Geodon

Administration Information for GEODON Capsules

Administer GEODON capsules orally with food. Swallow capsules whole, do not open, crush, or chew the capsules.

Schizophrenia

Bipolar I Disorder (Acute Mixed or Manic Episodes and Maintenance Treatment as an Adjunct to Lithium or Valproate)

Acute Treatment of Agitation in Schizophrenia

2.5 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant

At least 14 days must elapse between discontinuation of an MAOI (intended to treat psychiatric disorders) and initiation of therapy with GEODON. In addition, at least 3 days should be allowed after stopping GEODON before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.3), Warnings and Precautions (5.2), and Drug Interactions (7.1)].

Pregnancy

Lactation

Females and Males of Reproductive Potential

Pediatric Use

The safety and effectiveness of Geodon have not been established in pediatric patients.

Geodon was studied in one 4-week, placebo-controlled trial in patients 10 to 17 years of age with bipolar I disorder. However, the data were insufficient to fully assess the safety of Geodon in pediatric patients. Therefore, a safe and effective dose for use could not be established.

Geriatric Use

Of the total number of subjects in clinical studies of ziprasidone, 2.4 percent were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Nevertheless, the presence of multiple factors that might increase the pharmacodynamic response to ziprasidone, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period for some elderly patients.

Ziprasidone intramuscular has not been systematically evaluated in elderly patients (65 years and over).

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 twice daily dosing were similar among subjects with varying degrees of renal impairment (n=27), and subjects with normal renal function, indicating that dosage adjustment based upon the degree of renal impairment is not required. Ziprasidone is not removed by hemodialysis.

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 [see Clinical Pharmacology (12)].

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 twice daily for 5 days in subjects (n=13) with clinically significant (Childs-Pugh Class A and B) cirrhosis revealed an increase in AUC 0-12 of 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.

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.

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.

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 17 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 in placebo-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. GEODON is not approved for the treatment of patients with dementia-related psychosis. [see Boxed Warning, Warnings and Precautions (5.2)].

Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis

In placebo-controlled trials in elderly subjects with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. GEODON is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)].

QT Prolongation and Risk of Sudden Death

Ziprasidone use should be avoided in combination with other drugs that are known to prolong the QTc interval [see Contraindications (4.1) and Drug Interactions (7.4)]. Additionally, clinicians should be alert to the identification of other drugs that have been consistently observed to prolong the QTc interval. Such drugs should not be prescribed with ziprasidone. Ziprasidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias [see Contraindications (4)].

A study directly comparing the QT/QTc prolonging effect of oral ziprasidone with several other drugs effective in the treatment of schizophrenia was conducted in patient volunteers. In the first phase of the trial, ECGs were obtained at the time of maximum plasma concentration when the drug was administered alone. In the second phase of the trial, ECGs were obtained at the time of maximum plasma concentration while the drug was co-administered with an inhibitor of the CYP4503A4 metabolism of the drug.

In the first phase of the study, the mean change in QTc from baseline was calculated for each drug, using a sample-based correction that removes the effect of heart rate on the QT interval. The mean increase in QTc from baseline for ziprasidone ranged from approximately 9 to 14 msec greater than for four of the comparator drugs (risperidone, olanzapine, quetiapine, and haloperidol), but was approximately 14 msec less than the prolongation observed for thioridazine.

In the second phase of the study, the effect of ziprasidone on QTc length was not augmented by the presence of a metabolic inhibitor (ketoconazole 200 mg twice daily).

In placebo-controlled trials in adults, oral ziprasidone increased the QTc interval compared to placebo by approximately 10 msec at the highest recommended daily dose of 160 mg. In clinical trials with oral ziprasidone, the electrocardiograms of 2/2988 (0.06%) patients who received GEODON and 1/440 (0.23%) patients who received placebo revealed QTc intervals exceeding the potentially clinically relevant threshold of 500 msec. In the ziprasidone-treated patients, neither case suggested a role of ziprasidone. One patient had a history of prolonged QTc and a screening measurement of 489 msec; QTc was 503 msec during ziprasidone treatment. The other patient had a QTc of 391 msec at the end of treatment with ziprasidone and upon switching to thioridazine experienced QTc measurements of 518 and 593 msec.

