Ziprasidone (Systemic)


VA CLASSIFICATION
Primary: CN709

Commonly used brand name(s): Geodon.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antipsychotic—

Indications

Accepted

Schizophrenia (treatment)—Ziprasidone is indicated for the treatment of schizophrenia.{01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    467.42{01}

Mechanism of action/Effect:

The exact mechanism of action of ziprasidone is unknown. It is thought that the drug's efficacy in the treatment of schizophrenia is mediated through a combination of dopamine type 2 (D 2) and serotonin type 2 (5-HT2) antagonism. Antagonism at receptors other than those listed that have similar receptor affinities may explain some of the other therapeutic and side effects of ziprasidone. {01}

Absorption:

Ziprasidone is well absorbed after oral administration. {01}Absolute bioavailability of a 20-mg dose under fed conditions is approximately 60%. Absorption is increased up to two-fold in the presence of food.{01}

Distribution:

Mean apparent Volume of Distribution (VolD) — 1.5 L per kilogram of body weight (L/kg){01}.

Protein binding:

Very high ( > 99%) to plasma proteins. It is primarily bound to albumin and 1-acid glycoprotein. {01}

The in vitro plasma protein binding of ziprasidone was not altered by warfarin or propranolol, nor did ziprasidone alter the binding of these two drugs in human plasma. The potential for drug interactions due to displacement is minimal.
{01}
Biotransformation:

Ziprasidone is primarily cleared via hepatic metabolism, by three metabolic routes, to yield benzisothiazole (BITP) sulphoxide, BITP-sulphone, ziprasidone sulphoxide and S-methyl-dihydroziprasidone.{01}

Half-life:

Elimination—Mean terminal half-life is about 7 hours.{01}

Time to peak concentration:

6 to 8 hours{01}

Elimination:
    Renal—20 %, < 1% as unchanged drug.{01}
    Fecal—66 %, < 4% as unchanged drug.{01}


Precautions to Consider

Carcinogenicity

Lifetime carcinogenicity studies were done in Long Evans rats and CD-1 mice. Ziprasidone was administered for 24 months at doses of 2, 6, or 12 mg/kg/day in rats and 50, 100, or 200 mg/kg/day in mice (0.1 to 0.6 times the maximum recommended human dose [MRHD] of 200 mg/day on a mg/m2 basis, respectively).{01}

In the rat study there was no evidence of an increased incidence of tumors. In the mice, male mice there was no evidence of an increased incidence of tumors. In female mice there were dose related increases in the incidences of pituitary gland adenoma and carcinomas, and mammary gland adenocarcinoma at all doses tested (50 to 200 mg/kg/day or 1 to 5 times the MRHD on a mg/m2 basis). Proliferative changes in the pituitary gland and mammary glands of rodents have been observed following chronic administration of other antipsychotic agents and are considered to be prolactin mediated.{01}

Increases in serum prolactin were observed in a 1– month dietary study in female mice at doses of 100 and 200 mg/kg/day (or 2.5 and 5 times the MRHD on a mg/mg2 basis). Ziprasidone had no effect on serum prolactin in rats in a 5 week dietary study at the doses used in the carcinogenicity study. The relevance for human risk of the findings of the prolactin-mediated endocrine tumors in rodents is unknown{01}.

Mutagenicity

Ziprasidone was tested in the Ames bacterial mutation assay, the in vitro mammalian cell gene mutation mouse lymphoma assay, the in vitro chromosomal aberration assay in human lymphocytes, and the in vivo chromosomal aberration in mouse bone marrow. There was a reproducible mutagenic response in the Ames assay in one strain of S. typhimurium in the absence of metabolic activation. Positive results were obtained in both the in vitro mammalian cell gene mutation assay and the in vitro chromosomal aberration assay in human lymphocytes.{01}

Pregnancy/Reproduction
Fertility—
Ziprasidone was shown to increase copulation time in Sprague-Dawley rats in two fertility and early embryonic development studies at doses of 10 to 160 mg/kg/day (0.5 to 8 times the MRHD of 200 mg/day on a mg/m2 basis). Fertility rate was reduced at doses of 160 mg/kg/day (8 times the MRHD of 200 mg/day on a mg/m 2 basis). The effect on fertility appeared to be in the female since fertility was not impaired when males given 160 mg/kg/day (8 times the MRHD of 200 mg/day on a mg/m2 basis) were mated with untreated females. In a 6 month study in male rats given 200 mg/kg/day (10 times the MRHD on a mg/m2 basis) there were no treatment related findings observed in the testes.
{01}
Pregnancy—
There are no adequate and well controlled studies in humans.{01}

