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Physician’s Resource The physician’s psychoactive medication resource guide 25% of your patients taking an antidepressant will have weight gain and the weight gain is directly caused by the antidepressant.
Zyprexa Source: National Institute of Mental Health "Researchers and clinical psychopharmacologists do not fully know what causes schizophrenia. Side effects of Zyprexa include slowing of voluntary movement, expressionless face, rigidity and tremor of arms and head, abnormal toxicity of muscle tissues, and restlessness." Zyprexa Can Cause Diabetes - Eli Lilly is now trying to get the FDA to approve diabetes medication Could this be the scam of the century? Bring out Prozac, which has a diabetes side effect, then Zyprexa with the same side effect, they get approved a medication to treat the disease you created for millions? If you or I did this we would be thrown in jail. New Drug Application for Exenatide Submitted to FDA for Type 2 Diabetes June 30, 2004 Amylin Pharmaceuticals, Inc., (Nasdaq: AMLN) and Eli Lilly and Company (NYSE: LLY) today announced the submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for regulatory approval of exenatide. Exenatide is the first in a new class of medicines known as incretin mimetics under investigation for the treatment of type 2 diabetes. In clinical trials, exenatide has demonstrated reductions in blood sugar and improvements in markers of beta cell function. Patients in exenatide studies also lost weight. Back to top of page "The submission of the exenatide NDA is a significant milestone both for Amylin Pharmaceuticals and for our collaboration with Eli Lilly and Company," said Ginger Graham, president and CEO, Amylin Pharmaceuticals. "This NDA includes data on more than 1,800 subjects treated with exenatide. We believe the application provides the FDA with the necessary information to evaluate exenatide for use as a new therapeutic option for people living with type 2 diabetes." "The rapid increase in the prevalence of diabetes and the need for innovative new treatments has never been more critical than it is today," said John C. Lechleiter, Ph.D., executive vice president of pharmaceutical operations, Eli Lilly and Company. "Many patients with type 2 diabetes are struggling to control their blood sugar and, even with current oral therapies, find that they cannot reach their treatment goals. If approved, we believe exenatide could offer an important and novel treatment option for people with type 2 diabetes." The exenatide NDA is made up of three major components; chemistry and manufacturing, preclinical and clinical. The clinical component of the submission is based largely on 30-week data from three blinded pivotal trials of exenatide involving more than 1,400 patients who were unable to control their blood sugar on common oral therapies including metformin, sulfonylurea or a combination of both. The submission also includes 52-week open-label data from the extensions of these pivotal studies and from an additional open-label study. In the pivotal studies, exenatide demonstrated statistically significant, sustained reductions in average blood sugar levels as measured by hemoglobin A1c (A1C). Patients in these studies also demonstrated progressive reductions in weight, a secondary endpoint of the studies. The open-label studies demonstrated that the reductions in A1C were sustained through 52 weeks of treatment with average reductions of approximately 1.1 percent. Reductions in weight were also sustained through 52 weeks of treatment with average reductions of approximately eight pounds. In addition, the exenatide data showed improvements in beta cell function, as measured by HOMA-B and proinsulin to insulin ratios, and the restoration of first-phase insulin response, a fundamental response lost early in the development of type 2 diabetes. Exenatide was generally well tolerated across the pivotal trials. The most common adverse event reported was mild to moderate nausea, which occurred primarily at initiation of therapy. Exenatide is formulated as a sterile, injectable product that, if approved, will be delivered by a pen delivery system. About Diabetes Diabetes affects an estimated 194 million adults worldwide 1  and more than 18 million in the United States. 2  Approximately 90-95 percent of those affected have type 2 diabetes,
a disease in which the body does not produce enough insulin and the cells in the body do not respond normally to the insulin. According to the U.S. Center for Disease Control and Prevention’s National Health and Nutrition Examination Survey, approximately 60 percent of diabetes patients do not achieve target A1C levels with their current treatment regimen. According to the American Diabetes Association, patients with A1Cs above target are more likely to develop diabetes-related complications, such as kidney disease, blindness and heart disease. 3 ZYPREXA Olanzapine Tablets ZYPREXA ZYDIS Olanzapine Orally Disintegrating Tablets ZYPREXA IntraMuscular Olanzapine for Injection DESCRIPTION Contraindications ZYPREXA is contraindicated in patients with a known hypersensitivity to the product. For specific information about the contraindications of lithium or valproate, refer to the CONTRAINDICATIONS section of the package inserts for these other products. Warnings Hyperglycemia and Diabetes Mellitus – Hyperglycemia, in some cases extreme and associated with ketpacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including ZYPRXA, Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders the relationship between atypical antipsychotic use and hyperglycemia-related adverse events in not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. Safety Experience in Elderly Patients with Dementia-Related Psychosis – In placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of death in ZYPRXA-treated patients was significantly greater than placebo-treated patients (3.5% vs 1.5%, respectively). Risk factors that may predispose this patient population ot increased mortality when treated with ZYPRXA include age >80 years, sedation, concomitant use of benzodiazepines or presence of pulmonary conditions (e.g., pneumonia, with or without aspiration). ZYPRXA is not approved for the treatment of patients with dementia-related psychosis. Cerebrovascula Adverse Events, Including Stroke, in Elderly Patients with Dementia -Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in trials of ZYPREXA in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with ZYPREXA compared to patients treated with placebo. ZYPREXA is not approved for the treatment of patients with dementia- related psychosis. 