GEODON^®
(ziprasidone HCl)
Capsules

GEODON^®
(ziprasidone mesylate)
for Injection
FOR IM USE ONLY

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of seventeen placebo controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen in placebo-treated patients. Over the course of a typical 10 week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Geodon (ziprasidone) is not approved for the treatment of patients with Dementia-Related Psychosis.

GEODON^® is available as GEODON Capsules (ziprasidone hydrochloride) for oral administration and as GEODON for Injection (ziprasidone mesylate) for intramuscular injection. Ziprasidone is a psychotropic agent that is chemically unrelated to phenothiazine or butyrophenone antipsychotic agents. It has a molecular weight of 412.94 (free base), with the following chemical name: 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one. The empirical formula of C₂₁H₂₁ClN₄OS (free base of ziprasidone) represents the following structural formula:

GEODON Capsules contain a monohydrochloride, monohydrate salt of ziprasidone. Chemically, ziprasidone hydrochloride monohydrate is 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one, monohydrochloride, monohydrate. The empirical formula is C₂₁H₂₁ClN₄OS • HCl • H₂O and its molecular weight is 467.42. Ziprasidone hydrochloride monohydrate is a white to slightly pink powder.

GEODON Capsules are supplied for oral administration in 20 mg (blue/white), 40 mg (blue/blue), 60 mg (white/white), and 80 mg (blue/white) capsules. GEODON Capsules contain ziprasidone hydrochloride monohydrate, lactose, pregelatinized starch, and magnesium stearate.

GEODON for Injection contains a lyophilized form of ziprasidone mesylate trihydrate. Chemically, ziprasidone mesylate trihydrate is 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one, methanesulfonate, trihydrate. The empirical formula is C₂₁H₂₁ClN₄OS • CH₃SO₃H • 3H₂O and its molecular weight is 563.09.

GEODON for Injection is available in a single dose vial as ziprasidone mesylate (20 mg ziprasidone/mL when reconstituted according to label instructions - see Preparation for Administration) for intramuscular administration. Each mL of ziprasidone mesylate for injection (when reconstituted) contains 20 mg of ziprasidone and 4.7 mg of methanesulfonic acid solubilized by 294 mg of sulfobutylether β-cyclodextrin sodium (SBECD).

Ziprasidone exhibited high in vitro binding affinity for the dopamine D₂ and D₃, the serotonin 5HT_2A, 5HT_2C, 5HT_1A, 5HT_1D, and α₁-adrenergic receptors (K_i 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 (K_i=47 nM). Ziprasidone functioned as an antagonist at the D_2, 5HT_2A, and 5HT_1D receptors, and as an agonist at the 5HT_1A 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 (IC₅₀ >1 µM).

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.

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 α₁-adrenergic receptors may explain the orthostatic hypotension observed with this drug.

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.

An in vitro enzyme inhibition study utilizing human liver microsomes showed that ziprasidone had little inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and thus would not likely interfere with the metabolism of drugs primarily metabolized by these enzymes. In vivo studies have revealed no effect of ziprasidone on the pharmacokinetics of dextromethorphan, estrogen, progesterone, or lithium (see Drug Interactions under PRECAUTIONS).

In vivo studies have revealed an approximately 35% decrease in ziprasidone AUC by concomitantly administered carbamazepine, an approximately 35–40% increase in ziprasidone AUC by concomitantly administered ketoconazole, but no effect on ziprasidone's pharmacokinetics by cimetidine or antacid (see Drug Interactions under PRECAUTIONS).

Ziprasidone is indicated for the treatment of schizophrenia. When deciding among the alternative treatments available for this condition, 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). 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).

The efficacy of oral ziprasidone was established in short-term (4- and 6-week) controlled trials of schizophrenic inpatients (see CLINICAL PHARMACOLOGY).

In a placebo-controlled trial involving the follow-up for up to 52 weeks of stable schizophrenic inpatients, GEODON was demonstrated to delay the time to and rate of relapse. The physician who elects to use GEODON for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Ziprasidone is indicated for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. A mixed episode is characterized by the criteria for a manic episode in conjunction with those for a major depressive episode (depressed mood, loss of interest or pleasure in nearly all activities).

The efficacy of ziprasidone in acute mania was established in 2 placebo-controlled, double-blind, 3-week studies in patients meeting DSM-IV criteria for Bipolar I Disorder who currently displayed an acute manic or mixed episode with or without psychotic features (see CLINICAL PHARMACOLOGY).

