Geodon

Before receiving ziprasidone injection,

• tell your doctor and pharmacist if you are allergic to ziprasidone, any other medications, or any of the ingredients in ziprasidone injection. Ask your pharmacist for a list of the ingredients.
• tell your doctor if you are taking amiodarone (Cordarone, Nexterone, Pacerone), arsenic trioxide (Trisenox), chlorpromazine, disopyramide (Norpace), dofetilide (Tikosyn), dolasetron (Anzemet), dronedarone (Multaq), droperidol (Inapsine), gatifloxacin (no longer available in the U.S.), ibutilide (Corvert), halofantrine (Halfan) (no longer available in the U.S.), levomethadyl (ORLAAM) (no longer available in the U.S.), mefloquine, mesoridazine (no longer available in the U.S.), moxifloxacin (Avelox), pentamidine (NebuPent, Pentam), pimozide (Orap), probucol (no longer available in the U.S.), procainamide, quinidine (in Nuedexta), sotalol (Betapace, Sorine, Sotylize), sparfloxacin (no longer available in the U.S.), tacrolimus (Astagraf, Prograf), or thioridazine. Your doctor may not prescribe ziprasidone if you are taking one or more of these medications. Other medications may also interact with ziprasidone, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: antidepressants, carbamazepine (Carbatrol, Tegretol, Teril, others), certain antifungals such as ketoconazole (Extina, Nizoral), dopamine agonists such as bromocriptine (Cycloset, Parlodel), cabergoline, levodopa (in Sinemet), pergolide (Permax) (no longer available in the U.S.), and ropinirole (Requip), medications for high blood pressure, mental illness, seizures, or anxiety; and sedatives, sleeping pills, or tranquilizers. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have heart failure, QT prolongation (an irregular heart rhythm that can lead to fainting, loss of consciousness, seizures, or sudden death), or if you have recently had a heart attack. Your doctor will probably tell you not to receive ziprasidone injection.
• tell your doctor if you have or have had thoughts about harming or killing yourself, an irregular heartbeat, a stroke or ministroke, seizures, diabetes, dyslipidemia (high cholesterol levels), trouble keeping your balance, a low number of white blood cells, or heart, kidney, or liver disease. Also, tell your doctor if you low levels of potassium or magnesium in your blood, if you use or have ever used street drugs or have overused prescription medications, or have trouble swallowing. Also, tell your doctor if you have severe diarrhea or vomiting or you think you may be dehydrated.
• ask your doctor about the safe use of alcoholic beverages while you are receiving ziprasidone injection. Alcohol can make the side effects from ziprasidone injection worse.
• tell your doctor if you are pregnant, especially if you are in the last few months of your pregnancy, or if you plan to become pregnant or are breastfeeding. If you become pregnant while receiving ziprasidone, call your doctor. Ziprasidone may cause problems in newborns following delivery if it is given during the last months of pregnancy.
• you should know that ziprasidone injection may make you drowsy. Do not drive a car or operate machinery until you know how this medication affects you.
• you should know that alcohol can add to the drowsiness caused by this medication. Do not drink alcohol while receiving ziprasidone.
• you should know that you may experience hyperglycemia (increases in your blood sugar) while you are receiving this medication, even if you do not already have diabetes. If you have schizophrenia, you are more likely to develop diabetes than people who do not have schizophrenia, and receiving ziprasidone or similar medications may increase this risk. Tell your doctor immediately if you have any of the following symptoms while you are receiving ziprasidone: extreme thirst, frequent urination, extreme hunger, blurred vision, or weakness. It is very important to call your doctor as soon as you have any of these symptoms, because high blood sugar that is not treated can cause a serious condition called ketoacidosis. Ketoacidosis may become life-threatening if it is not treated at an early stage. Symptoms of ketoacidosis include dry mouth, nausea and vomiting, shortness of breath, breath that smells fruity, and decreased consciousness.
• you should know that ziprasidone injection may cause dizziness, lightheadedness, and fainting when you get up too quickly from a lying position. This is more common when you first start receiving ziprasidone. To avoid this problem, get out of bed slowly, resting your feet on the floor for a few minutes before standing up.
• you should know that ziprasidone injection may make it harder for your body to cool down when it gets very hot. Tell your doctor if you plan to do vigorous exercise or be exposed to extreme heat.

