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


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