The effectiveness of ziprasidone for longer-term use and for prophylactic use in mania has not been systematically evaluated in controlled clinical trials. Therefore, physicians who elect to use ziprasidone for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Ziprasidone 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 the agitation. "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. The efficacy of intramuscular ziprasidone for acute agitation in schizophrenia was established in single-day controlled trials of schizophrenic inpatients (see CLINICAL PHARMACOLOGY). 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.

Because of ziprasidone's dose-related prolongation of the QT interval and the known association of fatal arrhythmias with QT prolongation by some other drugs, ziprasidone is contraindicated in patients with a known history of QT prolongation (including congenital long QT syndrome), with recent acute myocardial infarction, or with uncompensated heart failure (see WARNINGS).

Pharmacokinetic/pharmacodynamic studies between ziprasidone and other drugs that prolong the QT interval have not been performed. An additive effect of ziprasidone and other drugs that prolong the QT interval cannot be excluded. Therefore, ziprasidone should not be given with dofetilide, sotalol, quinidine, other Class Ia and III anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol or tacrolimus. Ziprasidone is also contraindicated with drugs that have demonstrated QT prolongation as one of their pharmacodynamic effects and have this effect described in the full prescribing information as a contraindication or a boxed or bolded warning (see WARNINGS).

Ziprasidone is contraindicated in individuals with a known hypersensitivity to the product.

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Geodon (ziprasidone) is not approved for the treatment of patients with dementia-related psychosis (see Boxed Warning).

Ziprasidone use should be avoided in combination with other drugs that are known to prolong the QTc interval (see CONTRAINDICATIONS, and see Drug Interactions under PRECAUTIONS). Additionally, clinicians should be alert to the identification of other drugs that have been consistently observed to prolong the QTc interval. Such drugs should not be prescribed with ziprasidone. Ziprasidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias (see CONTRAINDICATIONS).

A study directly comparing the QT/QTc prolonging effect of oral ziprasidone with several other drugs effective in the treatment of schizophrenia was conducted in patient volunteers. In the first phase of the trial, ECGs were obtained at the time of maximum plasma concentration when the drug was administered alone. In the second phase of the trial, ECGs were obtained at the time of maximum plasma concentration while the drug was co-administered with an inhibitor of the CYP4503A4 metabolism of the drug.

In the first phase of the study, the mean change in QTc from baseline was calculated for each drug, using a sample-based correction that removes the effect of heart rate on the QT interval. The mean increase in QTc from baseline for ziprasidone ranged from approximately 9 to 14 msec greater than for four of the comparator drugs (risperidone, olanzapine, quetiapine, and haloperidol), but was approximately 14 msec less than the prolongation observed for thioridazine.

In the second phase of the study, the effect of ziprasidone on QTc length was not augmented by the presence of a metabolic inhibitor (ketoconazole 200 mg BID).

In placebo-controlled trials, oral ziprasidone increased the QTc interval compared to placebo by approximately 10 msec at the highest recommended daily dose of 160 mg. In clinical trials with oral ziprasidone, the electrocardiograms of 2/2988 (0.06%) patients who received GEODON and 1/440 (0.23%) patients who received placebo revealed QTc intervals exceeding the potentially clinically relevant threshold of 500 msec. In the ziprasidone-treated patients, neither case suggested a role of ziprasidone. One patient had a history of prolonged QTc and a screening measurement of 489 msec; QTc was 503 msec during ziprasidone treatment. The other patient had a QTc of 391 msec at the end of treatment with ziprasidone and upon switching to thioridazine experienced QTc measurements of 518 and 593 msec.

Some drugs that prolong the QT/QTc interval have been associated with the occurrence of torsade de pointes and with sudden unexplained death. The relationship of QT prolongation to torsade de pointes is clearest for larger increases (20 msec and greater) but it is possible that smaller QT/QTc prolongations may also increase risk, or increase it in susceptible individuals, such as those with hypokalemia, hypomagnesemia, or genetic predisposition. Although torsade de pointes has not been observed in association with the use of ziprasidone at recommended doses in premarketing studies and experience is too limited to rule out an increased risk, there have been rare post-marketing reports (in the presence of multiple confounding factors) (see ADVERSE REACTIONS; Other Events Observed During Post-marketing Use).

