Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2031
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Geodon (Capsule)
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Schizophrenia: When deciding among the alternative treatments available for schizophrenia, the prescriber should consider the finding of ziprasidone's greater capacity to prolong the QT/QTc interval compared to several other antipsychotic drugs .<br/>Initial Treatment: GEODON Capsules should be administered at an initial daily dose of 20 mg BID with food. In some patients, daily dosage may subsequently be adjusted on the basis of individual clinical status up to 80 mg BID. 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, ordinarily patients should be observed for improvement for several weeks before upward dosage adjustment. Efficacy in schizophrenia was demonstrated in a dose range of 20 to 100 mg BID in short-term, placebo-controlled clinical trials. There were trends toward dose response within the range of 20 to 80 mg BID, but results were not consistent. An increase to a dose greater than 80 mg BID is not generally recommended. The safety of doses above 100 mg BID has not been systematically evaluated in clinical trials.<br/>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, systematic evaluation of ziprasidone has shown that its efficacy in schizophrenia is maintained for periods of up to 52 weeks at a dose of 20 to 80 mg BID . No additional benefit was demonstrated for doses above 20 mg BID. Patients should be periodically reassessed to determine the need for maintenance treatment.<br/>Bipolar Mania:<br/>Initial Treatment: Oral ziprasidone should be administered at an initial daily dose of 40 mg BID with food. The dose should then be increased to 60 mg or 80 mg BID on the second day of treatment and subsequently adjusted on the basis of toleration and efficacy within the range 40���80 mg BID. In the flexible-dose clinical trials, the mean daily dose administered was approximately 120 mg .<br/>Maintenance Treatment: There is no body of evidence available from controlled trials to guide a clinician in the longer-term management of a patient who improves during treatment of mania with ziprasidone. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the use of ziprasidone in such longer-term treatment (i.e., beyond 3 weeks).<br/>Intramuscular Administration for Acute Agitation in Schizophrenia: The recommended dose is 10 to 20 mg administered as required up to a maximum dose of 40 mg per day. Doses of 10 mg may be administered every two hours; doses of 20 mg may be administered every four hours up to a maximum of 40 mg/day. Intramuscular administration of ziprasidone for more than three consecutive days has not been studied. If long-term therapy is indicated, oral ziprasidone hydrochloride capsules should replace the intramuscular administration as soon as possible. Since there is no experience regarding the safety of administering ziprasidone intramuscular to schizophrenic patients already taking oral ziprasidone, the practice of co-administration is not recommended.<br/>Dosing in Special Populations:<br/>Oral: Dosage adjustments are generally not required on the basis of age, gender, race, or renal or hepatic impairment.<br/>Intramuscular: Ziprasidone intramuscular 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. Dosing adjustments are not required on the basis of gender or race.<br/>Preparation for Administration: GEODON for Injection (ziprasidone mesylate) should only be administered by intramuscular injection. Single-dose vials require reconstitution prior to administration. Add 1.2 mL of Sterile Water for Injection to the vial and shake vigorously until all the drug is dissolved. Each mL of reconstituted solution contains 20 mg ziprasidone. To administer a 10 mg dose, draw up 0.5 mL of the reconstituted solution. To administer a 20 mg dose, draw up 1.0 mL of the reconstituted solution. Any unused portion should be discarded. Since no preservative or bacteriostatic agent is present in this product, aseptic technique must be used in preparation of the final solution. This medicinal product must not be mixed with other medicinal products or solvents other than Sterile Water for Injection. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
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GEODON is available as GEODON Capsules (ziprasidone hydrochloride) for oral administration and as GEODON for Injection (ziprasidone mesylate) for intramuscular injection. Ziprasidone is a psychotropic agent that is chemically unrelated to phenothiazine or butyrophenone antipsychotic agents. It has a molecular weight of 412.94 (free base), with the following chemical name: 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one. The empirical formula of CHClNOS (free base of ziprasidone) represents the following structural formula: GEODON Capsules contain a monohydrochloride, monohydrate salt of ziprasidone. Chemically, ziprasidone hydrochloride monohydrate is 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one, monohydrochloride, monohydrate. The empirical formula is CHClNOS���HCl���HO and its molecular weight is 467.42. Ziprasidone hydrochloride monohydrate is a white to slightly pink powder. GEODON Capsules are supplied for oral administration in 20 mg (blue/white), 40 mg (blue/blue), 60 mg (white/white), and 80 mg (blue/white) capsules. GEODON Capsules contain ziprasidone hydrochloride monohydrate, lactose, pregelatinized starch, and magnesium stearate. GEODON for Injection contains a lyophilized form of ziprasidone mesylate trihydrate. Chemically, ziprasidone mesylate trihydrate is 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one, methanesulfonate, trihydrate. The empirical formula is CHClNOS���CHSOH���3HO and its molecular weight is 563.09. GEODON for Injection is available in a single dose vial as ziprasidone mesylate (20 mg ziprasidone/mL when reconstituted according to label instructions - see Preparation for Administration) for intramuscular administration. Each mL of ziprasidone mesylate for injection (when reconstituted) contains 20 mg of ziprasidone and 4.7 mg of methanesulfonic acid solubilized by 294 mg of sulfobutylether��-cyclodextrin sodium (SBECD).
