Life-Threatening or Dangerous Side Effects

• Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients taking atypical antipsychotics

• Agranulocytosis (includes flu-like symptoms or signs of infection)

• Seizures (risk increases with dose)

• Neuroleptic malignant syndrome (more likely when clozapine is used with another agent)

• Pulmonary embolism (may include deep vein thrombosis or respiratory symptoms)

• Myocarditis

• Paralytic ileus

• Increased risk of death and cerebrovascular events in elderly patients with dementia-related psychosis

Weight Gain

• Frequent and can be significant in amount

• Can become a health problem in some

• More than for some other antipsychotics, but never say always as not a problem in everyone

Sedation

• Frequent and can be significant in amount

• Some patients may not tolerate it

• More than for some other antipsychotics, but never say always as not a problem in everyone

• Can wear off over time

• Can reemerge as dose increases and then wear off again over time

What to Do About Side Effects

• Patients must inform prescriber immediately of any flu-like symptoms, muscle rigidity, altered mental status, irregular pulse or blood pressure

• Take at bedtime to help reduce daytime sedation

• Sedation may wear off with time

• Start dosing low and increase slowly as side effects wear off at each dosing increment

• Weight loss, exercise programs, and medical management for high BMIs, diabetes, dyslipidemia

• Switch to another agent

Best Augmenting Agents for Side Effects

• Many side effects cannot be improved with an augmenting agent

CLOZAPINE: DOSING AND USE

Usual Dosage Range

• 300–450 mg/day

Dosage Forms

• Tablet 12.5 mg, 25 mg scored, 50 mg, 100 mg scored

• Orally disintegrating tablet 12.5 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg

• Oral suspension 50 mg/mL

How to Dose

• Initial 25 mg in 2 divided doses; increase by 25–50 mg/day each day until desired efficacy is reached; maintenance dose 300–450 mg/day; doses above 300 mg/day should be divided; increases in doses above 450 mg/day should be made weekly; maximum dose generally 900 mg/day

• See also Switching section below, after Pearls

Dosing Tips

• Prescriptions are generally given 1 week at a time for the first 6 months of treatment because of the risk of agranulocytosis; for months 6–12 prescriptions can generally be given 2 weeks at a time; after 12 months prescriptions can generally be given monthly

✽ Treatment should be suspended if absolute neutrophil count falls below 1,000/mm³

• Treatment should be suspended if white blood cell count falls below 2,000/mm³

• Treatment should be suspended if eosinophil count rises above 4,000/mm³, and continued once it falls below 3,000/mm³

• If treatment is discontinued for more than 2 days, it may need to be reinitiated at a lower dose and slowly increased in order to maximize tolerability

• Plasma half-life suggests twice daily administration, but in practice it may be given once a day at night

• Doses over 550 mg/day may require concomitant anticonvulsant administration to reduce the chances of a seizure

✽ Rebound psychosis may occur unless dose is very slowly tapered, by 100 mg/week or less

Overdose

• Sometimes lethal; changes in heart rhythm, excess salivation, respiratory depression, altered state of consciousness

Long-Term Use

• Treatment to reduce risk of suicidal behavior should be continued for at least 2 years

• Often used for long-term maintenance in treatment-resistant schizophrenia

Habit Forming

• No

How to Stop

• See Switching section of individual agents for how to stop clozapine, generally over at least 4 weeks

• Blood testing is necessary every week for 4 weeks following discontinuation, or until WBC ≥3,500/mm³ and ANC ≥2,000/mm³

✽ Rapid discontinuation may lead to rebound psychosis and worsening of symptoms

Pharmacokinetics

• Half-life 5–16 hours

• Metabolized by multiple CYP450 enzymes, including 1A2, 2D6, and 3A4

Drug Interactions

• Dose may need to be reduced if given in conjunction with CYP450 1A2 inhibitors (e.g., fluvoxamine)

• Dose may need to be raised if given in conjunction with CYP450 1A2 inducers (e.g., cigarette smoke)

• CYP450 2D6 inhibitors (e.g., paroxetine, fluoxetine, duloxetine) can raise clozapine levels, but dosage adjustment usually not necessary

• CYP450 3A4 inhibitors (e.g., nefazodone, fluvoxamine, fluoxetine) can raise clozapine levels, but dosage adjustment usually not necessary

• Clozapine may enhance effects of antihypertensive drugs