A study evaluating the QT/QTc prolonging effect of intramuscular ziprasidone, with intramuscular haloperidol as a control, was conducted in patient volunteers. In the trial, ECGs were obtained at the time of maximum plasma concentration following two injections of ziprasidone (20 mg then 30 mg) or haloperidol (7.5 mg then 10 mg) given four hours apart. Note that a 30 mg dose of intramuscular ziprasidone is 50% higher than the recommended therapeutic dose. The mean change in QTc from baseline was calculated for each drug, using a sample-based correction that removes the effect of heart rate on the QT interval. The mean increase in QTc from baseline for ziprasidone was 4.6 msec following the first injection and 12.8 msec following the second injection. The mean increase in QTc from baseline for haloperidol was 6.0 msec following the first injection and 14.7 msec following the second injection. In this study, no patients had a QTc interval exceeding 500 msec.

As with other antipsychotic drugs and placebo, sudden unexplained deaths have been reported in patients taking ziprasidone at recommended doses. The premarketing experience for ziprasidone did not reveal an excess risk of mortality for ziprasidone compared to other antipsychotic drugs or placebo, but the extent of exposure was limited, especially for the drugs used as active controls and placebo. Nevertheless, ziprasidone's larger prolongation of QTc length compared to several other antipsychotic drugs raises the possibility that the risk of sudden death may be greater for ziprasidone than for other available drugs for treating schizophrenia. This possibility needs to be considered in deciding among alternative drug products (see INDICATIONS AND USAGE).

Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.

It is recommended that patients being considered for ziprasidone treatment who are at risk for significant electrolyte disturbances, hypokalemia in particular, have baseline serum potassium and magnesium measurements. Hypokalemia (and/or hypomagnesemia) may increase the risk of QT prolongation and arrhythmia. Hypokalemia may result from diuretic therapy, diarrhea, and other causes. Patients with low serum potassium and/or magnesium should be repleted with those electrolytes before proceeding with treatment. It is essential to periodically monitor serum electrolytes in patients for whom diuretic therapy is introduced during ziprasidone treatment. Persistently prolonged QTc intervals may also increase the risk of further prolongation and arrhythmia, but it is not clear that routine screening ECG measures are effective in detecting such patients. Rather, ziprasidone should be avoided in patients with histories of significant cardiovascular illness, e.g., QT prolongation, recent acute myocardial infarction, uncompensated heart failure, or cardiac arrhythmia. Ziprasidone should be discontinued in patients who are found to have persistent QTc measurements >500 msec.

For patients taking ziprasidone who experience symptoms that could indicate the occurrence of torsade de pointes, e.g., dizziness, palpitations, or syncope, the prescriber should initiate further evaluation, e.g., Holter monitoring may be useful.

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.

The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients undergoing treatment with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, ziprasidone should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on ziprasidone, drug discontinuation should be considered. However, some patients may require treatment with ziprasidone despite the presence of the syndrome.

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. There have been few reports of hyperglycemia or diabetes in patients treated with GEODON. Although fewer patients have been treated with GEODON, it is not known if this more limited experience is the sole reason for the paucity of such reports. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies, which did not include GEODON, suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics included in these studies. Because GEODON was not marketed at the time these studies were performed, it is not known if GEODON is associated with this increased risk. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.

Please refer to the patient package insert. To assure safe and effective use of GEODON, the information and instructions provided in the patient information should be discussed with patients.

Patients being considered for ziprasidone treatment that are at risk of significant electrolyte disturbances should have baseline serum potassium and magnesium measurements. Low serum potassium and magnesium should be repleted before proceeding with treatment. Patients who are started on diuretics during ziprasidone therapy need periodic monitoring of serum potassium and magnesium. Ziprasidone should be discontinued in patients who are found to have persistent QTc measurements >500 msec (see WARNINGS).

Drug-drug interactions can be pharmacodynamic (combined pharmacologic effects) or pharmacokinetic (alteration of plasma levels). The risks of using ziprasidone in combination with other drugs have been evaluated as described below. All interactions studies have been conducted with oral ziprasidone. Based upon the pharmacodynamic and pharmacokinetic profile of ziprasidone, possible interactions could be anticipated:

• (1) Ziprasidone should not be used with any drug that prolongs the QT interval (see CONTRAINDICATIONS).
• (2)Given the primary CNS effects of ziprasidone, caution should be used when it is taken in combination with other centrally acting drugs.
• (3)Because of its potential for inducing hypotension, ziprasidone may enhance the effects of certain antihypertensive agents.
• (4)Ziprasidone may antagonize the effects of levodopa and dopamine agonists.

