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MACLEODS PHARMA
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ziprasidone hcl 80 mg capsule (generic geodon)

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Uses

Ziprasidone hydrochloride is used orally for the treatment of schizophrenia, as monotherapy for the acute treatment of bipolar manic or mixed episodes, and as adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder. Ziprasidone mesylate is used IM for acute agitation in schizophrenic patients.

When deciding among the alternative treatments available for the condition requiring treatment, clinicians should consider ziprasidone's greater capacity to prolong the QT or QTc (QT interval corrected for rate) interval compared with several other antipsychotic agents. QTc-interval prolongation has been associated in some other drugs with the ability to cause torsades de pointes and sudden death. In many cases, this would lead clinicians to the conclusion that other drugs should be tried first. The manufacturer states that it is not yet known whether ziprasidone will cause torsades de pointes or increase the rate of sudden death. In one large observational study (Ziprasidone Observational Study of Cardiac Outcomes [ZODIAC]), the incidence of nonsuicide mortality was not found to be higher in ziprasidone-treated patients compared with olanzapine-treated patients; however, the study design did not allow for evaluation of possible differences in the incidence of more uncommon outcomes, such as torsades de pointes and sudden death.(See Prolongation of QT Interval and Risk of Sudden Death under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Psychotic Disorders

Schizophrenia

Drug therapy is integral to the management of acute psychotic episodes in patients with schizophrenia and generally is required for long-term stabilization to sustain symptom remission or control and to minimize the risk of relapse. Antipsychotic agents are the principal class of drugs used for the management of all phases of schizophrenia. Patient response and tolerance to antipsychotic agents are variable, and patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.

Ziprasidone hydrochloride is used orally in the acute and maintenance management of schizophrenia in adults. Schizophrenia is a major psychotic disorder that frequently has devastating effects on various aspects of the patient's life and carries a high risk of suicide and other life-threatening behaviors. Manifestations of schizophrenia involve multiple psychologic processes, including perception (e.g., hallucinations), ideation, reality testing (e.g., delusions), emotion (e.g., flatness, inappropriate affect), thought processes (e.g., loose associations), behavior (e.g., catatonia, disorganization), attention, concentration, motivation (e.g., avolition, impaired intention and planning), and judgment. The principal manifestations of this disorder usually are described in terms of positive and negative (deficit) symptoms and, more recently, disorganized symptoms. Positive symptoms include hallucinations, delusions, bizarre behavior, hostility, uncooperativeness, and paranoid ideation, while negative symptoms include restricted range and intensity of emotional expression (affective flattening), reduced thought and speech productivity (alogia), anhedonia, apathy, and decreased initiation of goal-directed behavior (avolition). Disorganized symptoms include disorganized speech (thought disorder) and behavior and poor attention.

Efficacy of oral ziprasidone for the management of schizophrenia was evaluated in 5 placebo-controlled studies of variable duration (4 short-term [4-6 weeks] and one long-term [52 weeks]), principally in patients who met DSM-IIIR criteria for schizophrenia in hospital settings. Ziprasidone appears to be superior to placebo in improving both positive and negative manifestations in acute exacerbations of schizophrenia and in reducing the rate of relapse for up to 52 weeks.

Although results of a limited comparative study suggest that oral ziprasidone hydrochloride (160 mg daily) may be as effective as oral haloperidol (15 mg daily) in reducing positive symptoms of schizophrenia, a reliable and valid comparison of ziprasidone and haloperidol cannot be made at this time based solely on this study due to its relatively small sample size (90 patients), high dropout rate (51.1%), and brief duration (4 weeks). Data from a short-term controlled study also suggest that oral ziprasidone hydrochloride (mean dosage of 130 mg daily) is as effective as oral olanzapine (mean dosage of 11 mg daily) in the acute treatment of schizophrenia.

If oral ziprasidone is used for extended periods for the management of schizophrenia, the need for continued therapy should be reassessed periodically.(See Dosage and Administration: Dosage.)

The American Psychiatric Association (APA) considers most atypical antipsychotic agents first-line drugs for the management of the acute phase of schizophrenia (including first psychotic episodes), principally because of the decreased risk of adverse extrapyramidal effects and tardive dyskinesia, with the understanding that the relative advantages, disadvantages, and cost-effectiveness of conventional and atypical antipsychotic agents remain controversial. The APA states that, with the possible exception of clozapine for the management of treatment-resistant symptoms, there currently is no definitive evidence that one atypical antipsychotic agent will have superior efficacy compared with another agent in the class, although meaningful differences in response may be observed in individual patients. Conventional antipsychotic agents also may be an appropriate first-line option for some patients, including those who have been treated successfully in the past with or who prefer conventional agents. The choice of an antipsychotic agent should be individualized, considering past response to therapy, current symptomatology, concurrent medical conditions, other medications and treatments, adverse effect profile, and the patient's preference for a specific drug, including route of administration.