Ziprasidone comes as a capsule to take by mouth. It is usually taken twice a day with food. Take ziprasidone at around the same times every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take ziprasidone exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Your doctor may start you on a low dose of ziprasidone and gradually increase your dose.

Ziprasidone may help control your symptoms but will not cure your condition. It may take a few weeks or longer before you feel the full benefit of ziprasidone. Continue to take ziprasidone even if you feel well. Do not stop taking ziprasidone without talking to your doctor.

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include the following:

• drowsiness
• slurred speech
• sudden movements that you cannot control
• uncontrollable shaking of a part of the body
• anxiety

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>10%

Somnolence (11-15%)

Headache (11%)

Nausea (4-12%)

Extrapyramidal symptoms (2-31%)

Dizziness (3-16%)

1-10%

Respiratory disorders (1-8%)

Constipation (2-9%)

Dyspepsia (1-8%)

Rash (4-5%)

Tachycardia (2%)

Hypoesthesia (2%)

Priapism (1%)

Orthostatic hypotension (5%)

Xerostomia (1-5%)

Anorexia (2%)

Myalgia (2%)

Rhinitis (1-4%)

Cough (3%)

<1%

Syncope

Seizures

Frequency Not Defined

Prolongation of QT interval

Neuroleptic malignant syndrome (NMS)

Hyperprolactinemia

Drug reaction with eosinophilia and systemic syntoms

Postmarketing reports

Stevens-Johnson syndrome

GEODON is indicated for the treatment of schizophrenia, as monotherapy for the acute treatment of bipolar manic or mixed episodes, and as an adjunct to lithium or valproate for the maintenance treatment of bipolar disorder. GEODON intramuscular is indicated for acute agitation in schizophrenic patients. When deciding among the alternative treatments available for the condition needing treatment, the prescriber should consider the finding of ziprasidone's greater capacity to prolong the QT/QTc interval compared to several other antipsychotic drugs [see WARNINGS AND PRECAUTIONS]. Prolongation of the QTc interval is associated in some other drugs with the ability to cause torsade de pointes-type arrhythmia, a potentially fatal polymorphic ventricular tachycardia, and sudden death. In many cases this would lead to the conclusion that other drugs should be tried first. Whether ziprasidone will cause torsade de pointes or increase the rate of sudden death is not yet known [see WARNINGS AND PRECAUTIONS]

Schizophrenia

Geodon is indicated for the treatment of schizophrenia. The efficacy of oral ziprasidone was established in four short-term (4- and 6-week) controlled trials of adult schizophrenic inpatients and in one maintenance trial of stable adult schizophrenic inpatients [see Clinical Studies].

Bipolar I Disorder (Acute Mixed or Manic Episodes And Maintenance Treatment As An Adjunct To Lithium Or Valproate)

Geodon is indicated as monotherapy for the acute treatment of manic or mixed episodes associated with bipolar I disorder. Efficacy was established in two 3-week monotherapy studies in adult patients [see Clinical Studies].

Geodon is indicated as an adjunct to lithium or valproate for the maintenance treatment of bipolar I disorder. Efficacy was established in a maintenance trial in adult patients. The efficacy of Geodon as monotherapy for the maintenance treatment of bipolar I disorder has not been systematically evaluated in controlled clinical trials [see Clinical Studies].

Acute Treatment Of Agitation In Schizophrenia

GEODON intramuscular is indicated for the treatment of acute agitation in schizophrenic patients for whom treatment with ziprasidone is appropriate and who need intramuscular antipsychotic medication for rapid control of agitation. The efficacy of intramuscular ziprasidone for acute agitation in schizophrenia was established in single day controlled trials of agitated schizophrenic inpatients [see Clinical Trials]

“Psychomotor agitation” is defined in DSM-IV as “excessive motor activity associated with a feeling of inner tension”. Schizophrenic patients experiencing agitation often manifest behaviors that interfere with their diagnosis and care, e.g., threatening behaviors, escalating or urgently distressing behavior, or self-exhausting behavior, leading clinicians to the use of intramuscular antipsychotic medications to achieve immediate control of the agitation.

Since there is no experience regarding the safety of administering ziprasidone intramuscular to schizophrenic patients already taking oral ziprasidone, the practice of co-administration is not recommended.

Ziprasidone intramuscular is intended for intramuscular use only and should not be administered intravenously.

Mechanism Of Action

The mechanism of action of ziprasidone, as with other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that this drug's efficacy in schizophrenia is mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) antagonism. As with other drugs having efficacy in bipolar disorder, the mechanism of action of ziprasidone in bipolar disorder is unknown.