Some drugs that prolong the QT/QTc interval have been associated with the occurrence of torsade de pointes and with sudden unexplained death. The relationship of QT prolongation to torsade de pointes is clearest for larger increases (20 msec and greater) but it is possible that smaller QT/QTc prolongations may also increase risk, or increase it in susceptible individuals. Although torsade de pointes has not been observed in association with the use of ziprasidone in premarketing studies and experience is too limited to rule out an increased risk, there have been rare post-marketing reports (in the presence of multiple confounding factors) [see Adverse Reactions (6.2)].

A study evaluating the QT/QTc prolonging effect of intramuscular ziprasidone, with intramuscular haloperidol as a control, was conducted in patient volunteers. In the trial, ECGs were obtained at the time of maximum plasma concentration following two injections of ziprasidone (20 mg then 30 mg) or haloperidol (7.5 mg then 10 mg) given four hours apart. Note that a 30 mg dose of intramuscular ziprasidone is 50% higher than the recommended therapeutic dose. The mean change in QTc from baseline was calculated for each drug, using a sample-based correction that removes the effect of heart rate on the QT interval. The mean increase in QTc from baseline for ziprasidone was 4.6 msec following the first injection and 12.8 msec following the second injection. The mean increase in QTc from baseline for haloperidol was 6.0 msec following the first injection and 14.7 msec following the second injection. In this study, no patients had a QTc interval exceeding 500 msec.

As with other antipsychotic drugs and placebo, sudden unexplained deaths have been reported in patients taking ziprasidone at recommended doses. The premarketing experience for ziprasidone did not reveal an excess risk of mortality for ziprasidone compared to other antipsychotic drugs or placebo, but the extent of exposure was limited, especially for the drugs used as active controls and placebo. Nevertheless, ziprasidone’s larger prolongation of QTc length compared to several other antipsychotic drugs raises the possibility that the risk of sudden death may be greater for ziprasidone than for other available drugs for treating schizophrenia. This possibility needs to be considered in deciding among alternative drug products [see Indications and Usage (1)].

Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.

It is recommended that patients being considered for ziprasidone treatment who are at risk for significant electrolyte disturbances, hypokalemia in particular, have baseline serum potassium and magnesium measurements. Hypokalemia (and/or hypomagnesemia) may increase the risk of QT prolongation and arrhythmia. Hypokalemia may result from diuretic therapy, diarrhea, and other causes. Patients with low serum potassium and/or magnesium should be repleted with those electrolytes before proceeding with treatment. It is essential to periodically monitor serum electrolytes in patients for whom diuretic therapy is introduced during ziprasidone treatment. Persistently prolonged QTc intervals may also increase the risk of further prolongation and arrhythmia, but it is not clear that routine screening ECG measures are effective in detecting such patients. Rather, ziprasidone should be avoided in patients with histories of significant cardiovascular illness, e.g., QT prolongation, recent acute myocardial infarction, uncompensated heart failure, or cardiac arrhythmia. Ziprasidone should be discontinued in patients who are found to have persistent QTc measurements >500 msec.

For patients taking ziprasidone who experience symptoms that could indicate the occurrence of torsade de pointes, e.g., dizziness, palpitations, or syncope, the prescriber should initiate further evaluation, e.g., Holter monitoring may be useful.

5.4 Serotonin Syndrome

Ziprasidone can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, fentanyl, tramadol, meperidine, methadone, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., monoamine oxidase inhibitors (MAOIs) [see Contraindications (4.3), Adverse Reactions (6.2), Drug Interactions (7.3)].

Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

The concomitant use of GEODON with MAOIs is contraindicated. In addition, do not initiate GEODON in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking GEODON, discontinue GEODON before initiating treatment with the MAOI [see Contraindications (4.3), Drug Interactions (7.3)].

