Dosing Tips

✽ More may be much more: clinical practice suggests ziprasidone often under-dosed, then switched prior to adequate trials, perhaps due to unjustified fears of QTc prolongation

✽ Dosing many patients at 20–40 mg twice a day is too low and in fact activating, perhaps due to potent 5HT2C antagonist properties

✽ Paradoxically, such activation is often reduced by increasing the dose to 60–80 mg twice a day, perhaps due to increasing amounts of dopamine 2 receptor antagonism

✽ Best efficacy in schizophrenia and bipolar disorder is at doses >120 mg/day, but only a minority of patients are adequately dosed in clinical practice

✽ Recommended to be taken with food because food can double bioavailability by increasing absorption and thus increasing plasma drug levels

• Meals of a few hundred calories (e.g., turkey sandwich and a piece of fruit) or more are necessary to enhance the absorption of ziprasidone

• Some patients respond better to doses >160 mg/day and up to 320 mg/day in 2 divided doses (i.e., 80–160 mg twice a day)

• Many patients do well with a single daily oral dose, usually at bedtime

• QTc prolongation at 320 mg/day not significantly greater than at 160 mg/day

• Rather than raise the dose above these levels in acutely agitated patients requiring acute antipsychotic actions, consider augmentation with a benzodiazepine or conventional antipsychotic, either orally or intramuscularly

• Rather than raise the dose above these levels in partial responders, consider augmentation with a mood-stabilizing anticonvulsant, such as valproate or lamotrigine

• Children and elderly should generally be dosed at the lower end of the dosage spectrum

• Ziprasidone intramuscular can be given short-term, both to initiate dosing with oral ziprasidone or another oral antipsychotic and to treat breakthrough agitation in patients maintained on oral antipsychotics

• QTc prolongation of intramuscular ziprasidone is the same or less than with intramuscular haloperidol

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

Overdose

• Rarely lethal in monotherapy overdose; sedation, slurred speech, transitory hypertension

Long-Term Use

• Approved to delay relapse in long-term treatment of schizophrenia

• Often used for long-term maintenance in bipolar disorder and various behavioral disorders

Habit Forming

• No

How to Stop

• See Switching section of individual agents for how to stop ziprasidone

• Rapid oral discontinuation may lead to rebound psychosis and worsening of symptoms

Pharmacokinetics

• Mean half-life 6.6 hours

• Protein binding >99%

• Metabolized by CYP450 3A4

Drug Interactions

• Neither CYP450 3A4 nor CYP450 2D6 inhibitors significantly affect ziprasidone plasma levels

• Little potential to affect metabolism of drugs cleared by CYP450 enzymes

• May enhance the effects of antihypertensive drugs

• May antagonize levodopa, dopamine agonists

• May enhance QTc prolongation of other drugs capable of prolonging QTc interval

Other Warnings/Precautions

• Ziprasidone prolongs QTc interval more than some other antipsychotics

• Use with caution in patients with conditions that predispose to hypotension (dehydration, overheating)

• Priapism has been reported

• Dysphagia has been associated with antipsychotic use, and ziprasidone should be used cautiously in patients at risk for aspiration pneumonia

Do Not Use

• If patient is taking agents capable of significantly prolonging QTc interval (e.g., pimozide, thioridazine, selected antiarrhythmics, moxifloxacin, sparfloxacin)

• If there is a history of QTc prolongation or cardiac arrhythmia, recent acute myocardial infarction, uncompensated heart failure

• If there is a proven allergy to ziprasidone

ZIPRASIDONE: SPECIAL POPULATIONS

Renal Impairment

• No dose adjustment necessary

• Not removed by hemodialysis

• Intramuscular formulation should be used with caution

Hepatic Impairment

• No dose adjustment necessary

Cardiac Impairment

• Ziprasidone is contraindicated in patients with a known history of QTc prolongation, recent acute myocardial infarction, and uncompensated heart failure

• Should be used with caution in other cases of cardiac impairment because of risk of orthostatic hypotension

Elderly

• Some patients may tolerate lower doses better

• Although atypical antipsychotics are commonly used for behavioral disturbances in dementia, no agent has been approved for treatment of elderly patients with dementia-related psychosis

• Elderly patients with dementia-related psychosis treated with atypical antipsychotics are at an increased risk of death compared to placebo, and also have an increased risk of cerebrovascular events