[Posted 02/22/2011] ISSUE: FDA notified healthcare professionals that the Pregnancy section of drug labels for the entire class of antipsychotic drugs has been updated. The new drug labels now contain more and consistent information about the potential risk for abnormal muscle movements (extrapyramidal signs or EPS) and withdrawal symptoms in newborns whose mothers were treated with these drugs during the third trimester of pregnancy.
The symptoms of EPS and withdrawal in newborns may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty in feeding. In some newborns, the symptoms subside within hours or days and do not require specific treatment; other newborns may require longer hospital stays.
BACKGROUND: Antipsychotic drugs are used to treat symptoms of psychiatric disorders such as schizophrenia and bipolar disorder.
RECOMMENDATION: Healthcare professionals should be aware of the effects of antipsychotic medications on newborns when the medications are used during pregnancy. Patients should not stop taking these medications if they become pregnant without talking to their healthcare professional, as abruptly stopping antipsychotic medications can cause significant complications for treatment. For more information visit the FDA website at: [Web] and [Web].
Should be reserved for patients whose disease fails to respond adequately to appropriate courses of other antipsychotic agents because of a greater capacity to prolong the QT/QTc-interval compared with that of several other antipsychotic agents. (See Prolongation of QT Interval under Cautions)
IM injection used for rapid control of behaviors that interfere with diagnosis and care (e.g., threatening behaviors, escalating or urgently distressing behavior, self-exhausting behavior).
Bipolar Disorder
Treatment of acute manic and mixed epsiodes (with or without psychotic features) associated with bipolar 1 disorder.
Dosage and Administration
Administration
Administer orally or by IM injection.
Concomitant use of oral and IM ziprasidone not recommended by manufacturer.
Oral Administration
Administer orally twice daily with food.
IM Administration
Vials are for single use only.
Reconstitution
Reconstitute vial containing 20 mg with 1.2 mL of sterile water for injection to provide a solution containing 20 mg/mL. Do not use other solutions to reconstitute the injection, and do not admix with other drugs. Shake vigorously to ensure complete dissolution.
Observe strict aseptic technique since the drug contains no preservative. Discard unused portions.
Dosage
Available as ziprasidone hydrochloride or ziprasidone mesylate; oral dosage expressed in terms of hydrochloride monohydrate and IM dosage expressed in terms of ziprasidone.
Adults
Schizophrenia
Oral
Initially, 20 mg twice daily.
Dosage may be increased after a minimum of 2 days. Observe patients for several weeks prior to upward titrations of dosage to ensure use of the lowest effective dosage.
In patients responding to ziprasidone therapy, continue the drug as long as clinically necessary and tolerated, but at lowest possible effective dosage; periodically reassess need for continued therapy. Efficacy maintained for up to 52 weeks in clinical trials, but optimum duration of therapy currently is not known.
Acute Agitation in Schizophrenia
IM
Initially, 10–20 mg given as a single dose.
Repeat doses of 10 mg every 2 hours or 20 mg every 4 hours, up to a maximum cumulative dosage of 40 mg daily.
Oral therapy should replace IM therapy as soon as possible; safety and efficacy of administering ziprasidone IM injection for longer than 3 consecutive days not evaluated.
Bipolar Disorder
Oral
Initially, 40 mg twice daily on day 1. Increase dosage to 60 or 80 mg twice daily on the second day.
Subsequent dosage adjustments based on efficacy and tolerability may be made within a dosage range of 40–80 mg twice daily.
Efficacy for long-term use (i.e., >3 weeks) or for prophylactic use in patients with bipolar disorder not systematically evaluated. If used for extended periods, periodically reevaluate the long-term risks and benefits for the individual patient.
Prescribing Limits
Adults
Schizophrenia
Oral
Maximum 80 mg twice daily.
Acute Agitation
IM
Maximum cumulative dosage of 40 mg daily.
Bipolar Disorder
Oral
Maximum 80 mg twice daily.