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Pharmacodynamics: Ziprasidone exhibited high in vitro binding affinity for the dopamine Dand D, the serotonin 5HT, 5HT, 5HT, 5HT, and��-adrenergic receptors (Ks of 4.8, 7.2, 0.4, 1.3, 3.4, 2, and 10 nM, respectively), and moderate affinity for the histamine Hreceptor (K=47 nM). Ziprasidone functioned as an antagonist at the D5HT, and 5HTreceptors, and as an agonist at the 5HTreceptor. Ziprasidone inhibited synaptic reuptake of serotonin and norepinephrine. No appreciable affinity was exhibited for other receptor/binding sites tested, including the cholinergic muscarinic receptor (IC>1��M). The mechanism of action of ziprasidone, as with other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that this drug's efficacy in schizophrenia is mediated through a combination of dopamine type 2 (D) and serotonin type 2 (5HT) antagonism. As with other drugs having efficacy in bipolar disorder, the mechanism of action of ziprasidone in bipolar disorder is unknown. Antagonism at receptors other than dopamine and 5HTwith similar receptor affinities may explain some of the other therapeutic and side effects of ziprasidone. Ziprasidone's antagonism of histamine Hreceptors may explain the somnolence observed with this drug. Ziprasidone's antagonism of��-adrenergic receptors may explain the orthostatic hypotension observed with this drug.<br/>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.<br/>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.<br/>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��-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.<br/>Metabolism and Elimination: 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-methyl-dihydroziprasidone. 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-methyl-dihydroziprasidone is generated in two steps. The data indicate that the reduction reaction is mediated 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 by aldehyde oxidase. There are no known clinically relevant inhibitors or inducers of aldehyde oxidase.<br/>Intramuscular Pharmacokinetics:<br/>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.<br/>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.<br/>Special Populations:<br/>Age and Gender Effects: 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. Ziprasidone intramuscular has not been systematically evaluated in elderly patients (65 years and over).<br/>Race: No specific pharmacokinetic study was conducted to investigate the effects of race. Population pharmacokinetic evaluation has revealed no evidence of clinically significant race-related differences in the pharmacokinetics of ziprasidone. Dosage modifications for race are, therefore, not recommended.<br/>Smoking: 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.<br/>Renal Impairment: 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 BID 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.<br/>Hepatic Impairment: 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 BID for 5 days in subjects (n=13) with clinically significant (Childs-Pugh Class A and B) cirrhosis revealed an increase in AUCof 13% and 34% in Childs-Pugh Class A and B, respectively, compared to a matched control group (n=14). A half-life of 7.1 hours was observed in subjects with cirrhosis compared to 4.8 hours in the control group. 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.<br/>Drug-Drug Interactions: An in vitro enzyme inhibition study utilizing human liver microsomes showed that ziprasidone had little inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and thus would not likely interfere with the metabolism of drugs primarily metabolized by these enzymes. In vivo studies have revealed no effect of ziprasidone on the pharmacokinetics of dextromethorphan, estrogen, progesterone, or lithium . In vivo studies have revealed an approximately 35% decrease in ziprasidone AUC by concomitantly administered carbamazepine, an approximately 35���40% increase in ziprasidone AUC by concomitantly administered ketoconazole, but no effect on ziprasidone's pharmacokinetics by cimetidine or antacid .