Pharmacodynamics

Ziprasidone exhibited high in vitro binding affinity for the dopamine D2 and D3, the serotonin 5HT2A, 5HT2C, 5HT1A, 5HT1D, and α1 -adrenergic receptors (Ki s of 4.8, 7.2, 0.4, 1.3, 3.4, 2, and 10 nM, respectively), and moderate affinity for the histamine H1 receptor (Ki =47 nM). Ziprasidone functioned as an antagonist at the D2, 5HT2D, and 5HT1D receptors, and as an agonist at the 5HT1A receptor.  Ziprasidone inhibited synaptic reuptake of serotonin and norepinephrine. No appreciable affinity was exhibited for other receptor/binding sites tested, including the cholinergic muscarinic receptor (IC > 1 μM). Antagonism at receptors other than dopamine and 5HT2 with similar receptor affinities may explain some of the other therapeutic and side effects of ziprasidone. Ziprasidone's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Ziprasidone's antagonism of α -adrenergic receptors may explain the orthostatic hypotension observed with this drug.

Pharmacokinetics

Ziprasidone's activity is primarily due to the parent drug. The multiple-dose pharmacokinetics of ziprasidone are dose-proportional within the proposed clinical dose range, and ziprasidone accumulation is predictable with multiple dosing. Elimination of ziprasidone is mainly via hepatic metabolism with a mean terminal half-life of about 7 hours within the proposed clinical dose range. Steady-state concentrations are achieved within one to three days of dosing. The mean apparent systemic clearance is 7.5 mL/min/kg. Ziprasidone is unlikely to interfere with the metabolism of drugs metabolized by cytochrome P450 enzymes.

Ziprasidone is well absorbed after oral administration, reaching peak plasma concentrations in 6 to 8 hours. The absolute bioavailability of a 20 mg dose under fed conditions is approximately 60%. The absorption of ziprasidone is increased up to two-fold in the presence of food.

Ziprasidone has a mean apparent volume of distribution of 1.5 L/kg. It is greater than 99% bound to plasma proteins, binding primarily to albumin and α -acid glycoprotein. The in vitro plasma protein binding of ziprasidone was not altered by warfarin or propranolol, two highly protein-bound drugs, nor did ziprasidone alter the binding of these drugs in human plasma. Thus, the potential for drug interactions with ziprasidone due to displacement is minimal.

Ziprasidone is extensively metabolized after oral administration with only a small amount excreted in the urine ( < 1%) or feces ( < 4%) as unchanged drug. Ziprasidone is primarily cleared via three metabolic routes to yield four major circulating metabolites, benzisothiazole (BITP) sulphoxide, BITP-sulphone, ziprasidone sulphoxide, and S-methyldihydroziprasidone. Approximately 20% of the dose is excreted in the urine, with approximately 66% being eliminated in the feces. Unchanged ziprasidone represents about 44% of total drug-related material in serum. In vitro studies using human liver subcellular fractions indicate that S-methyldihydroziprasidone is generated in two steps. These studies indicate that the reduction reaction is mediated primarily by chemical reduction by glutathione as well as by enzymatic reduction by aldehyde oxidase and the subsequent methylation is mediated by thiol methyltransferase. In vitro studies using human liver microsomes and recombinant enzymes indicate that CYP3A4 is the major CYP contributing to the oxidative metabolism of ziprasidone. CYP1A2 may contribute to a much lesser extent. Based on in vivo abundance of excretory metabolites, less than one-third of ziprasidone metabolic clearance is mediated by cytochrome P450 catalyzed oxidation and approximately two-thirds via reduction. There are no known clinically relevant inhibitors or inducers of aldehyde oxidase.

Systemic Bioavailability: The bioavailability of ziprasidone administered intramuscularly is 100%. After intramuscular administration of single doses, peak serum concentrations typically occur at approximately 60 minutes post-dose or earlier and the mean half-life (T½) ranges from two to five hours. Exposure increases in a dose-related manner and following three days of intramuscular dosing, little accumulation is observed.

Metabolism and Elimination: Although the metabolism and elimination of IM ziprasidone have not been systematically evaluated, the intramuscular route of administration would not be expected to alter the metabolic pathways.

