Clozapine (Systemic)


VA CLASSIFICATION
Primary: CN709

Commonly used brand name(s): Clozaril.


Note: In the U.S. and Canada, clozapine is available only through pharmacies that agree to participate with physicians in a program to monitor patients' blood tests; a supply of medication sufficient to continue therapy until the next scheduled blood test may be dispensed if the results of the blood tests are within acceptable parameters. {03} {15}

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antipsychotic—
Note: Clozapine is an atypical antipsychotic {04} {05} {09} {10} {14} {17}.



Indications

Accepted

Schizophrenia (treatment)—Clozapine is indicated only in the management of severely ill schizophrenic patients who have failed to respond to other neuroleptic agents or who cannot tolerate the adverse effects produced by those agents {03} {15} {23}. Clozapine may produce a significant improvement in both the positive and negative symptoms of schizophrenia {04} {05}.
—Because of the significant risk of agranulocytosis and seizures associated with clozapine use, the patient should be given adequate trials with at least two different standard antipsychotic medications before clozapine therapy is initiated {03} {15} {23}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Tricyclic dibenzodiazepine derivative {03}.
Molecular weight—
    326.83 {02}
    Very slightly soluble in water {03}.

Mechanism of action/Effect:

The mechanism by which clozapine exerts its antipsychotic effect has not been defined. In some studies, clozapine has shown more dopamine blocking activity in the limbic region of the brain {04} {08} {09} {14} than in the neostriatum, but its potency is low in all regions. {15}{30}. These properties may account for the low extrapyramidal side effect profile of clozapine {15}. Clozapine interferes weakly with the binding of dopamine at D 1, D 2, D 3, and D 5 receptors, and moderately {30} at D 4 receptors {03} {15}. At alpha-adrenergic, cholinergic, histaminergic, and serotonergic receptors, clozapine acts as an antagonist {03} {15}. It is unclear whether a combination of these effects accounts for clozapine's superior {30}efficacy {05} {10}. Clozapine has little or no effect on serum prolactin concentrations {06} {16} {17}, because it does not bind potently to D 2receptors on mammotrophic cells of the anterior pituitary, under tonic control by {30} the tuberoinfundibular dopamine tract {21}.


Other actions/effects:

Clozapine may cause significant bone marrow suppression, which can lead to agranulocytosis {03}. Deaths have occurred {03}. The development of agranulocytosis has not been linked clearly to any patient characteristics and cannot be predicted reliably by either dose or duration of treatment {03}. However, the greatest incidences have been seen during the first 6 months of clozapine use {03} {15}, in patients older than 50 years of age {15}, and in patients of Jewish descent {03} {15}.

Electroencephalographic (EEG) studies show that clozapine increases delta and theta activity and slows dominant alpha frequencies {03}. Sharp wave activity and spike and wave complexes may also develop {03}. In some patients, the proportion of time spent in rapid eye movement (REM) sleep increases greatly and the REM sleep latency decreases greatly {03}. Also, dose-related seizures are associated with clozapine use at a cumulative incidence at 1 year of approximately 5% {03} {15} in patients receiving 600 to 900 mg per day {15}. Seizure incidence in patients receiving less than 300 mg per day of clozapine is about 1 to 2% {15}.

Clozapine has potent anticholinergic effects {03} {15}.

Absorption:

Rapid {04} {12} {13} and nearly complete {05} {12}. However, first-pass metabolism results in an absolute bioavailability of 50 to 60% {15}. Food does not affect the systemic bioavailability of clozapine {03}.

Distribution:

Rapid and extensive {01}; crosses the blood-brain barrier {01} {12}.

Protein binding:

Very high (95%) {05} {13} {15}.

Biotransformation:

Extensive {12} {13} hepatic metabolism to metabolites with limited or no activity {03} {12}. The cytochrome P450 1A2 (CYP1A2) isoenzyme is the primary isoenzyme involved in clozapine metabolism {15}. CYP2D6 is involved in clozapine metabolism to a lesser extent {15}.

Half-life:


Elimination:

8 hours (range, 4 to 12 hours) after a single 75-mg dose {03}; 12 hours (range, 4 to 66 hours) after reaching steady-state dosing of 100 mg twice a day {03}.


