ZIPRASIDONE HYDROCHLORIDE- ziprasidone hydrochloride_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 i 2 2A 1D 1A 50 Oral Pharmacokinetics Absorption: Distribution: 1 in vitro Metabolism and Elimination: In vitro In vitro in vivo.

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 see Warnings and Precautions ( 5. 3 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 Ziprasidone hydrochloride is an atypical antipsychotic. In choosing among treatments, prescribers should be aware of the capacity of ziprasidone hydrochloride to prolong the QT interval and may consider the use of other drugs first ( 1 treatment of schizophrenia 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 40-80 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 40-80 mg twice daily. 3 Administer ziprasidone capsules orally with food. Swallow capsules whole, do not open, crush, or chew the capsules. Dose Selection 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 [see Clinical Studies ( 14. 1 Acute Treatment of Manic or Mixed Episodes see Clinical Studies ( 14. 2 Maintenance Treatment (as an adjunct to lithium or valproate) see Clinical Studies ( 14.

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 To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc. at 1-888-943-3210 or 1-855-926-3384 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. 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 [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: 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 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 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: 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. None of these adverse reactions occurred individually at an incidence greater than 10% in bipolar mania trials. 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 hydrochloride. 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 Reproductive System and Breast Disorders: Nervous System Disorders: Psychiatric Disorders: Skin and subcutaneous Tissue Disorders: Urogenital System Disorders: Enuresis, urinary incontinence; Vascular Disorders:.

Do not use in patients with a known history of QT prolongation ( 4. 1 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: 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. [see Warnings and Precautions ( 5. 3 Ziprasidone is contraindicated in individuals with a known hypersensitivity to the product.

Pregnancy: 8. 1 Pregnancy Exposure Registry Risk Summary see Clinical Considerations see Data 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 Fetal/neonatal adverse reactions Data Human Data Animal Data 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 see Clinical Considerations Clinical Considerations Infertility Females see Warnings and Precautions ( 5. 1 The safety and effectiveness of ziprasidone hydrochloride 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 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: Ziprasidone should not be used in combination with other drugs that have demonstrated QT prolongation. 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 Ketoconazole max Cimetidine Antacid registered 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.

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 2 2 2 [see Warnings and Precautions ( 5.14 )]. Mutagenesis in vitro in vitro in vivo S. typhimurium in vitro in vitro Impairment of Fertility 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 results of the oral ziprasidone trials in adult bipolar I disorder, manic/mixed episode follow: in a 3-week placebo-controlled trial (n=210), the dose of ziprasidone was 40 mg twice daily on Day 1 and 80 mg twice daily on Day 2. Titration within the range of 40-80 mg twice daily (in 20 mg twice daily increments) was permitted for the duration of the study. Ziprasidone was significantly more effective than placebo in reduction of the MRS total score and the CGI-S score. The mean daily dose of ziprasidone in this study was 132 mg. In a second 3-week placebo-controlled trial (n=205), the dose of ziprasidone was 40 mg twice daily on Day 1. Titration within the range of 40-80 mg twice daily (in 20 mg twice daily increments) was permitted for the duration of study (beginning on Day 2). The mean daily dose of ziprasidone in this study was 112 mg. Maintenance Therapy.

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ZIPRASIDONE HYDROCHLORIDE- ziprasidone hydrochloride_capsule Product manual source documgent