Clinical Studies

Schizophrenia

The efficacy of oral ziprasidone in the treatment of schizophrenia was evaluated in 5 placebocontrolled studies, 4 short-term (4- and 6-week) trials and one maintenance trial. All trials were in adult inpatients, most of whom met DSM III-R criteria for schizophrenia. Each study included 2 to 3 fixed doses of ziprasidone as well as placebo. Four of the 5 trials were able to distinguish ziprasidone from placebo; one short-term study did not. Although a single fixed-dose haloperidol arm was included as a comparative treatment in one of the three short-term trials, this single study was inadequate to provide a reliable and valid comparison of ziprasidone and haloperidol.

Several instruments were used for assessing psychiatric signs and symptoms in these studies. The Brief Psychiatric Rating Scale (BPRS) and the Positive and Negative Syndrome Scale (PANSS) are both multi-item inventories of general psychopathology usually used to evaluate the effects of drug treatment in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients. A second widely used assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the Scale for Assessing Negative Symptoms (SANS) was employed for assessing negative symptoms in one trial.

The results of the oral ziprasidone trials in schizophrenia follow:

• In a 4-week, placebo-controlled trial (n=139) comparing 2 fixed doses of ziprasidone (20 and 60 mg twice daily) with placebo, only the 60 mg dose was superior to placebo on the BPRS total score and the CGI severity score. This higher dose group was not superior to placebo on the BPRS psychosis cluster or on the SANS.
• In a 6-week, placebo-controlled trial (n=302) comparing 2 fixed doses of ziprasidone (40 and 80 mg twice daily) with placebo, both dose groups were superior to placebo on the BPRS total score, the BPRS psychosis cluster, the CGI severity score and the PANSS total and negative subscale scores Although 80 mg twice daily had a numerically greater effect than 40 mg twice daily, the difference was not statistically significant.
• In a 6-week, placebo-controlled trial (n=419) comparing 3 fixed doses of ziprasidone (20, 60, and 100 mg twice daily) with placebo, all three dose groups were superior to placebo on the PANSS total score, the BPRS total score, the BPRS psychosis cluster, and the CGI severity score. Only the 100 mg twice daily dose group was superior to placebo on the PANSS negative subscale score.  There was no clear evidence for a dose-response relationship within the 20 mg twice daily to 100 mg twice daily dose range.
• In a 4-week, placebo-controlled trial (n=200) comparing 3 fixed doses of ziprasidone (5, 20, and 40 mg twice daily), none of the dose groups was statistically superior to placebo on any outcome of interest.
• A study was conducted in stable chronic or subchronic (CGI-S ≤ 5 at baseline) schizophrenic inpatients (n=294) who had been hospitalized for not less than two months. After a 3-day single-blind placebo run-in, subjects were randomized to one of 3 fixed doses of ziprasidone (20 mg, 40 mg, or 80 mg twice daily) or placebo and observed for relapse. Patients were observed for “impending psychotic relapse,” defined as CGI-improvement score of ≥ 6 (much worse or very much worse) and/or scores ≥ 6 (moderately severe) on the hostility or uncooperativeness items of the PANSS on two consecutive days. Ziprasidone was significantly superior to placebo in time to relapse, with no significant difference between the different dose groups. There were insufficient data to examine population subsets based on age and race. Examination of population subsets based on gender did not reveal any differential responsiveness.

Bipolar I Disorder (Acute Mixed Or Manic Episodes And Maintenance Treatment As An Adjunct To Lithium Or Valproate)

The efficacy of ziprasidone was established in 2 placebo-controlled, double-blind, 3-week monotherapy studies in patients meeting DSM-IV criteria for bipolar I disorder, manic or mixed episode with or without psychotic features. Primary rating instruments used for assessing manic symptoms in these trials were: (1) the Mania Rating Scale (MRS), which is derived from the Schedule for Affective Disorders and Schizophrenia-Change Version (SADS-CB) with items grouped as the Manic Syndrome subscale (elevated mood, less need for sleep, excessive energy, excessive activity, grandiosity), the Behavior and Ideation subscale (irritability, motor hyperactivity, accelerated speech, racing thoughts, poor judgment) and impaired insight; and (2) the Clinical Global Impression-Severity of Illness Scale (CGI-S), which was used to assess the clinical significance of treatment response.