Time to peak concentration:

Average, 2.5 hours (range, 1 to 6 hours) {03} {15}. Steady-state concentrations are attained in 8 to 10 days {04} {13}.

Peak serum concentration:

Steady-state peak and minimum plasma concentrations of clozapine average 319 nanograms per mL (range, 102 to 771 nanograms per mL) and 122 nanograms per mL (range, 41 to 343 nanograms per mL), respectively, at a dosage of 100 mg two times a day {03}. At steady-state, administration of 37.5 mg, 75 mg, and 100 mg of clozapine two times a day produced linearly dose-proportional changes in the area under the plasma concentration–time curve and in the peak and minimum plasma concentrations of clozapine {03}.

Duration of action:

4 to 12 hours {01}.

Elimination:


Renal—
        Approximately 50% of an administered dose, only trace amounts as unchanged clozapine {03}.



Fecal—
        Approximately 30% of an administered dose, only trace amounts as unchanged clozapine {03}.



Precautions to Consider

Carcinogenicity

Long-term studies in mice and rats given clozapine in doses approximately seven times the typical human dose on a mg per kg of body weight (mg/kg) basis demonstrated no potential carcinogenicity {03} {05} {13}.

Tumorigenicity

Animal studies have shown no abnormalities {13}.

Mutagenicity

Clozapine was not found to be genotoxic or mutagenic when assayed in appropriate bacterial and mammalian tests {03}.

Pregnancy/Reproduction

Pregnancy—
Clozapine crosses the placenta {05} {13}. Adequate and well-controlled studies in humans have not been done {03}.

Studies in animals have not shown that clozapine causes adverse effects on the fetus {03}.

FDA Pregnancy Category B {03}.

Breast-feeding

Animal studies have suggested that clozapine may be distributed into breast milk {03}. Clozapine may cause sedation, decreased suckling, restlessness or irritability, seizures, and cardiovascular instability in the nursing infant {20} {21} {22} {27}.

Pediatrics

Appropriate studies on the relationship of age to the effects of clozapine have not been performed in children up to 16 years of age {15}. Safety and efficacy have not been established {03} {15}.


Geriatrics


No information is available on the relationship of age to the effects of clozapine in geriatric patients. However, the elderly may be at greater risk for orthostatic hypotension {20}, and for anticholinergic side effects such as confusion and excitement {21}. Also, elderly males are more likely to have age-related prostatic hypertrophy, which requires caution in the use of clozapine {03}.


Dental

Although hypersalivation occurs as a frequent consequence of clozapine administration {11} {17} {18}, peripheral anticholinergic effects of clozapine may decrease or inhibit salivary flow, thus contributing to the development of caries, periodontal disease, oral candidiasis, and discomfort {28}.

The leukopenic and thrombocytopenic effects of clozapine may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal, and patients should be instructed in proper oral hygiene, including caution in the use of regular toothbrushes, dental floss, and toothpicks. {28}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Clozapine metabolism is mediated mainly by cytochrome P450 1A2 (CYP1A2) and to a lesser extent by CYP2D6 {15}. Interactions with other medications that are metabolized by these isoenzymes (e.g., encainide, flecainide, propafenone) or that induce or inhibit (e.g., quinidine) the cytochrome P450 enzymes, in addition to those listed below, should be considered {03} {15}. Dosage adjustments of either clozapine or the other medication may be required {03}.
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alcohol {13} or
» Central nervous system (CNS) depression–producing medications, other {05} {13} (see Appendix II)    (concurrent use with clozapine may increase the severity and frequency of CNS depressant effects)


Anticholinergics, other (see Appendix II)     (concurrent use with clozapine may potentiate the anticholinergic effects of these medications {03})


» Bone marrow depressants, other {03} {05} (see Appendix II)    (concurrent use with clozapine may potentiate the myelosuppressive effects of these medications {03})


Carbamazepine {03} or
Phenytoin {03} or
Smoking tobacco {20} {22} {24} {25} {26}    (concurrent use may decrease the plasma concentrations of clozapine, reducing the effectiveness of a given clozapine dose; discontinuation may increase the plasma concentrations of clozapine {03} {15})


