No

Antipsychotic Agent, Dibenzodiazepine

Management of treatment of refractory schizophrenia

B

Hypersensitivity to clozapine or any component of the formulation; history of agranulocytosis or granulocytopenia with clozapine; uncontrolled epilepsy; severe central nervous system depression or comatose state; myeloproliferative disorders or use with other agents which have a well-known risk of agranulocytosis or bone marrow suppression

Medication should not be stopped abruptly; taper off over 1-2 weeks. WBC testing should occur weekly for the first 6 months of therapy; thereafter, if acceptable, WBC counts are maintained (WBC >3000/mm³, ANC >1500/mm³) then WBC counts can be monitored every other week. WBCs must be monitored weekly for the first 4 weeks after therapy discontinuation. Significant risk of agranulocytosis, potentially life-threatening. Use with caution in patients receiving other marrow suppressive agents. Elderly patients are more susceptible to adverse effects (including cardiovascular, anticholinergic, and tardive dyskinesia).

May cause orthostatic hypotension and tachycardia; use with caution in patients at risk of hypotension or in patients where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). Concurrent use of psychotropics and benzodiazepines may increase the risk of severe cardiopulmonary reactions. Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold.

Has been associated with benign, self-limiting fever (<100.4 F, usually within first three weeks). However, clozapine may also be associated with severe febrile reactions, including neuroleptic malignant syndrome (NMS). Clozapine's potential for extrapyramidal reactions appears to be extremely low.

May cause anticholinergic effects; use with caution in patients with urinary retention, benign prostatic hypertrophy, narrow-angle glaucoma, xerostomia, visual problems, constipation, or history of bowel obstruction.

Eosinophilia has been reported to occur with clozapine and may require temporary or permanent interruption of therapy. Pulmonary embolism has been associated with clozapine therapy. May cause hyperglycemia - use with caution in patients with diabetes or other disorders of glucose regulation. Use with caution in patients with hepatic disease or impairment - hepatitis has been reported as a consequence of therapy.

Rare cases of thromboembolism, including pulmonary embolism and stroke resulting in fatalities, have been associated with clozapine.

>10%:

Cardiovascular: Tachycardia, orthostasis (up to 25%)

Central nervous system: Drowsiness, dizziness

Gastrointestinal: Constipation, unusual weight gain, diarrhea, sialorrhea

Genitourinary: Urinary incontinence

1% to 10%:

Cardiovascular: EKG changes, hypertension, hypotension, syncope

Central nervous system: Akathisia, seizures, headache, nightmares, akinesia, confusion, insomnia, fatigue, myoclonic jerks

Dermatologic: Rash

Gastrointestinal: Abdominal discomfort, heartburn, xerostomia, nausea, vomiting

Hematologic: Eosinophilia, leukopenia

Neuromuscular & skeletal: Tremor

Miscellaneous: Diaphoresis (increased), fever

<1%: Myocardial infarction, congestive heart failure, myocarditis, pericarditis, pericardial effusion, arrhythmias, tardive dyskinesia, neuroleptic malignant syndrome, difficult urination, impotence, agranulocytosis, granulocytopenia, thrombocytopenia, rigidity, blurred vision, thromboembolism, pulmonary embolism, stroke

Symptoms of overdose include altered states of consciousness, tachycardia, hypotension, hypersalivation, respiratory depression

Following initiation of essential overdose management, toxic symptom treatment and supportive treatment should be initiated. Hypotension usually responds to I.V. fluids or Trendelenburg positioning. If unresponsive to these measures, the use of a parenteral inotrope may be required. Seizures commonly respond to diazepam (I.V. 5-10 mg bolus in adults every 15 minutes if needed up to a total of 30 mg; I.V. 0.25-0.4 mg/kg/dose up to a total of 10 mg in children) or to phenytoin or phenobarbital; critical cardiac arrhythmias often respond to I.V. phenytoin (15 mg/kg up to 1 g), while other antiarrhythmics can be used. Neuroleptics often cause extrapyramidal symptoms (eg, dystonic reactions) requiring management with benztropine mesylate I.V. 1-2 mg (adults) may be effective. These agents are generally effective within 2-5 minutes.

CYP1A2, 2C (minor), 2E1, 3A3/4 enzyme substrate, CYP2D6 enzyme substrate (minor)

Carbamazepine, phenytoin, and primidone increase the hepatic metabolism of clozapine; monitor for altered response

Cigarette smoking may enhance the metabolism of clozapine; larger doses may be required compared to nonsmokers

Clarithromycin, cimetidine, erythromycin, fluoxetine, fluvoxamine, paroxetine, sertraline, and troleandomycin may inhibit the metabolism of clozapine; monitor for altered clozapine effect; use alternative agents

Clozapine may reverse the pressor effect of epinephrine

Valproic acid may cause reductions in clozapine concentrations; monitor for altered response

Dispensed in "clozapine patient system" packaging

Clozapine is a weak dopamine₁ and dopamine₂ receptor blocker, but blocks D₁-D₅ receptors; in addition, it blocks the serotonin₂, alpha-adrenergic, histamine H₁, and cholinergic receptors

Metabolism: Undergoes extensive metabolism primarily to unconjugated forms

Elimination: In urine

Oral:

Elderly; Dose selection and titration should be cautious

Most pharmacology textbooks state that in presence of phenothiazines, systemic doses of epinephrine paradoxically decrease the blood pressure. This is the so called "epinephrine reversal" phenomenon. This has never been observed when epinephrine is given by infiltration as part of the anesthesia procedure.

Many patients may experience orthostatic hypotension with clozapine; precautions should be taken; do not use atropine-like drugs for xerostomia in patients taking clozapine because of significant potentiation

Use exactly as directed (do not increase dose or frequency); may cause physical and/or psychological dependence. Do not discontinue without consulting prescriber. Avoid excess alcohol or caffeine and other prescription or OTC medications not approved by prescriber. Maintain adequate hydration (2-3 L/day of fluids unless instructed to restrict fluid intake). You may experience headache, excess drowsiness, dizziness, or blurred vision (use caution driving or when engaging in tasks requiring alertness until response to drug is known); dry mouth, nausea, vomiting (small frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); or postural hypotension (use caution climbing stairs or when changing position from lying or sitting to standing). Report persistent CNS effects (insomnia, depression, altered consciousness); palpitations, rapid heartbeat, severe dizziness; vision changes; hypersalivation, tearing, sweating; difficulty breathing; or worsening of condition. Breast-feeding precautions: Do not breast-feed.

Benign, self-limiting temperature elevations sometimes occur during the first 3 weeks of treatment, weekly CBC mandatory

Tablet: 25 mg, 100 mg

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