clozapine Clozaril
Pharmacologic classification: tricyclic dibenzodiazepine derivative Therapeutic classification: antipsychotic drug Pregnancy risk category B
Available forms Available by prescription only Tablets: 25 mg, 100 mg
Indications and dosages Treatment of schizophrenia in severely ill patients unresponsive to other therapies. Adults: Initially, 12.5 mg P.O. once or twice daily, adjusted upward at 25 to 50 mg daily (if tolerated) to a daily dose of 300 to
450 mg by end of 2 weeks. Individual dosage is based on clinical response, patient tolerance, and adverse reactions. Subsequent
dosage increases should occur no more than once or twice weekly and shouldn’t exceed 100 mg. Many patients respond to doses
of 300 to 600 mg daily, but some patients require as much as 900 mg daily. Don’t exceed 900 mg daily.
Pharmacodynamics Antipsychotic action: Clozapine binds to dopamine receptors (D-1, D-2, D-3, D-4, and D-5) within the limbic system of the CNS. It also may interfere
with adrenergic, cholinergic, histaminergic, and serotoninergic receptors.
Pharmacokinetics Absorption: Food doesn’t appear to interfere with bioavailability. Only 27% to 50% of the dose reaches systemic circulation. Distribution: About 97% bound to serum proteins. Metabolism: Metabolism is nearly complete; very little unchanged drug appears in the urine. Excretion: About 50% appears in the urine and 30% in the feces, mostly as metabolites. Elimination half-life appears to be proportional
to dose and may range from 4 to 66 hours.
Route |
Onset |
Peak |
Duration |
P.O. |
Unknown |
2 1/2 hr |
4-12 hr
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Contraindications and precautions Contraindicated in patients with uncontrolled epilepsy or history of clozapine-induced agranulocytosis; in patients with
a WBC count below 3,500/mm3; in patients with severe CNS depression or coma; in patients taking other drugs that suppress bone marrow function; and in
those with myelosuppressive disorders. Use cautiously in patients with renal, hepatic, or cardiac disease, prostatic hyperplasia, or angle-closure glaucoma and
in those receiving general anesthesia. Use cautiously with other drugs metabolized by cytochrome P-450 2D6, including antidepressants, phenothiazines, carbamazepine,
and type IC antiarrhythmics (propafenone, flecainide, encainide) or drugs that inhibit this enzyme, such as quinidine.
Interactions Drug-drug. Anticholinergics: May potentiate anticholinergic effects of clozapine. Avoid use together. Antihypertensives: May potentiate hypotensive effects. Check blood pressure frequently. Benzodiazepines: Causes risk of respiratory arrest and severe hypotension. Avoid use together. Bone marrow suppressants: Increases bone marrow toxicity. Use together cautiously. CNS-active drugs: May cause additive effects. Use together cautiously. Digoxin, highly protein-bound drugs, warfarin: Increases levels of these drugs. Monitor patient closely for adverse reactions. Phenytoin: Decreases phenytoin levels and may lower seizure threshold. Avoid use together. Drug-herb. Nutmeg: May reduce effectiveness of drug. Discourage use together. Drug-food. Beverages containing caffeine: May inhibit antipsychotic effects of clozapine. Monitor patient closely. Drug-lifestyle. Alcohol use: Increases CNS depression. Discourage alcohol use. Smoking: May reduce plasma clozapine levels. Discourage smoking.
Adverse reactions CNS: drowsiness, sedation,seizures, dizziness, syncope, vertigo, headache, tremor, disturbed sleep or nightmares, restlessness, hypokinesia or akinesia, agitation,
rigidity, akathisia, confusion, fatigue, insomnia, hyperkinesia, weakness, lethargy, ataxia, slurred speech, depression, myoclonus,
anxiety, neuroleptic malignant syndrome, fever. CV: tachycardia, hypotension, hypertension, chest pain, cardiomyopathy, ECG changes, orthostatic hypotension. EENT: visual disturbances. GI: dry mouth, nausea, vomiting, excessive salivation, heartburn, constipation, diarrhea. GU: urinary abnormalities (urinary frequency or urgency, urine retention), incontinence, abnormal ejaculation. Hematologic: leukopenia, agranulocytosis, eosinophilia, neutropenia, thrombocytopenia. Metabolic: weight gain. Musculoskeletal: muscle pain or spasm, muscle weakness. Skin: rash, diaphoresis. After abrupt withdrawal of long-term therapy: Possible abrupt recurrence of psychotic symptoms. Monitor patient closely.
Effects on lab test results May decrease WBC and granulocyte counts.
Overdose and treatment Fatalities have occurred at doses exceeding 2.5 g. Symptoms include drowsiness, delirium, coma, hypotension, hypersalivation,
tachycardia, respiratory depression, and, rarely, seizures. Treat symptomatically. Establish an airway and ensure adequate ventilation. Gastric lavage with activated charcoal and sorbitol
may be effective. Monitor vital signs. Avoid epinephrine (and derivatives), quinidine, and procainamide when treating hypotension
and arrhythmias.
Special considerations Monitor for the development of cardiomyopathy. If diagnosis is confirmed, stop drug unless the benefit clearly outweighs the
risks. When discontinuing clozapine therapy, drug must be withdrawn gradually (over a 1- to 2-week period). However, changes in the
patient’s clinical status (including the development of leukopenia) may require abrupt discontinuation of the drug. If so,
monitor patient closely for recurrence of psychotic symptoms. To reinstate therapy in patients withdrawn from drug, follow usual guidelines for dosage buildup. However, re-exposure of
the patient may increase the risk and severity of adverse reactions. If therapy was terminated for WBC counts of less than
2,000/mm3 or granulocyte counts of less than 1,000/mm3, drug shouldn’t be reinstated. Clozapine is associated with an increased risk of fatal myocarditis especially during, but not limited to, first month of
therapy. For patients in whom myocarditis is suspected (unexplained fatigue, dyspnea, tachypnea, chest pain, tachycardia,
fever, palpitations, and other signs or symptoms of heart failure or ECG abnormalities, such as ST-T wave abnormalities or
arrhythmias), clozapine therapy should be discontinued immediately. Drug shouldn’t be rechallenged. Obtain baseline CBC before starting therapy. Don’t start drug if WBC count is lower than 3,500/mm3. Monitor CBC weekly during treatment, and for at least 4 weeks after drug is discontinued. Some patients experience transient fevers (temperature of more than 100.4° F [38° C]), especially in the first 3 weeks of
therapy. Breast-feeding patients Drug appears in breast milk. Women taking clozapine shouldn’t breast-feed. Pediatric patients Safety in children hasn’t been established. Geriatric patients Elderly patients may require reduced dosages, because they may be more sensitive to adverse reactions.
Patient education Warn patient about risk of developing agranulocytosis. Safe use of drug requires blood tests weekly during treatment. Advise patient to promptly report flulike symptoms, fever, sore throat, or other signs of infection. Also, tell him to report
unexplained fatigue, difficulty breathing, irregular heart rate, or leg or ankle swelling. Advise patient to call before taking OTC drugs or alcohol. Tell patient that ice chips or sugarless candy or gum may relieve dry mouth. Warn patient to rise slowly to upright position to avoid orthostatic hypotension.
Reactions may be common, uncommon, life-threatening, or
COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use
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