Ziprasidone mesylate is used IM for the management of acute agitation in adults with schizophrenia for whom treatment with ziprasidone is appropriate and who require an IM antipsychotic agent for rapid control of behaviors that interfere with diagnosis and care (e.g., threatening behaviors, escalating or urgently distressing behavior, self-exhausting behavior). The efficacy of IM ziprasidone for the management of acute agitation in schizophrenia was established in single-day controlled trials in hospital settings. Because there is no experience regarding the safety of administering ziprasidone IM to schizophrenic patients already receiving oral ziprasidone, concomitant use of oral and IM formulations of ziprasidone is not recommended.

For additional information on the symptomatic management of schizophrenia, including treatment recommendations and results of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) research program,

Bipolar Disorder

Ziprasidone hydrochloride is used orally as monotherapy for the acute treatment of manic and mixed episodes (with or without psychotic features) associated with bipolar I disorder in adults. The drug is also used orally as adjunctive therapy with lithium or valproate for the maintenance treatment of bipolar I disorder in adults. According to DSM-IV criteria, manic episodes are distinct periods lasting 1 week or longer (or less than 1 week if hospitalization is required) of abnormally and persistently elevated, expansive, or irritable mood accompanied by at least 3 (or 4 if the mood is only irritability) of the following 7 symptoms: grandiosity, reduced need for sleep, pressure of speech, flight of ideas, distractability, increased goal-directed activity (socially, at work or school, or sexually) or psychomotor agitation, and engaging in high-risk behavior (e.g., unrestrained buying sprees, sexual indiscretions, foolish business investments).

Efficacy of ziprasidone monotherapy in the treatment of acute manic and mixed episodes has been demonstrated in 2 short-term (i.e., 3 weeks' duration), double-blind, placebo-controlled trials in patients who met DSM-IV criteria for bipolar I disorder and who met diagnostic criteria for an acute manic or mixed episode (with or without psychotic features). The principal rating instruments used for assessing manic symptoms in these trials were the Mania Rating Scale (MRS), which is derived from the Schedule for Affective Disorders and Schizophrenia-Change Version (SADS-C) with items grouped as the Manic Syndrome subscale (e.g., 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 the Clinical Global Impression-Severity of Illness Scale (CGI-S), which was used to assess the clinical significance of treatment response.

In the first 3-week, placebo-controlled monotherapy trial, ziprasidone hydrochloride was given at an initial dosage of 40 mg twice daily on the first day and 80 mg twice daily on the second day; dosage adjustment in 20-mg twice daily increments within a dosage range of 40-80 mg twice daily was then permitted for the remainder of the study. The mean dosage of ziprasidone hydrochloride in this study was 132 mg daily. In the second 3-week, placebo-controlled monotherapy trial, patients also were given an initial dosage of ziprasidone hydrochloride 40 mg twice daily on the first day; subsequent dosage titration in 20-mg twice daily increments within a dosage range of 40-80 mg twice daily was permitted. The mean dosage of ziprasidone hydrochloride in this study was 112 mg daily. Ziprasidone was superior to placebo in the reduction of the MRS total score and the CGI-S score in both of these studies.

The manufacturer states that the efficacy of ziprasidone as monotherapy for the maintenance treatment of bipolar I disorder has not been systematically evaluated in controlled studies.

Efficacy of ziprasidone as adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder has been demonstrated in a double-blind, placebo-controlled study of 6 months' duration in adult outpatients who met DSM-IV criteria for bipolar I disorder with a recent or current manic or mixed episode (with or without psychotic features). In the open-label phase, patients were stabilized on ziprasidone combined with either lithium or valproate for at least 8 weeks; patients were then randomized into the double-blind phase where they continued to receive lithium or valproate in addition to either ziprasidone (40-80 mg twice daily) or placebo. The primary outcome measure was time to recurrence of a mood episode (manic, mixed, or depressed) requiring intervention. Ziprasidone given in conjunction with lithium or valproate was superior to placebo in increasing the time to recurrence of a mood episode in this study.

If ziprasidone is used for extended periods as adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder, the need for continued therapy should be reassessed periodically.(See Dosage and Administration: Dosage.)

For the initial management of less severe manic or mixed episodes in patients with bipolar disorder, current APA recommendations state that monotherapy with lithium, valproate (e.g., valproate sodium, valproic acid, divalproex), or an antipsychotic such as olanzapine may be adequate. For more severe manic or mixed episodes, combination therapy with an antipsychotic and lithium or valproate is recommended as first-line therapy.

Dosage and Administration

Administration

Ziprasidone hydrochloride is available as capsules and is administered orally twice daily with food for optimal absorption. Absorption of ziprasidone is increased up to twofold in the presence of food. Ziprasidone mesylate is administered only by IM injection and should not be administered IV.