Cimetidine or
Erythromycin    (clozapine plasma concentrations may be increased, increasing the risk of developing adverse effects {03} {15})


Highly protein-bound medications, other, such as:
Digitoxin
Warfarin    (concurrent use with clozapine may result in increased serum concentrations of these medications; also, clozapine may be displaced from its binding sites by these medications {03})


» Hypotension-producing medications, other {03} (see Appendix II), especially
Benzodiazepines or
Psychotropic medications, other    (concurrent use with clozapine may cause additive hypotensive effects; epinephrine should not be used in the treatment of clozapine-induced hypotension because of a possible reverse epinephrine effect {03})

    (very rarely, circulatory collapse, respiratory arrest, and cardiac arrest have accompanied orthostatic hypotension in patients receiving clozapine alone or with benzodiazepines or other psychotropic medications; although drug interaction has not been established as the mechanism for these events, clozapine should be introduced with caution in patients receiving other psychotropic medications {03})


» Lithium {13}    (concurrent use with clozapine may increase the risk of seizures, confusional states, neuroleptic malignant syndrome, and dyskinesias {13} {20})


» Selective serotonin reuptake inhibitors (SSRIs)    (three-fold {30}elevations in clozapine serum concentrations have been reported during concurrent use with fluvoxamine {15}; lesser elevations have been reported during concurrent use with other SSRIs [fluoxetine, paroxetine, sertraline] {15}; patients should be monitored closely, and a reduced clozapine dosage should be considered {03})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» CNS depression, severe {03} {05}    (may be potentiated)


» Myeloproliferative disorders {03} {05} , specifically:
Blood dyscrasias, or history of {05} {13}
Bone marrow depression {15}    (may be potentiated)


Risk-benefit should be considered when the following medical problems exist
Cardiovascular disorders {05}    (increased risk of blood pressure alterations and arrhythmias)


» Glaucoma, narrow-angle, predisposition to or
» Intestinal motility impairment or
» Prostatic hypertrophy    (conditions may be exacerbated by the potent anticholinergic effects of clozapine {03} {15})


Hepatic function impairment    (metabolism of clozapine may be altered; also, hepatitis has been reported with clozapine use in patients with normal hepatic function and in patients with impaired hepatic function {03})


Renal function impairment {03}    (excretion of clozapine may be altered)


» Seizure disorders, or history of {05}    (risk of seizures may be increased)



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Because of the risk of myocarditis, the patient should be instructed to report immediately any unexplained fatigue, dyspnea, tachypnea, fever, chest pain, palpitations, tachycardia or other signs or symptoms of heart failure. Myocarditis should be considered in patients who present with electrocardiographic findings such as ST-T wave abnormalities or arrhythmias. Patients who present with tachycardia during the first month of therapy should be closely monitored for other signs of myocarditis. Clozapine therapy should be promptly discontinued if myocarditis is suspected. Patients with clozapine-related myocarditis should not be rechallenged with clozapine{29}.
» White blood cell (WBC) and differential counts    (WBC and differential counts are required prior to initiation of therapy. If the baseline WBC count is less than 3500 per mm 3, clozapine therapy should not be initiated. WBC counts are required at specified intervals during therapy, and weekly for 4 weeks after clozapine is discontinued. Clozapine is supplied to the patient in quantities sufficient to continue treatment only until the next required blood test and only if the previous blood tests have been performed and the results are within an acceptable range. Repeat WBC and differential counts are recommended if, at any time during clozapine therapy, any of the following three events occurs: the WBC count drops below 3500 per mm 3; the WBC count drops substantially [³ 3000 per mm 3 either as a single drop or as a cumulative drop over 3 weeks or less], even if total WBC count remains above 3500 per mm 3; or immature forms are present {03}.)