In vitro studies revealed little potential for ziprasidone to interfere with the metabolism of drugs cleared primarily by CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and little potential for drug interactions with ziprasidone due to displacement (see CLINICAL PHARMACOLOGY, Pharmacokinetics).

The effect of ziprasidone on labor and delivery in humans is unknown.

It is not known whether, and if so in what amount, ziprasidone or its metabolites are excreted in human milk. It is recommended that women receiving ziprasidone should not breast feed.

The safety and effectiveness of ziprasidone in pediatric patients have not been established.

Of the approximately 4500 patients treated with ziprasidone in clinical studies, 2.4% (109) were 65 years of age or over. In general, there was no indication of any different tolerability of ziprasidone or for reduced clearance of ziprasidone in the elderly compared to younger adults. Nevertheless, the presence of multiple factors that might increase the pharmacodynamic response to ziprasidone, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period for some elderly patients.

The premarketing development program 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. 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.

The premarketing development program 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 events 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. Adverse experiences were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and tabulations that follow, standard COSTART dictionary terminology has been used to classify reported adverse events.

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

The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side effect incidence rate in the population studied.

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.

Table 3 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy (up to 6 weeks) in predominantly patients with schizophrenia, including only those events 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.

Table 4 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy (up to 3 weeks) in patients with bipolar mania, including only those events 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 event occurrence on the basis of this demographic factor.

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

Following is a ul of COSTART terms that reflect treatment-emergent adverse events 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 events are included except those already uled in Table 3 or elsewhere in labeling, those event terms that were so general as to be uninformative, events reported only once and that did not have a substantial probability of being acutely life-threatening, events that are part of the illness being treated or are otherwise common as background events, and events considered unlikely to be drug-related. It is important to emphasize that, although the events reported occurred during treatment with ziprasidone, they were not necessarily caused by it.

Events are further categorized by body system and uled in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients (only those not already uled in the tabulated results from placebo-controlled trials appear in this uling); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.

Body as a Whole: Frequent: abdominal pain, flu syndrome, fever, accidental fall, face edema, chills, photosensitivity reaction, flank pain, hypothermia, motor vehicle accident.

Cardiovascular System: Frequent: tachycardia, hypertension, postural hypotension; Infrequent: bradycardia, angina pectoris, atrial fibrillation; Rare: first degree AV block, bundle branch block, phlebitis, pulmonary embolus, cardiomegaly, cerebral infarct, cerebrovascular accident, deep thrombophlebitis, myocarditis, thrombophlebitis.

Digestive System: Frequent: anorexia, vomiting; Infrequent: rectal hemorrhage, dysphagia, tongue edema; Rare: gum hemorrhage, jaundice, fecal impaction, gamma glutamyl transpeptidase increased, hematemesis, cholestatic jaundice, hepatitis, hepatomegaly, leukoplakia of mouth, fatty liver deposit, melena.

Endocrine: Rare: hypothyroidism, hyperthyroidism, thyroiditis.

Hemic and Lymphatic System: Infrequent: anemia, ecchymosis, leukocytosis, leukopenia, eosinophilia, lymphadenopathy; Rare: thrombocytopenia, hypochromic anemia, lymphocytosis, monocytosis, basophilia, lymphedema, polycythemia, thrombocythemia.

Metabolic and Nutritional Disorders: Infrequent: thirst, transaminase increased, peripheral edema, hyperglycemia, creatine phosphokinase increased, alkaline phosphatase increased, hypercholesteremia, dehydration, lactic dehydrogenase increased, albuminuria, hypokalemia; Rare: BUN increased, creatinine increased, hyperlipemia, hypocholesteremia, hyperkalemia, hypochloremia, hypoglycemia, hyponatremia, hypoproteinemia, glucose tolerance decreased, gout, hyperchloremia, hyperuricemia, hypocalcemia, hypoglycemic reaction, hypomagnesemia, ketosis, respiratory alkalosis.

Musculoskeletal System: Frequent: myalgia; Infrequent: tenosynovitis; Rare: myopathy.

