder with an antipsychotic medication to which the patient has previously responded may be resumed.

HOW SUPPLIED

CLOZARIL® (clozapine) is available as 25 mg and 100 mg round, pale-yellow, uncoated tablets with a facilitated score on one side.

CLOZARIL® (clozapine) Tablets

25 mg

Engraved with “CLOZARIL” once on the periphery of one side.

Engraved with a facilitated score and “25” once on the other side.

Bottle of 100........................................................NDC 0078-0126-05
Bottle of 500........................................................NDC 0078-0126-08
Unit dose packages of 100: 2 x 5 strips, 10 blisters per strip ............................NDC 0078-0126-06

100 mg

Engraved with “CLOZARIL” once on the periphery of one side.

Engraved with a facilitated score and “100” once on the other side.

Bottle of 100........................................................NDC 0078-0127-05
Bottle of 500........................................................NDC 0078-0127-08
Unit dose packages of 100: 2 x 5 strips, 10 blisters per strip ............................NDC 0078-0127-06

Store and Dispense

Storage temperature should not exceed 30°C (86°F). Drug dispensing should not ordinarily exceed a weekly supply.

If a patient is eligible for White Blood Cell (WBC) count and Absolute Neutrophil Count (ANC) testing every 2 weeks, then a two-week supply of CLOZARIL can be dispensed. If a patient is eligible for WBC count and ANC testing every 4 weeks, then a four-week supply of CLOZARIL can be dispensed. Dispensing should be contingent upon the WBC count and ANC test results.

SIDE EFFECTS

Associated with Discontinuation of Treatment

Sixteen percent of 1,080 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 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.

Extrapyramidal Symptoms

Dystonia

Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Clozapine, an atypical antipsychotic, is associated with a low incidence of dystonia (see WARNINGS, Tardive Dyskinesia).

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 premarket 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 Premarketing 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.

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 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 coadministration, 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, coadministration 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.

 

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