GEODON- ziprasidone mesylate_injection, powder, lyophilized, for solution

The mechanism of action of ziprasidone in the treatment of the listed indications could be mediated through a combination of dopamine type 2 (D 2 2 Ziprasidone binds with relatively high affinity to the dopamine D 2 3 2A 2C 1A 1D 1 i 1 i 2, 2A 1D 1A 50 Oral 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. Absorption Distribution 1 in vitro Metabolism and Elimination In vitro In vitro in vivo Intramuscular Pharmacokinetics Systemic Bioavailability ½ Metabolism and Elimination.

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 (5. 3) [see Warnings and Precautions (5. 3) GEODON is an atypical antipsychotic. In choosing among treatments, prescribers should be aware of the capacity of GEODON to prolong the QT interval and may consider the use of other drugs first ( 1 GEODON capsules are indicated for the: 1 1 1 GEODON for injection is indicated for the: 1 Schizophrenia [see Clinical Studies (14. 1) Bipolar I Disorder (Acute Mixed or Manic Episodes and Maintenance Treatment as an Adjunct to Lithium or Valproate) [see Clinical Studies (14. 2) [see Clinical Studies (14. 2) Acute Treatment of Agitation in Schizophrenia [see Clinical Studies (14. 1) 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.

4 Administer GEODON capsules orally with food. Swallow capsules whole, do not open, crush, or chew the capsules. Dose Selection GEODON capsules should be administered at an initial daily dose of 20 mg twice daily with food. In some patients, daily dosage may subsequently be adjusted on the basis of individual clinical status up to 80 mg twice daily. Dosage adjustments, if indicated, should generally occur at intervals of not less than 2 days, as steady-state is achieved within 1 to 3 days. In order to ensure use of the lowest effective dose, patients should ordinarily be observed for improvement for several weeks before upward dosage adjustment. Efficacy in schizophrenia was demonstrated in a dose range of 20 mg to 100 mg twice daily in short-term, placebo-controlled clinical trials. There were trends toward dose response within the range of 20 mg to 80 mg twice daily, but results were not consistent. An increase to a dose greater than 80 mg twice daily is not generally recommended. The safety of doses above 100 mg twice daily has not been systematically evaluated in clinical trials [see Clinical Studies (14. 1)] Maintenance Treatment While there is no body of evidence available to answer the question of how long a patient treated with ziprasidone should remain on it, a maintenance study in patients who had been symptomatically stable and then randomized to continue ziprasidone or switch to placebo demonstrated a delay in time to relapse for patients receiving GEODON [see Clinical Studies (14. 1) Acute Treatment of Manic or Mixed Episodes In adults oral ziprasidone should be administered at an initial daily dose of 40 mg twice daily with food. The dose may then be increased to 60 mg or 80 mg twice daily on the second day of treatment and subsequently adjusted on the basis of tolerance and efficacy within the range 40 mgen dash80 mg twice daily. In the flexible-dose clinical trials, the mean daily dose administered was approximately 120 mg [see Clinical Studies (14. 2) Maintenance Treatment (as an adjunct to lithium or valproate) Continue treatment at the same dose on which the patient was initially stabilized, within the range of 40 mgen dash80 mg twice daily with food. Patients should be periodically reassessed to determine the need for maintenance treatment [see Clinical Studies (14. 2) Intramuscular Dosing The recommended dose is 10 mg 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. Ziprasidone intramuscular is intended for intramuscular use only and should not be administered intravenously. Intramuscular Preparation for Administration GEODON for Injection (ziprasidone mesylate) should only be administered by intramuscular injection and should not be administered intravenously. Single-dose vials require reconstitution prior to administration. 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.