The results of the oral ziprasidone trials in adult bipolar I disorder, manic/mixed episode follow: in a 3- week placebo-controlled trial (n=210), the dose of ziprasidone was 40 mg twice daily on Day 1 and 80 mg twice daily on Day 2. Titration within the range of 40–80 mg twice daily (in 20 mg twice daily increments) was permitted for the duration of the study. Ziprasidone was significantly more effective than placebo in reduction of the MRS total score and the CGI-S score. The mean daily dose of ziprasidone in this study was 132 mg. In a second 3-week placebo-controlled trial (n=205), the dose of ziprasidone was 40 mg twice daily on Day 1. Titration within the range of 40–80 mg twice daily (in 20 mg twice daily increments) was permitted for the duration of study (beginning on Day 2). Ziprasidone was significantly more effective than placebo in reduction of the MRS total score and the CGI-S score. The mean daily dose of ziprasidone in this study was 112 mg.

The efficacy of ziprasidone as adjunctive therapy to lithium or valproate in the maintenance treatment of bipolar I disorder was established in a placebo-controlled trial in patients who met DSM-IV criteria for bipolar I disorder. The trial included patients whose most recent episode was manic or mixed, with or without psychotic features. In the open-label phase, patients were required to be stabilized on ziprasidone plus lithium or valproic acid for at least 8 weeks in order to be randomized. In the doubleblind randomized phase, patients continued treatment with lithium or valproic acid and were randomized to receive either ziprasidone (administered twice daily totaling 80 mg to 160 mg per day) or placebo. Generally, in the maintenance phase, patients continued on the same dose on which they were stabilized during the stabilization phase. The primary endpoint in this study was time to recurrence of a mood episode (manic, mixed or depressed episode) requiring intervention, which was defined as any of the following: discontinuation due to a mood episode, clinical intervention for a mood episode (e.g., initiation of medication or hospitalization), or Mania Rating Scale score ≥ 18 or a MADRS score ≥ 18 (on 2 consecutive assessments no more than 10 days apart). A total of 584 subjects were treated in the open-label stabilization period. In the double-blind randomization period, 127 subjects were treated with ziprasidone, and 112 subjects were treated with placebo. Ziprasidone was superior to placebo in increasing the time to recurrence of a mood episode. The types of relapse events observed included depressive, manic, and mixed episodes. Depressive, manic, and mixed episodes accounted for 53%, 34%, and 13%, respectively, of the total number of relapse events in the study.

Acute Treatment Of Agitation In Schizophrenia

The efficacy of intramuscular ziprasidone in the management of agitated schizophrenic patients was established in two short-term, double-blind trials of schizophrenic subjects who were considered by the investigators to be “acutely agitated” and in need of IM antipsychotic medication. In addition, patients were required to have a score of 3 or more on at least 3 of the following items of the PANSS: anxiety, tension, hostility and excitement. Efficacy was evaluated by analysis of the area under the curve (AUC) of the Behavioural Activity Rating Scale (BARS) and Clinical Global Impression (CGI) severity rating. The BARS is a seven point scale with scores ranging from 1 (difficult or unable to rouse) to 7 (violent, requires restraint). Patients' scores on the BARS at baseline were mostly 5 (signs of overt activity [physical or verbal], calms down with instructions) and as determined by investigators, exhibited a degree of agitation that warranted intramuscular therapy. There were few patients with a rating higher than 5 on the BARS, as the most severely agitated patients were generally unable to provide informed consent for participation in premarketing clinical trials.

Both studies compared higher doses of ziprasidone intramuscular with a 2 mg control dose. In one study, the higher dose was 20 mg, which could be given up to 4 times in the 24 hours of the study, at interdose intervals of no less than 4 hours. In the other study, the higher dose was 10 mg, which could be given up to 4 times in the 24 hours of the study, at interdose intervals of no less than 2 hours.

The results of the intramuscular ziprasidone trials follow:

1. In a one-day, double-blind, randomized trial (n=79) involving doses of ziprasidone intramuscular of 20 mg or 2 mg, up to QID, ziprasidone intramuscular 20 mg was statistically superior to ziprasidone intramuscular 2 mg, as assessed by AUC of the BARS at 0 to 4 hours, and by CGI severity at 4 hours and study endpoint.
2. In another one-day, double-blind, randomized trial (n=117) involving doses of ziprasidone intramuscular of 10 mg or 2 mg, up to QID, ziprasidone intramuscular 10 mg was statistically superior to ziprasidone intramuscular 2 mg, as assessed by AUC of the BARS at 0 to 2 hours, but not by CGI severity.

