ZIPRASIDONE- ziprasidone_capsule

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 2 2A 1D 1A 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 Metabolism and Elimination:.

Ziprasidone capsules are 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. 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 Warnings and Precautions ( 5. 3 Schizophrenia Ziprasidone capsules are indicated for the treatment of schizophrenia in adults [see Clinical Studies ( 14. 1 Bipolar I Disorder (Acute Mixed or Manic Episodes and Maintenance Treatment as an Adjunct to Lithium or Valproate) Ziprasidone capsules are indicated as monotherapy for the acute treatment of adults with manic or mixed episodes associated with bipolar I disorder [see Clinical Studies ( 14. 2 Ziprasidone capsules are indicated as an adjunct to lithium or valproate for the maintenance treatment of bipolar I disorder in adults [see Clinical Studies ( 14. 2 Ziprasidone capsule is an atypical antipsychotic. In choosing among treatments, prescribers should be aware of the capacity of ziprasidone capsule to prolong the QT interval and may consider the use of other drugs first (1) Ziprasidone capsules are indicated for the: treatment of schizophrenia in adults. ( 1 acute treatment of adults as monotherapy of manic or mixed episodes associated with bipolar I disorder. ( 1 maintenance treatment of bipolar I disorder as an adjunct to lithium or valproate in adults.

Administer capsules orally with food. Do not open, crush, or chew. 1 Schizophrenia: Initiate at 20 mg twice daily. Daily dosage may be adjusted up to 80 mg twice daily. Dose adjustments should occur at intervals of not less than 2 days. Safety and efficacy has been demonstrated in doses up to 100 mg twice daily. The lowest effective dose should be used. 2 ) Acute treatment of manic/mixed episodes of bipolar I disorder: Initiate at 40 mg twice daily. Increase to 60 mg or 80 mg twice daily on day 2 of treatment. Subsequent dose adjustments should be based on tolerability and efficacy within the range of 40 to 80 mg twice daily. 3 ) Maintenance treatment of bipolar I disorder 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 to 80 mg twice daily. 3 ) Administer ziprasidone capsules orally with food. Swallow capsules whole, do not open, crush, or chew the capsules. Dose Selection Ziprasidone 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 ziprasidone capsules [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 mg to 80 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 mg to 80 mg twice daily with food. Patients should be periodically reassessed to determine the need for maintenance treatment [see Clinical Studies ( 14.

Commonly observed adverse reactions (incidence >=5% and at least twice the incidence for placebo) were : Schizophrenia: Somnolence, respiratory tract infection. 1) Manic and Mixed Episodes Associated with Bipolar Disorder: Somnolence, extrapyramidal symptoms, dizziness, akathisia, abnormal vision, asthenia, vomiting (6. 1) To report SUSPECTED ADVERSE REACTIONS, contact NorthStar Rx LLC at 1-800-206-7821 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. Adverse reactions during exposure were obtained by collecting voluntarily reported adverse experiences, as well as results of physical examinations, vital signs, weights, laboratory analyses, ECGs, and results of ophthalmologic examinations. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Adverse Findings Observed in Short-Term, Placebo-Controlled Trials with Oral Ziprasidone The following findings are based on the short-term placebo-controlled premarketing trials for schizophrenia (a pool of two 6-week, and two 4-week fixed-dose trials) and bipolar mania (a pool of two 3-week flexible-dose trials) in which ziprasidone was administered in doses ranging from 10 to 200 mg/day. Commonly Observed Adverse Reactions in Short Term-Placebo-Controlled Trials The following adverse reactions were the most commonly observed adverse reactions associated with the use of ziprasidone (incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients (ziprasidone incidence at least twice that for placebo): Schizophrenia trials (see Table 11) Somnolence Respiratory Tract Infection Bipolar trials (see Table 12) Somnolence Extrapyramidal Symptoms which includes the following adverse reaction terms: extrapyramidal syndrome, hypertonia, dystonia, dyskinesia, hypokinesia, tremor, paralysis and twitching. None of these adverse reactions occurred individually at an incidence greater than 10% in bipolar mania trials. Dizziness which includes the adverse reaction terms dizziness and lightheadedness. Akathisia Abnormal Vision Asthenia Vomiting SCHIZOPHRENIA Adverse Reactions Associated With Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials of Oral Ziprasidone 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* 14 8 Somnolence 14 7 Akathisia 8 7 Dizziness** 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 * 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. ** Dizziness includes the adverse reaction terms dizziness and lightheadedness. Dose Dependency of Adverse Reactions in Short-Term, Fixed-Dose, Placebo-Controlled Trials Extrapyramidal Symptoms (EPS) Dystonia Class Effect: Vital Sign Changes Warnings and Precautions (5. 9 ECG Changes - 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 Cardiovascular System Frequent Infrequent Rare Digestive System Frequent Infrequent Rare Endocrine Rare Hemic and Lymphatic System Infrequent Rare Metabolic and Nutritional Disorders Infrequent Rare Musculoskeletal System Frequent Infrequent Rare Nervous System Frequent Infrequent Rare Respiratory System Frequent Infrequent Rare Skin and Appendages Infrequent Special Senses Frequent Infrequent Rare Urogenital System Infrequent Rare BIPOLAR DISORDER Acute Treatment of Manic or Mixed Episodes in Adults Adverse Reactions Associated With Discontinuation of Treatment in Short Term, Placebo-Controlled Trials 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* 31 12 Dizziness** 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 * Extrapyramidal Symptoms includes the following adverse reaction terms: extrapyramidal syndrome, hypertonia, dystonia, dyskinesia, hypokinesia, tremor, paralysis and twitching. 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. The following adverse reactions have been identified during post-approval use of ziprasidone. 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: Warnings and Precautions (5. 3) Digestive System Disorders: Psychiatric Disorders: Urogenital System Disorders: Vascular Disorders:.