<br/>Clinical Trials:<br/>Schizophrenia: 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 long-term (52-week) trial. All trials were in 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: 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.<br/>Bipolar Mania: The efficacy of ziprasidone in acute mania was established in 2 placebo-controlled, double-blind, 3-week studies in patients meeting DSM-IV criteria for Bipolar I Disorder with an acute 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 bipolar mania follow:<br/>Acute Agitation in Schizophrenic Patients: 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 theBARS 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 pre-marketing 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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GEODON Capsules are differentiated by capsule color/size and are imprinted in black ink with "Pfizer" and a unique number. GEODON Capsules are supplied for oral administration in 20 mg (blue/white), 40 mg (blue/blue), 60 mg (white/white), and 80 mg (blue/white) capsules. They are supplied in the following strengths and package configurations:<br/>Storage and Handling: GEODON Capsules should be stored at 25��C (77��F); excursions permitted to 15���30��C (59���86��F) [See USP Controlled Room Temperature]. GEODON for Injection is available in a single dose vial as ziprasidone mesylate (20 mg ziprasidone/mL when reconstituted according to label instructions - see Preparation for Administration) for intramuscular administration. Each mL of ziprasidone mesylate for injection (when reconstituted) affords a colorless to pale pink solution that contains 20 mg of ziprasidone and 4.7 mg of methanesulfonic acid solubilized by 294 mg of sulfobutylether��-cyclodextrin sodium (SBECD).<br/>Storage and Handling: GEODON for Injection should be stored at 25��C (77��F); excursions permitted to 15���30��C (59���86��F) [See USP Controlled Room Temperature] in dry form. Protect from light. Following reconstitution, GEODON for Injection can be stored, when protected from light, for up to 24 hours at 15�����30��C (59�����86��F) or up to 7 days refrigerated, 2�����8��C (36�����46��F).
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WARNING:<br/>Increased Mortality in Elderly Patients with Dementia-Related Psychosis���: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death inplacebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increasemortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Geodon (ziprasidone) is not approved for the treatment of patients with Dementia-Related Psychosis .
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Human Experience: In premarketing trials involving more than 5400 patients and/or normal subjects, accidental or intentional overdosage of oral ziprasidone was documented in 10 patients. All of these patients survived without sequelae. In the patient taking the largest confirmed amount, 3240 mg, the only symptoms reported were minimal sedation,slurring of speech, and transitory hypertension (200/95). In post-marketing use, adverse events reported in association with ziprasidone overdose generally included extrapyramidal symptoms, somnolence, tremor, and anxiety.<br/>Management of Overdosage: 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 aspirationwith 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��antagonism associated with ziprasidone may worsen hypotension. Similarly, it is reasonable to expect that the alpha-adrenergic-blocking properties of bretylium might be additive to those of ziprasidone, resulting in problematic hypotension. In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. There is no specific antidote to ziprasidone, and it is not dialyzable. The possibility of multiple drug involvement should be considered. Close medical supervision and monitoring should continue until the patient recovers.