Commonly observed adverse reactions (incidence >=5% and at least twice the incidence for placebo) were : Schizophrenia 6. 1 Manic and Mixed Episodes Associated with Bipolar Disorder 6. 1 Intramuscular administration 6. 1 To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 in adults 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 Bipolar trials (see Table 12 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. 8) 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. Table 11: Treatment-Emergent Adverse Reaction Incidence In Short-Term Oral Placebo-Controlled Trials en dash Schizophrenia Percentage of Patients Reporting Reaction Body System/Adverse Reaction Ziprasidone (N=702) Placebo (N=273) Body as a Whole Asthenia 5 3 Accidental Injury 4 2 Chest Pain 3 2 Cardiovascular Tachycardia 2 1 Digestive Nausea 10 7 Constipation 9 8 Dyspepsia 8 7 Diarrhea 5 4 Dry Mouth 4 2 Anorexia 2 1 Nervous Extrapyramidal Symptoms Extrapyramidal Symptoms 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 5% in schizophrenia trials. 14 8 Somnolence 14 7 Akathisia 8 7 Dizziness Dizziness includes the adverse reaction terms dizziness and lightheadedness. 8 6 Respiratory Respiratory Tract Infection 8 3 Rhinitis 4 2 Cough Increased 3 1 Skin and Appendages Rash 4 3 Fungal Dermatitis 2 1 Special Senses Abnormal Vision 3 2 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) Dystonia - Class Effect: Vital Sign Changes [see Warnings and Precautions (5. 9) ECG Changes - [see Warnings and Precautions (5. 3) 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 Adverse reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions: Frequent - Infrequent - Rare 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, hypoglycemicreaction, 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 BIPOLAR DISORDER Acute Treatment of Manic or Mixed Episodes in Adults 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. Table 12: Treatment-Emergent Adverse Reactions Incidence In Short-Term Oral Placebo-Controlled Trials en dash Manic and Mixed Episodes Associated With Bipolar Disorder Percentage of Patients Reporting Reaction Body System/Adverse Reaction Ziprasidone (N=279) Placebo (N=136) Body as a Whole Headache 18 17 Asthenia 6 2 Accidental Injury 4 1 Cardiovascular Hypertension 3 2 Digestive Nausea 10 7 Diarrhea 5 4 Dry Mouth 5 4 Vomiting 5 2 Increased Salivation 4 0 Tongue Edema 3 1 Dysphagia 2 0 Musculoskeletal Myalgia 2 0 Nervous Somnolence 31 12 Extrapyramidal Symptoms Extrapyramidal Symptoms 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. 31 12 Dizziness Dizziness includes the adverse reaction terms dizziness and lightheadedness. 16 7 Akathisia 10 5 Anxiety 5 4 Hypesthesia 2 1 Speech Disorder 2 0 Respiratory Pharyngitis 3 1 Dyspnea 2 1 Skin and Appendages Fungal Dermatitis 2 1 Special Senses Abnormal Vision 6 3 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%). Table 13: Treatment-Emergent Adverse Reaction Incidence In Short-Term Fixed-Dose Intramuscular Trials Percentage of Patients Reporting Reaction Body System/Adverse Reaction Ziprasidone 2 mg (N=92) Ziprasidone 10 mg (N=63) Ziprasidone 20 mg (N=41) Body as a Whole Headache 3 13 5 Injection Site Pain 9 8 7 Asthenia 2 0 0 Abdominal Pain 0 2 0 Flu Syndrome 1 0 0 Back Pain 1 0 0 Cardiovascular Postural Hypotension 0 0 5 Hypertension 2 0 0 Bradycardia 0 0 2 Vasodilation 1 0 0 Digestive Nausea 4 8 12 Rectal Hemorrhage 0 0 2 Diarrhea 3 3 0 Vomiting 0 3 0 Dyspepsia 1 3 2 Anorexia 0 2 0 Constipation 0 0 2 Tooth Disorder 1 0 0 Dry Mouth 1 0 0 Nervous Dizziness 3 3 10 Anxiety 2 0 0 Insomnia 3 0 0 Somnolence 8 8 20 Akathisia 0 2 0 Agitation 2 2 0 Extrapyramidal Syndrome 2 0 0 Hypertonia 1 0 0 Cogwheel Rigidity 1 0 0 Paresthesia 0 2 0 Personality Disorder 0 2 0 Psychosis 1 0 0 Speech Disorder 0 2 0 Respiratory Rhinitis 1 0 0 Skin and Appendages Furunculosis 0 2 0 Sweating 0 0 2 Urogenital Dysmenorrhea 0 2 0 Priapism 1 0 0 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: [see Warnings and Precautions (5. 3) Digestive System Disorders: Reproductive System and Breast Disorders: Nervous System Disorders: Psychiatric Disorders: Skin and subcutaneous Tissue Disorders: Urogenital System Disorders: Vascular Disorders:.