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, including ZYPREXA. 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 bot 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 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. Tardive Dyskinesia – A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated 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 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, ZYPREXA 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 (1) who suffer from a chronic illness that 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 ZYPREXA, drug discontinuation should be considered. However, some patients may require treatment with ZYPREXA despite the presence of the syndrome. For specific information about the warnings of lithium or valproate, refer to the WARNINGS section of the package inserts for these other products. Precautions General Hemodynamic Effects – ZYPREXA may induce orthostatic hypotension associated with sizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, -adrenergic antagonistic properties. Hypotension,probably reflecting its α bradycardia with or without hypotension, tachycardia, and syncope were also reported during the clinical trials with intramuscular ZYPREXA for injection. In an open-label clinical pharmacology study in non-agitated patients with schizophrenia in which the safety and tolerability of intramuscular ZYPREXA were evaluated under a maximal dosing regimen (three 10 mg doses administered 4 hours apart), approximately one-third of these patients experienced a significant orthostatic decrease in systolic blood pressure (i.e., decrease ≥30 mmHg) (see DOSAGE AND ADMINISTRATION). Syncope was reported in 0.6% (15/2500) of ZYPREXA-treated patients in phase 2-3 oral ZYPREXA studies and in 0.3% (2/722) of ZYPREXA-treated patients with agitation in the intramuscular ZYPREXA for injection studies. Three normal volunteers in phase 1 studies with intramuscular ZYPREXA experienced hypotension, bradycardia, and sinus pauses of up to 6 seconds that spontaneously resolved (in 2 cases the events occurred on intramuscular olanzapine, and in 1 case, on oral ZYPREXA). The risk for this sequence of hypotension, bradycardia, and sinus pause may be greater in nonpsychiatric patients compared to psychiatric patients who are possibly more adapted to certain effects of psychotropic drugs. For oral ZYPREZA therapy, the risk of orthostatic hypotension and syncope may be minimized by initiating therapy with 5 mg QD ( see DOSAGE AND ADMINISTRATION). A more gradual titration to the target dose should be considered if hypotension occurs. For intramuscular ZYPREXA for injection therapy, patients should remain recumbent if drowsy or dizzy after injection until examination has indicated that they are not experiencing postural hypotension and/or bradycardia. ZYPREXA should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension dehydration, hypovolemia, and treatment with antihypertensive medications) where the occurrence of syncope, or hypotension and/or bradycardia might put the patient at increased medical risk. Seizures – During premarketing testing, seizures occurred in 0.9% (22/2500) of ZYPREXA-treated patients. There were confounding factors that may have contributed to the occurrence of seizures in many of these cases. ZYPREXA 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. Hyperprolactinemia - As with other drugs that antagonize dopamine D² receptors, ZYPREXA elevates prolactin levels, and a modest elevation persist during chronic administration. 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 of this type. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-evaluation compounds, the clinical significance of elevated serum prolactin levels is unknown for most patients, As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in the ZYPREXA carcinogenicity studies conducted n mice and rats (see Carcinogenesis). However, neither clinical studies nor epidemiologic studies have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive. Transaminase Elevations – In placebo-controlled studies, clinically significant ALT (SGPT) elevation (≥3 times the upper limit of the normal range) were observed in 2% (6/243) of patients exposed to ZYPREXA compared to none (0/115) of the placebo patients. None of these patients experienced jaundice. In two of these patients, liver enzymes decreased toward normal despite continued treatment and in two others, enzymes decreased upon discontinuation of ZYPREXA. In the remaining two patients, one, seropositive for hepatitis C, and persistent enzyme elevation for four months after discontinuation, and the other had insufficient follow-up to determine if enzymes normalized. Within the larger premarketing database of about 2400 patients with baseline SGPT ≤90 IU/L, the incidence of SGPT elevation to >200 IU/L was 2% (50/2381). Again, none of these patients experienced jaundice or other symptoms attributable to live impairment and most had transient changes that tended to normalize while ZYPREXA treatment was continued. Among 2500 patients in oral ZYPREXA clinical trials, about 1% (23/2500) discontinued treatment due to transaminase increases. Caution should be exercised inpatients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic drugs. Periodic assessment of transaminases is recommended in patients with significant hepatic desease (see Laboratory Tests). Potential for Cognitive and Motor Impairment – Somnolence was a commonly reported adverse event associated with ZYPREXA treatment, occurring at an incidence of 26% in ZYPREXA patients compared to 15% in placebo patients. This adverse event was also dose related. Somnolence led to discontinuation in 0.4% (9/2500) of patients in the premarketing database. Since ZYPREXA has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that ZYPREXA therapy does not affect them adversely. Body Temperature Regulation – Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ZYPREXA 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. Dysphagia – Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advance