The commercially available lyophilized powder of ziprasidone mesylate for injection must be reconstituted prior to administration by adding 1.2 mL of sterile water for injection to single-dose vials of ziprasidone to provide a solution containing 20 mg/mL. Other solutions should not be used to reconstitute ziprasidone mesylate injection, and the drug should not be admixed with other drugs. The vials should then be shaken vigorously to ensure complete dissolution. Strict aseptic technique must be observed since the drug contains no preservative or bacteriostatic agent. Following reconstitution, ziprasidone mesylate for injection is stable for 24 hours when protected from light and stored at 15-30°C or for up to 7 days when refrigerated at 2-8°C. Ziprasidone mesylate injection should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Dosage

Dosage of ziprasidone hydrochloride is expressed in terms of the hydrochloride monohydrate. Dosage of ziprasidone mesylate is expressed in terms of ziprasidone.

Schizophrenia

Oral Dosage

For the symptomatic management of schizophrenia, the recommended initial adult dosage of ziprasidone hydrochloride is 20 mg orally twice daily. In some patients, dosage may be increased based on clinical status up to 80 mg twice daily. Dosage adjustments, if indicated, generally should occur at intervals of not less than 2 days, since steady-state concentrations of the drug are achieved within 1-3 days. To ensure use of the lowest effective dosage, however, it is recommended that patients be observed for several weeks prior to upward titrations of ziprasidone dosage. The effective dosage of ziprasidone hydrochloride in short-term clinical studies generally ranged from 20-100 mg twice daily. Although there were trends toward a dose response within a dosage range of 20-80 mg twice daily, results were not consistent. The manufacturer states that dosages exceeding 80 mg twice daily generally are not recommended, and safety of dosages exceeding 100 mg twice daily has not been established.

The optimum duration of ziprasidone therapy currently is not known, but maintenance therapy with ziprasidone hydrochloride 20-80 mg twice daily has been shown to be effective for up to 52 weeks. However, the manufacturer states that no additional benefit has been demonstrated for ziprasidone hydrochloride dosages beyond 20 mg twice daily. Patients responding to ziprasidone therapy should continue to receive the drug as long as clinically necessary and tolerated, but at the lowest possible effective dosage, and the need for continued therapy with the drug should be reassessed periodically.

The American Psychiatric Association (APA) states that prudent long-term treatment options in patients with schizophrenia with remitted first episodes or multiple episodes include either indefinite maintenance therapy or gradual discontinuance of the antipsychotic agent with close follow-up and a plan to reinstitute treatment upon symptom recurrence. Discontinuance of antipsychotic therapy should be considered only after a period of at least 1 year of symptom remission or optimal response while receiving the antipsychotic agent. In patients who have had multiple previous psychotic episodes or 2 psychotic episodes within 5 years, indefinite maintenance antipsychotic treatment is recommended.

IM Dosage

For the prompt control of acute agitation in patients with schizophrenia, the recommended initial adult IM dose of ziprasidone is 10-20 mg given as a single dose. Depending on patient response, doses of 10 or 20 mg may be repeated every 2 or 4 hours, respectively, up to a maximum cumulative dose of 40 mg daily.

Oral therapy should replace IM therapy as soon as possible. Safety and efficacy of administering ziprasidone mesylate IM injection for longer than 3 consecutive days have not been evaluated. Because there is no experience regarding the safety of administering ziprasidone mesylate IM injection to patients with schizophrenia who already are receiving oral ziprasidone hydrochloride, the concomitant use of oral and IM formulations of ziprasidone is not recommended by the manufacturer.

Bipolar Disorder

Oral Dosage

For the acute treatment of manic or mixed episodes associated with bipolar disorder (with or without psychotic features), the recommended initial adult dosage of ziprasidone hydrochloride is 40 mg orally twice daily on the first day of therapy. Dosage may then be increased to 60 or 80 mg twice daily on the second day of therapy. Subsequent dosage adjustments based on efficacy and tolerability may be made within a dosage range of 40-80 mg twice daily. In the flexible-dosage clinical trials, the mean dosage of ziprasidone hydrochloride was approximately 120 mg daily.

For the maintenance treatment of bipolar I disorder (as adjunctive therapy to either lithium or valproate) in adults, ziprasidone should be continued at the same dosage on which the patient was initially stabilized within the dosage range of 40-80 mg orally twice daily. The manufacturer of ziprasidone states that the need for continued maintenance therapy should be reassessed periodically.

Special Populations

Dosage adjustment of oral ziprasidone is generally not required in patients with renal or hepatic impairment. Although dosage adjustment of oral ziprasidone is generally not necessary in geriatric patients, the manufacturer states that use of lower initial dosages and slower titration may be considered in some geriatric patients. In addition, dosage adjustment of oral ziprasidone is generally not necessary based on gender or race.(See Specific Populations under Cautions: Warnings/Precautions.)

Because the cyclodextrin excipient present in ziprasidone for IM injection is cleared by renal filtration, IM ziprasidone should be administered with caution in patients with renal impairment. Dosage adjustment of IM ziprasidone is not recommended based on gender or race.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Cautions

Contraindications

Known history of QT-interval prolongation (including congenital long QT syndrome), recent acute myocardial infarction, or uncompensated heart failure.(See Prolongation of QT Interval and Risk of Sudden Death under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Concomitant therapy with drugs that prolong the QT interval.(See Prolongation of QT Interval and Risk of Sudden Death under Warnings/Precautions: Other Warnings and Precautions, in Cautions and also see Drug Interactions: Drugs that Prolong QT Interval.)