Geodon is a prescription medication used to treat symptoms of schizophrenia and bipolar disorder. Geodon belongs to a group of drugs called atypical antipsychotics. It is believed to work by lessening the effects of certain chemicals in the brain involved with schizophrenia and bipolar disorder.

This medication comes in a capsule and suspension form and is usually taken twice daily with food.

This medication is available in an injectable form to be given directly into the muscle (IM) by a healthcare professional.

Common side effects of Geodon include nausea, constipation, and drowsiness. Do not drive or operate machinery until you know how this medication affects you.

Ziprasidone is not for use in psychotic conditions related to dementia. Ziprasidone may cause heart failure, sudden death, or pneumonia in older adults with dementia-related conditions.

Do not use this medication if you have a personal or family history of "Long QT syndrome," if you have recently had a heart attack, or if you have uncontrolled heart failure.

Stop taking ziprasidone and call your doctor right away if you feel dizzy or light-headed, have a fast or pounding heartbeat, or if you faint. This could be signs of a serious heart rhythm problem.

There are many other medicines that can cause serious or life-threatening medical problems if you take them together with ziprasidone. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Absorption

Bioavailability

Absolute bioavailability is approximately 60% following a 20-mg oral dose under fed conditions.1

Peak plasma concentrations occur 6–8 hours after oral administration or about 1 hour after IM injection or earlier.1

Food

Food increases oral absorption up to twofold.1

Special Populations

Mean AUC was 13 and 34% higher in individuals with Child-Pugh class A and B hepatic impairment, respectively, compared with that of those in the control group.1

Distribution

Extent

Manufacturer states not known whether the drug or its metabolites are distributed into milk in humans.1 However, a low concentration of ziprasidone in milk was reported in one woman; the milk/plasma ratio was 0.06 and the relative infant dose was estimated to be 1.2% of the weight-normalized maternal dose.109

Plasma Protein Binding

>99% bound to plasma proteins, principally to albumin and α1-acid glycoprotein.1

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 CYP3A4.1

Elimination Route

Approximately 20% of a dose is excreted in the urine and about 66% in feces, principally as metabolites.1 Not removed by hemodialysis.1

Half-life

Mean terminal half-life following oral administration is about 7 hours;1 following IM administration, the half-life is 2–5 hours.1

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.1

Pharmacokinetics of oral ziprasidone similar among individuals with varying degrees of renal impairment and those with normal renal function.1 IM ziprasidone not studied in patients with renal impairment.1

Storage

Oral

25°C (may be exposed to 15–30°C).1

Parenteral

25°C (may be exposed to 15–30°C).1 Protect from light.1

Following reconstitution, may store at 15–30°C protected from light for up to 24 hours or at 2–8°C for up to 7 days.1

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical trials for oral ziprasidone included approximately 5700 patients and/or normal subjects exposed to one or more doses of ziprasidone. Of these 5700, over 4800 were patients who participated in multiple-dose effectiveness trials, and their experience corresponded to approximately 1831 patient-years. These patients include: (1) 4331 patients who participated in multiple-dose trials, predominantly in schizophrenia, representing approximately 1698 patient-years of exposure as of February 5, 2000; and (2) 472 patients who participated in bipolar mania trials representing approximately 133 patient-years of exposure. An additional 127 patients with bipolar disorder participated in a long-term maintenance treatment study representing approximately 74.7 patient-years of exposure to ziprasidone. The conditions and duration of treatment with ziprasidone included open-label and double-blind studies, inpatient and outpatient studies, and short-term and longer-term exposure.

Clinical trials for intramuscular ziprasidone included 570 patients and/or normal subjects who received one or more injections of ziprasidone. Over 325 of these subjects participated in trials involving the administration of multiple doses.

Adverse reactions during exposure were obtained by collecting voluntarily reported adverse experiences, as well as results of physical examinations, vital signs, weights, laboratory analyses, ECGs, and results of ophthalmologic examinations.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Adverse Findings Observed in Short-Term, Placebo-Controlled Trials with Oral Ziprasidone

The following findings are based on the short-term placebo-controlled premarketing trials for schizophrenia (a pool of two 6-week, and two 4-week fixed-dose trials) and bipolar mania (a pool of two 3-week flexible-dose trials) in which ziprasidone was administered in doses ranging from 10 to 200 mg/day.