Developmental toxicity was demonstrated in animal studies, including possible teratogenic effects at doses similar to human therapeutic doses. When ziprasidone was administered to pregnant rabbits during organogenesis, an increased incidence of fetal structural abnormalities (ventricular septal defects and other cardiovascular malformations and kidney alterations) were observed at doses of 30 mg/kg/day (3 times the MRHD of 200 mg/ day on a mg/m2 basis). There was no evidence to suggest that these developmental effects were secondary to maternal toxicity.{01}

The developmental no effect dose was 10 mg/kg/day (equivalent to the MRHD on a mg/m2 basis). In rats, embryofetal toxicity (decreased fetal weights, delayed skeletal ossification) was observed following administration of 10 to 160 mg/kg/day (0.5 to 8 times the MRHD of 200 mg/day on a mg/m2 basis) during organogenesis or throughout gestation, but there was no evidence of teratogenicity. Doses of 40 and 60 mg/kg/day (2 and 8 times the MRHD on a mg/m 2 basis) were associated with maternal toxicity. The developmental no-effect dose was 5 mg/kg/day (0.2 times the MRHD of 200 mg/day on a mg/m2 basis).{01}

There was an increase in the number of pups born dead and a decrease in postnatal survival throughout the first 4 days of lactation among the offspring of female rats treated during gestation and lactation with doses of 10 mg/kg/day (0.5 times the MRHD of 200 mg/day on a mg/m2 basis) or greater. Offspring developmental delays and neurobehavioral functional impairment were observed at doses of 5 mg/kg/day (0.2 times the MRHD of 200 mg/day on a mg/m2 basis) or greater. A no-effect level was not established for these effects.{01}

Effect on labor and delivery is unknown.{01}

FDA Pregnancy Category C{01}

Breast-feeding

Is is not known whether ziprasidone is distributed into human breast milk. Breast-feeding is not recommended in women receiving ziprasidone.{01}

Pediatrics

No information is available on the relationship of age to the effects of ziprasidone in the pediatric population. Safety and efficacy have not been established.{01}


Geriatrics


Although appropriate studies on the relationship of age to the effects of ziprasidone have not been performed, geriatrics-specific problems are not expected to limit the usefulness of ziprasidone in the elderly. However, elderly patients are more likely to age-related medical problems which may require a lower starting dose, slower titration, and careful monitoring during the initial dosing period.{01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Antihypertensive agents    (ziprasidone has the potential for inducing hypotension, and it may enhance the effects of certain antihypertensive agents; risk of priapism increases with concomitant use of ziprasidone and alpha-adrenergic blocking agents)

{01}
Carbamazepine     (may decrease the AUC of ziprasidone, this effect may be greater as doses increase)

{01}
CNS stimulation-producing medications (see Appendix II) and
CNS depression-producing medications (see Appendix II)    (given the primary CNS effects of ziprasidone caution should be used when using other centrally acting drugs)

{01}
Ketoconazole and
CYP3A4 hepatic enzyme inhibitors, other    (may increase the AUC and the Cmax of ziprasidone )

{01}
Levodopa and
Dopamine agonists    (ziprasidone may antagonize the effects of these drugs)

{01}
» QT Interval prolongation drugs, including:
Arsenic trioxide
Chlorpromazine
Class Ia and III anti-arrhythmics
Dofetilide
Dolasetron mesylate
Droperidol
Gatifloxacin
Halofantrine
Levomethadyl acetate
Mefloquine
Mesoridazine
Moxifloxacin
Pentamidine
Pimozide
Probucol
Quinidine
Sotalol
Sparfloxacin
Tacrolimus
Thioridazine     (concurrent use of these medications with ziprasidone is contraindicated; dose related prolongation of the QT interval with ziprasidone and the known associated fatal arrhythmias with QT prolongation by some other drugs; associated with torsade de pointes-type arrhythmia, a potentially fatal polymorphic ventricular tachycardia, and sudden death.{01}{02})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Prolactin     (ziprasidone elevates prolactin levels, clinical significance is unknown; hyperprolactinemia linked to one-third of human breast cancers, in vitro, but no studies to date associate ziprasidone and tumorigenesis in humans{01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
»
Acute myocardial infarction, recent, or
Bradycardia
Cardiac arrhythmias, history of, or
QT prolongation, history of or congenital, or
Heart failure, uncompensated    (certain cardiovascular circumstances may increase the risk of QT prolongation, arrhythmia, torsade de pointes, and risk of sudden death)