Known hypersensitivity to ziprasidone.

Warnings/Precautions

Warnings

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Geriatric patients with dementia-related psychosis treated with antipsychotic drugs appear to be at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks) revealed an approximate 1.6- to 1.7-fold increase in mortality among geriatric patients receiving atypical antipsychotic drugs (i.e., aripiprazole, olanzapine, quetiapine, risperidone) compared with that observed in patients receiving placebo. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with 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 antipsychotics, treatment with conventional (first-generation) antipsychotics may increase mortality; 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 remains unclear. The manufacturer states that ziprasidone is not approved for the treatment of patients with dementia-related psychosis. (See Dysphagia under Warnings/Precautions: Other Warnings and Precautions, in Cautions and also see Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Other Warnings and Precautions

Prolongation of QT Interval and Risk of Sudden Death

Prolongation of the QT interval can result in an occurrence of ventricular arrhythmias (e.g., torsades de pointes) and/or sudden death. In one study, oral ziprasidone prolonged the QTc interval (QT interval corrected for rate) from baseline on ECG by a mean of 9-14 msec more than that observed in patients receiving risperidone, olanzapine, quetiapine, or haloperidol, but approximately 14 msec less than that observed in patients receiving thioridazine. In a study evaluating the QT/QTc prolongation effect of IM ziprasidone, the mean increase in QTc interval from baseline following 2 IM injections of ziprasidone (20 mg, then 30 mg, which is 50% higher than the recommended therapeutic dose) or haloperidol (7.5 mg, then 10 mg), given 4 hours apart, was 12.8 or 14.7 msec, respectively. Ziprasidone's larger prolongation of the QTc interval compared with several other antipsychotic agents raises the possibility that the risk of sudden death may be greater for ziprasidone than for other available drugs used in the treatment of schizophrenia. Although torsades de pointes was not associated with ziprasidone therapy when the drug was administered at recommended dosages in premarketing clinical studies, and experience with the drug is too limited to rule out an increased risk, rare postmarketing cases of torsades de pointes (in the presence of multiple confounding factors) have been reported.

Sudden unexplained deaths have been reported in patients receiving ziprasidone or other antipsychotic agents at recommended dosages. Although premarketing experience with ziprasidone did not demonstrate an excess risk of mortality compared with that of other antipsychotic agents, the extent of exposure was limited. The greater risk of QT-interval prolongation compared with several other antipsychotic agents raises the possibility that the risk of sudden death may be greater with ziprasidone than for other antipsychotic agents. This possibility should be considered in deciding among alternative antipsychotic agents. (See Uses.)

Patients at particular risk of torsades de pointes and/or sudden death include those with bradycardia, hypokalemia, or hypomagnesemia; those receiving concomitant therapy with other drugs that prolong the QTc interval; and those with congenital prolongation of the QT interval. The manufacturer states that ziprasidone should be avoided in patients with a history of clinically important cardiovascular disease (e.g., QT-interval prolongation [including congenital long QT syndrome], recent acute myocardial infarction, uncompensated heart failure, history of cardiac arrhythmias) and in those receiving concomitant therapy with other drugs that prolong the QTc interval.(See Cautions: Contraindications and Drug Interactions: Drugs that Prolong QT Interval.)

Baseline serum potassium and magnesium concentrations should be determined in patients at risk for substantial electrolyte disturbances, particularly hypokalemia, and hypokalemia or hypomagnesemia should be corrected prior to initiating ziprasidone therapy. In addition, serum electrolytes should be monitored periodically in patients who initiate diuretic therapy while receiving ziprasidone. Clinical and ECG monitoring of cardiac function, including appropriate ambulatory ECG monitoring (e.g., Holter monitoring), is recommended during ziprasidone therapy in patients with symptoms that could indicate torsades de pointes (e.g., dizziness, palpitations, syncope). Ziprasidone therapy should be discontinued in patients who have persistent QTc interval measurements exceeding 500 msec.

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported in patients receiving antipsychotic agents, including rare cases associated with ziprasidone therapy.(See Advice to Patients.)

Severe Cutaneous Adverse Reactions

Drug reaction with eosinophilia and systemic symptoms (DRESS; also known as multiorgan hypersensitivity reaction) has been reported in patients receiving ziprasidone. DRESS, which is fatal in some cases, consists of a combination of 3 or more of the following manifestations: cutaneous reaction (e.g., rash, exfoliative dermatitis), eosinophilia, fever, lymphadenopathy, and one or more systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, pericarditis, and pancreatitis.