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ziprasidone hydrochloride
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Geodon (Capsule)
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Premarketing experience: The premarketing development program for oral ziprasidone included approximately 5700 patients and/or normal subjects exposed to one or more doses of ziprasidone. Of these 5700, over 4800 were patients who participated in multiple-dose effectiveness trials, and their experience corresponded to approximately 1831 patient-years. These patients include: (1) 4331 patients who participated in multiple-dose trials, predominantly in schizophrenia, representing approximately 1698 patient-years of exposure as of February 5, 2000; and (2) 472 patients who participated in bipolar mania trials representing approximately 133 patient-years of exposure. The conditions and duration of treatment with ziprasidone included open-label and double-blind studies, inpatient and outpatient studies, and short-term and longer-term exposure. The premarketing development program for intramuscular ziprasidone included 570 patients and/or normal subjects who received one or more injections of ziprasidone. Over 325 of these subjects participated in trials involving the administration of multiple doses. Adverse events during exposure were obtained by collecting voluntarily reported adverse experiences, as well as results of physical examinations, vital signs, weights, laboratory analyses, ECGs, and results of ophthalmologic examinations. Adverse experiences were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and tabulations that follow, standard COSTART dictionary terminology has been used to classify reported adverse events. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side effect incidence rate in the population studied.<br/>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.<br/>Adverse Events Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials of Oral Ziprasidone:<br/>Schizophrenia: Approximately 4.1% (29/702) of ziprasidone-treated patients in short-term, placebo-controlled studies discontinued treatment due to an adverse event, compared with about 2.2% (6/273) on placebo. The most common event associated with dropout was rash, including 7 dropouts for rash among ziprasidone patients (1%) compared to no placebo patients .<br/>Bipolar Mania: Approximately 6.5% (18/279) of ziprasidone-treated patients in short-term, placebo-controlled studies discontinued treatment due to an adverse event, compared with about 3.7% (5/136) on placebo. The most common events associated with dropout in the ziprasidone-treated patients were akathisia, anxiety, depression, dizziness, dystonia, rash and vomiting, with 2 dropouts for each of these events among ziprasidone patients (1%) compared to one placebo patient each for dystonia and rash (1%) and no placebo patients for the remaining adverse events.<br/>Commonly Observed Adverse Events in Short-Term, Placebo-Controlled Trials: The most commonly observed adverse events 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) are shown in Tables 1 and 2.<br/>Adverse Events Occurring at an Incidence of 2% or More Among Ziprasidone-Treated Patients in Short-Term, Oral, Placebo-Controlled Trials: Table 3 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy (up to 6 weeks) in predominantly patients with schizophrenia, including only those events that occurred in 2% or more of patients treated with ziprasidone and for which the incidence in patients treated with ziprasidone was greater than the incidence in placebo-treated patients. Table 4 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy (up to 3 weeks) in patients with bipolar mania, including only those events that occurred in 2% or more of patients treated with ziprasidone and for which the incidence in patients treated with ziprasidone was greater than the incidence in placebo-treated patients. Explorations for interactions on the basis of gender did not reveal any clinically meaningful differences in the adverse event occurrence on the basis of this demographic factor.<br/>Dose Dependency of Adverse Events 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 event to dose for the following events: asthenia, postural hypotension, anorexia, dry mouth, increased salivation, arthralgia, anxiety, dizziness, dystonia, hypertonia, somnolence, tremor, rhinitis, rash, and abnormal vision.<br/>Extrapyramidal Symptoms (EPS): The incidence of reported EPS (which included the adverse event terms extrapyramidal syndrome, hypertonia, dystonia, dyskinesia, hypokinesia, tremor, paralysis and twitching) for ziprasidone-treated patients in the short-term, placebo-controlled schizophrenia trials was 14% vs. 8% for placebo. Objectively collected data from those trials on the Simpson-Angus Rating Scale (for EPS) and the Barnes Akathisia Scale (for akathisia) did not generally show a difference between ziprasidone and placebo.