{01}{02}
» Hypersensitivity to ziprasidone
» Uncorrected electrolyte disorders, including:
Hypokalemia
Hypomagnesemia    (may increase the risk of QT prolongation, arrhythmia, torsade de pointes, and risk of sudden death)

{01}{02}
Risk-benefit should be considered when the following medical problems exist
Neuroleptic Malignant Syndrome (NMS)    (potentially fatal symptom complex [e.g., hyperpyrexia, muscle rigidity, altered mental status, evidence of autonomic instability, elevated creatinine phosphokinase, myoglobinuria, acute renal failure] has been reported in association with administration of antipsychotic drugs ; management includes immediate discontinuation of the antipsychotic drugs and other non-necessary drugs, intensive symptomatic treatment and medical monitoring and treatment of any comitant serious medical problems for which there is a treatment; after recovery from NMS, if antipsychotic therapy is required, careful monitoring is warranted as antipsychotic therapy is reintroduced{01})


Tardive Dyskinesia    (potentially irreversible, involuntary, dyskinetic movements may develop in patients undergoing treatment with antipsychotic drugs; more likely to occur in the elderly, especially elderly women; risk of irreversible tardive dyskinesia increases with duration of treatment and total cumulative dose; therapy should be given at the smallest dose and for the shortest duration; if signs and symptoms of tardive dyskinesia appear, consider drug discontinuation; some patients may require treatment with ziprasidone despite the presence of the syndrome{01})


Seizures, history of, or
Alzheimer's dementia    (use with caution in patients with a history of seizures or with conditions that potentially lower the seizure threshold; use with caution due to increased risk of aspiration pneumonia)



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Magnesium, serum and
» Potassium, serum    (baseline measurements should be taken in patients who are at risk for significant electrolyte disturbances [e.g., diuretic therapy, diarrhea], and patients with low values should be replenished before treatment begins; periodic monitoring of serum electrolytes should be done in patients who are started on diuretics during ziprasidone treatment.)

{01}
» QTc interval    (ziprasidone therapy should be discontinued in patients with persistent QTc measurements > 500 msec{01}; occurrence of symptoms of torsade de pointes [e.g., dizziness, palpitations, or syncope] warrant further evaluation with a Holter monitor{01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Tachycardia (fast, pounding, or irregular heartbeat or pulse; palpitations){01}

Incidence rare
    
Cardiac arrhythmias {01}(dizziness; feeling faint or fainting; fast or racing heartbeat; pounding or irregular heartbeat)
    
convulsions {01}(seizures)
    
priapism {01}(persistent, painful erection )—may require surgical intervention
    
syncope {02}( fainting)



Those indicating need for medical attention only if they continue or are bothersome

Note: Asthenia, orthostatic hypotension, anorexia, dry mouth, increased salivation, arthralgia, anxiety, dizziness, dystonia, hypertonia, somnolence, tremor, rhinitis, rash, and abnormal vision may be dose-related{01}

Incidence more frequent
    
Asthenia (lack or loss of strength; weakness){01}
    
akathisia (involuntary movements )
    
constipation {01}
    
diarrhea
    
dizziness {01}
    
dyspepsia (acid or sour stomach ; belching ; heartburn ; indigestion ; stomach discomfort upset or pain){01}
    
extrapyramidal syndrome ( difficulty in speaking ; drooling ; loss of balance control; muscle trembling, jerking, or stiffness ; restlessness ; shuffling walk; stiffness of limbs; twisting movements of body; uncontrolled movements, especially of face, neck, and back){01}
    
nausea
    
rash {01}— may require antihistamine or steroid therapy or discontinuation of ziprasidone
    
somnolence (sleepiness or unusual drowsiness){01}
    
weight gain {01}

Incidence less frequent
    
Abnormal vision (change in vision){01}
    
anorexia (loss of appetite ; weight loss)
    
dry mouth {01}
    
dystonia ( inability to move eyes; increased blinking or spasms of eyelid; sticking out of tongue; trouble in breathing, speaking, or swallowing; uncontrolled twisting movements of neck, trunk, arms, or legs; unusual facial expressions ; weakness of arms and legs){01}
    
fungal dermatitis (red, itchy skin){01}
    
hypertonia (muscle tightness){01}
    
myalgia (muscle ache)
    
orthostatic hypotension {01}(feeling faint upon standing)
    
rhinitis ( stuffy nose; runny nose; sneezing){01}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute effects
    
Sedation (drowsiness; sleepiness)
    
slurring of speech
    
transitory hypertension

{01}
Treatment of overdose
There is no specific antidote for ziprasidone {01}. Treatment is essentially symptomatic and supportive.