Alzheimer’s disease. ZYPREXA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. Suicide – The possibility of a suicide attempt is inherent in schizophrenia and in bipolar disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for ZYPREXA should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Use in Patients with Concomitant Illness – Clinical experience with ZYPREXA in patients with certain concomitant systemic illnesses (see Renal Impairment and Hepatic Impairment under CLINICAL PHARMACOLOGY, Special Populations) is limited. ZYPREXA exhibits in vitro muscarinic receptor affinity. In premarketing clinical trials with ZYPREXA, ZYPREXA was associated with constipation, dry mouth, and tachycardia, all adverse events possibly related to cholinergic antagonism. Such adverse events were not often the basis for discontinuations from ZYPREXA, but ZYPREXA should be used with caution in patients with clinically significant prostatic hypertrophy, narrow angle glaucoma, or a history of paralytic ileus. In five placebo-controlled studies of XYPREXA in elderly patients with dementia-related psychosis (n=1184), the following treatment- emergent adverse events were reported in ZYPREXA-treated patients at an incidence of at least 2% and significantly greater than placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth and visual hallucinations. The rate of discontinuation due to adverse events was significantly greater with ZYPREXA than placebo (13% vs. 7%). As with other CNS-active drugs, ZYPREXA should be used with caution in elderly patients with dementia. ZYPREXA is not approved for the treatment of patients with dementia-related psychosis. If the prescriber elects to treat elderly patients with dementia-related psychosis, vigilance should be exercised (see WARNINGS). ZYPREXA 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 orthostatic hypotension with ZYPREXA, caution should be observed in cardiac patients (see Hemodynamic Effects). For specific information about the precautions of lithium or valproate, refer to PRECAUTIONS section of the package inserts for these other products. Information of Patients Physicians are advised to discuss the following issues with patients for whom they prescribe ZYPREXA: Orthostatic Hypotension – Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose titration and in association with the use of concomitant drugs that may potentiate the orthostatic effect of ZYPREXA, e.g., diazepam or alcohol (see Drug Interactions). Interference with Cognitive and Motor Performance – Because ZYPREXA has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that ZYPREXA therapy does not affect them adversely. Pregnancy – Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with ZYPREXA. Nursing – Patients should be advised not to breast-feed an infant if they are taking ZYPREXA. Concomitant Medication – Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions. Alcohol – Patients should be advised to avoid alcohol while taking ZYPREXA. Heat Exposure and Dehydration – Patients should be advised regarding appropriate care in avoiding overheating and dehydration. Phenylketonurics – ZYPREXA ZYDIS (Olanzapine orally disintegrating tablets) contains phenylalanine (0.34, 0.45,0.67, or 1.90 mg per 5, 10, 15, or 20 mg tablet, respectively). Laboratory Tests Periodic assessment of transaminases is recommended in patients with significant hepatic disease (see Transaminase Elevations). Drug Interactions The risks of using ZYPREXA in combination with other drugs have not been extensively evaluated in systematic studies. Given the primary CNS effects of ZYPREXA, caution should be used when ZYPREXA is taken in comination with other centrally acting drugs and alcohol. Because of its potential for inducing hypotension, ZYPREXA, may enhance the effects of certain antihypertensive agents. ZYPREXA may antagonize the effects of levadopa and dopamine agonists. The Effect of Other Drugs on ZYPREXA – Agents that induce CYP1A2 or glucuronyl transferase enzymes, such as omeprazole and rifamipin, may cause an increase in ZYPREXA clearance. Inhibitors of CYP1A2 could potentially inhibit ZYPREXA clearance. Although ZYPREXA is metabolized by multiple enzyme systems, induction or inhibition of a single enzyme may appreciably alter ZYPREXCA clearance. Therefore, a dosage increase (for induction) or a dosage decrease (for inhibition) may need to be considered with specific drugs. Charcoal – The admini9stration of activated charcoal (1g) reduced the Cmax and AUC of oral ZYPREXA by about 60%. A peak ZYPREXA levels are not typically obtained until about 6 hours after dosing, Charcoal may be a useful treatment for ZYPREXA overdose. Cimetidine and Antacids – Single doses of cimetidine (800 mg) or aluminum- and magnesium-containing antacids did not affect the oral bioavailability of ZYPREXA. Carbamazepine – Carbamazepine therapy (200 mg bid) causes an approximately 50% increase in the clearance of ZYPREXA. This increase is likely due to the fact that carbamazepine is a potent inducer of CYP1A2 activity. Higher daily doses of carbamazepine may cause an even greater increase in ZYPREXA clearance. Ethanol – Ethanol (45 mg/70 kg single dose) did not have an effect on ZYPREXA pharmacokinetics. Fluoxetine – Fluoxetine (60 mg single dose of 60 mg daily for 8 days) causes a small (mean 16%) increase in the maximum concentration of ZYPREXA and a small (mean 16%) decrease in ZYPREXA clearance. The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended. FZyprexaamine – FZyprexaamine, a CYP1A2 inhibitor, decreases the clearance of ZYPREXA. This results in a mean increase in ZYPREXA Cmax following fZyprexaamine of 54% in female nonsmokers and 77% in male smokers. The mean increase in ZYPREXAAUC is 52% and 108%, respectively. Lower doses of ZYPREXA should be considered in patients receiving concomitant treatment with fZyprexaamine. Warfin – Warfin (20 mg single dose) did not affect ZYPREXA pharmacokinetics. Effect of ZYPREXA on Other Drugs – In vitro studies utilizing human liver microsomes suggest that ZYPREXA has little potential to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Thus, ZYPREXA is unlikely to cause clinically important drug interactions mediated by these enzymes. Lithium – Multiple doses of ZYPREXA (10 mg for 8 days) did not influence the kinetics of lithium. Therefore, concomitant ZYPREXA