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Clozapine

Pronunciation

Pronunciation: KLOE-za-peen
Class: Antipsychotic agent/dibenzapine derivative

Trade Names

Clozapine
- Tablets 12.5 mg
- Tablets 50 mg
- Tablets 200 mg

Clozaril
- Tablets 25 mg
- Tablets 100 mg

FazaClo
- Tablets, orally disintegrating 12.5 mg
- Tablets, orally disintegrating 25 mg
- Tablets, orally disintegrating 100 mg
- Tablets, orally disintegrating 150 mg
- Tablets, orally disintegrating 200 mg

Apo-Clozapine (Canada)
Gen-Clozapine (Canada)

Pharmacology

Interferes with dopamine binding at D 1 , D 2 , D 3 , and D 5 receptors in the CNS; has high affinity for the D 4 receptor; antagonizes adrenergic, cholinergic, histaminergic, and serotonergic neurotransmission.

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Pharmacokinetics

Absorption

C max is approximately 319 ng/mL (at steady state for tablets) and 413 ng/mL (at steady state for orally disintegrating tablets). T max is approximately 2.5 h (tablets) and 2.3 h (orally disintegrating tablets).

Distribution

Approximately 97% protein bound.

Metabolism

Extensively metabolized.

Elimination

The half-life is approximately 8 h (single dose) and approximately 12 h (steady state). Approximately 50% is excreted in urine and 30% in feces as metabolites.

Indications and Usage

Management of severely ill schizophrenic patients who have not responded to or cannot tolerate standard antipsychotic drug treatment; to reduce risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for reexperiencing suicidal behavior.

Contraindications

History of clozapine-induced agranulocytosis or severe granulocytopenia; myeloproliferative disorders; simultaneous administration with other agents known to cause bone marrow suppression; severe CNS depression or comatose states; uncontrolled epilepsy; paralytic ileus; hypersensitivity to product.

Dosage and Administration

Adults Initial dose

PO 12.5 mg daily or twice daily; increase by 25 to 50 mg daily up to 300 to 450 mg daily by the end of 2 wk. May then increase dose in increments not to exceed 100 mg once or twice per week (max, 900 mg daily).

General Advice

  • Only available through a distribution system that ensures monitoring of WBC counts.
  • If reinitiating treatment in patient who has been off clozapine (2 or more days since last dose), ensure that dose is retitrated, starting at 12.5 mg once or twice daily.
  • Administer prescribed dose without regard to meals. Administer with food if GI upset occurs.
  • Allow adequate time for patient to respond to a dose before escalation to a higher dose.
  • Drug dispensing is contingent upon WBC count and absolute neutrophil count (ANC) test results, and should not ordinarily exceed a weekly supply.
  • Patients who discontinued for WBC counts below 2,000/mm 3 or an ANC below 1,000/mm 3 must not be restarted on clozapine.
  • Orally disintegrating tablets
  • Remove tablet from blister pack just prior to use. Do not push tablet through foil. Peel foil from blister and gently remove tablet from blister.
  • Place tablet in mouth immediately after removing from blister pack, allow to disintegrate, and swallow with saliva. No water is needed to take the tablet.
  • Tablets contain phenylalanine, a component of aspartame.

Storage/Stability

Store between 59° and 86°F. Protect orally disintegrating tablets from moisture.

Drug Interactions

Agents that suppress bone marrow

Risk or severity of bone marrow suppression may be increased.

Alcohol, CNS depressants, general anesthesia

Use with caution because of CNS effects of clozapine.

Anticholinergics

Anticholinergic effects may be potentiated.

Antihypertensives

Hypotensive effects may be potentiated.

Barbiturates (eg, phenobarbital)

May decrease concentrations and pharmacologic effects of clozapine.

Benzodiazepines, psychotropic drugs (eg, haloperidol)

Consider the possibility of occurrence of orthostatic hypotension if clozapine therapy is initiated in a patient receiving agents from one of these classes.

CYP2D6 substrates (eg, antidepressants, phenothiazines)

Use with caution.