To decrease absorption:
Gastric lavage should be considered. Activated charcoal may be administered with a laxative. The risk of aspiration with induced emesis is increased if the patient is obtunded, seizing, or experiencing dystonic movements of the head and neck.{01}



To enhance elimination:
Ziprasidone is not dialyzable{01}.



Specific treatment:
Maintain an open airway and ensure adequate oxygenation and ventilation.{01}

For treatment of severe extrapyramidal symptoms: Administration of anticholinergic agents may be indicated {01}.

For treatment of arrhythmias caused by ziprasidone toxicity: Selection of an appropriate antiarrhythmic agent—Use of disopyramide, procainamide, or quinidine may add to ziprasidone toxicity by prolonging the QT interval {01}.

For treatment of hypotension or circulatory collapse: Selection of an appropriate sympathomimetic—Beta-adrenergic stimulation properties of epinephrine or dopamine may worsen the hypotension induced by ziprasidone's alpha-adrenergic blockade {01}

Also, the alpha-adrenergic blocking properties of bretylium may add to ziprasidone's effects, producing problematic hypotension {01}.



Monitoring:
Cardiovascular monitoring should begin immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. {01}



Supportive care:
Supportive measures such as establishing intravenous lines, hydration, correction of electrolyte imbalance, oxygenation, and support of ventilatory function are essential for maintaining the vital functions of the patient.{01}

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Ziprasidone (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to ziprasidone.
Other medications, especially QT interval prolongation drugs.
Other medical problems, especially cardiac disease, including recent acute myocardial infarction, bradycardia, cardiac arrhythmias, QT prolongation, uncompensated heart failure; uncorrected electrolyte disorders, including hypokalemia and hypomagnesemia

Proper use of this medication

» Proper dosing
Swallow capsules whole, do not chew
Taking as soon as possible; not taking if almost time for next scheduled dose; not doubling doses

Proper storage

Precautions while using this medication
» Importance of close monitoring by physician

» Obtaining medical attention if fainting, dizziness, fast, racing, pounding, or irregular heartbeat, or other unusual symptoms occur

» Caution while performing activities requiring mental alertness, driving or operating machinery due to potential to impair judgment, thinking, or motor skills

Avoid situations involving high temperature or humidity, due to potential interference with ability of the body to adjust to heat

Avoid use of alcohol


Side/adverse effects
Signs of potential side effects, especially, tachycardia, cardiac arrhythmias, convulsions, priapism, and syncope


General Dosing Information
Ziprasidone should be administered with food.

Dosage adjustments, if needed, should occur at intervals of not less than 2 days, but more appropriately, patients should be observed for improvement for several weeks before upward dose adjustment to ensure use of the lowest effective dose.

Periodically reassess to determine the need for maintenance treatment.{01}

Dispense/prescribe a small number of doses to reduce the risk of attempted overdose.{01}


Oral Dosage Forms

ZIPRASIDONE CAPSULES

Usual Adult Dose
Schizophrenia
Oral, initial dose 20 mg twice a day, taken with food. Dose may be adjusted, at intervals of not less than 2 days, up to 80 mg twice a day.{01}


Usual adult prescribing limits
The safety and efficacy of doses over 100 mg twice a day has not been evaluated in clinical trials, and an increase to a dose above 80 mg twice a day is not recommended.{01}

Usual Pediatric Dose
Safety and efficacy have not been established.
{01}
Usual Geriatric Dose
See Usual adult dose.

Usual geriatric prescribing limits
See Usual adult prescribing limits.

Strength(s) usually available
U.S.—


20 mg (Rx) [Geodon (lactose) (pregelatinized starch) (magnesium stearate)]{01}


40 mg (Rx) [Geodon (lactose) (pregelatinized starch) (magnesium stearate)]{01}


60 mg (Rx) [Geodon (lactose) (pregelatinized starch) (magnesium stearate)]{01}


80 mg (Rx) [Geodon (lactose) (pregelatinized starch) (magnesium stearate)]{01}

Packaging and storage:
Store between 15 and 30°C (59 and 86 °F).{01}



Developed: 05/30/2001
Revised: 09/06/2002



References
  1. Product Information: Geodon™, ziprasidone, Pfizer Inc, New York, NY (PI issued 2/2001) reviewed 5/2001.
  1. Product Information: Geodon™, ziprasidone, Pfizer Inc, New York, NY (PI revised 2/2002) reviewed 5/2002.
Hide
(web5)