<br/>Dystonia: Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.<br/>Vital Sign Changes: Ziprasidone is associated with orthostatic hypotension .<br/>Weight Gain: The proportions of patients meeting a weight gain criterion of���7% of body weight were compared in a pool of four 4- and 6- week placebo-controlled schizophrenia clinical trials, revealing a statistically significantly greater incidence of weight gain for ziprasidone (10%) compared to placebo (4%). A median weight gain of 0.5 kg was observed in ziprasidone patients compared to no median weight change in placebo patients. In this set of clinical trials, weight gain was reported as an adverse event in 0.4% and 0.4% of ziprasidone and placebo patients, respectively. During long-term therapy with ziprasidone, a categorization of patients at baseline on the basis of body mass index (BMI) revealed the greatest mean weight gain and highest incidence of clinically significant weight gain (>7% of body weight) in patients with low BMI (<23) compared to normal (23���27) or overweight patients (>27). There was a mean weight gain of 1.4 kg for those patients with a "low" baseline BMI, no mean change for patients with a "normal" BMI, and a 1.3 kg mean weight loss for patients who entered the program with a "high" BMI.<br/>ECG Changes: Ziprasidone is associated with an increase in the QTc interval . In the schizophrenia trials, ziprasidone was associated with a mean increase in heart rate of 1.4 beats per minute compared to a 0.2 beats per minute decrease among placebo patients.<br/>Other Adverse Events Observed During the Premarketing Evaluation of Oral Ziprasidone: Following is a list of COSTART terms that reflect treatment-emergent adverse events as defined in the introduction to the ADVERSE REACTIONS section reported by patients treated with ziprasidone in schizophrenia trials at multiple doses>4 mg/day within the database of 3834 patients. All reported events are included except those already listed in Table 3 or elsewhere in labeling, those event terms that were so general as to be uninformative, events reported only once and that did not have a substantial probability of being acutely life-threatening, events that are part of the illness being treated or are otherwise common as background events, and events considered unlikely to be drug-related. It is important to emphasize that, although the events reported occurred during treatment with ziprasidone, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Body as a Whole: Frequent: abdominal pain, flu syndrome, fever, accidental fall, face edema, chills, photosensitivity reaction, flank pain, hypothermia, motor vehicle accident. Cardiovascular System: Frequent: tachycardia, hypertension, postural hypotension; Infrequent: bradycardia, angina pectoris, atrial fibrillation; Rare: first degree AV block, bundle branch block, phlebitis, pulmonary embolus, cardiomegaly, cerebral infarct, cerebrovascular accident, deep thrombophlebitis, myocarditis, thrombophlebitis. Digestive System: Frequent: anorexia, vomiting; Infrequent: rectal hemorrhage, dysphagia, tongue edema; Rare: gum hemorrhage, jaundice, fecal impaction, gamma glutamyl transpeptidase increased, hematemesis, cholestatic jaundice, hepatitis, hepatomegaly, leukoplakia of mouth, fatty liver deposit, melena. Endocrine: Rare: hypothyroidism, hyperthyroidism, thyroiditis. Hemic and Lymphatic System: Infrequent: anemia, ecchymosis, leukocytosis, leukopenia, eosinophilia, lymphadenopathy; Rare: thrombocytopenia, hypochromic anemia, lymphocytosis, monocytosis, basophilia, lymphedema, polycythemia, thrombocythemia. Metabolic and Nutritional Disorders: Infrequent: thirst, transaminase increased, peripheral edema, hyperglycemia, creatine phosphokinase increased, alkaline phosphatase increased, hypercholesteremia, dehydration, lactic dehydrogenase increased, albuminuria, hypokalemia; Rare: BUN increased, creatinine increased, hyperlipemia, hypocholesteremia, hyperkalemia, hypochloremia, hypoglycemia, hyponatremia, hypoproteinemia, glucose tolerance decreased, gout, hyperchloremia, hyperuricemia, hypocalcemia, hypoglycemic reaction, hypomagnesemia, ketosis, respiratory alkalosis. Musculoskeletal System: Frequent: myalgia; Infrequent: tenosynovitis; Rare: myopathy. Nervous System: Frequent: agitation, extrapyramidal syndrome, tremor, dystonia, hypertonia, dyskinesia, hostility, twitching, paresthesia, confusion, vertigo, hypokinesia, hyperkinesia, abnormal gait, oculogyric crisis, hypesthesia, ataxia, amnesia, cogwheel rigidity, delirium, hypotonia, akinesia, dysarthria, withdrawal syndrome, buccoglossal syndrome, choreoathetosis, diplopia, incoordination, neuropathy; Infrequent: paralysis; Rare: myoclonus, nystagmus, torticollis, circumoral paresthesia, opisthotonos, reflexes increased, trismus. Respiratory System: Frequent: dyspnea; Infrequent: pneumonia, epistaxis; Rare: hemoptysis, laryngismus. Skin and Appendages: Infrequent: maculopapular rash, urticaria, alopecia, eczema, exfoliative dermatitis, contact dermatitis, vesiculobullous rash. Special Senses: Frequent: fungal dermatitis; Infrequent: conjunctivitis, dry eyes, tinnitus, blepharitis, cataract, photophobia; Rare: eye hemorrhage, visual field defect, keratitis, keratoconjunctivitis. Urogenital System: Infrequent: impotence, abnormal ejaculation, amenorrhea, hematuria, menorrhagia, female lactation, polyuria, urinary retention, metrorrhagia, male sexual dysfunction, anorgasmia, glycosuria; Rare: gynecomastia, vaginal hemorrhage, nocturia, oliguria, female sexual dysfunction, uterine hemorrhage.