Nervous System: Frequent: agitation, extrapyramidal syndrome, tremor, dystonia, hypertonia, dyskinesia, hostility, twitching, paresthesia, confusion, vertigo, hypokinesia, hyperkinesia, abnormal gait, oculogyric crisis, hypesthesia, ataxia, amnesia, cogwheel rigidity, delirium, hypotonia, akinesia, dysarthria, withdrawal syndrome, buccoglossal syndrome, choreoathetosis, diplopia, incoordination, neuropathy; Infrequent: paralysis; Rare: myoclonus, nystagmus, torticollis, circumoral paresthesia, opisthotonos, reflexes increased, trismus.

Respiratory System: Frequent: dyspnea; Infrequent: pneumonia, epistaxis; Rare: hemoptysis, laryngismus.

Skin and Appendages: Infrequent: maculopapular rash, urticaria, alopecia, eczema, exfoliative dermatitis, contact dermatitis, vesiculobullous rash.

Special Senses: Frequent: fungal dermatitis; Infrequent: conjunctivitis, dry eyes, tinnitus, blepharitis, cataract, photophobia; Rare: eye hemorrhage, visual field defect, keratitis, keratoconjunctivitis.

Urogenital System: Infrequent: impotence, abnormal ejaculation, amenorrhea, hematuria, menorrhagia, female lactation, polyuria, urinary retention, metrorrhagia, male sexual dysfunction, anorgasmia, glycosuria; Rare: gynecomastia, vaginal hemorrhage, nocturia, oliguria, female sexual dysfunction, uterine hemorrhage.

Adverse event reports not uled above that have been received since market introduction include rare occurrences of the following (no causal relationship with ziprasidone has been established): Cardiac Disorders: Tachycardia, torsade de pointes (in the presence of multiple confounding factors - see WARNINGS); Digestive System Disorders: Swollen tongue; 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; Reproductive System and Breast Disorders: Galactorrhea, priapism; Skin and subcutaneous Tissue Disorders: Allergic reaction (such as allergic dermatitis, angioedema, orofacial edema, urticaria), rash; Urogenital System Disorders: Enuresis, urinary incontinence; Vascular Disorders: Postural hypotension, syncope.

Ziprasidone is not a controlled substance.

Ziprasidone has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. While the clinical trials did not reveal any tendency for drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which ziprasidone will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of ziprasidone misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

In premarketing trials involving more than 5400 patients and/or normal subjects, accidental or intentional overdosage of oral ziprasidone was documented in 10 patients. All of these patients survived without sequelae. In the patient taking the largest confirmed amount, 3240 mg, the only symptoms reported were minimal sedation, slurring of speech, and transitory hypertension (200/95).

In post-marketing use, adverse events reported in association with ziprasidone overdose generally included extrapyramidal symptoms, somnolence, tremor, and anxiety.

In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Intravenous access should be established and gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizure, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.

Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects that might be additive to those of ziprasidone.

Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids. If sympathomimetic agents are used for vascular support, epinephrine and dopamine should not be used, since beta stimulation combined with α₁ antagonism associated with ziprasidone may worsen hypotension. Similarly, it is reasonable to expect that the alpha-adrenergic-blocking properties of bretylium might be additive to those of ziprasidone, resulting in problematic hypotension.

In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. There is no specific antidote to ziprasidone, and it is not dialyzable. The possibility of multiple drug involvement should be considered. Close medical supervision and monitoring should continue until the patient recovers.

When deciding among the alternative treatments available for schizophrenia, 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).

The recommended dose is 10 to 20 mg administered as required up to a maximum dose of 40 mg per day. Doses of 10 mg may be administered every two hours; doses of 20 mg may be administered every four hours up to a maximum of 40 mg/day. Intramuscular administration of ziprasidone for more than three consecutive days has not been studied.

If long-term therapy is indicated, oral ziprasidone hydrochloride capsules should replace the intramuscular administration as soon as possible.

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.

GEODON for Injection (ziprasidone mesylate) should only be administered by intramuscular injection. Single-dose vials require reconstitution prior to administration.