    (for the first 6 months of continuous clozapine therapy, WBC counts should be performed weekly. If during this 6-month period the patient has an interruption in clozapine therapy of £ 1 month, and there have been no abnormal blood events [WBC count < 3000 per mm 3 or absolute neutrophil count (ANC) < 1500 per mm 3] {03}, the 6-month period of weekly monitoring may be resumed from where it was left off. However, if the patient has an interruption in clozapine therapy of > 1 month, weekly monitoring is required for a 6-month period starting from the date of reinitiation of clozapine. If the patient has had no abnormal blood events through 6 months of weekly monitoring {03}, and in the clinical judgment of the physician it is deemed appropriate {07} {15}, monitoring frequency may be decreased to once every other week {03} {15})

    (if a patient has met the criteria for every-other-week monitoring and subsequently has an interruption in clozapine therapy of £ 1 year, monitoring may be resumed at a frequency of once every other week with reinitiation of clozapine. However, if there is an interruption in clozapine therapy of > 1 year, a 6-month period of weekly monitoring with no abnormal blood events must again be completed before monitoring frequency may be decreased to once every other week {03}.)

    (if any abnormal blood event that does not require permanent discontinuation of clozapine occurs [WBC count of 2000 to 3000 per mm 3 or ANC of 1000 to 1500 per mm 3], regardless of how long the patient has been taking clozapine or whether the patient is on a weekly or every-other-week monitoring schedule, monitoring should be performed every week for 6 months following the event {03})

    (if WBC and differential counts reveal a WBC count of 3000 to 3500 per mm 3 and an ANC > 1500 per mm 3, WBC and differential counts should be performed twice weekly {03})

    (if the WBC count falls below 3000 per mm 3 or the ANC falls below 1500 per mm 3, clozapine should be discontinued, WBC and differential counts performed daily, and the patient monitored for flu-like symptoms or other symptoms suggesting infection. If, subsequently, the WBC count exceeds 3000 per mm 3, the ANC exceeds 1500 per mm 3, and no signs of infection develop in these patients, clozapine may be resumed; however, WBC and differential counts should be performed at least twice weekly until the WBC count is greater than 3500 per mm 3 {03})

    (if a differential count reveals an eosinophil count above 4000 per mm 3, clozapine should be discontinued until the eosinophil count falls below 3000 per mm 3 {03})

    (if the WBC count falls below 2000 per mm 3 or the ANC falls below 1000 per mm 3, clozapine should be permanently discontinued and WBC and differential counts should be performed daily; bone marrow aspiration should be considered to ascertain the patient's granulopoietic status; protective isolation and antibiotic therapy should be instituted if indicated. These patients should not be rechallenged with clozapine, because agranulocytosis may occur with a shorter latency period {03})

    (after discontinuation of clozapine, WBC counts should be performed every week for 4 weeks even if no abnormal blood events occurred during treatment {03})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Cardiovascular effects, specifically tachycardia {04} {05} {06} {09} {11} {13} {17} ( fast or irregular heartbeat), hypotension {04} {05} {06} {09} {11} {17} (low blood pressure), or orthostatic hypotension {04} {13} {14} (dizziness or fainting)—especially when getting up from a lying or sitting position
    
fever {04} {05} {06} {08} {11} {13}

Incidence less frequent
    
Agitation {05} ( unusual anxiety, nervousness, or irritability)
    
akathisia {04} {05} {11} {17} ( restlessness or need to keep moving)
    
confusion {05}
    
difficulty in accommodation {05} {11} {13} (blurred vision)
    
electrocardiogram (ECG) changes {04} {17}
    
hypertension {04} {05} {06} {11} (dizziness; severe or continuing headaches; increase in blood pressure)
    
syncope {05}{11}{13}(fainting)

Incidence rare
    
Blood dyscrasias, specifically agranulocytosis {04} {05} {06} {08} {10} {11} {12} {13} {14} (chills; fever; sore throat ; unusual tiredness or weakness), eosinophilia {03} ( fever), granulocytopenia {04} {05} {06} (chills; fever; sore throat ; sores, ulcers, or white spots on lips or in mouth; unusual tiredness or weakness ), leukopenia {05} {18} (chills; fever; sore throat), or thrombocytopenia {11} {13} ( unusual bleeding or bruising)
    
deep-vein thrombosis {03} (swelling or pain in leg), or pulmonary embolism {03} (chest pain; cough; fainting; fast heartbeat; sudden shortness of breath)
    
extrapyramidal effects, specifically akinesia {04} or hypokinesia {05} {11} (absence of or decrease in movement), rigidity {04} {05} {17} (severe muscle stiffness ), or tremor {04} {05} {11} {17} (trembling or shaking)—less frequent
    
hepatitis {03} (dark urine; decreased appetite; nausea; vomiting; yellow eyes or skin)
    
hyperglycemia {03} (increased appetite; increased thirst; increased urination; weakness)
    
impotence {04} (decreased sexual ability)
    
insomnia or disturbed sleep {05} (trouble in sleeping)
    
mental depression {11}
    
myocarditis {29}(chest pain or discomfort; fast heartbeat; fever and chills; troubled breathing; )—post-marketing data 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{29}.
    