FDA has reviewed 6 cases of DRESS associated with ziprasidone use worldwide that were reported to its adverse event reporting system. The 6 cases were temporally associated with ziprasidone, with an onset of symptoms from about 11-30 days after initiation of ziprasidone therapy. In 3 of these cases, discontinuance and reinitiation of the drug resulted in recurrence of symptoms with a faster time to onset. In half of the cases, other drugs associated with DRESS were used concomitantly. The cases reported serious outcomes, including hospitalization; however, no deaths were reported.

Other severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, have been reported in patients treated with ziprasidone. Severe cutaneous adverse reactions are sometimes fatal.

Ziprasidone therapy should be immediately discontinued if DRESS or other severe cutaneous adverse reactions are suspected, and supportive care should be initiated. Corticosteroid therapy should be considered in cases with extensive organ involvement. (See Rash under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Tardive Dyskinesia

Because use of antipsychotic agents, including ziprasidone, may be associated with tardive dyskinesia (a syndrome of potentially irreversible, involuntary, dyskinetic movements), ziprasidone should be prescribed in a manner that is most likely to minimize the occurrence of this syndrome. Chronic antipsychotic treatment generally should be reserved for patients with a chronic illness that is known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the lowest dosage and the shortest duration of treatment producing a satisfactory clinical response should be sought, and the need for continued treatment should be reassessed periodically.

The American Psychiatric Association (APA) currently recommends that patients receiving atypical antipsychotic agents be assessed clinically for abnormal involuntary movements every 12 months and that patients considered to be at increased risk for tardive dyskinesia be assessed every 6 months. If signs and symptoms of tardive dyskinesia appear in a ziprasidone-treated patient, ziprasidone discontinuance should be considered; however, some patients may require continued treatment with the drug despite presence of the syndrome.

Metabolic Changes

Atypical antipsychotic agents have been associated with metabolic changes that may increase cardiovascular and cerebrovascular risk, including hyperglycemia, dyslipidemia, and body weight gain. While all of these drugs produce some metabolic changes, each drug has its own specific risk profile. (See Hyperglycemia and Diabetes Mellitus, see Dyslipidemia, and also see Weight Gain under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients receiving atypical antipsychotic agents. While confounding factors such as an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population make it difficult to establish with certainty the relationship between use of agents in this drug class and glucose abnormalities, epidemiologic studies (which did not include ziprasidone) suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotic agents included in the studies (e.g., clozapine, olanzapine, quetiapine, risperidone); it remains to be determined whether ziprasidone also is associated with this increased risk. Although there have been few reports of hyperglycemia or diabetes in patients receiving ziprasidone, it is not known whether the paucity of such reports is due to relatively limited experience with the drug.

Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics currently are not available. While some evidence suggests that the risk for diabetes may be greater with some atypical antipsychotics (e.g., clozapine, olanzapine) than with others (e.g., aripiprazole, asenapine, iloperidone, lurasidone, quetiapine, risperidone, ziprasidone) in the class, available data are conflicting and insufficient to provide reliable estimates of relative risk associated with use of the various atypical antipsychotics.

The manufacturers of atypical antipsychotic agents state that patients with preexisting diabetes mellitus in whom therapy with an atypical antipsychotic is initiated should be closely monitored for worsening of glucose control; those with risk factors for diabetes (e.g., obesity, family history of diabetes) should undergo fasting blood glucose testing upon therapy initiation and periodically throughout treatment. Any patient who develops manifestations of hyperglycemia (including polydipsia, polyuria, polyphagia, and weakness) during treatment with an atypical antipsychotic should undergo fasting blood glucose testing. (See Advice to Patients.) In some cases, patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the suspect drug; in other cases, hyperglycemia resolved with discontinuance of the antipsychotic.

For further information on managing the risk of hyperglycemia and diabetes mellitus associated with atypical antipsychotic agents,

Dyslipidemia

Undesirable changes in lipid parameters have been observed in patients treated with some atypical antipsychotics; however, ziprasidone generally does not appear to adversely affect the lipid profile in most patients receiving the drug.

Weight Gain

Weight gain has been observed with atypical antipsychotic therapy. Although ziprasidone generally appears to be associated with no or minimal weight gain and a lower risk of weight gain than some other atypical antipsychotic agents (e.g., clozapine, olanzapine, quetiapine, risperidone), the manufacturer recommends clinical monitoring of weight in patients receiving the drug.

For additional information on metabolic effects associated with atypical antipsychotic agents, see Hyperglycemia and Diabetes Mellitus under Warnings/Precautions: Other Warnings and Precautions, in Cautions.

Rash

Rash and/or urticaria, possibly related to dosage and/or duration of therapy, occurred in about 5% of patients in premarketing clinical studies and necessitated discontinuance of the drug in about 17% of these cases. Although the occurrence of rash was related to the dosage of ziprasidone, the finding may also be explained by the longer exposure time in patients receiving higher dosages of the drug. Several ziprasidone-treated patients with rash had signs and symptoms of associated systemic illness (e.g., elevated leukocyte count). Adjunctive treatment with antihistamines or corticosteroids and/or drug discontinuance may be required. Ziprasidone should be discontinued if an alternative etiology of rash cannot be identified. (See Severe Cutaneous Adverse Reactions under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Orthostatic Hypotension

Orthostatic hypotension and associated adverse effects (e.g., dizziness, tachycardia, syncope) may occur during ziprasidone therapy in some patients, particularly during the initial dosage titration period, because of the drug's α1-adrenergic blocking activity. (See Description.) Syncope was reported in 0.6% of ziprasidone-treated patients in clinical studies.