administration does not require dosage adjustment of lithium. Valproate – Studies in vitro using human liver microsomes determined that ZYPREXA has little potential to inhibit the major metabolic pathway, glucuronidation, of valproate. Further valproate has little effect on the metabolism of ZYPREXA in vitro. In vivo administration of ZYPREXA (10 mg daily for 2 weeks) did not affect the steady state plasma concentrations of valproate. Therefore, concomitant ZYPREXA administration does not require dosage adjustment of valproate. Single doses of ZYPREXA did not affect the pharmacokinetics of imipramine or its active metabolite desipramine, and warfarin. Multiple doses of ZYPREXA did not influence the kinetics of diazepam and its active metabolite N-desmethyldiazepam, ethanol, or biperiden. However, the co-administration of either diazepam or ethanol with ZYPREXA potentiated the orthostatic hypotension observed with ZYPREXA. Multiple doses of ZYPREXA did not affect the pharmacokinetics of theophylline or its metabolites. Lorazepam – Administration of intramuscular lorazepam (2 mg) 1 hour after intramuscular ZYPREXA for injection (5 mg) did not significantly affect the pharmacokinetics of ZEPRXA, unconjugated lorazepam, or total lorazepam. However, this co-administration of intramuscular lorazepam and intramuscular ZYPREXA for infection added to the somnolence observed with either drug alone. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis – Oral carcinogenicity studies were conducted in mice and rats. ZYPREXA was administered to mice in tow 78-week studies at doses of 3, 10, 30/20 mg/kg/day (equivalent to 0.8-5 times the maximum recommended human daily oral dose on a mg/m² basis) and 0.25, 2, 8 mg/kg/day (equivalent to 0.06-2 times the maximum recommended human daily oral dose on a (mg/m² basis). Rats were dosed for 2 years at doses of 0.25, 1, 2.5, 4 mg/kg/day (males) and 0.25, 1, 4, 8 mg/kg/day (females)(equivalent to 0.13-2 and 0.13-4 times the maximum recommended human daily oral dose on a mg/m² basis, respectively). The incidence of liver hemangiomas and hemangiosarcomas was significantly increased in one mouse study in female mice dosed at 8mg/kg/day (2 times the maximum recommended human daily oral dose on a mg/m² basis). These tumors were not increased in another mouse study in females dosed at 10 or 30/20 mg/kg/day (2-5 times the maximum recommended human daily oral dose on a mg/m² basis); in this study, there was a high incidence of early mortalities in males of the 30/20 mg/kg/day group. The incidence of mammary gland adenomas and adenocarcinomas was significantly increased in female mice dosed at ≥2 mg/kg/day and in female rats dosed at ≥4 mg/kg/day (0.5 and 2 times the maximum recommended human daily oral dose on a mg/m² basis, respectively). Antipsychotic drugs have been shown to chronically elebate prolactin levels in rodents. Serum prolactin levels were not measured during the ZYPREXA cacinogenicty studies; however, measurements during subchronic toxicity studies showed that ZYPREXA elevated serum prolactin levels up to 4-fold in rats at the same doses used in the carcinogenicity study. An increase in mammary gland neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin mediated. The relevance for human risk of the finding of prolactin mediated endocrine tumors in rodents is unknown (see Hyperprelactinemia under PRECAUTIONS, General). Mutagenesis – No evidence of mutagenic potential for ZYPREXA was found in the Ames reverse mutation test, in vivo micronucleus test in mice, the chromosomal aberration test in Chinese hamster ovary cells, unscheduled DNA synthesis test in rat hepatocytes, induction of forward mutation test in mouse lymphoma cells, or in vivo sister chromatid exchange test in bone marrow if Chinese hamsters. Impairment of Fertility – In an oral fertility and reproductive performance study in rats, male mating performance, but not fertility, was impaired at a dose of 22.34 mg/kg/day and female fertility was decreased at a dose of 3 mg/kg/day (11 and 1.5 times the maximum recommended human daily oral dose on a mg/m² basis, respectively). Discontinuance of ZYPREXA treatment reversed the effects on male mating performance. In female rats, the precoital period was increased and the mating index reduced at 5 mg/kg/day (2.5 times the maximum recommended human daily oral dose on a mg/m² basis). Diestrous was prolonged and estrous delayed at 1.1 mg/kg/day (0.6 times the maximum recommended human daily oral dose on a mg/m² basis); therefore ZYPREXA may produce a delay in ovulation. Pregnancy Pregnancy Category C – In oral reproduction studies in rats at doses up to 18 mg/kg/day and in rabbits at doses up to 30 mg/kg/day (9 and 30 times the maximum recommended human daily oral dose on a mg/m² basis, respectively) no evidence of teratogenicity was observed. In an oral rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed at a dose of 18 mg/kg/day (9 times the maximum recommended human daily oral dose on a mg/m² basis). Gestation was prolonged at 10 mg/kg/day (5 times the maximum recommended human daily oral dose on a mg/m² basis). In an oral rabbit teratology study, fetal toxicity (manifested as increased resorptions and decreased fetal weight) occurred at a maternally toxic dose of 30 mg/kg/day (30 times the maximum recommended human daily oral dose on a mg/m² basis). Placental transfer of ZYPREXA occurs in rat pups. There are no adequate and well-controlled trials with ZYPREXA in pregnant females. Seven pregnancies were observed during clinical trials with ZYPREXA, including 2 resulting in normal births, 1 resulting in neonatal death due to a cardiovascular defect, 3 therapeutic abortions, and 1 spontaneous abortion. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery Parturition in rats was not affected by ZYPREXA. The effect of ZYPREXA on labor and delivery in humans is unknown. Nursing Mothers ZYPREXA was excreted in milk of treated rats during lactation. It is not known if ZYPREXA is excreted in human milk. It is recommended that women receiving ZYPREXA should not breast-feed. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of the 2500 patients in premarketing clinical studies with oral ZYPREXA, 11% (263) were 65 years of age or over. In patients with schizophrenia, there was no indication of any different tolerability of ZYPREXA in the elderly compared to younger patients. Studies in elderly patients with dementia-related psychosis have suggested that there may be a different tolerability profile in this population compared to younger patients with schizophrenia. As with other CNS-active drugs, ZYPREXA should be used with caution in elderly patients with dementia. ZYPREXA is not approved for the treatment of patients with dementia-related psychosis. If the prescriber elects to treat elderly patients with dementia-related psychosis, vigilance should be exercised. Also, the presence of factors that might decrease paharmacokinetic clearance or increase the pharmacodynamic response to ZYPREXA should lead to consideration of a lower starting dose for any geriatric patient (see WARNINGS, PRECAUTIONS, AND DOSAGE AND ADMINISTRATION). Adverse Reactions The information below is derived from a clinical trial database for ZYPREXA consisting of 8661 patients with approximately 4165 patient-years of exposure to oral ZYPREXA and 722 patients with exposure to intramuscular ZYPREXA for injection. This database includes: (1) 2500 patients who participated in multiple-dose oral ZYPREXA premarketing trials in schizophrenia and Alzheimer’s disease representing approximately 1122 patient-years of exposure as of February 14, 1995; (2) 182 patients who participated in oral ZYPREXA premarketing bipolar mania trials representing approximately 66 patient-years of exposure; (3) 191 patients who participated in an oral ZYPREXA trial of patients having various psychiatric symptoms in association with Alzheimer’s disease representing approximately 29 patient-years of exposures; (4) 5788 patients form 88 additional oral ZYPREXA clinical trials as of December 31, 2001; and (5) 722 patients who participated in intramuscular ZYPREXA for injection premarketing trials in agitated patients with schizophrenia, Bipolar I Disorder (manic or mixed episodes), or dementia. In addition, information from the premarketing 6-week clinical study database for ZYPREXA in combination with lithium or valproate, consisting of 224 patients who participated in bipolar mania trials with approximately 22 patient-years of exposure, is included below. The conditions and duration of treatment with ZYPREXA varied greatly and included (in overlapping categories) open-label and double- blind phases of studies, inpatients and outpatients, fixed-dose and dose-titration studies, and short-term or longer-term exposure. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analytes, ECGs. Chest x-rays, and results of ophthalmologic examinations. Certain portions of the discussion below relating to objective or numeric safety parameters, namely, dose-dependent adverse events, vital sign changes, weight gain, laboratory changes, and ECG changes are derived from studies in patients with schizophrenia and have not been duplicated for bipolar mania or agitation. However, this information is also generally applicable to bipolar mania and agitation. Adverse events during exposure were obtained by spontaneous report and recorded by clinical investigators using terminaology of their won choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse event without first grouping similar types of events into a smaller number of standardized event categories. In the tables and tabulations that follow, standard COSTART dictionary terminology has been used initially to classify reported adverse events. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. The reported events do not include those event terms that were so general as to be uninformative. Events listed elsewhere in labeling may not be repeated below. It is important to emphasize that, although the events occurred during treatment with ZYPREXA, they were not necessarily caused by it. The entire label should be read to gain a complete understanding of the safety profile of ZYPREXA. The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators, The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the adverse event incidence in the population studied. Incidence of Adverse Events in Short-Term, Placebo-Controlled and Combination Trials The following findings are based on premarketing trials of (1) oral ZYPREXA for schizophrenia, bipolar mania, a subsequent trial of patients having various psychiatric symptoms in association with Alzheimer’s disease, and premarketing combination trials, and (2) intramuscular ZYPREXA for injection in agitated patients with schizophrenia or bipolar mania. Adverse Events Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials Schizophrenia – Overall, there was no difference in the incidence of discontinuation due to adverse events (5% for oral ZYPREXA vs. 6% for placebo). However, discontinuations due to increased in SGPT were considered to be drug related (2% for oral ZYPREXA vs. 0% for placebo) (see PRECAUTIONS). Bipolar Mania Monotherapy – Overall, there was no difference in the incidence of discontinuation due to adverse events (2% for oral ZYPREXA vs. 2% for placebo). Agitation – Overall, there was no difference in the incidence of discontinuation due to adverse events (0.4% for intramuscular ZYPREXA for injection vs. 0% for placebo). Adverse Events Associated with Discontinuation of Treatment in Short-Term Combination Trials Bipolar Mania Combination Therapy – In a study of patients who were already tolerating either lithium or valproate as monotherapy, discontinuation rates due to adverse events were 11% for the combination of oral ZYPREXA with lituium or valproate compared to 2% for patients who remained on lithium or valproate monotherapy. Discontinuations with the combination of oral ZYPREXA and lithium or valproate that occurred in more than 1 patient were: somnolence (3%), weight gain (1%), and peripheral edema (1%). Commonly Observed Adverse Events in Short-Term, Placebo-Controlled Trials The most commonly observed adverse events associated with the use of oral ZYPREXA (incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients (ZYPREXA incidence at least twice that for placebo) were: Common Treatment-Emergent Adverse Events Associated with the Use of Oral ZYPREXA in 6- Week Trials - SCHIZOPHRENIA Percentage of Patients Reporting Event Adverse Event ZYPREXA Placebo (N=248) (N=118) Postural hypotension 5 2 Constipation 9 3 Weight gain 6 1 Dizziness 11 4 Personality disorder¹ 8 4 Akathisia 5 1 ¹Personality disorder is the COSTART term for