Monitor all patients taking GEODON for the emergence of serotonin syndrome. Discontinue treatment with GEODON and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of GEODON with other serotonergic drugs is clinically warranted, inform patients of the increased risk of serotonin syndrome and monitor for symptoms.

Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.

The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

Severe Cutaneous Adverse Reactions

Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients undergoing treatment with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, ziprasidone should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on ziprasidone, drug discontinuation should be considered. However, some patients may require treatment with ziprasidone despite the presence of the syndrome.

Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Rash

In premarketing trials with ziprasidone, about 5% of patients developed rash and/or urticaria, with discontinuation of treatment in about one-sixth of these cases. The occurrence of rash was related to dose of ziprasidone, although the finding might also be explained by the longer exposure time in the higher dose patients. Several patients with rash had signs and symptoms of associated systemic illness, e.g., elevated WBCs. Most patients improved promptly with adjunctive treatment with antihistamines or steroids and/or upon discontinuation of ziprasidone, and all patients experiencing these reactions were reported to recover completely. Upon appearance of rash for which an alternative etiology cannot be identified, ziprasidone should be discontinued.

Orthostatic Hypotension

Ziprasidone may induce orthostatic hypotension associated with dizziness, tachycardia, and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α1-adrenergic antagonist properties. Syncope was reported in 0.6% of the patients treated with ziprasidone.

Ziprasidone should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications).

Falls

Antipsychotic drugs (which include GEODON) may cause somnolence, postural hypotension, and motor and sensory instability, which could lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

Leukopenia, Neutropenia, and Agranulocytosis

In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents. Agranulocytosis (including fatal cases) has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue GEODON at the first sign of decline in WBC in the absence of other causative factors.

Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue GEODON and have their WBC followed until recovery.

Seizures

During clinical trials, seizures occurred in 0.4% of patients treated with ziprasidone. There were confounding factors that may have contributed to the occurrence of seizures in many of these cases. As with other antipsychotic drugs, ziprasidone should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer’s dementia. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia. Ziprasidone and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [see Boxed Warning].

Hyperprolactinemia

As with other drugs that antagonize dopamine D2 receptors, ziprasidone elevates prolactin levels in humans. Increased prolactin levels were also observed in animal studies with this compound, and were associated with an increase in mammary gland neoplasia in mice; a similar effect was not observed in rats [see Nonclinical Toxicology (13.1)]. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer.

Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds, the clinical significance of elevated serum prolactin levels is unknown for most patients. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density.

Potential for Cognitive and Motor Impairment

Somnolence was a commonly reported adverse reaction in patients treated with ziprasidone. In the 4- and 6-week placebo-controlled trials in adults, somnolence was reported in 14% of patients on ziprasidone compared to 7% of placebo patients. Somnolence led to discontinuation in 0.3% of the patients in short-term clinical trials in adults.

Since ziprasidone has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating hazardous machinery until they are reasonably certain that ziprasidone therapy does not affect them adversely.

Priapism

One case of priapism was reported in the premarketing database. While the relationship of the reaction to ziprasidone use has not been established, other drugs with alpha-adrenergic blocking effects have been reported to induce priapism, and it is possible that ziprasidone may share this capacity. Severe priapism may require surgical intervention.

Body Temperature Regulation

Although not reported with ziprasidone in premarketing trials, disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ziprasidone for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

Suicide

The possibility of a suicide attempt is inherent in psychotic illness or bipolar disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for ziprasidone should be written for the smallest quantity of capsules consistent with good patient management in order to reduce the risk of overdose.

Patients with Concomitant Illnesses

Clinical experience with ziprasidone in patients with certain concomitant systemic illnesses is limited [see Use in Specific Populations (8.6), (8.7)].

Ziprasidone has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical studies. Because of the risk of QTc prolongation and orthostatic hypotension with ziprasidone, caution should be observed in cardiac patients. [see Warnings and Precautions (5.3), (5.10)].