Ziprasidone should be used with particular caution in patients with known cardiovascular disease (e.g., history of myocardial infarction or ischemic heart disease, heart failure, conduction abnormalities), cerebrovascular disease, or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy).

Leukopenia, Neutropenia, and Agranulocytosis

In clinical trial and/or postmarketing experience, leukopenia and neutropenia have been temporally related to antipsychotic agents. Agranulocytosis (including fatalities) also has been reported with other antipsychotic agents.

Possible risk factors for leukopenia and neutropenia include preexisting low leukocyte count and a history of drug-induced leukopenia or neutropenia. Patients with a preexisting low leukocyte count or a history of drug-induced leukopenia or neutropenia should have their complete blood count monitored frequently during the first few months of therapy. Ziprasidone should be discontinued at the first sign of a decline in leukocyte count in the absence of other causative factors.

Patients with clinically important neutropenia should be carefully monitored for fever or other signs or symptoms of infection and promptly treated if such signs and symptoms occur. In patients with severe neutropenia (absolute neutrophil count [ANC] less than 1000/mm), ziprasidone should be discontinued and the leukocyte count monitored until recovery occurs. Lithium reportedly has been used successfully in the treatment of several cases of leukopenia associated with aripiprazole, clozapine, and some other drugs; however, further clinical experience is needed to confirm these anecdotal findings.

Seizures

Seizures occurred in 0.4% of patients receiving ziprasidone in clinical trials. Ziprasidone should be used with caution in patients with a history of seizures or with conditions that may lower the seizure threshold (e.g., dementia of the Alzheimer's type); conditions that lower the seizure threshold may be more prevalent in patients 65 years of age or older.

Dysphagia

Esophageal dysmotility and aspiration have been associated with the use of antipsychotic agents. Aspiration pneumonia is a common cause of morbidity and mortality in geriatric patients, particularly in those with advanced Alzheimer's dementia. Ziprasidone should be used with caution in patients at risk for aspiration pneumonia. (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Warnings/Precautions: Warnings, in Cautions and see also Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Hyperprolactinemia

Similar to other antipsychotic agents and drugs with dopamine D2 antagonistic activity, ziprasidone can cause elevated serum prolactin concentrations. Prolactin concentrations exceeding 22 ng/mL were reported in about 20% of patients receiving ziprasidone in phase 2 or 3 clinical studies compared with about 4, 46, or 89% of those receiving placebo, haloperidol, or risperidone, respectively. Clinical disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been associated with prolactin-elevating drugs. In addition, chronic hyperprolactinemia associated with hypogonadism may lead to decreased bone density.

If ziprasidone therapy is considered in a patient with previously detected breast cancer, clinicians should consider that approximately one-third of human breast cancers are prolactin dependent in vitro.

Cognitive and Motor Impairment

Like other antipsychotic agents, ziprasidone potentially may impair judgment, thinking, or motor skills. Somnolence was reported in 14% of ziprasidone-treated patients compared with 7% of placebo recipients in short-term clinical trials.(See Advice to Patients.)

Priapism

Several cases of priapism have been reported in ziprasidone-treated patients. Although a causal relationship to ziprasidone has not been established, antipsychotic agents and other drugs with α-adrenergic blocking activity have been reported to cause priapism, and ziprasidone shares this pharmacologic effect. (See Description.) Severe priapism may require surgical intervention.

Body Temperature Regulation

Although not reported in premarketing clinical studies with ziprasidone, disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents.

The manufacturer recommends appropriate caution when ziprasidone is used in patients who will be experiencing conditions that may contribute to an elevation in core body temperature (e.g., strenuous exercise, extreme heat, concomitant use of agents with anticholinergic activity, dehydration).

Suicide

Suicide is an attendant risk with psychotic illness or bipolar disorder; high-risk patients should be closely supervised. Ziprasidone should be prescribed in the smallest quantity consistent with good patient management to reduce the risk of overdosage.

Concomitant Illnesses

Experience with ziprasidone in patients with certain concomitant diseases is limited.(See Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Warnings/Precautions: Warnings, in Cautions.)

Ziprasidone has not been adequately evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable cardiovascular disease and patients with these conditions were excluded from premarketing clinical studies. Because of the risk of QTc-interval prolongation and orthostatic hypotension associated with ziprasidone, the manufacturer states that the drug should be used with caution in patients with cardiovascular disease. (See Prolongation of QT Interval and Risk of Sudden Death under Warnings/Precautions: Other Warnings and Precautions, in Cautions and also see Orthostatic Hypotension under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Specific Populations

Pregnancy

Category C.