Commonly Observed Adverse Reactions in Short Term-Placebo-Controlled Trials

The following adverse reactions were the most commonly observed adverse reactions associated with the use of ziprasidone (incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients (ziprasidone incidence at least twice that for placebo):

Schizophrenia trials (see Table 11)

• Somnolence
• Respiratory Tract Infection

Bipolar trials (see Table 12)

• Somnolence
• Extrapyramidal Symptoms which includes the following adverse reaction terms: extrapyramidal syndrome, hypertonia, dystonia, dyskinesia, hypokinesia, tremor, paralysis and twitching. None of these adverse reactions occurred individually at an incidence greater than 10% in bipolar mania trials.
• Dizziness which includes the adverse reaction terms dizziness and lightheadedness.
• Akathisia
• Abnormal Vision
• Asthenia
• Vomiting

SCHIZOPHRENIA

Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials of Oral Ziprasidone

Approximately 4.1% (29/702) of ziprasidone-treated patients in short-term, placebo-controlled studies discontinued treatment due to an adverse reaction, compared with about 2.2% (6/273) on placebo. The most common reaction associated with dropout was rash, including 7 dropouts for rash among ziprasidone patients (1%) compared to no placebo patients [see Warnings and Precautions (5.7)].

Adverse Reactions Occurring at an Incidence of 2% or More Among Ziprasidone-Treated Patients in Short-Term, Oral, Placebo-Controlled Trials

Table 11 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during acute therapy (up to 6 weeks) in predominantly patients with schizophrenia, including only those reactions that occurred in 2% or more of patients treated with ziprasidone and for which the incidence in patients treated with ziprasidone was greater than the incidence in placebo-treated patients.

Dose Dependency of Adverse Reactions in Short-Term, Fixed-Dose, Placebo-Controlled Trials

An analysis for dose response in the schizophrenia 4-study pool revealed an apparent relation of adverse reaction to dose for the following reactions: asthenia, postural hypotension, anorexia, dry mouth, increased salivation, arthralgia, anxiety, dizziness, dystonia, hypertonia, somnolence, tremor, rhinitis, rash, and abnormal vision.

Extrapyramidal Symptoms (EPS) - The incidence of reported EPS (which included the adverse reaction terms extrapyramidal syndrome, hypertonia, dystonia, dyskinesia, hypokinesia, tremor, paralysis and twitching) for ziprasidone-treated patients in the short-term, placebo-controlled schizophrenia trials was 14% vs. 8% for placebo. Objectively collected data from those trials on the Simpson-Angus Rating Scale (for EPS) and the Barnes Akathisia Scale (for akathisia) did not generally show a difference between ziprasidone and placebo.

Dystonia - Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Vital Sign Changes - Ziprasidone is associated with orthostatic hypotension [see Warnings and Precautions (5.8)]

ECG Changes - Ziprasidone is associated with an increase in the QTc interval [see Warnings and Precautions (5.2)]. In the schizophrenia trials, ziprasidone was associated with a mean increase in heart rate of 1.4 beats per minute compared to a 0.2 beats per minute decrease among placebo patients.

Other Adverse Reactions Observed During the Premarketing Evaluation of Oral Ziprasidone

Following is a list of COSTART terms that reflect treatment-emergent adverse reactions as defined in the introduction to the ADVERSE REACTIONS section reported by patients treated with ziprasidone in schizophrenia trials at multiple doses >4 mg/day within the database of 3834 patients. All reported reactions are included except those already listed in Table 11 or elsewhere in labeling, those reaction terms that were so general as to be uninformative, reactions reported only once and that did not have a substantial probability of being acutely life-threatening, reactions that are part of the illness being treated or are otherwise common as background reactions, and reactions considered unlikely to be drug-related. It is important to emphasize that, although the reactions reported occurred during treatment with ziprasidone, they were not necessarily caused by it.

Adverse reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions:

Frequent - adverse reactions occurring in at least 1/100 patients (≥1.0% of patients) (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing);

Infrequent - adverse reactions occurring in 1/100 to 1/1000 patients (in 0.1–1.0% of patients)

Rare – adverse reactions occurring in fewer than 1/1000 patients (<0.1% of patients).