neuroleptic malignant syndrome (NMS) {03} ( convulsions; difficult or fast breathing ; fast heartbeat or irregular pulse; fever; high or low [irregular] blood pressure; increased sweating; loss of bladder control ; severe muscle stiffness; unusually pale skin; unusual tiredness or weakness)
    
seizures {04} {05} {09} {18}
    
tardive dyskinesia {03} (lip smacking or puckering; puffing of cheeks; rapid or worm-like movements of tongue; uncontrolled chewing movements; uncontrolled movements of arms and legs)
    
trouble in urinating {05}

Note: Liver function tests should be performed immediately in any patient who develops signs or symptoms of hepatitis during treatment with clozapine {03}. If test values are significantly elevated or if the patient shows signs of jaundice, clozapine should be discontinued {03}.
Several cases of NMS have occurred in patients receiving clozapine alone or concomitantly with lithium or other CNS-active agents {03}.
For seizures, a dose-dependent relationship has been suggested {05}, with seizures occurring in 1 to 2% of patients receiving low doses (< 300 mg per day), in 3 to 4% of patients receiving moderate doses (300 to 599 mg per day), and in 5% of patients receiving high doses (³ 600 mg per day) of clozapine {01} {15}. Patients with a history of epilepsy or other predisposing factors may be at greater risk of developing seizures {05}.
Although no confirmed cases of tardive dyskinesia have been attributed to clozapine, the possibility of occurrence cannot be ruled out {03}. The smallest dose and shortest duration of treatment should be used, with periodic reassessment of need for clozapine treatment {03}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Constipation {04} {05} {06} {13} {17} {18}
    
dizziness {04} {05} {06} {08} {11} or lightheadedness {04}
    
drowsiness {04} {05} {06} {08}
    
headache {04} {05} {06} {11}
    
hypersalivation {04} {05} {06} {09} {11} {13} {17} {18} (increased watering of mouth)
    
nausea or vomiting {04} {05} {06} {08} {11}
    
unusual weight gain {05} {09} {13} {18}

Note: Salivation may be profuse, very fluid, and especially prevalent during sleep {03} {15}. It has been suggested by the manufacturer that this effect may be ameliorated in some cases by a reduction of clozapine dosage {03} {15} or by use of a peripherally acting anticholinergic medication {15}; however, caution should be used since additive anticholinergic effects may lead to toxicity in some patients {20}.


Incidence less frequent
    
Abdominal discomfort or heartburn {05}
    
dryness of mouth {04} {05} {06} {11}
    
hyperhidrosis {05} {11} (increased sweating )





Overdose
For specific information on the agents used in the management of clozapine overdose, see:


Charcoal, Activated (Oral-Local) monograph;


Dihydroergotamine in Vascular Headache Suppressants, Ergot Derivative–containing (Systemic) monograph;


Norepinephrine in Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic) monograph; and/or


Physostigmine (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Cardiac arrhythmias or tachycardia {03} {13} ( fast, slow, or irregular heartbeat)
    
delirium {03} ( unusual excitement, nervousness, or restlessness; hallucinations)
    
drowsiness, severe {03} {13} or coma {03}
    
hypersalivation {03} (increased watering of the mouth)
    
hypotension {03} {13} (dizziness or fainting)
    
respiratory depression {03} {13} or failure {03} ( slow, irregular, or troubled breathing)
    
seizures {03}


Note: Aspiration pneumonia has also been reported {03} {15}.
Deaths have occurred, generally at clozapine doses > 2500 mg {03}. However, overdoses as low as 400 mg in adults and 50 to 200 mg in young children have resulted in coma {15}. Patients have recovered from doses > 4000 mg {03}.


Treatment of overdose
There is no specific antidote for clozapine {03} {15}. Treatment of overdose is symptomatic and supportive.

