Ziprasidone

Pronunciation: (zi-PRAS-i-done)
Class: Benzisoxazole derivative

Trade Names

Geodon
- Capsules 20 mg
- Capsules 40 mg
- Capsules 60 mg
- Capsules 80 mg
- Injection, lyophilized powder for solution 20 mg/mL (after reconstitution)

Pharmacology

Antipsychotic activity, apparently because of dopamine and serotonin receptor antagonism.

Pharmacokinetics

Absorption

Well absorbed after oral administration. T _max is approximately 6 to 8 h (oral) or 60 min (IM). Oral bioavailability is approximately 60%. Bioavailability of IM is 100%. Absorption increased 2-fold in the presence of food.

Distribution

Vd is 1.5 L/kg. Approximately 99% bound to plasma proteins, primarily albumin and alpha-1 acid glycoprotein.

Metabolism

Ziprasidone is extensively metabolized. CYP3A4 is the major CYP isoenzyme contributing to the oxidative metabolism of ziprasidone.

Elimination

The half-life is approximately 7 h (oral) or 2 to 5 h (IM). Cl is approximately 7.5 mL/min/kg. Approximately 20% of the dose is excreted in urine and 66% eliminated in feces. Unchanged ziprasidone represents approximately 44% of total drug-related material in serum.

Special Populations

Renal Function Impairment

Because ziprasidone is highly metabolized, renal impairment is not likely to have a major effect on the pharmacokinetics.

Hepatic Function Impairment

Increases the AUC of ziprasidone.

Elderly

No difference in pharmacokinetics in patients older than 65 y of age compared with patients 18 to 45 y of age.

Gender

No difference in pharmacokinetics between men and women.

Race

Population pharmacokinetic evaluation has not revealed differences based on race.

Smoking

No pharmacokinetic differences have been found between smokers and nonsmokers.

Indications and Usage

Treatment of schizophrenia (oral only); as monotherapy for the acute treatment of manic or mixed episodes associated with bipolar I disorder (oral only); as adjunct to lithium or valproate for the maintenance treatment of bipolar I disorder (oral only); treatment of acute agitation in schizophrenic patients (IM only).

Unlabeled Uses

Treatment of autism and Tourette syndrome.

Contraindications

Concurrent use with drugs known to prolong the QT interval (eg, arsenic trioxide, chlorpromazine, dofetilide, dolasetron, droperidol, gatifloxacin, halofantrine, levomethadyl, mefloquine, mesoridazine, moxifloxacin, other class IA and III antiarrhythmics, pentamidine, pimozide, probucol, quinidine, sotalol, sparfloxacin, tacrolimus, or thioridazine); history of QT prolongation (including congenital long QT syndrome); recent acute MI; uncompensated heart failure; known hypersensitivity to the product.

Dosage and Administration

Agitation in Schizophrenia
Adults

IM 10 mg every 2 h or 20 mg every 4 h, up to 40 mg/day. IM administration for longer than 3 days has not been studied.

Bipolar I disorder
Adults

PO Start with 40 mg twice daily. Increase dosage to 60 or 80 mg twice daily on the second day of treatment. Subsequently, adjust the dosage based on tolerance and efficacy within the range of 40 to 80 mg twice daily. Use as an adjunct to lithium or valproate during maintenance therapy.

Schizophrenia
Adults

PO Start with 20 mg twice daily. The dosage may be adjusted up to 80 mg twice daily. Generally, dosage adjustments should occur at intervals of not less than 2 days. Maintenance dosage is 20 to 80 mg twice daily.

General Advice

Because there is no experience regarding the safety of administering ziprasidone IM to patients with schizophrenia who are already taking oral ziprasidone, coadministration is not recommended.

Oral
Administer with food.

IM
For IM administration only. Not for intradermal, subcutaneous, or IV administration.
Reconstitute powder for injection with 1.2 mL of sterile water for injection. Each mL of reconstituted solution contains ziprasidone 20 mg.
Do not mix with other medications or use other diluents.
Discard any unused solution. Do not save unused solution for later administration.

Storage/Stability

Store capsules and vials between 59° and 86°F. Protect vials from light. Following reconstitution of powder for injection, when protected from light, injection can be stored for up to 24 h between 59° and 86°F, or for up to 7 days if refrigerated (36° to 46°F).

Drug Interactions

Alcohol, CNS-acting drugs

May cause additive CNS effects, including impairment of motor skills. Avoid concurrent use or use with caution.