designation non-aggressive objectionable behavior Common Treatment-Emergent Adverse Events Associated with the Use of Oral ZYPREXA in 3- Week and 4- Week Trials – BIPOLAR MANIA Percentage of Patients Reporting Event Adverse Event ZYPREXA Placebo (N=125) (N=129) Asthenia 15 6 Dry Mouth 22 7 Constipation 11 5 Dyspepsia 11 5 Increased appetite 6 3 Somnolence 35 13 Dizziness 18 6 Tremor 6 3 There was one adverse event (somnolence) observed at an incidence of 5% or greater among intramuscular ZYPREXA for injection- treated patients and not observed at an equivalent incidence among placebo-treated patients (ZYPREXA incidence at least twice that for placebo) during the placebo-controlled premarketing studies. The incidence of somnolence during the 24 hour IM treatment period in clinical trials in agitated patients with schizophrenia or bipolar mania was 6% for intramuscular ZYPREXA for injection and 3% for placebo. Adverse Events Occurring at an Incidence of 2% or More Among Oral ZYPREXA Treated Patients in Short-Term, Placebo-Controlled Trials Table 1 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred in 2% or more of patients treated with oral ZYPREXA (doses ≥2.5 mg/day) and with incidence greater than placebo who participated in the acute phase of placebo-controlled trials. Table 1 Treatment-Emergent Adverse Events: Incidence in Short-Term, Placebo-Controlled Clinical Trials¹ With Oral ZYPREXA Percentage of Patients Reporting Event ZYPREXA Placebo Body System/Adverse Event (N=532) (N=294)___ Body as a Whole Accidental Injury 12 8 Asthenia 10 9 Fever 6 2 Back Pain 5 2 Chest Pain 3 1_________ Cardiovascular System Postural Hypotension 3 1 Tachycardia 3 1 Hypertension 2 1_________ Digestive System Dry Mouth 9 5 Constipation 9 4 Dyspepsia 7 5 Vomiting 4 3 Increased appetite 3 2_________ Hemic and Lymphatic System Ecchymosis 5 3_________ Metabolic and Nutritional Disorders Weight gain 5 3 Peripheral edema 3 1_________ Musculoskeletal System Extremity pain (other than joint 5 3 Joint pain 5 3_________ Nervous System Somnolence 29 13 Insomnia 12 11 Dizziness 11 4 Abnormal gait 6 1 Tremor 4 3 Akathisia 3 2 Hypertonia 3 2 Articulation impairment 2 1_________ Respiratory System Rhinitis 7 6 Cough increased 6 3 Pharyngitis 4 3_________ Special Senses Amblyopia 3 2_________ Urogenital System Urinary Incontinence 2 1 Urinary tract infection 2 1_________ ¹ Events reported by at least 2% of patients treated with ZYPREXA, except the following events which had an incidence equal to or less than placebo: abdominal pain, agitation anorexia, anxiety, apathy, confusion, depression, diarrhea, dysmenorrhea², hallucinations, headache, hostility, hyperkinesias, myalgia, nausea, nervousness, paranoid reaction, personality disorder³, rash, thinking abnormal, weight loss. ²Denominator used was for females only (ZYPREXA, N=201; placebo, N=114). ³Personality disorder is the COSTART term for designating non-aggressive objectionable behavior. Commonly Observed Adverse Events in Short-Term Combination Trials In the bipolar mania combination placebo-controlled trials, the most commonly observed adverse events associated with the combination of ZYPREXA and lithium or valproate (incidence of ≥5% and at least twice placebo) were: Common Treatment-Emergent Adverse Events Associated with the Use of Oral ZYPREXA in 6- Week combination Trials – BIPOLAR MANIA Percentage of Patients Reporting Event Adverse Event ZYPREXA with Placebo with Lithium or valproate Lithium or valproate (N=229) (N=115) Dry Mouth 32 9 Weight Gain 26 7 Increased appetite 24 8 Dizziness 14 7 Back Pain 8 4 Constipation 8 4 Speech disorder 7 1 Increased Salivation 6 2 Amnesia 5 2 Paresthesia 5 2 Adverse Events Occurring at an Incidence of 2% or More Among ZYPREXA-Treated Patients in Short-Term Combination Trials Table 2 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred in 2% or more of patients treated with the combination of ZYPREXA (dosed ≥5% mg/day) and lithium or valproate and with incidence greater than lithium or valproate alone who participated in the acute phase of placebo-controlled combination trials. Table 2 Treatment-Emergent Adverse Events: Incidence in Short-Term, Placebo-Controlled Combination Clinical Trials With Oral ZYPREXA Percentage of Patients Reporting Event ZYPREXA with Placebo with lithium or valproate lithium or valproate Body System/Adverse Event (N=229) (N=115) Body as a Whole Asthenia 18 13 Back Pain 8 4 Accidental injury 4 2 Chest pain 3 2___________ Cardiovascular System Hypertension 2 1___________ Digestive System Dry Mouth 32 9 Increased appetite 24 8 Thirst 10 6 Constipation 8 4 Increased salivation 6 2___________ Metabolic and Nutritional Disorders Weight gain 26 7 Peripheral edema 6 4 Edema 2 1___________ Nervous System Somnolence 52 27 Tremor 23 13 Depression 18 17 Dizziness 14 7 Speech Disorder 7 1 Amnesia 5 2 Paresthesia 5 2 Apathy 4 3 Confusion 4 1 Euphoria 3 2 Incoordination 2 0__________ Respiratory System Pharyngitis 4 1 Dyspnea 3 1__________ Skin Appendages Sweating 3 1 Acne 2 0 Dry Skin 2 0__________ Special Senses Amblyopia 9 5 Abnormal vision 2 0__________ Urogential System Dysmenorrhea² 2 0 Vaginitis² 2 0__________ ¹Events reported by at least 2% of patients treated with ZYPREXA, except the following events which had an incidence equal to or less than placebo: abdominal pain, abnormal dreams, abnormal ejaculation, agitation, adathisia, anorexia, anxiety, arthralgia, cough increased, diarrhea, dyspepsia, emotional lability, fever, flatulence, flu syndrome, headache, hostilitym, insomnia, libido decreased, libido increased, menstrual disorder², myalgia, nausea, nervousness, pain, paranoid reaction, personality disorder, rash, rhinitis, sleep disorder, thinking abnormal, vomiting. ²Denominator used was for females only (ZYPREXA, N=128; placebo, N=51) For specific information about the adverse reactions observed with lithium or valproate, refer to the ADVERSE REACTIONS section of the package inserts for these other products. Adverse Events Occurring at an Incidence of 1% or More Among Intramuscular ZYPREXA for Injection - Treated Patient s in Short- Term, Placebo-Controlled Trials Table 3 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred in 1% or more of patients treated with intramuscular ZYPREXA for injection (dose range of 2.5-10.0 mg/injection) and with incidence greater than placebo who participated in the