Add 1.2 mL of Sterile Water for Injection to the vial and shake vigorously until all the drug is dissolved. Each mL of reconstituted solution contains 20 mg ziprasidone. To administer a 10 mg dose, draw up 0.5 mL of the reconstituted solution. To administer a 20 mg dose, draw up 1.0 mL of the reconstituted solution. Any unused portion should be discarded. Since no preservative or bacteriostatic agent is present in this product, aseptic technique must be used in preparation of the final solution. This medicinal product must not be mixed with other medicinal products or solvents other than Sterile Water for Injection.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

GEODON Capsules are differentiated by capsule color/size and are imprinted in black ink with "Pfizer" and a unique number. GEODON Capsules are supplied for oral administration in 20 mg (blue/white), 40 mg (blue/blue), 60 mg (white/white), and 80 mg (blue/white) capsules. They are supplied in the following strengths and package configurations:

GEODON Capsules should be stored at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [See USP Controlled Room Temperature].

GEODON for Injection is available in a single dose vial as ziprasidone mesylate (20 mg ziprasidone/mL when reconstituted according to label instructions - see Preparation for Administration) for intramuscular administration. Each mL of ziprasidone mesylate for injection (when reconstituted) affords a colorless to pale pink solution that contains 20 mg of ziprasidone and 4.7 mg of methanesulfonic acid solubilized by 294 mg of sulfobutylether β-cyclodextrin sodium (SBECD).

GEODON for Injection should be stored at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [See USP Controlled Room Temperature] in dry form. Protect from light. Following reconstitution, GEODON for Injection can be stored, when protected from light, for up to 24 hours at 15°–30°C (59°–86°F) or up to 7 days refrigerated, 2°–8°C (36°–46°F).

GEODON^® Capsules
(ziprasidone HCl)

Information for patients taking GEODON or their caregivers

This summary contains important information about GEODON. It is not meant to take the place of your doctor's instructions. Read this information carefully before you take GEODON. Ask your doctor or pharmacist if you do not understand any of this information or if you want to know more about GEODON.

What Is GEODON?

GEODON is a type of prescription medicine called a psychotropic, also known as an atypical antipsychotic. GEODON can be used to treat symptoms of schizophrenia and acute manic or mixed episodes associated with bipolar disorder.

Who Should Take GEODON?

Only your doctor can know if GEODON is right for you. GEODON may be prescribed for you if you have schizophrenia or acute manic or mixed episodes associated with bipolar disorder.

Symptoms of schizophrenia may include:

• hearing voices, seeing things, or sensing things that are not there (hallucinations)
• beliefs that are not true (delusions)
• unusual suspiciousness (paranoia)
• becoming withdrawn from family and friends

Symptoms of manic or mixed episodes of bipolar disorder may include:

• extremely high or irritable mood
• increased energy, activity, and restlessness
• racing thoughts or talking very fast
• easily distracted
• little need for sleep

If you show a response to GEODON, your symptoms may improve. If you continue to take GEODON there is less chance of your symptoms returning. Do not stop taking the capsules even when you feel better without first discussing it with your doctor.

It is also important to remember that GEODON capsules should be taken with food.

What is the most important safety information I should know about GEODON?

GEODON is not approved for the treatment of patients with dementia-related psychosis. Elderly patients with a diagnosis of psychosis related to dementia treated with atypical antipsychotics are at an increased risk of death when compared to patients who are treated with placebo (a sugar pill).

GEODON is an effective drug to treat the symptoms of schizophrenia and the manic or mixed episodes of bipolar disorder. However, one potential side effect is that it may change the way the electrical current in your heart works more than some other drugs. The change is small and it is not known whether this will be harmful, but some other drugs that cause this kind of change have in rare cases caused dangerous heart rhythm abnormalities. Because of this, GEODON should be used only after your doctor has considered this risk for GEODON against the risks and benefits of other medications available for treating schizophrenia or bipolar manic and mixed episodes.

Your risk of dangerous changes in heart rhythm can be increased if you are taking certain other medicines and if you already have certain abnormal heart conditions. Therefore, it is important to tell your doctor about any other medicines that you take, including non-prescription medicines, supplements, and herbal medicines. You must also tell your doctor about any heart problems you have or have had.

Who should NOT take GEODON?

Elderly patients with a diagnosis of psychosis related to dementia. GEODON is not approved for the treatment of these patients.

Anything that can increase the chance of a heart rhythm abnormality should be avoided. Therefore, do not take GEODON if:

• You have certain heart diseases, for example, long QT syndrome, a recent heart attack, severe heart failure, or certain irregularities of heart rhythm (discuss the specifics with your doctor)
• You are currently taking medications that should not be taken in combination with ziprasidone, for example, dofetilide, sotalol, quinidine, other Class Ia and III anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol or tacrolimus.