To decrease absorption—Initiation of gastric lavage or administration of activated charcoal within 6 hours of ingestion, if possible {15}. Administration of activated charcoal, which may be used with sorbitol, may be as effective as or more effective than induction of emesis or gastric lavage {03} {15}.

Specific treatment—Considering use of physostigmine {05} {13}, dihydroergotamine {13}, angiotensin {13}, or norepinephrine {13} to counteract anticholinergic symptoms {13}. Not using epinephrine or derivatives in treatment of hypotension {03} {13}. Not using quinidine or procainamide in treatment of cardiac arrhythmias {03}.

Monitoring—Monitoring of cardiac and vital signs; continued monitoring of patient for several days because of risk of delayed effects {03} {15}.

Supportive care—Establishment and maintenance of a patent airway, ensuring adequate oxygenation and ventilation {03} {15}. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.

Note: Forced diuresis, dialysis, hemoperfusion, and exchange transfusions are not likely to be of benefit {15} due to clozapine's high degree of protein binding {13}.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Clozapine (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:

Pregnancy—Crosses the placenta





Breast-feeding—May cause sedation, decreased suckling, and restlessness or irritability in nursing infant





Use in the elderly—Greater risk of orthostatic hypotension and anticholinergic side effects in these patients





Dental—Clozapine-induced blood dyscrasias may result in infections, delayed healing, and bleeding; dry mouth may cause caries and candidiasis; hypersalivation occurs frequently
Other medications, especially alcohol, other CNS depression–producing medications, other bone marrow depressants, other hypotension-producing medications, lithium, or selective serotonin reuptake inhibitors
Other medical problems, especially severe CNS depression, myeloproliferative disorders, predisposition to narrow-angle glaucoma, intestinal motility impairment, prostatic hypertrophy, and seizure disorders

Proper use of this medication
» Compliance with therapy; not taking more or less medication than prescribed

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses; not taking if clozapine has not been taken in 2 or more days but contacting physician for instructions

» Proper storage

Precautions while using this medication
» Regular visits to physician to check progress of therapy and to laboratory for blood tests required to continue treatment

» Contacting physician for instruction before resuming clozapine use if clozapine has not been taken for ³ 2 days

Checking with physician before discontinuing medication; gradual dosage reduction may be needed

Avoiding use of alcoholic beverages or other CNS depressants during therapy

» Immediately reporting to physician any lethargy, weakness, fever, sore throat, or other sign or symptom of infection that occurs during clozapine treatment because of the risk of blood dyscrasias

» Immediately reporting to physician any unexplained fatigue, dyspnea, tachypnea, fever, chest pain, palpitations, or other signs or symptoms of heart failure that occur during clozapine treatment because of the risk of myocarditis

Possible drowsiness, blurred vision, or seizures; not driving, swimming, climbing, operating machinery, or doing other things that require alertness or accurate vision

Possible orthostatic hypotension; caution when getting up from a lying or sitting position

Possible dryness of mouth; using sugarless gum or candy, ice, or saliva substitute for relief; checking with physician or dentist if dryness of mouth continues for more than 2 weeks


Side/adverse effects
Signs of potential side effects, especially cardiovascular effects, fever, agitation, akathisia, confusion, difficulty in accommodation, ECG changes, hypertension, syncope, blood dyscrasias, deep-vein thrombosis or pulmonary embolism, extrapyramidal effects, hepatitis, hyperglycemia, impotence, insomnia or disturbed sleep, mental depression, or myocarditis, neuroleptic malignant syndrome, seizures, tardive dyskinesia, or trouble in urinating


General Dosing Information
Clozapine dosage must be individualized by cautious titration from the lower dosage range. A divided dosing schedule should be used, the need for clozapine periodically reassessed, and the patient maintained at the lowest possible dosage level. Cautious titration and divided doses are necessary to minimize the risks of hypotension, seizure, and sedation. {03}

Because of the risk of blood dyscrasias, the patient should be instructed to report immediately any lethargy, weakness, fever, sore throat, or other sign or symptom of infection that occurs during clozapine treatment {03}.

Because of the continuing risks of seizure and agranulocytosis, a patient who does not show acceptable clinical benefit should not receive extended clozapine therapy {03}.