BIPOLAR DISORDER

Acute Treatment of Manic or Mixed Episodes

Adverse Reactions Associated with Discontinuation of Treatment in Short Term, Placebo-Controlled Trials

Approximately 6.5% (18/279) of ziprasidone-treated patients in short-term, placebo-controlled studies discontinued treatment due to an adverse reaction, compared with about 3.7% (5/136) on placebo. The most common reactions associated with dropout in the ziprasidone-treated patients were akathisia, anxiety, depression, dizziness, dystonia, rash and vomiting, with 2 dropouts for each of these reactions among ziprasidone patients (1%) compared to one placebo patient each for dystonia and rash (1%) and no placebo patients for the remaining adverse reactions.

Adverse Reactions Occurring at an Incidence of 2% or More Among Ziprasidone-Treated Patients in Short-Term, Oral, Placebo-Controlled Trials

Table 12 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during acute therapy (up to 3 weeks) in patients with bipolar mania, including only those reactions that occurred in 2% or more of patients treated with ziprasidone and for which the incidence in patients treated with ziprasidone was greater than the incidence in placebo-treated patients.

Explorations for interactions on the basis of gender did not reveal any clinically meaningful differences in the adverse reaction occurrence on the basis of this demographic factor.

INTRAMUSCULAR ZIPRASIDONE

Adverse Reactions Occurring at an Incidence of 1% or More Among Ziprasidone-Treated Patients in Short-Term Trials of Intramuscular Ziprasidone

Table 13 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during acute therapy with intramuscular ziprasidone in 1% or more of patients.

In these studies, the most commonly observed adverse reactions associated with the use of intramuscular ziprasidone (incidence of 5% or greater) and observed at a rate on intramuscular ziprasidone (in the higher dose groups) at least twice that of the lowest intramuscular ziprasidone group were headache (13%), nausea (12%), and somnolence (20%).

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Geodon. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reaction reports not listed above that have been received since market introduction include rare occurrences of the following : Cardiac Disorders: Tachycardia, torsade de pointes (in the presence of multiple confounding factors), [see Warnings and Precautions (5.2)]; Digestive System Disorders: Swollen Tongue; Reproductive System and Breast Disorders: Galactorrhea, priapism; Nervous System Disorders: Facial Droop, neuroleptic malignant syndrome, serotonin syndrome (alone or in combination with serotonergic medicinal products), tardive dyskinesia; Psychiatric Disorders: Insomnia, mania/hypomania; Skin and subcutaneous Tissue Disorders: Allergic reaction (such as allergic dermatitis, angioedema, orofacial edema, urticaria), rash, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS); Urogenital System Disorders: Enuresis, urinary incontinence; Vascular Disorders: Postural hypotension, syncope.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Lifetime carcinogenicity studies were conducted with ziprasidone in Long Evans rats and CD-1 mice. Ziprasidone was administered for 24 months in the diet at doses of 2, 6, or 12 mg/kg/day to rats, and 50, 100, or 200 mg/kg/day to mice (0.1 to 0.6 and 1 to 5 times the maximum recommended human dose [MRHD] of 200 mg/day on a mg/m2 basis, respectively). In the rat study, there was no evidence of an increased incidence of tumors compared to controls. In male mice, there was no increase in incidence of tumors relative to controls. In female mice, there were dose-related increases in the incidences of pituitary gland adenoma and carcinoma, 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 and mammary glands of rodents have been observed following chronic administration of other antipsychotic agents and are considered to be prolactin-mediated. Increases in serum prolactin were observed in a 1-month dietary study in female, but not male, mice at 100 and 200 mg/kg/day (or 2.5 and 5 times the MRHD on a mg/m2 basis). Ziprasidone had no effect on serum prolactin in rats in a 5-week dietary study at the doses that were used in the carcinogenicity study. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown [see Warnings and Precautions (5.13)].

Mutagenesis

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 assay 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.

Impairment of Fertility

Ziprasidone was shown to increase time to copulation 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 160 mg/kg/day (8 times the MRHD on a mg/m2 basis). There was no effect on fertility at 40 mg/kg/day (2 times the MRHD on a mg/m2 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 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.

NDC 0049-3960-60

Pfizer

Geodon®
ziprasidone HCl

20 mg*

60 Capsules
Rx only

NDC 0049-3970-60

Pfizer

Geodon®
ziprasidone HCl

40 mg*

60 Capsules
Rx only

NDC 0049-3980-60

Pfizer

Geodon®
ziprasidone HCl

60 mg*

60 Capsules
Rx only

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Breastfeeding is not recommended during use of this drug. Excreted into human milk: Unknown Excreted into animal milk: Unknown The effects in the nursing infant are unknown.