Laboratory Tests

Patients being considered for ziprasidone treatment that are at risk of significant electrolyte disturbances should have baseline serum potassium and magnesium measurements. Low serum potassium and magnesium should be replaced before proceeding with treatment. Patients who are started on diuretics during Ziprasidone therapy need periodic monitoring of serum potassium and magnesium. Ziprasidone should be discontinued in patients who are found to have persistent QTc measurements >500 msec [see Warnings and Precautions (5.3)].

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical trials in adults for oral ziprasidone included approximately 5700 patients and/or normal subjects exposed to one or more doses of ziprasidone. Of these 5700, over 4800 were patients who participated in multiple-dose effectiveness trials, and their experience corresponded to approximately 1831 patient-years. These patients include: (1) 4331 patients who participated in multiple-dose trials, predominantly in schizophrenia, representing approximately 1698 patient-years of exposure as of February 5, 2000; and (2) 472 patients who participated in bipolar mania trials representing approximately 133 patient-years of exposure. An additional 127 patients with bipolar disorder participated in a long-term maintenance treatment study representing approximately 74.7 patient-years of exposure to ziprasidone. The conditions and duration of treatment with ziprasidone included open-label and double-blind studies, inpatient and outpatient studies, and short-term and longer-term exposure.

Clinical trials 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 reactions during exposure were obtained by collecting voluntarily reported adverse experiences, as well as results of physical examinations, vital signs, weights, laboratory analyses, ECGs, and results of ophthalmologic examinations.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Adverse Findings Observed in Short-Term, Placebo-Controlled Trials with Oral Ziprasidone

The following findings are based on the short-term placebo-controlled premarketing trials for schizophrenia (a pool of two 6-week, and two 4-week fixed-dose trials) and bipolar mania (a pool of two 3-week flexible-dose trials) in which ziprasidone was administered in doses ranging from 10 to 200 mg/day.

Commonly Observed Adverse Reactions in Short Term-Placebo-Controlled Trials

The following adverse reactions were the most commonly observed adverse reactions associated with the use of ziprasidone (incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients (ziprasidone incidence at least twice that for placebo):

Schizophrenia trials (see Table 11)

•

Somnolence

•

Respiratory Tract Infection

Bipolar trials (see Table 12)

•

Somnolence

•

Extrapyramidal Symptoms which includes the following adverse reaction terms: extrapyramidal syndrome, hypertonia, dystonia, dyskinesia, hypokinesia, tremor, paralysis and twitching. None of these adverse reactions occurred individually at an incidence greater than 10% in bipolar mania trials.

•

Dizziness which includes the adverse reaction terms dizziness and lightheadedness.

•

Akathisia

•

Abnormal Vision

•

Asthenia

•

Vomiting

SCHIZOPHRENIA

Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials of Oral Ziprasidone

Approximately 4.1% (29/702) of ziprasidone-treated patients in short-term, placebo-controlled studies discontinued treatment due to an adverse reaction, compared with about 2.2% (6/273) on placebo. The most common reaction associated with dropout was rash, including 7 dropouts for rash among ziprasidone patients (1%) compared to no placebo patients [see Warnings and Precautions (5.9)].

Adverse Reactions Occurring at an Incidence of 2% or More Among Ziprasidone-Treated Patients in Short-Term, Oral, Placebo-Controlled Trials

Table 11 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during acute therapy (up to 6 weeks) in predominantly patients with schizophrenia, including only those reactions that occurred in 2% or more of patients treated with ziprasidone and for which the incidence in patients treated with ziprasidone was greater than the incidence in placebo-treated patients.

Dose Dependency of Adverse Reactions in Short-Term, Fixed-Dose, Placebo-Controlled Trials

An analysis for dose response in the schizophrenia 4-study pool revealed an apparent relation of adverse reaction to dose for the following reactions: asthenia, postural hypotension, anorexia, dry mouth, increased salivation, arthralgia, anxiety, dizziness, dystonia, hypertonia, somnolence, tremor, rhinitis, rash, and abnormal vision.