Do not use in patients with a known history of QT prolongation (4. 1) Do not use in patients with recent acute myocardial infarction (4. 1) Do not use in patients with uncompensated heart failure (4. 1) Do not use in combination with other drugs that have demonstrated QT prolongation (4. 1) Do not use in patients with known hypersensitivity to ziprasidone (4. 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: in patients with a known history of QT prolongation (including congenital long QT syndrome) in patients with recent acute myocardial infarction in patients with uncompensated heart failure 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. other 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 and Precautions (5. 3) Ziprasidone is contraindicated in individuals with a known hypersensitivity to the product.

Pregnancy: (8. 1) Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including ziprasidone capsules, 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 ziprasidone capsules, 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 ziprasidone capsules, 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 ziprasidone capsules 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 ziprasidone capsules 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 ziprasidone have not been established in pediatric patients. Pediatric information is approved for Viatris Specialty LLC’s Geodon (ziprasidone HCl) capsules. However, due to Viatris Specialty LLC’s marketing exclusivity rights, this drug product is not labeled with that information. 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. 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. 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 0-12 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 studies utilizing human liver enzymes, ziprasidone is not a substrate for CYP1A2; smoking should therefore not have an effect on the pharmacokinetics of ziprasidone. Consistent with these in vitro results, population pharmacokinetic evaluation has not revealed any significant pharmacokinetic differences between smokers and nonsmokers.

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: Ziprasidone should not be used in combination with other drugs that have demonstrated QT prolongation. 3 The absorption of ziprasidone is increased up to two-fold in the presence of food. 10) The full prescribing information contains additional drug interactions. (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 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. There is little potential for drug interactions with ziprasidone due to displacement [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 C max 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 results, a study in normal healthy volunteers showed that ziprasidone did not alter the metabolism of dextromethorphan, a CYP2D6 model substrate, to its major metabolite, dextrorphan. There was no statistically significant change in the urinary dextromethorphan/dextrorphan ratio. 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.

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 Warnings and Precautions (5. 14) Mutagenesis Ziprasidone was tested in the Ames bacterial mutation assay, the in vitro mammalian cell gene mutation mouse lymphoma assay, the in vitro chromosomal aberration assay in human lymphocytes, and the in vivo chromosomal aberration assay in mouse bone marrow. There was a reproducible mutagenic response in the Ames assay in one strain of S. typhimurium in the absence of metabolic activation. Positive results were obtained in both the in vitro mammalian cell gene mutation assay and the in vitro chromosomal aberration assay in human lymphocytes. Impairment of Fertility Ziprasidone was shown to increase time to copulation in Sprague-Dawley rats in two fertility and early embryonic development studies at doses of 10 to 160 mg/kg/day (0. 5 to 8 times the MRHD of 200 mg/day 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: In a 4-week, placebo-controlled trial (n=139) comparing 2 fixed doses of ziprasidone (20 and 60 mg twice daily) with placebo, only the 60 mg dose was superior to placebo on the BPRS total score and the CGI severity score. This higher dose group was not superior to placebo on the BPRS psychosis cluster or on the SANS. In a 6-week, placebo-controlled trial (n=302) comparing 2 fixed doses of ziprasidone (40 and 80 mg twice daily) with placebo, both dose groups were superior to placebo on the BPRS total score, the BPRS psychosis cluster, the CGI severity score and the PANSS total and negative subscale scores. Although 80 mg twice daily had a numerically greater effect than 40 mg twice daily, the difference was not statistically significant. In a 6-week, placebo-controlled trial (n=419) comparing 3 fixed doses of ziprasidone (20, 60, and 100 mg twice daily) with placebo, all three dose groups were superior to placebo on the PANSS total score, the BPRS total score, the BPRS psychosis cluster, and the CGI severity score. Only the 100 mg twice daily dose group was superior to placebo on the PANSS negative subscale score. There was no clear evidence for a dose-response relationship within the 20 mg twice daily to 100 mg twice daily dose range. In a 4-week, placebo-controlled trial (n=200) comparing 3 fixed doses of ziprasidone (5, 20, and 40 mg twice daily), none of the dose groups was statistically superior to placebo on any outcome of interest. A study was conducted in stable chronic or subchronic (CGI-S 6 (much worse or very much worse) and/or scores >6 (moderately severe) on the hostility or uncooperativeness items of the PANSS on two consecutive days. Ziprasidone was significantly superior to placebo in time to relapse, with no significant difference between the different dose groups. There were insufficient data to examine population subsets based on age and race. Examination of population subsets based on gender did not reveal any differential responsiveness. 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 >= 8 (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.

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