CYP-450 inducers (eg, carbamazepine, nicotine, phenytoin, rifampin)

May reduce clozapine plasma levels, decreasing the effectiveness.

CYP-450 inhibitors (eg, caffeine, cimetidine, ciprofloxacin, citalopram, erythromycin, ketoconazole, modafinil, nefazodone, risperidone, ritonavir, SSRIs)

May elevate clozapine plasma levels, increasing the risk of adverse reactions. Concurrent use with ritonavir is contraindicated.

Drugs metabolized by CYP2D6 (eg, amitriptyline, flecainide, vinblastine)

Clozapine may inhibit CYP2D6 activity and make individuals with normal CYP2D6 metabolic activity resemble poor metabolizers. Coadminister clozapine with agents metabolized by this enzyme with caution.

Tramadol

Increased risk of seizures may occur during coadministration.

Type 1C antiarrhythmics (eg, flecainide, propafenone)

Use with caution.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Tachycardia (25%); hypotension (9%); syncope (6%); hypertension (4%); chest pain/angina, ECG change/cardiac abnormality (1%); atrial or ventricular fibrillation, cardiomyopathy, deep vein thrombosis, myocarditis (postmarketing).

CNS

Somnolence (46%); drowsiness/sedation (39%); dizziness (27%); insomnia (20%); vertigo (19%); headache (7%); tremor (6%); agitation, disturbed sleep/nightmares, hypokinesia/akinesia, restlessness (4%); akathisia, confusion, rigidity, seizures (3%); fatigue (2%); anxiety, ataxia, depression, hyperkinesia, lethargy, slurred speech, weakness (1%); abnormal EEG, delirium, exacerbation of psychosis, mild cataplexy, myoclonus, paresthesia, status epilepticus (postmarketing).

Dermatologic

Rash (2%); erythema multiforme, Stevens-Johnson syndrome (postmarketing).

EENT

Visual disturbances (5%); nasal congestion, throat discomfort (1%); narrow-angle glaucoma, periorbital edema (postmarketing).

GI

Salivary hypersecretion (48%); salivation (31%); constipation (25%); nausea, vomiting (17%); dyspepsia (14%); dry mouth (6%); abdominal discomfort/heartburn (4%); nausea/vomiting (3%); diarrhea (2%); anorexia (1%); acute pancreatitis, dysphagia, fecal impaction, intestinal obstruction/paralytic ileus, salivary gland swelling (postmarketing).

Genitourinary

Urinary abnormalities (2%); abnormal ejaculation, incontinence, urinary retention, urinary urgency/frequency (1%); acute interstitial nephritis, priapism (postmarketing).

Hematologic

Leukopenia/decreased WBC/neutropenia (3%); agranulocytosis, eosinophilia (1%); elevated hemoglobin/hematocrit, erythrocyte sedimentation rate increase, sepsis, thrombocytopenia, thrombocytosis (postmarketing).

Hepatic

Liver test abnormalities (1%); cholestasis, hepatitis, jaundice (postmarketing).

Metabolic

Weight increase (31%); hypercholesterolemia, hyperglycemia, hypertriglyceridemia, hyperuricemia, hyponatremia, weight loss (postmarketing).

Musculoskeletal

Back pain, leg or neck pain, muscle pain or ache, muscle spasm, muscle weakness (1%); dystonia, myasthenic syndrome, rhabdomyolysis (postmarketing).

Respiratory

Dyspnea (1%); aspiration, pleural effusion, pulmonary embolism (postmarketing).

Miscellaneous

Sweating (6%); fever (5%); tongue numb/sore (1%); CPK elevation, hypersensitivity reactions, photosensitivity, overdose, sepsis, vasculitis (postmarketing).

Precautions

Warnings

Agranulocytosis

Life-threatening agranulocytosis can occur. Baseline WBC and ANC should be done before initiation of treatment, during treatment, and for at least 4 wk after discontinuing treatment.

Seizures

Use of clozapine has been associated with seizures. There is a greater likelihood at higher doses. Administer with caution to patients with a history of seizures or other predisposing factors.