Extrapyramidal Symptoms (EPS)

The incidence of reported EPS (which included the adverse reaction 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.

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.

Vital Sign Changes

Ziprasidone is associated with orthostatic hypotension [see Warnings and Precautions (5.10)].

ECG Changes

Ziprasidone is associated with an increase in the QTc interval [see Warnings and Precautions (5.3)]. 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.

Other Adverse Reactions Observed During the Premarketing Evaluation of Oral Ziprasidone

Following is a list of COSTART terms that reflect treatment-emergent adverse reactions as defined in the introduction to the ADVERSE REACTIONS section reported by patients treated with ziprasidone in schizophrenia trials at multiple doses >4 mg/day within the database of 3834 patients. All reported reactions are included except those already listed in Table 11 or elsewhere in labeling, those reaction terms that were so general as to be uninformative, reactions reported only once and that did not have a substantial probability of being acutely life-threatening, reactions that are part of the illness being treated or are otherwise common as background reactions, and reactions considered unlikely to be drug-related. It is important to emphasize that, although the reactions reported occurred during treatment with ziprasidone, they were not necessarily caused by it.

Adverse reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions:

Frequent - adverse reactions occurring in at least 1/100 patients (≥1.0% of patients) (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing);

Infrequent - adverse reactions occurring in 1/100 to 1/1000 patients (in 0.1-1.0% of patients)

Rare - adverse reactions occurring in fewer than 1/1000 patients (<0.1% of 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

BIPOLAR DISORDER

Acute Treatment of Manic or Mixed Episodes in Adults

Adverse Reactions Associated with Discontinuation of Treatment in Short Term, Placebo-Controlled Trials

Approximately 6.5% (18/279) of ziprasidone-treated patients in short-term, placebo-controlled studies discontinued treatment due to an adverse reaction, compared with about 3.7% (5/136) on placebo. The most common reactions associated with dropout in the ziprasidone-treated patients were akathisia, anxiety, depression, dizziness, dystonia, rash and vomiting, with 2 dropouts for each of these reactions among ziprasidone patients (1%) compared to one placebo patient each for dystonia and rash (1%) and no placebo patients for the remaining adverse reactions.

Adverse Reactions Occurring at an Incidence of 2% or More Among Ziprasidone-Treated Patients in Short-Term, Oral, Placebo-Controlled Trials

Table 12 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during acute therapy (up to 3 weeks) in patients with bipolar mania, including only those reactions that occurred in 2% or more of patients treated with ziprasidone and for which the incidence in patients treated with ziprasidone was greater than the incidence in placebo-treated patients.

Explorations for interactions on the basis of gender did not reveal any clinically meaningful differences in the adverse reaction occurrence on the basis of this demographic factor.

INTRAMUSCULAR ZIPRASIDONE

Adverse Reactions Occurring at an Incidence of 1% or More Among Ziprasidone-Treated Patients in Short-Term Trials of Intramuscular Ziprasidone

Table 13 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during acute therapy with intramuscular ziprasidone in 1% or more of patients.

In these studies, the most commonly observed adverse reactions 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%).

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of GEODON. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reaction reports not listed above that have been received since market introduction include rare occurrences of the following : Cardiac Disorders: Tachycardia, torsade de pointes (in the presence of multiple confounding factors), [see Warnings and Precautions (5.3)]; Digestive System Disorders: Swollen Tongue; Reproductive System and Breast Disorders: Galactorrhea, priapism; 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, somnambulism; Skin and subcutaneous Tissue Disorders: Allergic reaction (such as allergic dermatitis, angioedema, orofacial edema, urticaria), rash, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS); Urogenital System Disorders: Enuresis, urinary incontinence; Vascular Disorders: Postural hypotension, syncope.