Cautions
Contraindications
Known history of QT interval prolongation (including congenital long QT syndrome), recent AMI, or uncompensated heart failure. (See Prolongation of QT Interval under Cautions.)
Increased Mortality in Geriatric Patients with Dementia-related Psychosis
Possible increased risk of death with use of atypical antipsychotics in geriatric patients with dementia-related psychosis. (See Boxed Warning and see Geriatric Use under Cautions.)
Atypical antipsychotics are not approved for the treatment of dementia-related psychosis.
Prolongation of QT Interval
Greater capacity to prolong the QT/QTc interval compared with that of several other antipsychotic agents.
Experience is too limited to rule out the possibility that ziprasidone may be associated with a greater risk of ventricular arrhythmias (e.g., torsades de pointes) and/or sudden death than other antipsychotic agents.
Patients at particular risk of torsades de pointes include those with bradycardia, hypokalemia, or hypomagnesemia, those receiving concomitant therapy with other drugs that prolong the QTc interval, and those with congenital prolongation of QTc interval. (See Contraindications under Cautions.) Avoid ziprasidone therapy in patients with history of cardiac arrhythmias.
Determine baseline serum potassium and magnesium concentrations in patients at risk for substantial electrolyte disturbances, particularly those receiving concomitant diuretic therapy. Correct hypokalemia or hypomagnesemia prior to initiating ziprasidone.
Clinical and ECG monitoring of cardiac function, including appropriate ambulatory ECG monitoring (e.g., Holter monitoring), is recommended during ziprasidone therapy in patients with symptoms that could indicate torsades de pointes (e.g., dizziness, palpitations, syncope).
Discontinue ziprasidone if the QTc interval exceeds 500 msec.
Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, may occur in patients receiving antipsychotic agents.
Tardive Dyskinesia
Tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements, has been reported. Consider discontinuance of ziprasidone.
Hyperglycemia and Diabetes Mellitus
Severe hyperglycemia, sometimes associated with ketoacidosis, hyperosmolar coma, or death, reported in patients receiving atypical antipsychotic agents. Closely monitor patients with preexisting diabetes mellitus for worsening of glucose control, and perform fasting glucose tests at baseline and periodically for patients with risk factors for diabetes (e.g., obesity, family history of diabetes). If manifestations of hyperglycemia occur, test for diabetes mellitus.
Sensitivity Reactions
Rash
Rash and/or urticaria, possibly related to dose and/or duration of therapy, reported. Adjunctive treatment with antihistamines or steroids and/or drug discontinuance may be required. Discontinue ziprasidone if alternative etiology of rash cannot be identified.
General Precautions
Cardiovascular Effects
Orthostatic hypotension reported, particularly during initial dosage titration period. Use with caution in patients with known cardiovascular or cerebrovascular disease and/or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy).
Nervous System Effects
Possible risk of seizures; use with caution in patients with a history of seizures or with conditions known to lower the seizure threshold (e.g., dementia of the Alzheimer’s type, geriatric patients).
Disruption of ability to reduce core body temperature possible; use caution in patients exposed to conditions that may contribute to an elevation in core body temperature (e.g., dehydration, extreme heat, strenuous exercise, concomitant use of anticholinergic agents).
Somnolence reported. Potential impairment of judgment, thinking, or motor skills.
GI Effects
Esophageal dysmotility and aspiration possible; use with caution in patients at risk for aspiration pneumonia (e.g., geriatric patients, those with advanced Alzheimer’s dementia). (See Boxed Warning and see Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Cautions.)
Suicide
Attendant risk with psychotic illnesses; closely supervise high-risk patients. Prescribe in the smallest quantity consistent with good patient management to reduce the risk of overdosage.
Not known whether ziprasidone is distributed into milk. Women receiving ziprasidone should not breast-feed.
Pediatric Use
Safety and efficacy not established in children <18 years of age.
Geriatric Use
No substantial differences in safety of oral ziprasidone relative to younger adults.
Lower initial dosages, slower titration, and careful monitoring during the initial dosing period may be advisable in some geriatric patients.
IM ziprasidone mesylate not systematically evaluated in geriatric patients.
