Ziprasidone

Class

Second Generation Antipsychotic

Neuroscience-based Nomenclature (NbN)

Pharmacological Target

Dopamine, serotonin

Mode of Action

Receptor Antagonist (D2, 5-HT2)

Brand Name

Geodon, Zeldox

Monograph

Monograph Link

Adverse Reactions

  EPS
  Galactorrhea
  Sedation
  Dizziness
  Weight gain (low)
  QTc issues
  Risk of tardive dyskinesia
  NMS

Warnings

  Class Warning: Increased Mortality in Elderly Patients with Dementia Elderly patients with dementia treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of thirteen placebo-controlled trials with various atypical antipsychotics (modal duration of 10 weeks) in these patients showed a mean 1.6-fold increase in the death rate in the drug-treated patients. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.
  Class Warning: Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

QTc Prolongation (Per product monograph)

  Ziprasidone should also not be used in patients with congenital long QT syndrome, or in patients with a history of cardiac arrhythmias, with recent acute myocardial infarction, or with uncompensated heart failure.
  If patients with stable cardiac disease are treated, an ECG review should be considered before treatment is started.
  Persistently prolonged QT/QTc intervals may also increase the risk of further prolongation and arrhythmia, but it is not clear that routine screening ECG measures are effective in detecting such patients. Rather, if cardiac symptoms, such as palpitations, vertigo, syncope or seizures occur then the possibility of a malignant cardiac arrhythmia should be considered and a cardiac evaluation including an ECG should be performed. If the QTc interval for a patient is >500 msec, then it is recommended that the treatment be stopped.
  It is recommended that patients being considered for ziprasidone treatment who are at risk for significant electrolyte disturbances (e.g., diuretic therapy, protracted diarrhea or vomiting, water intoxication, eating disorder, and alcoholism), have baseline serum potassium and magnesium measurements performed and levels corrected if necessary. Hypokalemia (and/or hypomagnesemia) may increase the risk of QT prolongation and arrhythmia. It is essential to periodically monitor serum electrolytes in patients for whom diuretic therapy is introduced during ziprasidone treatment.

HEALTH CANADA’S QT/QTc GUIDELINES

  In the general population, certain circumstances may increase the risk of the occurrence of torsades de pointes in association with the use of drugs that prolong the QT/QTc interval, including (1) bradycardia; (2) electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, or hypocalcemia); (3) concomitant use of other drugs that prolong the QT/QTc interval; (4) presence of congenital prolongation of the QT interval; (5) family history of sudden cardiac death at <50 years; (6) personal history of cardiac disease or arrhythmias; (7) acute neurological events, e.g., stroke; (8) being female or 65 years of age or older; (9) nutritional deficits e.g., eating disorders; (10) diabetes mellitus.
  Per product monograph: Ziprasidone should not be used in combination with other drugs that are known to prolong the QT/QTc interval.

Bioavailability (Oral)

  30% (60% with food)
  Absorption is increased up to two-fold in the presence of food

Volume of distribution (Vd)

1.5 L/Kg

Protein binding

99% (primarily to ?1-acid glycoprotein and albumin)

Elimination half-life

  6 – 10 hours
  No change in elderly or renal disease
  Prolonged in hepatic disease

Time to peak (Tmax)

6 – 8 hours

Metabolism

  Less than one-third metabolized via CYP3A4
  Approx. two-thirds metabolized via aldehyde oxidase

Excretion

  Urine: 20% (<1% unchanged)
  Feces: 66% (<4% unchanged)

Renal impairment

  No dose adjustment of ziprasidone is required in patients with renal impairment.

Hepatic mpairment

  Lower doses should be considered for hepatic insufficiency, considering that <1% of ziprasidone is cleared renally, and there is a lack of experience with ziprasidone in patients with severe hepatic impairment.

Potential for Other Drugs to Affect Ziprasidone

  Coadministration of potent CYP3A4 inhibitors has the potential of increasing ziprasidone serum concentrations. The clinical importance of this potential has not been clearly defined.
  Coadministration of potent CYP3A4 induces has the potential of decreasing ziprasidone serum concentrations. The clinical importance of this potential has not been clearly defined.

Potential for Ziprasidone to Affect Other Drugs

  In vitro studies revealed little potential for ziprasidone to interfere with the metabolism of drugs cleared primarily by CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Consistent with these in vitro results, studies in normal healthy volunteers showed that ziprasidone did not alter the metabolism of dextromethorphan, a CYP2D6 model substrate, nor of ethinyl estradiol, a CYP3A4 substrate. Thus, ziprasidone is unlikely to cause clinically important drug interactions mediated by these enzymes