2 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: 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: [see Warnings and Precautions (5. 3) Ziprasidone is contraindicated in individuals with a known hypersensitivity to the product.

Pregnancy 8. 1 Renal Impairment: 8. 6 Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including GEODON, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth. org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs, including GEODON, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations (see Data (see Clinical Considerations In animal studies, ziprasidone administration to pregnant rats and rabbits during organogenesis caused developmental toxicity at doses similar to recommended human doses, and was teratogenic in rabbits at 3 times the maximum recommended human dose (MRHD). Rats exposed to ziprasidone during gestation and lactation exhibited increased perinatal pup mortality and delayed neurobehavioral and functional development of offspring at doses less than or similar to human therapeutic doses. ( see Data The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/neonatal adverse reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including GEODON, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. Animal Data When ziprasidone was administered to pregnant rabbits during the period of organogenesis, an increased incidence of fetal structural abnormalities (ventricular septal defects and other cardiovascular malformations, and kidney alterations) was observed at a dose of 30 mg/kg/day (3 times the MRHD of 200 mg/day based on mg/m 2 2 2 2 2 There was an increase in the number of pups born dead and a decrease in postnatal survival through the first 4 days of lactation among the offspring of female rats treated during gestation and lactation with doses of 10 mg/kg/day (0. 5 times the MRHD based on mg/m 2 2 Risk Summary Limited data from a published case report indicate the presence of ziprasidone in human milk. Although there are no reports of adverse effects on a breastfed infant exposed to ziprasidone via breast milk, there are reports of excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements) in infants exposed to other atypical antipsychotics through breast milk (see Clinical Considerations Clinical Considerations Infants exposed to GEODON should be monitored for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements). Infertility Females Based on the pharmacologic action of ziprasidone (D2 antagonism), treatment with GEODON may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions (5. 15) Nonclinical Toxicology (13. 1) The safety and effectiveness of Geodon have not been established in pediatric patients. Geodon was studied in one 4-week, placebo-controlled trial in patients 10 to 17 years of age with bipolar I disorder. However, the data were insufficient to fully assess the safety of Geodon in pediatric patients. Therefore, a safe and effective dose for use could not be established. Of the total number of subjects in clinical studies of ziprasidone, 2. 4 percent were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 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. Ziprasidone intramuscular has not been systematically evaluated in elderly patients (65 years and over). Because ziprasidone is highly metabolized, with less than 1% of the drug excreted unchanged, renal impairment alone is unlikely to have a major impact on the pharmacokinetics of ziprasidone. The pharmacokinetics of ziprasidone following 8 days of 20 mg twice daily dosing were similar among subjects with varying degrees of renal impairment (n=27), and subjects with normal renal function, indicating that dosage adjustment based upon the degree of renal impairment is not required. Ziprasidone is not removed by hemodialysis. Intramuscular ziprasidone has not been systematically evaluated in elderly patients or in patients with hepatic or renal impairment. As the cyclodextrin excipient is cleared by renal filtration, ziprasidone intramuscular should be administered with caution to patients with impaired renal function [see Clinical Pharmacology (12) As ziprasidone is cleared substantially by the liver, the presence of hepatic impairment would be expected to increase the AUC of ziprasidone; a multiple-dose study at 20 mg twice daily for 5 days in subjects (n=13) with clinically significant (Childs-Pugh Class A and B) cirrhosis revealed an increase in AUC 0en dash12 In a multiple-dose (8 days of treatment) study involving 32 subjects, there was no difference in the pharmacokinetics of ziprasidone between men and women or between elderly (>65 years) and young (18 to 45 years) subjects. Additionally, population pharmacokinetic evaluation of patients in controlled trials has revealed no evidence of clinically significant age or gender-related differences in the pharmacokinetics of ziprasidone. Dosage modifications for age or gender are, therefore, not recommended. Based on in vitro in vitro.