In animals, ziprasidone demonstrated developmental toxicity, including possible teratogenic effects at dosages similar to human therapeutic dosages.

Neonates exposed to antipsychotic agents during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Symptoms reported to date have included agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder. Neonates exhibiting such symptoms should be monitored. The complications have varied in severity; some neonates recovered within hours to days without specific treatment while others have required intensive care unit support and prolonged hospitalization.

National Pregnancy Registry for Atypical Antipsychotics at 866-961-2388; clinicians are encouraged to enroll women from 18-45 years of age exposed to ziprasidone during pregnancy.

The effect of ziprasidone on labor and delivery is unknown.

Lactation

The manufacturer states that it is not known whether ziprasidone or its metabolites are distributed into milk. However, a low concentration of ziprasidone in breast milk was reported in one woman; the milk to plasma ratio was 0.06 and the relative infant dose was estimated to be 1.2% of the weight-normalized maternal dose. The manufacturer recommends that women receiving ziprasidone not breast-feed.

Pediatric Use

Safety and efficacy of ziprasidone have not been established in pediatric patients younger than 18 years of age.

Geriatric Use

In clinical studies evaluating oral ziprasidone hydrochloride, 2.4% of patients were 65 years of age and older. Although no overall differences in safety or efficacy of oral ziprasidone were observed between geriatric and younger adults and other reported clinical experience has not identified differences in responses between geriatric and younger patients receiving the drug, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out. Because multiple factors may increase the pharmacodynamic response to ziprasidone or cause poorer tolerance or orthostasis, lower initial dosages, slower titration, and careful monitoring during the initial dosing period should be considered in some geriatric patients.(See Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Warnings/Precautions: Warnings, in Cautions.)

Ziprasidone mesylate IM injection has not been systematically evaluated in geriatric patients.

In a multiple-dose study and a population pharmacokinetic evaluation of oral ziprasidone, no clinically important differences in pharmacokinetics were observed between geriatric and younger adults.

Geriatric patients with dementia-related psychosis treated with ziprasidone are at an increased risk of death compared with those treated with placebo. The manufacturer states that ziprasidone is not approved for the treatment of patients with dementia-related psychosis (see Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Warnings/Precautions: Warnings, in Cautions). For additional information on the use of antipsychotic agents in the management of dementia-related psychosis, .

Hepatic Impairment

In individuals with clinically important cirrhosis given oral ziprasidone hydrochloride (20 mg twice daily for 5 days), ziprasidone areas under the plasma concentration-time curve (AUCs) were increased by 13 and 34% in those with Child-Pugh class A and B cirrhosis, respectively, compared with matched controls. The elimination half-life of oral ziprasidone was also increased in individuals with cirrhosis compared with matched controls (7.1 versus 4.8 hours, respectively). Dosage adjustment of oral ziprasidone in patients with hepatic impairment is not required.

Ziprasidone for IM injection has not been systematically evaluated in patients with hepatic impairment.

Renal Impairment

Pharmacokinetics of oral ziprasidone hydrochloride (20 mg twice daily for 8 days) were similar between individuals with varying degrees of renal impairment and those with normal renal function, suggesting that dosage adjustment based on the degree of renal impairment is generally not necessary. Ziprasidone is not removed by hemodialysis.

Ziprasidone for IM injection has not been systematically evaluated in patients with renal impairment. However, commercially available ziprasidone for injection, when reconstituted, contains methanesulfonic acid solubilized to sulfobutylether β-cyclodextrin sodium, an excipient that is cleared by renal filtration. Therefore, IM ziprasidone should be used with caution in patients with renal impairment.

Common Adverse Effects

Adverse effects occurring in 5% or more of patients with schizophrenia receiving oral ziprasidone and at a frequency at least twice the that reported with placebo include somnolence and respiratory tract infection.

Adverse effects occurring in 5% or more of patients with bipolar mania receiving oral ziprasidone and at a frequency at least twice that reported with placebo include somnolence, extrapyramidal symptoms, dizziness, akathisia, abnormal vision, asthenia, and vomiting.

Adverse effects occurring in 5% or more of patients with schizophrenia receiving IM ziprasidone 10 or 20 mg and at a frequency at least twice that reported among those receiving IM ziprasidone 2 mg include somnolence, headache, and nausea.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Cytochrome P-450 (CYP) isoenzyme 3A4 (CYP3A4) inducers (e.g., carbamazepine) and CYP3A4 inhibitors (e.g., ketoconazole): Potential pharmacokinetic interaction (altered ziprasidone metabolism).

Inhibitors or inducers of CYP 1A2, 2C9, 2C19, or 2D6 isoenzymes: Pharmacokinetic interaction unlikely.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, or 3A4: Pharmacokinetic interaction unlikely.