Arsenic trioxide, chlorpromazine, cisapride, dofetilide, dolasetron, droperidol, gatifloxacin, mefloquine, moxifloxacin, pentamidine, pimozide, probucol, quinidine, sotalol, tacrolimus, thioridazine, and other drugs known to prolong the QT interval

Contraindicated because of increased risk of torsades de pointes or other malignant ventricular arrhythmias.

Antihypertensive agents

Hypotensive effects may be enhanced. Coadminister with caution and closely monitor BP.

Carbamazepine

May reduce ziprasidone levels, decreasing the efficacy. Adjust ziprasidone dose as needed.

CYP3A4 inhibitors (eg, ketoconazole)

May elevate ziprasidone levels, increasing the risk of toxicity. Monitor the clinical response and adjust the ziprasidone dose as needed.

Diuretic therapy (eg, thiazides [hydrochlorothiazide])

Hypokalemia resulting from diuretic therapy may increase the risk of QT prolongation and life-threatening arrhythmias. Low serum potassium or magnesium should be corrected before proceeding with ziprasidone therapy. Periodically monitor serum electrolytes.

Dopamine, epinephrine

For the treatment of ziprasidone-induced hypotension, do not use dopamine, epinephrine, or other sympathomimetics with beta-agonist activity because beta stimulation may worsen the hypotension caused by the ziprasidone-induced alpha blockage.

Dopamine agonists, levodopa

Effects may be antagonized. Coadminister with caution.

Food

The absorption of ziprasidone is increased up to 2-fold in the presence of food. Ziprasidone should be taken with food.

Tramadol

The risk of seizures may be increased. Coadminister with caution.

Adverse Reactions

CNS

Extrapyramidal symptoms, somnolence (31%); headache (18%); dizziness (16%); akathisia (10%); asthenia (6%); anxiety (5%); insomnia (3%); agitation, hypesthesia, paresthesia, personality disorder, speech disorder (2%); psychosis (1%); abnormal gait, akinesia, amnesia, ataxia, buccoglossal syndrome, choreoathetosis, cogwheel rigidity, confusion, delirium, dysarthria, dyskinesia, dystonia, hostility, hyperkinesia, hypertonia, hypokinesia, hypotonia, incoordination, neuropathy, paresthesia, tremor, twitching, vertigo, withdrawal syndrome (at least 1%); facial droop, mania/hypomania, NMS, serotonin syndrome, tardive dyskinesia (postmarketing).

Cardiovascular

Postural hypotension (5%); hypertension (3%); bradycardia, tachycardia (2%); vasodilation (1%); syncope, torsades de pointes (postmarketing).

Dermatologic

Rash (4%); fungal dermatitis, furunculosis, sweating (2%).

EENT

Abnormal vision (6%); rhinitis (4%); pharyngitis (3%); diplopia, oculogyric crisis (at least 1%).

GI

Nausea (12%); constipation (9%); dyspepsia (8%); diarrhea, dry mouth, vomiting (5%); increased salivation (4%); tongue edema (3%); abdominal pain, anorexia, dysphagia, rectal hemorrhage (2%); tooth disorder (1%).

Genitourinary

Dysmenorrhea (2%); priapism (1%); enuresis, galactorrhea, urinary incontinence (postmarketing).

Hypersensitivity

Allergic reaction (including allergic dermatitis), angioedema, orofacial edema, urticaria (postmarketing).

Local

Injection-site pain (9%).

Metabolic

Weight gain (10%).

Musculoskeletal

Myalgia (2%); back pain (1%).

Respiratory

Respiratory tract infection (8%); increased cough (3%); dyspnea (2%).

Miscellaneous

Chest pain (3%); accidental fall, chills, face edema, fever, flank pain, flu syndrome, hypothermia, photosensitivity reaction (at least 1%).

Precautions

Warnings

Increased mortality

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death compared with placebo. Over the course of a 10-wk controlled trial, the rate of death in drug-treated patients was approximately 4.5% compared with 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be CV (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Ziprasidone is not approved for the treatment of patients with dementia-related psychosis.

Monitor

Ensure that patients at risk of electrolyte disturbances have baseline serum potassium and magnesium measurements. Correct low levels before proceeding with treatment. Periodically monitor potassium and magnesium in patients started on diuretic treatment during ziprasidone therapy. Discontinue treatment in patients who have persistent QTc measurements more than 500 msec. In patients with a preexisting low WBC or a history of drug-induced leukopenia/neutropenia, frequently monitor CBC during the first few months of therapy. Carefully monitor patients with neutropenia for fever and other signs or symptoms of infection. Regularly monitor patients with an established diagnosis of diabetes mellitus for worsening of glucose control. Patients with risk factors for diabetes who are starting treatment should undergo initial and periodic fasting blood glucose testing. Monitor any patient treated with atypical antipsychotics for symptoms of hyperglycemia, including polydipsia, polyuria, polyphagia, and weakness.