Myocarditis

There is an increased risk of fatal myocarditis, especially during, but not limited to, the first month of therapy. Promptly discontinue clozapine if myocarditis is suspected.

CV and respiratory effects

Orthostatic hypotension can occur. Rarely, collapse can be profound and accompanied by respiratory and/or cardiac arrest. Orthostatic hypotension is more likely to occur during initial dose titration in association with rapid dose escalation. Caution is advised when clozapine is started in patients taking a benzodiazepine or other psychotropic agent because cardiac arrest, collapse, and respiratory arrest have occurred.

Increased mortality

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death compared with placebo. Although the causes of death were varied, most of the deaths appeared to be either CV (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Clozapine is not approved for the treatment of dementia-related psychosis.


Monitor

Baseline WBC and ANC should be done before initiation of treatment, during treatment, and for at least 4 wk after discontinuing treatment. The frequency of hematologic monitoring should be based on various stages of therapy (eg, initiation of therapy) or results from WBC count and ANC monitoring tests (eg, moderate leukopenia). Consult the manufacturer's information for additional details regarding the treatment of patients under the various conditions (eg, severe leukopenia). Regularly monitor patients with an established diagnosis of diabetes mellitus who are started on clozapine for worsening of glucose control. Patients with risk factors for diabetes mellitus (eg, family history of diabetes, obesity) who are started on treatment should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Monitor any patient being treated for symptoms of hypoglycemia, including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment should undergo fasting blood glucose testing. Monitor patients for signs and symptoms of tardive dyskinesia (eg, involuntary, dyskinetic movements) and infection. Monitor patients for signs and symptoms of cardiomyopathy (especially exertional dyspnea, fatigue, orthopnea, paroxysmal nocturnal dyspnea, and peripheral edema). Perform LFTs immediately in patients who develop nausea, vomiting, and/or anorexia.


Pregnancy

Category B .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Approach dose selection with caution, taking into consideration decreased renal, hepatic, and cardiac function, and other concomitant disease and drug therapy.

Hepatic Function

Use caution when administering clozapine to patients who have concurrent hepatic disease. Hepatitis has been reported in patients with normal and preexisting abnormalities in liver function.

Special Risk Patients

Use great caution in patients with renal or cardiac disease, narrow-angle glaucoma, pulmonary disease, enlarged prostate, or history of seizures; seizures are more likely at higher doses.

Cardiomyopathy

Has been reported. In clozapine-treated patients who developed cardiomyopathy, approximately 80% were younger than 50 y of age and the duration of treatment was more than 6 mo in 65% of reports.

Cognitive and motor performance

Because of initial sedation, mental and/or physical abilities may be impaired, especially during the first few days of therapy.

ECG changes

Some patients experience ECG repolarization changes during treatment. Several have experienced significant cardiac events, including ischemic changes, MI, nonfatal arrhythmias, and sudden, unexplained death.

Fever

May experience transient temperature elevations above 100.4°F, with peak incidence within first 3 wk of treatment.

General anesthesia

Because of the CNS effects of clozapine, caution is advised in patients receiving general anesthesia.

GI

Varying degrees of impairment of intestinal peristalsis, ranging from constipation to intestinal obstruction, fecal impaction, and paralytic ileus, have been associated with clozapine use.

Hyperglycemia and diabetes mellitus

Severe hyperglycemia, possibly leading to ketoacidosis, has been reported.

NMS

This potentially fatal condition has been reported in association with antipsychotic drugs. Signs and symptoms include hyperpyrexia, muscle rigidity, altered mental status, irregular pulse or BP, tachycardia, diaphoresis, and cardiac arrhythmias.

Phenylketonurics

Orally disintegrating tablets contain phenylalanine, a component of aspartame; use with caution in patients with phenylketonuria.

Pulmonary embolism

Consider the possibility in patients who present with deep vein thrombosis, acute dyspnea, chest pain, or other respiratory signs or symptoms.