Metabolic Pathway

Approximately two-thirds of ziprasidone is metabolized via a combination of chemical reduction by glutathione and enzymatic reduction by aldehyde oxidase. There are no known clinically relevant inhibitors or inducers of aldehyde oxidase. Less than one-third of ziprasidone metabolic clearance is mediated by cytochrome P450 catalyzed oxidation.

In Vitro Studies

An in vitro enzyme inhibition study utilizing human liver microsomes showed that ziprasidone had little inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and thus would not likely interfere with the metabolism of drugs primarily metabolized by these enzymes. There is little potential for drug interactions with ziprasidone due to displacement [see Clinical Pharmacology (12.3)].

Pharmacodynamic Interactions

•

Ziprasidone should not be used with any drug that prolongs the QT interval [see Contraindications (4.1)].

•

Given the primary CNS effects of ziprasidone, caution should be used when it is taken in combination with other centrally acting drugs.

•

Because of its potential for inducing hypotension, ziprasidone may enhance the effects of certain antihypertensive agents.

•

Ziprasidone may antagonize the effects of levodopa and dopamine agonists.

•

Risk of serotonin syndrome with concomitant therapy with other serotonergic drugs such as SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort [see Contraindications (4.3), Warnings and Precautions (5.4), Adverse Reactions (6.2)].

Pharmacokinetic Interactions

Lithium

Ziprasidone at a dose of 40 mg twice daily administered concomitantly with lithium at a dose of 450 mg twice daily for 7 days did not affect the steady-state level or renal clearance of lithium. Ziprasidone dosed adjunctively to lithium in a maintenance trial of bipolar patients did not affect mean therapeutic lithium levels.

Oral Contraceptives

In vivo studies have revealed no effect of ziprasidone on the pharmacokinetics of estrogen or progesterone components. Ziprasidone at a dose of 20 mg twice daily did not affect the pharmacokinetics of concomitantly administered oral contraceptives, ethinyl estradiol (0.03 mg) and levonorgestrel (0.15 mg).

Dextromethorphan

Consistent with in vitro results, a study in normal healthy volunteers showed that ziprasidone did not alter the metabolism of dextromethorphan, a CYP2D6 model substrate, to its major metabolite, dextrorphan. There was no statistically significant change in the urinary dextromethorphan/dextrorphan ratio.

Valproate

A pharmacokinetic interaction of ziprasidone with valproate is unlikely due to the lack of common metabolic pathways for the two drugs. Ziprasidone dosed adjunctively to valproate in a maintenance trial of bipolar patients did not affect mean therapeutic valproate levels.

Other Concomitant Drug Therapy

Population pharmacokinetic analysis of schizophrenic patients enrolled in controlled clinical trials has not revealed evidence of any clinically significant pharmacokinetic interactions with benztropine, propranolol, or lorazepam.

Food Interaction

The absolute bioavailability of a 20 mg dose under fed conditions is approximately 60%. The absorption of ziprasidone is increased up to two-fold in the presence of food [see Clinical Pharmacology (12.3)].

Mechanism of Action

The mechanism of action of ziprasidone in the treatment of the listed indications could be mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) antagonism.

Pharmacodynamics

Ziprasidone binds with relatively high affinity to the dopamine D2 and D3, serotonin 5HT2A, 5HT2C, 5HT1A, 5HT1D, and α1-adrenergic receptors (Kis of 4.8, 7.2, 0.4, 1.3, 3.4, 2, and 10 nM, respectively), and with moderate affinity to the histamine H1 receptor (Ki=47 nM). Ziprasidone is an antagonist at the D2, 5HT2A, and 5HT1D receptors, and an agonist at the 5HT1A receptor. Ziprasidone inhibited synaptic reuptake of serotonin and norepinephrine. No appreciable affinity was exhibited for other receptor/binding sites tested, including the cholinergic muscarinic receptor (IC50 >1 μM).