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: 4. 10 7 Approximately two-thirds of ziprasidone is metabolized via a combination of chemical reduction by glutathione and enzymatic reduction by aldehyde oxidase. There are no known clinically relevant inhibitors or inducers of aldehyde oxidase. Less than one-third of ziprasidone metabolic clearance is mediated by cytochrome P450 catalyzed oxidation. An in vitro [see Clinical Pharmacology (12. 3) Ziprasidone should not be used with any drug that prolongs the QT interval [see Contraindications (4. 1) Given the primary CNS effects of ziprasidone, caution should be used when it is taken in combination with other centrally acting drugs. Because of its potential for inducing hypotension, ziprasidone may enhance the effects of certain antihypertensive agents. Ziprasidone may antagonize the effects of levodopa and dopamine agonists. Carbamazepine Carbamazepine is an inducer of CYP3A4; administration of 200 mg twice daily for 21 days resulted in a decrease of approximately 35% in the AUC of ziprasidone. This effect may be greater when higher doses of carbamazepine are administered. Ketoconazole Ketoconazole, a potent inhibitor of CYP3A4, at a dose of 400 mg QD for 5 days, increased the AUC and Cmax of ziprasidone by about 35en dash40%. Other inhibitors of CYP3A4 would be expected to have similar effects. Cimetidine Cimetidine at a dose of 800 mg QD for 2 days did not affect ziprasidone pharmacokinetics. Antacid The co-administration of 30 mL of Maaloxregistered with ziprasidone did not affect the pharmacokinetics of ziprasidone. Ziprasidone at a dose of 40 mg twice daily administered concomitantly with lithium at a dose of 450 mg twice daily for 7 days did not affect the steady-state level or renal clearance of lithium. Ziprasidone dosed adjunctively to lithium in a maintenance trial of bipolar patients did not affect mean therapeutic lithium levels. In vivo Consistent with in vitro A pharmacokinetic interaction of ziprasidone with valproate is unlikely due to the lack of common metabolic pathways for the two drugs. Ziprasidone dosed adjunctively to valproate in a maintenance trial of bipolar patients did not affect mean therapeutic valproate levels. Population pharmacokinetic analysis of schizophrenic patients enrolled in controlled clinical trials has not revealed evidence of any clinically significant pharmacokinetic interactions with benztropine, propranolol, or lorazepam. 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 [see Clinical Pharmacology (12.

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

OVERDOSAGE
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, 3,240 mg, the only symptoms reported were minimal sedation, slurring of speech, and transitory hypertension (200/95). Adverse reactions reported with ziprasidone overdose included extrapyramidal symptoms, somnolence, tremor, and anxiety. [see Adverse Reactions (6. 2) 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 alpha 1 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.
NONCLINICAL TOXICOLOGY
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. 6 and 1 to 5 times the maximum recommended human dose (MRHD) of 200 mg/day based on mg/m 2 2 2 [see Warnings and Precautions (5. 14) Mutagenesis Ziprasidone was tested in the Ames bacterial mutation assay, the in vitro in vitro in vivo S. typhimurium in vitro in vitro 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 based on mg/m 2 2 2 2.
CLINICAL STUDIES
The efficacy of oral ziprasidone in the treatment of schizophrenia was evaluated in 5 placebo-controlled 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: Acute Manic and Mixed Episodes Associated With Bipolar I Disorder 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 : Maintenance Therapy 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 double-blind 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. , 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. 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: .

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