Possible increased risk of death in geriatric patients with dementia-related psychosis. Substantial (1.6- to 1.7-fold) increase in mortality rate reported in geriatric patients with dementia who received atypical antipsychotic agents (e.g., aripiprazole, olanzapine, quetiapine, risperidone) for treatment of behavioral disorders; most fatalities resulted from cardiac-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).
Atypical antipsychotics are not approved for the treatment of dementia-related psychosis. (See Boxed Warning and see Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Cautions.)
Renal Impairment
Commercially available ziprasidone mesylate injections contain sulfobutylether β-cyclodextrin sodium, an excipient that is cleared by renal filtration; use with caution.
Common Adverse Effects
Oral therapy for schizophrenia: somnolence, respiratory tract infection.
IM therapy for acute agitation in schizophrenia: somnolence, headache, nausea.
Interactions
Ziprasidone is metabolized by the CYP3A4 isoenzyme; CYP1A2 also may contribute but to a much lesser extent. Little inhibitory effect on CYP isoenzymes 1A2, 2C9, 2C19, 2D6, or 3A4; pharmacokinetic interaction unlikely with drugs metabolized by these isoenzymes.
Drugs Affecting Hepatic Microsomal Enzymes
Potential pharmacokinetic interactions (altered metabolism) with inhibitors or inducers of CYP3A4.
Pharmacokinetic interaction with inhibitors or inducers of CYP1A2, CYP2C9, CYP2C19, or CYP2D6 are unlikely.
Drugs That Prolong QT Interval
Potential pharmacologic interaction (additive effect on QT interval prolongation; concomitant use contraindicated) when used with drugs that prolong the QTc interval. Ziprasidone also is contraindicated in patients receiving drugs shown to cause QT prolongation as an effect and for which this effect is described in the full prescribing information as a contraindication or a boxed or bolded warning. (See Contraindications and Prolongation of QT Interval under Cautions.)
Absolute bioavailability is approximately 60% following a 20 mg oral dose under fed conditions.
Peak plasma concentrations occur 6–8 hours after oral administration or about 1 hour after IM injection.
Food
Food increases the absorption up to twofold.
Distribution
Extent
Not known whether the drug is distributed into milk in humans.
Plasma Protein Binding
>99% bound to plasma proteins, principally to albumin and α1-acid glycoprotein.
Elimination
Metabolism
Extensively metabolized in the liver principally via reduction by aldehyde oxidase; about one-third of metabolic clearance is mediated by CYP isoenzymes, principally CYP3A4.
Elimination Route
Approximately 20% of a dose is excreted in the urine and about 66% in feces, principally as metabolites. Not removed by hemodialysis.
Half-life
Mean terminal half-life following oral administration is about 7 hours; following IM administration, the half-life is 2–5 hours.
Special Populations
In patients with clinically important (Child-Pugh class A or B) cirrhosis, half-life increased by 2.3 hours compared with that of patients in the control group.
Stability
Storage
Oral
Capsules
15–30°C.
Parenteral
Powder for Injection
15–30°C.
Following reconstitution, store at 15–30°C protected from light for up to 24 hours or at 2–8°C for up to 7 days.
Actions
Exact mechanism of antipsychotic action has not been fully elucidated; may involve antagonism of central type 2 serotonergic (5-HT2) receptors and central dopamine D2 receptors.
Precise mechanism of antimanic action has not been fully elucidated.
Antagonism of other receptors (e.g., histamine H1 receptors, α1-adrenergic receptors) may contribute to other therapeutic and adverse effects (e.g., orthostatic hypotension, somnolence).
Advice to Patients
Importance of taking medication exactly as prescribed by the clinician.
Importance of avoiding driving, operating machinery, or performing hazardous tasks until gain experience with the drug’s effects.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription or OTC drugs, dietary supplements, and herbal products, as well as any concomitant illnesses (e.g., diabetes mellitus, seizures, dementia).
Importance of avoiding alcohol during ziprasidone therapy.
Importance of avoiding overheating or dehydration.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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