Pharmacokinetics

Carcinogenesis, Mutagenesis, Impairment of Fertility

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 maintenance trial. All trials were in adult inpatients, most of whom met DSM III-R criteria for schizophrenia. Each study included 2 to 3 fixed doses of ziprasidone as well as placebo. Four of the 5 trials were able to distinguish ziprasidone from placebo; one short-term study did not. Although a single fixed-dose haloperidol arm was included as a comparative treatment in one of the three short-term trials, this single study was inadequate to provide a reliable and valid comparison of ziprasidone and haloperidol.

Several instruments were used for assessing psychiatric signs and symptoms in these studies. The Brief Psychiatric Rating Scale (BPRS) and the Positive and Negative Syndrome Scale (PANSS) are both multi-item inventories of general psychopathology usually used to evaluate the effects of drug treatment in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients. A second widely used assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the Scale for Assessing Negative Symptoms (SANS) was employed for assessing negative symptoms in one trial.

The results of the oral ziprasidone trials in schizophrenia follow:

•

In a 4-week, placebo-controlled trial (n=139) comparing 2 fixed doses of ziprasidone (20 and 60 mg twice daily) with placebo, only the 60 mg dose was superior to placebo on the BPRS total score and the CGI severity score. This higher dose group was not superior to placebo on the BPRS psychosis cluster or on the SANS.

•

In a 6-week, placebo-controlled trial (n=302) comparing 2 fixed doses of ziprasidone (40 and 80 mg twice daily) with placebo, both dose groups were superior to placebo on the BPRS total score, the BPRS psychosis cluster, the CGI severity score and the PANSS total and negative subscale scores. Although 80 mg twice daily had a numerically greater effect than 40 mg twice daily, the difference was not statistically significant.

•

In a 6-week, placebo-controlled trial (n=419) comparing 3 fixed doses of ziprasidone (20, 60, and 100 mg twice daily) with placebo, all three dose groups were superior to placebo on the PANSS total score, the BPRS total score, the BPRS psychosis cluster, and the CGI severity score. Only the 100 mg twice daily dose group was superior to placebo on the PANSS negative subscale score. There was no clear evidence for a dose-response relationship within the 20 mg twice daily to 100 mg twice daily dose range.

•

In a 4-week, placebo-controlled trial (n=200) comparing 3 fixed doses of ziprasidone (5, 20, and 40 mg twice daily), none of the dose groups was statistically superior to placebo on any outcome of interest.

•

A study was conducted in stable chronic or subchronic (CGI-S ≤5 at baseline) schizophrenic inpatients (n=294) who had been hospitalized for not less than two months. After a 3-day single-blind placebo run-in, subjects were randomized to one of 3 fixed doses of ziprasidone (20 mg, 40 mg, or 80 mg twice daily) or placebo and observed for relapse. Patients were observed for “impending psychotic relapse,” defined as CGI-improvement score of ≥6 (much worse or very much worse) and/or scores ≥6 (moderately severe) on the hostility or uncooperativeness items of the PANSS on two consecutive days. Ziprasidone was significantly superior to placebo in time to relapse, with no significant difference between the different dose groups. There were insufficient data to examine population subsets based on age and race. Examination of population subsets based on gender did not reveal any differential responsiveness.

Bipolar I Disorder (Acute Mixed or Manic Episodes and Maintenance Treatment as an Adjunct to Lithium or Valproate)

Acute Treatment of Agitation in Schizophrenia

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 the BARS 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 premarketing 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:

(1)

In a one-day, double-blind, randomized trial (n=79) involving doses of ziprasidone intramuscular of 20 mg or 2 mg, up to QID, ziprasidone intramuscular 20 mg was statistically superior to ziprasidone intramuscular 2 mg, as assessed by AUC of the BARS at 0 to 4 hours, and by CGI severity at 4 hours and study endpoint.

(2)

In another one-day, double-blind, randomized trial (n=117) involving doses of ziprasidone intramuscular of 10 mg or 2 mg, up to QID, ziprasidone intramuscular 10 mg was statistically superior to ziprasidone intramuscular 2 mg, as assessed by AUC of the BARS at 0 to 2 hours, but not by CGI severity.