• Geodon

• An atypical antipsychotic

• Treatment of schizophrenia (oral)
• As monotherapy for acute treatment of manic or mixed episodes associated with bipolar I disorder (oral)
• Maintenance treatment of bipolar I disorder as an adjunct to lithium or valproate (oral)
• Acute treatment of agitation in schizophrenic patients for whom treatment with ziprasidone is appropriate and who need IM antipsychotic medication for rapid control of agitation (Injection)  

General Notes: Capsules: Take with food. IM: Add 1.2 mL of sterile water for injection (SWFI) to vial and shake vigorously until all the drug is dissolved. Draw up 0.5 mL of reconstituted solution to administer a 10 mg dose; draw up 1 mL of reconstituted solution to administer a 20 mg dose. Do not mix with other medicinal products or solvents other than SWFI

• None
  

• Intramuscular ziprasidone should be administered with caution to patients with impaired function.  

• None

• Capsules:  20 mg, 40 mg, 60 mg, 80 mg
• Injection:  20 mg/mL   

• Known history of QT prolongation
• Patients with recent acute myocardial infarction 
• Patients with uncompensated heart failure
• In combination with other drugs that have demonstrated QT prolongation
• Known hypersensitivity to ziprasidone

• Schizophrenia:
• Somnolence
• Respiratory tract infection
• Manic and mixed episodes associated with bipolar disorder:
• Somnolence
• Extrapyramidal symptoms
• Dizziness
• Akathisia
• Abnormal vision
• Asthenia
• Vomiting 
• Intramuscular administration:
• Headache
• Nausea
• Somnolence
  

• Symptoms may include minimal sedation, slurring of speech, transitory hypertension, extrapyramidal symptoms, somnolence, tremor, and anxiety.  
• 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.
• 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 ?1 antagonism associated with ziprasidone may worsen hypotension.  
• In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered.  
• Ziprasidone is not dialyzable. 
• The possibility of multiple drug involvement should be considered.    

• None

• Category C  

• Breastfeeding is not recommended.  

• Scientific Name:
  
• 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one Ziprasidone capsules contain a monohydrochloride, monohydrate salt of ziprasidone: ziprasidone hydrochloride monohydrate is 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one, monohydrochloride, monohydrate
  

• Ziprasidone for injection contains a lyophilized form of ziprasidone mesylate trihydrate: 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one, methanesulfonate, trihydrate
• Empirical Formula:
  
• Free base of ziprasidone: C21H21CIN4OS 
• Ziprasidone hydrochloride monohydrate: C21H21CIN4OS.HCl.H2O
• Ziprasidone for injection: C21H21ClN4OS.CH3SO3H.3H2O
• Molecular Weight: 
  
• Free base: 412.94 
• Ziprasidone hydrochloride monohydrate:  467.42
• Ziprasidone for injection:  563.09
  

• 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: Ziprasidone is well absorbed after oral administration, reaching peak plasma concentrations in 6 to 8 hours. The absolute bioavailability of a 20 mg dose under fed conditions is approximately 60%. The absorption of ziprasidone is increased up to two-fold in the presence of food.
• Distribution: Ziprasidone has a mean apparent volume of distribution of 1.5 L/kg. It is greater than 99% bound to plasma proteins, binding primarily to albumin and ?1-acid glycoprotein. The in vitro plasma protein binding of ziprasidone was not altered by warfarin or propranolol, two highly protein-bound drugs, nor did ziprasidone alter the binding of these drugs in human plasma. Thus, the potential for drug interactions with ziprasidone due to displacement is minimal.    
• Metabolism: Ziprasidone is extensively metabolized after oral administration with only a small amount excreted in the urine (<1%) or feces (<4%) as unchanged drug. Ziprasidone is primarily cleared via three metabolic routes to yield four major circulating metabolites, benzisothiazole (BITP) sulphoxide, BITP-sulphone, ziprasidone sulphoxide, and S-methyldihydroziprasidone.
• Elimination: Approximately 20% of the dose is excreted in the urine, with approximately 66% being eliminated in the feces. Unchanged ziprasidone represents about 44% of total drug-related material in serum. In vitro studies using human liver subcellular fractions indicate that S-methyldihydroziprasidone is generated in two steps. These studies indicate that the reduction reaction is mediated primarily by chemical reduction by glutathione as well as by enzymatic reduction by aldehyde oxidase and the subsequent methylation is mediated by thiol methyltransferase. In vitro studies using human liver microsomes and recombinant enzymes indicate that CYP3A4 is the major CYP contributing to the oxidative metabolism of ziprasidone. CYP1A2 may contribute to a much lesser extent. Based on in vivo abundance of excretory metabolites, less than one-third of ziprasidone metabolic clearance is mediated by cytochrome P450 catalyzed oxidation and approximately two-thirds via reduction. There are no known clinically relevant inhibitors or inducers of aldehyde oxidase.
• Intramuscular Pharmacokinetics
• Systemic Bioavailability: The bioavailability of ziprasidone administered intramuscularly is 100%. After intramuscular administration of single doses, peak serum concentrations typically occur at approximately 60 minutes post-dose or earlier and the mean half-life (T?) ranges from two to five hours. Exposure increases in a dose-related manner and following three days of intramuscular dosing, little accumulation is observed.
• Metabolism and Elimination: Although the metabolism and elimination of IM ziprasidone have not been systematically evaluated, the intramuscular route of administration would not be expected to alter the metabolic pathways.

• Patients should be instructed to take ziprasidone capsules with food for optimal absorption.
• Patients should be advised to inform their healthcare providers of the following: history of QT prolongation; recent acute myocardial infarction; uncompensated heart failure; prescription of other drugs that have demonstrated QT prolongation; risk for significant electrolyte abnormalities; and history of cardiac arrhythmia.  
• Patients should be instructed to report the onset of any conditions that put them at risk for significant electrolyte disturbances, hypokalemia in particular, including but not limited to he initiation of diuretic therapy or prolonged diarrhea.  
• Patients should be instructed to report symptoms such as dizziness, palpitations, or syncope to the prescriber.  
• Patients should be instructed to report to their healthcare provider at the earliest onset any signs or symptoms that may be associated with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). 
• Patients should be advised to inform their healthcare provider of any medicines they are taking, including non-prescription medicines, supplements, and herbal medicines. 
• Patients should be advised to inform their healthcare provider if they are pregnant, might be pregnant, or plan to get pregnant.  
• Patients should also be advised to inform their healthcare provider if they are breast-feeding or plan to breast-feed.  
• Patients should be advised to be careful when operating machinery or driving a motor vehicle as ziprasidone may cause sleepiness.    

• Ziprasidone (Geodon).  Product Insert.  Pfizer Inc. New York, NY.  2014.