Suicide

At least 2 y of treatment is recommended to maintain a reduction of risk for suicidal behavior. After 2 y, assess the patient's risk of suicidal behavior. If the health care provider's assessment indicates that a significant risk of suicidal behavior is still present, treatment should be continued. If the health care provider's assessment is that the patient is no longer at risk of suicidal behavior, treatment may be discontinued and treatment with an antipsychotic medication to which the patient previously responded may be resumed.

Tardive dyskinesia

This syndrome of potentially irreversible, involuntary dyskinetic movements has occurred with other antipsychotic agents. Incidence is highest among elderly patients, especially women.

Withdrawal of medication

For planned discontinuation of therapy, gradually reduce dosage over 1 to 2 wk. If abrupt discontinuation is required (eg, leukopenia), carefully observe the patient for recurrence of psychotic symptoms and symptoms of cholinergic rebound (eg, headache, nausea, vomiting).

Overdosage

Symptoms

Aspiration pneumonia, cardiac arrhythmias, coma, delirium, drowsiness, excessive salivation, hypotension, respiratory depression or failure, seizures, tachycardia.

Patient Information

  • Explain name, dose, action, and potential adverse reactions of drug, including risk of developing agranulocytosis, seizures, myocarditis, and tardive dyskinesia.
  • Ensure patient or caregiver understands that medication will only be provided in 1- or 2-wk supplies, depending on frequency of WBC count monitoring. Ensure patient knows how to obtain refills so that therapy is continued without interruption.
  • Instruct patient to take prescribed dose without regard to meals but to take with food if stomach upset occurs.
  • Instruct patient taking orally disintegrating tablet to keep tablet in unopened blister until just before use. Instruct patient to remove tablet by peeling the foil from the back of the blister and then to immediately place the tablet (or half tablet if ordered) in mouth, allow the tablet to disintegrate, and then swallow with saliva.
  • Advise patient that dose will be started low and then increased until max benefit is obtained.
  • Advise patient to notify health care provider if condition does not improve or worsens.
  • Advise patient that if medication needs to be discontinued, it will be slowly withdrawn over a period of 1 to 2 wk unless safety concerns (eg, low WBC count) require a more rapid withdrawal.
  • Instruct patient not to stop taking clozapine when feeling better.
  • Instruct diabetic patient to monitor blood glucose more frequently when drug is started or dose is changed and to inform health care provider of significant changes in readings.
  • Tell patient to immediately report altered mental status, change in personality or mood, chest pain, fever, flu-like symptoms, frequent urination, general body discomfort, involuntary body or facial movements, lethargy, mucous membrane sores or other signs of possible infection, muscle rigidity, pounding in the chest, rapid or difficult breathing, rapid or irregular heartbeat, seizures, sore throat, sweating, swelling of feet or ankles, unexplained fatigue, unexplained shortness of breath, unquenchable thirst, weakness, or weight gain to health care provider.
  • Advise patient to avoid strenuous activity during periods of high temperature or humidity.
  • Instruct patient to avoid alcoholic beverages and sedatives (eg, diazepam) while taking clozapine.
  • Instruct patient to get up slowly from lying or sitting position and to avoid sudden position changes to prevent postural hypotension. Advise patient to report dizziness with position changes to health care provider. Caution patient that hot tubs and hot showers or baths may make dizziness worse.
  • Advise patient to take sips of water, suck on ice chips or sugarless hard candy, or chew sugarless gum if dry mouth occurs.
  • Advise patient taking antihypertensives to monitor BP at regular intervals.
  • Advise patient with phenylketonuria that the orally disintegrating tablet contains phenylalanine.
  • Advise patient that drug may impair judgment, thinking, or motor skills or cause drowsiness, and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.
  • Advise patient with history of seizures or factors predisposing to seizures that drug may cause seizures and not to engage in any activity in which sudden loss of consciousness could cause serious risk to patient or others (eg, driving, swimming, climbing).
  • Advise patient that follow-up visits and weekly blood cell counts will be required to monitor therapy and to keep appointments.

Copyright © 2009 Wolters Kluwer Health.

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