If clozapine is to be discontinued, the dosage should be tapered gradually over 1 to 2 weeks if possible {03}. However, if abrupt termination is necessary, the patient should be monitored for recurrence of psychotic symptoms {03}, as rapid decompensation has occurred after sudden withdrawal {04} {13}.

Caution should be exercised in restarting clozapine. The mechanisms by which clozapine's adverse effects occur are unknown. The possibility exists that agranulocytosis will be more likely and more severe when clozapine is restarted in a patient who has previously received clozapine if, for example, an immune-mediated mechanism is involved. Any patient whose white blood cell (WBC) count falls below 2000 per mm 3 or whose absolute neutrophil count falls below 1000 per mm 3 should not be restarted on clozapine. {03}

For treatment of adverse effects


Neuroleptic malignant syndrome (NMS):
Treatment is essentially symptomatic and supportive and may include the following {19}:
   • Discontinuing clozapine immediately.
   • Hyperthermia—Administering antipyretics (aspirin or acetaminophen); using cooling blanket.
   • Dehydration—Restoring fluids and electrolytes.
   • Cardiovascular instability—Monitoring blood pressure and cardiac rhythm closely. Use of sodium nitroprusside may allow vasodilation with subsequent heat loss from the skin in patients with less dominant muscle rigidity.
   • Hypoxia—Administering oxygen; considering airway insertion and assisted ventilation.
   • Muscle rigidity—Administering dantrolene sodium (100 to 300 mg a day orally in divided doses; or 1.25 to 1.5 mg per kg of body weight [mg/kg], intravenously); or administering amantadine (100 mg twice daily) or bromocriptine (5 mg three times a day) to restore central balance of dopamine and acetylcholine at the receptor site.



Tardive dyskinesia:
No known effective treatment. Although no confirmed cases of tardive dyskinesia have been attributed to clozapine, the dosage of clozapine should be lowered or medication discontinued at earliest signs of tardive dyskinesia to prevent irreversible effects.



Agranulocytosis:
If the WBC count falls below 2000 per mm 3 or the granulocyte count falls below 1000 per mm 3 {03}:
   • Discontinuing clozapine immediately.
   • Considering bone marrow aspiration to determine granulopoietic status.
   • Placing patient in protective isolation with close observation if granulopoiesis is deficient.
   • Monitoring WBC and differential counts daily until normal levels return.
   • Performing appropriate cultures and instituting appropriate antibiotic therapy if signs of infection occur.
   • Not rechallenging patient with clozapine.



Oral Dosage Forms

CLOZAPINE TABLETS

Usual adult dose
Antipsychotic
Oral, initially 12.5 mg (one half of a 25-mg tablet) one or two times a day, the dosage being increased in increments of 25 to 50 mg a day, if tolerated, to achieve a dose of 300 to 450 mg a day by the end of two weeks. Subsequent dosage increments should not exceed 100 mg one or two times a week {03}.

If reinitiating clozapine treatment two or more days since the last dose was taken, an initial dosage of 12.5 mg (one half of a 25-mg tablet) one or two times a day is recommended. However, titration to an effective dosage may proceed more rapidly than initial titration if the medication is well-tolerated. In any patient who experienced respiratory or cardiac arrest during initial dosing but who was then successfully titrated to a therapeutic dosage, titration of clozapine following reinitiation should proceed with great caution after an interruption in therapy of ³ 24 hours duration. {03}


Note: For malnourished patients, or those with hepatic, renal, or cardiovascular disease, dosage should be titrated more slowly than for other patients {13}.


Usual adult prescribing limits
900 mg per day {03}.

Usual pediatric dose
Children younger than 16 years of age
Safety and efficacy have not been established {03} {15}.


Strength(s) usually available
U.S.—


25 mg (Rx) [Clozaril (scored) (lactose){03}][Generic] (scored){23}


100 mg (Rx) [Clozaril (scored) (lactose){03}][Generic] (scored){23}

Canada—


25 mg (Rx) [Clozaril (scored) (lactose){15}]


100 mg (Rx) [Clozaril (scored) (lactose){15}]

Packaging and storage:
Store below 30 °C (86 °F) {03} {15}, in a tight container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid alcoholic beverages.