short-term, placebo-controlled trials in agitated patients with schizophrenia or bipolar mania. Table 3 Treatment-Emergent Adverse Events: Incidence in Short-term (24 Hour), Placebo-Controlled Clinical Trials With Intramuscular ZYPREXA for Injection In Agitated Patients with Schizophrenia or Bipolar Mania¹ Percentage of Patients Reporting Event ZYPREXA Placebo Body System/Adverse Event (N=415) (N=150)____ Body as a whole Asthenia 2 1________________ Cardiovascular System Hypotension 2 0 Postural Hypotension 1 0________________ Nervous System Somnolence 6 3 Dizziness 4 2 Tremor 1 0________________ ¹ Events reported by at least 1% of patients treated with ZYPREXA for injection, except the following events which had an incidence equal to or less than placebo: agitation, anxiety, dry mouth, headache, hypertension, insomnia, nervousness. Additional Findings Observed in Clinical Trials The following findings are based on clinical trials. Dose Dependency of Adverse Events in Short-Term, Placebo-Controlled Trials Extrapyramidal Symptoms – The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by categorical analyses of formal rating scales during acute therapy in a controlled clinical trial comparing oral ZYPREXA at 3 fixed doses with placebo in the treatment of schizophrenia. TREATMENT-EMERGENT EXTRAPYRAMIDAL SYMPTOMS ASSESSED BY RATING SCALES INCIDENCE IN A FIXED DOSAGE RANGE, PLACEBO-CONTROLLED CLINICAL TRIAL OF ORAL ZYPREXA IN SCHIZOPHRENIA – ACUTE PHASE* Percentage of Patients Reporting event ZYPREXA ZYPREXA ZYPREXA Placebo 5±2.5 mg/day 10±2.5 mg/day 15±2.5 mg/day Parkinson 15 14 12 14 Akathisia² 23 16 19 27 * No statistically significant differences. ¹ Percentage of patients with a Simpson-Angus Scale total score >3. ² Percentage of patients with a Barnes Akathisia Scale global score ≥2. The following table enumerates the percentage of patients with treatement-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse events during acute therapy in the same controlled clinical trial comparing ZYPREXA at 3 fixed doses with placebo in the treatment of schizophrenia. TREATMENT-EMERGENT EXTRAPYRAMIDAL SYMPTOMS ASSESSED BY ADVERSE EVENTS INCIDENCE IN A FIXED DOSAGE RANGE, PLACEBO-CONTROLLED CLINICAL TRIAL OF ORAL ZYPREXA IN SCHIZOPHRENIA – ACUTE PHASE Percentage of Patients Reporting Event ZYPREXA ZYPREXA ZYPREXA Placebo 5±2.5 mg/day 10±2.5 mg/day 15±2.5 mg/day (N=68) (N=65) (N=64) (N=69) Dystonic events¹ 1 3 2 3 Parkinsonism events² 10 8 14 20 Akathisia events³ 1 5 11* 10* Dykinetic events4 4 0 2 1 Residual events5 1 2 5 1 Any extrapyramidal event 16 15 25 32* * Statistically significantly different from placebo. ¹ Patients with the following COSTART terms were counted in this category: dystonia, generalized spasm, neck rigidity, oculogyric crisis, opisthotonos, toricollis. ² Patients with the following COSTART terms were counted in this category: akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, masked facies, tremor. ³ Patients with the following COSTART terms were counted in this category: akathisia, hyperkinesias. 4 Patients with the following COSTART terms were counted in this category: buccoglossal syndrome, choreoathetosis, dyskinesia, tardive dyskinesia. 5 Patients with the following COSTART terms were counted in this category: movement disorder, myoclonus, twitching. The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by categorical analyses of formal rating scales during controlled clinical trials comparing fixed doses of intramuscular ZYPREXA for injection with placebo in agitation. Patients in each dose group could receive up to three injections during the trials (see CLINICAL PHARMACOLOGY). Patient assessments were conducted during the 24 hours following the initial dose of intramuscular ZYPREXA for injection. There were no statistically significant differences from placebo. TREATMENT-EMERGENT EXTRAPYRAMIDAL SYMPTOMS ASSESSED BY RATING SCALES INCIDENCE IN A FIXED DOSE, PLACEBO-CONTROLLED CLINICAL TRIAL OF INTRAMUSCULAR ZYPREXA FOR INJECTION IN AGITATED PATIENTS WITH SCHIZOPHRENIA* Percentage of Patients Reporting Event ZYPREXA ZYPREXA ZYPREXA ZYPREXA IM IM IM IM Placebo 2.5 mg 5 mg 7.5 mg 10 mg Parkinsonism¹ 0 0 0 0 3 Akathisia² 0 0 5 0 0 * No statistically significant differences. ¹ Percentage of patients with a Simpson-Angus total score >3 ² Percentage of patients with a Barnes Akathisia Scale global score ≥2. The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse events in the same controlled clinical trial comparing fixed doses of intramuscular ZYPREXA fro injection with placebo in agitated patients with schizophrenia. There were no statistically significant differences from placebo. TREATEMENT-EMERGENT EXTRAPYRAMYDAL SYMPTOMS ASSESSED BY ADVERSE EVETNS INCIDENCE IN A FIXED DOSE, PLACEBO-CONTROLLED CLINICAL TRIAL OF INTRAMUSCULAR ZYPREXA FOR INFECTION IN AGITATED PATIENTS WITH SCHIZOPHRENIA* Percentage of Patients Reporting Event ZYPREXA ZYPREXA ZYPERXA ZYPREXA IM IM IM IM Placebo 2.5 mg 5 mg 7.5 mg 10 mg (N=45) (N=48) (N=45) (N=46) (N=46) Dystonic events¹ 0 0 0 0 0 Parkinsonism events² 0 4 2 0 0 Akathisia events³ 0 2 0 0 0 Dyskinetic events4 0 0 0 0 0 Residual events5 0 0 0 0 0 Any extrapyramidal 0 4 2 0 0 * No statistically significant differences. ¹ Patients with the following COSTART terms were counted in this category: dystonia, generalized spasm, neck rigidity, oculogyric crisis, opisthotonos, toricollis. ² Patients with the following COSTART terms were counted in this category: akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, masked facies, tremor. ³ Patients with the following COSTART terms were counted in this category: akathisia, hyperkinesias. 4 Patients with the following COSTART terms were counted in this category: buccoglossal syndrome, choreoathetosis, dyskinesia, tardive dyskinesia. 