Drugs that Prolong QT Interval

Potential pharmacologic interaction (additive effect on QT-interval prolongation; concomitant use contraindicated) when ziprasidone is used with drugs that are known or consistently observed to prolong the QT interval (e.g., dofetilide, quinidine, sotalol, other class Ia and III antiarrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, gatifloxacin, moxifloxacin, sparfloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate [no longer commercially available in the US], dolasetron mesylate, probucol, tacrolimus). Ziprasidone also is contraindicated in patients receiving drugs shown to cause QT prolongation as an effect and for which this effect is described in the full prescribing information as a contraindication or a boxed or bolded warning.(See Cautions: Contraindications and see also Prolongation of QT Interval and Risk of Sudden Death under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Protein-bound Drugs

Pharmacokinetic interactions due to protein-binding displacement unlikely.

Antacids

Concomitant administration of an antacid containing aluminum hydroxide and magnesium hydroxide (Maalox 30 mL) did not have a clinically important effect on the pharmacokinetics of single-dose oral ziprasidone (40 mg).

Anticholinergic Agents

Potential pharmacologic interaction (possible disruption of body temperature regulation); ziprasidone should be used with caution in patients concurrently receiving drugs with anticholinergic activity.(See Body Temperature Regulation under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Hypotensive Agents

Potential pharmacologic interaction (additive hypotensive effects). Because of its α1-adrenergic blocking activity and potential to cause orthostatic hypotension, ziprasidone should be used with particular caution in patients receiving other drugs that can cause hypotension. (See Orthostatic Hypotension under Warnings/Precautions: Other Warnings and Precautions, in Cautions and see also Advice to Patients.)

CNS Agents or Alcohol

Potential pharmacologic interaction (additive CNS effects). Caution is advised when ziprasidone and other CNS agents are used concomitantly; use of alcohol during ziprasidone therapy should be avoided.

Benztropine

A population pharmacokinetic analysis in schizophrenic patients has not revealed evidence of a clinically important pharmacokinetic interaction between ziprasidone and benztropine.

Carbamazepine

Concomitant administration of carbamazepine (200 mg twice daily for 21 days), an inducer of CYP3A4, with ziprasidone resulted in an approximate 35% decrease in ziprasidone's area under the concentration-time curve (AUC); this effect may be greater with higher dosages of carbamazepine.

Cimetidine

Concomitant administration of cimetidine (800 mg daily for 2 days), a CYP3A4 inhibitor, did not have a clinically important effect on the pharmacokinetics of single-dose oral ziprasidone (40 mg).

Dextromethorphan

Consistent with in vitro results, ziprasidone did not alter the metabolism of dextromethorphan, a CYP2D6 substrate, or its major metabolite dextrorphan in healthy individuals.

Diuretics

The manufacturer states that patients initiated on diuretic therapy while receiving ziprasidone require periodic monitoring of serum electrolytes (e.g., potassium and magnesium concentrations). (See Prolongation of QT Interval and Risk of Sudden Death under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Ketoconazole and Other CYP3A4 Inhibitors

Concomitant administration of ketoconazole (400 mg daily for 5 days), a potent CYP3A4 inhibitor, with ziprasidone increased the AUC and peak plasma concentrations of ziprasidone by about 35-40%. Other inhibitors of CYP3A4 are expected to have similar effects.

Levodopa and Dopamine Agonists

Potential pharmacologic interaction (antagonistic effects).

Lithium

Concomitant administration of lithium (450 mg twice daily for 7 days) with ziprasidone (40 mg twice daily) did not affect the steady-state serum concentrations or renal clearance of lithium. Ziprasidone given adjunctively to lithium in a maintenance clinical trial in patients with bipolar disorder did not affect mean therapeutic lithium concentrations.

Lorazepam

A population pharmacokinetic analysis in schizophrenic patients has not revealed evidence of a clinically important pharmacokinetic interaction between ziprasidone and lorazepam.

Oral Contraceptives

In vivo, ziprasidone did not affect the pharmacokinetics of estrogen or progesterone components. Ziprasidone (20 mg twice daily) did not affect the pharmacokinetics of concurrently administered ethinyl estradiol (0.03 mg) and levonorgestrel (0.15 mg).

Propranolol

A population pharmacokinetic analysis in schizophrenic patients has not revealed evidence of a clinically important pharmacokinetic interaction between ziprasidone and propranolol.

Propranolol did not alter the plasma protein binding of ziprasidone in vitro, and vice versa.

Valproate

A pharmacokinetic interaction between ziprasidone and valproate appears unlikely because of the lack of common metabolic pathways for the 2 drugs. Ziprasidone given adjunctively to valproate in a maintenance clinical trial in patients with bipolar disorder did not affect mean therapeutic valproate concentrations.

Warfarin

Warfarin did not alter the plasma protein binding of ziprasidone in vitro, and vice versa.

Smoking

In vitro studies indicate that ziprasidone is not a substrate for CYP1A2, which is induced by smoking. In a population pharmacokinetic analysis, no substantial pharmacokinetic differences were reported between smokers and nonsmokers receiving the drug.

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