Ziprasidone

Trade Names:
Geodon
- Capsules 20 mg (as hydrochloride)
- Capsules 40 mg (as hydrochloride)
- Capsules 60 mg (as hydrochloride)
- Capsules 80 mg (as hydrochloride)
- Powder for injection 20 mg/mL (as mesylate) (after reconstitution)

Pharmacology

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

Pharmacokinetics

Absorption

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

Distribution

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

Metabolism

Ziprasidone is extensively metabolized. It is unlikely to interfere with metabolism of drugs metabolized by CYP-450. CYP3A4 is the major CYP isoenzyme contributing to the oxidative metabolism of ziprasidone.

Elimination

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

Special Populations

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

Increases the AUC of ziprasidone.

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

No difference in pharmacokinetics between men and women.

Population pharmacokinetic evaluation has not revealed differences based on race.

No pharmacokinetic differences have been found between smokers and nonsmokers.

Indications and Usage

Treatment of schizophrenia (oral only); treatment of acute manic or mixed episodes associated with bipolar disorder (oral only); treatment of acute agitation in schizophrenic patients (IM only).

Unlabeled Uses

Treatment of autism and Tourette syndrome (oral only).

Contraindications

Drugs known to prolong the QT interval (eg, pimozide, quinidine, sotalol); history of QT prolongation; recent acute MI; uncompensated heart failure; known hypersensitivity to the product.

Dosage and Administration

IM 10 to 20 mg/day (max, 40 mg/day). Doses of 10 mg may be given every 2 h; doses of 20 mg may be given every 4 h, up to 40 mg/day.

PO Start with 40 mg twice daily with food. 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.

PO Start with 20 mg twice daily with food. 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 with food.

General Advice

• Because there is no experience regarding the safety of administering ziprasidone IM to schizophrenic patients already taking oral ziprasidone, coadministration is not recommended.

• 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.
• Do not administer if particulate matter, cloudiness, or discoloration is noted.
• Discard any unused solution. Do not save unused solution for later administration.

Storage/Stability

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

Drug Interactions

May cause additive CNS effects.

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

Hypotensive effects may be enhanced.

May reduce ziprasidone levels, decreasing the efficacy.

Effects may be antagonized.

May elevate ziprasidone levels, increasing the risk of toxicity.

Laboratory Test Interactions

None well documented.

Adverse Reactions

CNS

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

Cardiovascular

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

Dermatologic

Rash (4%); fungal dermatitis, sweating (IM) (2%); allergic reaction (including allergic dermatitis), angioedema, orofacial edema, urticaria (postmarketing).

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%); anorexia, dysphagia, rectal hemorrhage (IM) (2%); tooth disorder (1% [IM]).

Genitourinary

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

Local

Injection-site pain (9%).

Metabolic

Weight gain (10%).

Musculoskeletal

Myalgia (2%).

Respiratory

Respiratory disorder (eg, cold symptoms, upper respiratory tract infection) (8%); increased cough (3%); dyspnea (2%).

Miscellaneous

Asthenia (6%); accidental injury (4%); chest pain (3%); back pain (1% [IM]); abdominal pain, accidental fall, chills, face edema, fever, flank pain, flu-like syndrome, hypothermia, motor vehicle accident, photosensitivity reaction (at least 1%).

Precautions

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Use with caution.

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.

Hyperglycemia and diabetes mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, may occur. Monitor patients with established diagnosis of diabetes mellitus regularly for worsening of glucose control.

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 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 4% to 5% of patients, leading to discontinuation of treatment in about 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 patient to review patient information leaflet before starting therapy and with each refill.
• Advise patient 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 patient to take prescribed dose twice daily.
• Advise patient to take each dose with food to increase absorption and efficacy.
• Advise patient to swallow capsules whole.
• Advise patient that if a dose is missed, to take it as soon as possible and then return to the normal schedule. Instruct patient not to double the dose to catch up.
• Advise patient that dose will be started low and then increased until max benefit is obtained.
• Instruct patient to not stop taking ziprasidone when feeling better.
• Tell patient to immediately report altered mental status, dizziness, fainting, high fever, irregular pulse, muscle rigidity, palpitations, rash, seizures, or sweating to health care provider.
• Advise patient to notify health care provider of the following: change in personality or mood, excessive drowsiness, involuntary body or facial movements, rapid pulse, weight gain.
• Advise patient to avoid strenuous activity during periods of high temperature or humidity.
• Instruct patient to avoid alcoholic beverages and sedatives (eg, diazepam) while taking ziprasidone.
• Instruct patient to get up slowly from lying or sitting position and to avoid sudden position changes to prevent postural hypotension. Advise patient to report dizziness with position changes to health care provider. Caution patient that hot tubs and hot showers or baths may make dizziness worse.
• Advise patient taking antihypertensives to monitor BP at regular intervals.
• Advise patient 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.

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