What To Tell Your Doctor Before You Start GEODON

Only your doctor can decide if GEODON is right for you. Before you start GEODON, be sure to tell your doctor if you:

• have had any problem with the way your heart beats or any heart related illness or disease
• any family history of heart disease, including recent heart attack
• have had any problem with fainting or dizziness
• are taking or have recently taken any prescription medicines
• are taking any over-the-counter medicines you can buy without a prescription, including natural/herbal remedies
• have had any problems with your liver
• are pregnant, might be pregnant, or plan to get pregnant
• are breast feeding
• are allergic to any medicines
• have ever had an allergic reaction to ziprasidone or any of the other ingredients of GEODON capsules. Ask your doctor or pharmacist for a ul of these ingredients
• have low levels of potassium or magnesium in your blood

Your doctor may want you to get additional laboratory tests to see if GEODON is an appropriate treatment for you.

GEODON And Other Medicines

There are some medications that may be unsafe to use when taking GEODON, and there are some medicines that can affect how well GEODON works. While you are on GEODON, check with your doctor before starting any new prescription or over-the-counter medications, including natural/herbal remedies.

How To Take GEODON

• Take GEODON only as directed by your doctor.
• Swallow the capsules whole.
• Take GEODON capsules with food.
• It is best to take GEODON at the same time each day.
• GEODON may take a few weeks to work. It is important to be patient.
• Do not change your dose or stop taking your medicine without your doctor's approval.
• Remember to keep taking your capsules, even when you feel better.

Possible Side Effects

Because these problems could mean you're having a heart rhythm abnormality, contact your doctor IMMEDIATELY if you:

• Faint or lose consciousness
• Feel a change in the way that your heart beats (palpitations)

Common side effects of GEODON include the following and should also be discussed with your doctor if they occur:

• Feeling unusually tired or sleepy
• Nausea or upset stomach
• Constipation
• Dizziness
• Restlessness
• Abnormal muscle movements, including tremor, shuffling, and uncontrolled involuntary movements
• Diarrhea
• Rash
• Increased cough / runny nose

If you develop any side effects that concern you, talk with your doctor. It is particularly important to tell your doctor if you have diarrhea, vomiting, or another illness that can cause you to lose fluids. Your doctor may want to check your blood to make sure that you have the right amount of important salts after such illnesses.

For a ul of all side effects that have been reported, ask your doctor or pharmacist for the GEODON Professional Package Insert.

What To Do For An Overdose

In case of an overdose, call your doctor or poison control center right away or go to the nearest emergency room.

Other Important Safety Information

A serious condition called neuroleptic malignant syndrome (NMS) can occur with all antipsychotic medications including GEODON. Signs of NMS include very high fever, rigid muscles, shaking, confusion, sweating, or increased heart rate and blood pressure. NMS is a rare but serious side effect that could be fatal. Therefore, tell your doctor if you experience any of these signs.

Adverse events related to high blood sugar (hyperglycemia), sometimes serious, have been reported in patients treated with atypical antipsychotics. There have been few reports of hyperglycemia or diabetes in patients treated with GEODON, and it is not known if GEODON is associated with these events. Patients treated with an atypical antipsychotic should be monitored for symptoms of hyperglycemia.

Dizziness caused by a drop in your blood pressure may occur with GEODON, especially when you first start taking this medication or when the dose is increased. If this happens, be careful not to stand up too quickly, and talk to your doctor about the problem.

Before taking GEODON, tell your doctor if you are pregnant or plan on becoming pregnant. It is advised that you don't breast feed an infant if you are taking GEODON.

Because GEODON can cause sleepiness, be careful when operating machinery or driving a motor vehicle.

Since medications of the same drug class as GEODON may interfere with the ability of the body to adjust to heat, it is best to avoid situations involving high temperature or humidity.

It is best to avoid consuming alcoholic beverages while taking GEODON.

Call your doctor immediately if you take more than the amount of GEODON prescribed by your doctor.

GEODON has not been shown to be safe or effective in the treatment of children and teenagers under the age of 18 years old.

Keep GEODON and all medicines out of the reach of children.

How To Store GEODON

Store GEODON capsules at room temperature (59°–86°F or 15°–30°C).

For More Information About GEODON

This sheet is only a summary. GEODON is a prescription medicine and only your doctor can decide if it is right for you. If you have any questions or want more information about GEODON, talk with your doctor or pharmacist. You can also visit www.geodon.com.