Pregnancy

Category C . Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms after delivery.

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Use with caution. Consider a lower starting dose, slower titration, and careful monitoring during initial dosing period.

Renal Function

Because the cyclodextrin excipient in the IM formulation is cleared by renal filtration, use ziprasidone IM with caution in patients with renal impairment.

Body temperature regulation

Antipsychotic agents disrupt the ability to reduce core body temperature. Use with caution in patients who will experience conditions that may contribute to an elevation in core body temperature (eg, concomitant anticholinergic therapy, exposure to extreme heat, strenuous exercise, subject to dehydration).

Cognitive and motor performance

Because of initial sedation, mental and/or physical abilities may be impaired, especially during the first few days or weeks of therapy.

CV effects

QT prolongation with increased risk of life-threatening CV events may occur. The risk of torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval may be increased in certain circumstances, including bradycardia, concomitant use of other drugs that prolong the QTc interval, hypokalemia or hypomagnesemia, and the presence of congenital prolongation of the QT interval.

Dysphagia

Use with caution in patients at risk of aspiration pneumonia.

Hematologic effects

Leukopenia/neutropenia and agranulocytosis (including fatal cases) have been reported.

Hyperglycemia and diabetes mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, may occur.

Hyperprolactinemia

Patients treated with antipsychotic agents often have elevation in prolactin levels; however, there is no evidence of increased breast tumor risk.

NMS

This potentially fatal condition has been reported in association with antipsychotic agents. Signs and symptoms include altered mental status, cardiac arrhythmias, diaphoresis, hyperpyrexia, irregular pulse or BP, muscle rigidity, and tachycardia.

Orthostatic hypotension

Orthostatic hypotension and syncope may occur.

Priapism

Priapism may occur and has been reported with other drugs that have alpha-adrenergic blocking effects. Severe priapism may require surgical intervention.

Rash

Rash and/or urticaria may occur in approximately 5% of patients, leading to discontinuation of treatment in approximately one-sixth of the cases. The rash appears to be dose-related.

Seizures

May occur; use with caution in patients with a history of seizures.

Suicide

Inherent in psychotic illness; use with caution and dispense in small quantities. Observe adults and children treated with antidepressants for clinical worsening, suicidality, and unusual changes in behavior. Prescribe the smallest quantity consistent with good patient management in order to reduce the risk of overdose.

Tardive dyskinesia

A potentially irreversible syndrome of involuntary body and facial movements may occur.

Overdosage

Symptoms

Anxiety, extrapyramidal symptoms, sedation, slurred speech, somnolence, transient hypertension, tremor.

Patient Information

Advise patients to review patient information leaflet before starting therapy and with each refill.
Advise patients receiving injectable ziprasidone that medication will be prepared and administered by a health care provider in a medical setting. When possible, oral therapy will replace IM administration.
Instruct patients to take prescribed oral dose twice daily.
Advise patients to take each oral dose with food to increase absorption and efficacy.
Advise patients to swallow capsules whole.
Advise patients that dose will be started low and then increased until maximum benefit is obtained.
Instruct patients to not stop taking ziprasidone when feeling better.
Tell patients to immediately report altered mental status, dizziness, fainting, high fever, irregular pulse, muscle rigidity, palpitations, rash, seizures, or sweating to their health care provider.
Advise patients to notify their health care provider of the following: change in personality or mood, excessive drowsiness, involuntary body or facial movements, rapid pulse, weight gain.
Advise patients to avoid strenuous activity during periods of high temperature or humidity.
Instruct patients to avoid alcoholic beverages and sedatives (eg, diazepam) while taking ziprasidone.
Instruct patients to get up slowly from lying or sitting position and to avoid sudden position changes to prevent postural hypotension. Advise patients to report dizziness with position changes to health care provider. Caution patients that hot tubs and hot showers or baths may make dizziness worse.
Advise patients to inform their health care provider of any history of QT prolongation, recent acute MI, uncompensated heart failure, or history of cardiac arrhythmias, and if they have any risks for significant electrolyte abnormalities.
Advise patients taking antihypertensives to monitor BP at regular intervals.
Advise patients that drug may impair judgment, thinking, or motor skills, or cause drowsiness, and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.