<br/>Adverse Findings Observed in Trials of Intramuscular Ziprasidone:<br/>Adverse Events Occurring at an Incidence of 1% or More Among Ziprasidone-Treated Patients in Short-Term Trials of Intramuscular Ziprasidone: Table 5 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy with intramuscular ziprasidone in 1% or more of patients. In these studies, the most commonly observed adverse events 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%).<br/>Other Events Observed During Post-marketing Use: Adverse event reports not listed above that have been received since market introduction include rare occurrences of the following (no causal relationship with ziprasidone has been established): Cardiac Disorders: Tachycardia, torsade de pointes (in the presence of multiple confounding factors - see WARNINGS); Digestive System Disorders: Swollen tongue; Nervous System Disorders: Facial droop, neuroleptic malignant syndrome, serotonin syndrome (alone or in combination with serotonergic medicinal products), tardive dyskinesia; Psychiatric Disorders: Insomnia, mania/hypomania; Reproductive System and Breast Disorders: Galactorrhea, priapism; Skin and subcutaneous Tissue Disorders: Allergic reaction (such as allergic dermatitis, angioedema, orofacial edema, urticaria), rash; Urogenital System Disorders: Enuresis, urinary incontinence; Vascular Disorders: Postural hypotension, syncope.
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Schizophrenia: Ziprasidone is indicated for the treatment of schizophrenia. When deciding among the alternative treatments available for this condition, the prescriber should consider the finding of ziprasidone's greater capacity to prolong the QT/QTc interval compared to several other antipsychotic drugs . Prolongation of the QTc interval is associated in some other drugs with the ability to cause torsade de pointes-type arrhythmia, a potentially fatal polymorphic ventricular tachycardia, and sudden death. In many cases this would lead to the conclusion that other drugs should be tried first. Whether ziprasidone will cause torsade de pointes or increase the rate of sudden death is not yet known . The efficacy of oral ziprasidone was established in short-term (4- and 6-week) controlled trials of schizophrenic inpatients . In a placebo-controlled trial involving the follow-up for up to 52 weeks of stable schizophrenic inpatients, GEODON was demonstrated to delay the time to and rate of relapse. The physician who elects to use GEODON for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.<br/>Bipolar Mania: Ziprasidone is indicated for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. A mixed episode is characterized by the criteria for a manic episode in conjunction with those for a major depressive episode (depressed mood, loss of interest or pleasure in nearly all activities). The efficacy of ziprasidone in acute mania was established in 2 placebo-controlled, double-blind, 3-week studies in patients meeting DSM-IV criteria for Bipolar I Disorder who currently displayed an acute manic or mixed episode with or without psychotic features . The effectiveness of ziprasidone for longer-term use and for prophylactic use in mania has not been systematically evaluated in controlled clinical trials. Therefore, physicians who elect to use ziprasidone for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient .<br/>Acute Agitation in Schizophrenic Patients: Ziprasidone intramuscular is indicated for the treatment of acute agitation in schizophrenic patients for whom treatment with ziprasidone is appropriate and who need intramuscular antipsychotic medication for rapid control of the agitation. "Psychomotor agitation" is defined in DSM-IV as "excessive motor activity associated with a feeling of inner tension." Schizophrenic patients experiencing agitation often manifest behaviors that interfere with their diagnosis and care, e.g., threatening behaviors, escalating or urgently distressing behavior, or self-exhausting behavior, leading clinicians to the use of intramuscular antipsychotic medications to achieve immediate control of the agitation. The efficacy of intramuscular ziprasidone for acute agitation in schizophrenia was established in single-day controlled trials of schizophrenic inpatients . 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.
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Geodon
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