Note: Clozapine may be dispensed only upon presentation of acceptable white blood cell (WBC) count results and only in a quantity sufficient to cover the time until the next scheduled blood test {03} {15} {23}.




Revised: 06/12/2002



References
  1. CLOZARIL (Sandoz) Hospital Formulary Information Packet, l989.
  1. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention Inc; 1997. p. 187.
  1. Clozapine package insert (Clozaril, Novartis—US), Rev 3/98, Rec 6/98.
  1. Bablenis E, Weber SS, Wagner RL. Clozapine: a novel antipsychotic agent. DICP Ann Pharmacother l989 Feb; 23: 109-15.
  1. Ereshefsky L, Watanabe MD, Tran-Johnson TK. Clozapine: an atypical antipsychotic. Clin Pharm 1989; 8: 691-709.
  1. Kane J, Honigfeld G, Singer J, et al. Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry l988; 45: 789-96.
  1. Personal communication, Medical Information Department, Novartis Pharmaceuticals—US, 6/19/98.
  1. Honigfeld G, Patin J, Singer J. Clozapine: antipsychotic activity in treatment-resistant schizophrenics. Advances in Therapy l984 Mar; 1(2): 77-97.
  1. Small JG, Milstein V, Marhenke JD, et al. Treatment outcome with clozapine in tardive dyskinesia, neuroleptic sensitivity, and treatment-resistant psychosis. J Clin Psychiatry l987 Jul; 48(7): 263-7.
  1. Lowe III JA, Seeger TF, Vinick FJ. Atypical antipsychotics—recent findings and new perspectives. Med Res Rev l988; 8(4): 475-97.
  1. Panteleeva GP, Tsutsul Kovskaya MY, Belyaev BS, et al. Clozapine in the treatment of schizophrenic patients: an international multicenter trial. Clin Ther 1987; 10(1): 57-68.
  1. Balant-Gorgia AE, Balant L. Antipsychotic drugs: clinical pharmacokinetics of potential candidates for plasma concentration monitoring. Clin Pharmacokinet l987 Aug; 13(2): 65-90.
  1. Wolters EC, Hurwitz TA, Peppard RF, et al. Clozapine: an antipsychotic agent in Parkinson's disease? Clin Neuropharmacol 1989 Apr; 12(2): 83-90.
  1. Hayes PE. Dopamine receptors and new therapies for schizophrenia. Wellcome Trends in Hospital Pharmacy 1989 Oct: 8-10.
  1. Clozapine product monograph (Clozaril, Novartis—Canada), Rev 2/25/98, Rec 6/17/98.
  1. Kane JM, Cooper TB, Sachar EJ, et al. Clozapine: plasma levels and prolactin response. Psychopharmacology 1981; 73: 184-7.
  1. Claghorn J, Honigfeld G, Abuzzahab FS, et al. The risks and benefits of clozapine versus chlorpromazine. J Clin Psychopharmacol l987 Dec; 7(6): 377-84.
  1. Lindstrom LH. The effect of long-term treatment with clozapine in schizophrenia: a retrospective study in 96 patients treated with clozapine for up to 13 years. Acta Psychiatr Scand 1988; 77: 524-9.
  1. Birkhimer LJ, DeVane CL. The neuroleptic malignant syndrome: presentation and treatment. Drug Intell Clin Pharm 1984 Jun; 18: 462-5.
  1. Panelist comment, 3/90.
  1. Panelist comment, 3/90.
  1. Panelist comment, 3/90.
  1. Clozapine package insert (Zenith Goldline—US), Rev 10/97, Rec 1/98.
  1. Panelist comment, 3/90.
  1. Panel concensus, 3/90.
  1. Haring C, Meise U, Humpel C, et al. Dose-related plasma levels of clozapine: influence of smoking, behavior, sex and age. Psychopharmacology l989; 99 (Suppl): S38-S40.
  1. Manufacturer comment, 4/90.
  1. Dentistry Advisory Panel, 1987-8.
  1. Product Information: Clozaril®, clozapine, Novartis, East Hanover, NJ, (PI revised 2/2002) reviewed 3/2002.
  1. Expert Committee comment, 6/2002.
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