5 Patients with the following COSTART terms were counted in this category: movement disorder, myoclonus, twitching. Other Adverse Events - The following table addresses dose relatedness for other adverse events using data from a schizophrenia trial involving fixed dosage ranges of oral ZYPREXA. It enumerates the percentage of patients with treatment-emergent adverse events for the three fixed-dose range groups and placebo. The data were analyzed using the Cochran-Armitage test, excluding the placebo group, and the table includes only those adverse events for which there was a statistically significant trend. Percentage of Patients Reporting Event ZYPREXA ZYPREXA ZYPREXA Adverse Event Placebo 5±2.5 mg/day 10±2.5 mg/day 15±2.5 mg/day (N=68) (N=65) (N=64) (N=69) Asthenia 15 8 9 20 Dry Mouth 4 3 5 13 Nausea 9 0 2 9 Somnolence 16 20 30 39 Tremor 3 0 5 7 Vital Sign Changes – Oral ZYPREXA was associated with orthostatic hypotension and tachycardia in clinical trials. Intramuscular ZYPREXA for injection was associated with bradycardia, hypotension, and tachycardia in clinical trials (see PRECAUTIONS). Weight Gain – In placebo-controlled, 6-week studies, weight gain was reported in 5.6% of ZYREXA patients compared to 0.8% of placebo patients. ZYPREXA patients gained an average of 2.8 kg, compared to an average 0.4 kg weight loss in placebo patients: 29% of ZYPREXA patients gained greater than 7% of their baseline weight, compared to 3% of placebo patients. A categorization of patients at baseline on the basis of body mass index (BMI) revealed a significantly greater effect in patients with low BMI compared to normal or overweight patients; nevertheless, weight gain was greater in all 3 ZYPREXA groups compared to the placebo group. During long- term continuation therapy with ZYPREXA (238 median days of exposure), 56% of ZYPREXA patients met the criterion for having gained greater than 7% of their baseline weight. Average weight gain during long-term therapy was 5.4 kg. Laboratory Changes – An assessment of the premarketing experience for ZYPREXA revealed an association with asymptomatic increases in SGPT, SGOT, and GGT (see PRECAUTIONS). ZYPREXA administration was also associated with increases in serum prolactin (see PRECAUTIONS), with an asymptomatic elevation of the eosinophil count in 0.3% of patients, and with an increase in CPK. Given the concern about neutropenia associated with other psychotropic compounds and the finding of leukopenia associated with the administration of ZYPREXA in several animal models (see ANIMAL TOXICOLOGY), careful attention was given to examination of hematologic parameters in premarketing studies with ZYPREXA. There was no indication of a risk of clinically significant neutropenia associated with ZYPREXA treatment in the premarketing database for this drug. ECG Changes – Between-group comparisons for pooled placebo-controlled trials revealed no statistically significant ZYPREXA/placebo differences in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc, and PR intervals. ZYPREXA use was associated with a mean increase in heart rate of 2.4 beats per minute compared to no change among placebo patients. This slight tendency to tachycardia may be related to ZYPREXA’s potential for inducing orthostatic changes (see PRECAUTIONS). Other Adverse Events Observed During the Clinical Trial Evaluation of ZYPREXA Following is a list of terms that reflect treatment-emergent adverse events reported by patients treated with oral ZYPREXA (at multiple doses ≥1 mg/day) in clinical trials (8661 patients, 4165 patient-years of exposure). This listing may not include those events already listed in previous tables or elsewhere in labeling, those events for which a drug cause was remote, those event terms which were so general as to be uninformative, and those events reported only once or twice which did not have a substantial probability of being acutely life-threatening. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions:  frequent adverse events are those occurring in at least 1/100 patients (only those not already listed in the tabulated results for placebo-  controlled trials appear in this listing): infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those  occurring in fewer than 1/1000 patients.  Body as a Whole – Frequent: dental pain and flu syndrome; Infrequent: abdomen enlarged, chills, face edema, intentional injury,  malaise, moniliasis , neck pain, neck rigidity, pelvic pain, photosensitivity reaction, and suicide attempt; Rare: chills and fever,  hangover effect, and sudden death.  Cardiovascular System – Frequent: hypotension; Infrequent: atrial fibrillation, bradycardia, cerebrovascular accident, congestive heart  failure, heart arrest, hemorrhage, migraine, pallor, palpitation, vasocilatation, and ventricular extrasystoles; Rare: arteritis, heart failure,  and pulmonary embolus. Digestive System – Frequent: flatulence, increased salivation, and thirst; Infrequent: dysphagia, esophagitis, fecal impaction, fecal  incontinence, gastritis, gastroenteritis,gingivitis, hepatitis, melena, mouth ulceration, nausea and vomiting, oral moniliasis, periodontal  abscess, rectal hemorrhage, stomatitis, toungue edema, and tooth caries; Rare: aphthous stomatitis, enteritis, eructation, esophageal  ulcer, glossitis, ileus, intestinal obstruction, liver fatty deposit, and tongue discoloration.  Endocrine System – Infrequent: diabetes mellitus; Rare: diabetic acidosis and goiter. Hemic and Lymphatic System – Infrequent: anemia, cyanosis, leukocytosis, seukopenia, lymphadenopathy, and thrombocytopenia;  Rare: normocytic anemia and thrombocythemia. Metobolic and Nutrional Disorders – Infrequent: acidosis, alkaline phosphatase increased, bilirubinemia, dehydration,  hypercholesteremia, hyperglycemia, hyperlipemia, hyperuricemia, hypoglycemia, hypokalemia, hyponatremia, lower extremity edema,  and upper extremity edema; Rare: gout, hyperkalemia, hypernatremia, hypoproteinemia, ketosis, and water intoxication.  Musculoskeletal System – Frequent: joint stiffness and twitching; Infrequent: arthritis, arthrosis, leg cramps, and myasthenia; Rare:  bone pain, bursitis, myopathy, osteoporosis, and rheumatoid arthritis. Nervous System – Frequent: abnormal dreams, amnesia, delusions, emotional libility, euphoria, manic reaction, paresthesia, and  schizophrenic reaction; Infrequent: akinesia, alcohol misuse, antisocial reaction, ataxia, CNS stimulation, cogwheel rigidity, delirium,  dementia, depersonalization, dysarthria, facial paralysis, hypesthesia, hypokinesia, hypotonia, incoordination, libido decreased, libido  increased, obsessive conpulsive symptoms, phobias, somatization, stimulant misuse, stupor, stuttering, Tardive dyskinesia, vertigo,  and withdrawal syndrom; Rare: circumoral paresthesia, coma, encephalopathy, neuralgia, neuropathy nystagmus, paralysis,  subarachnoid hemorrhage, and tobacco misuse. Respiratory System – Frequent: dyspnea; Infrequent: apnea, asthma, epistazis, hemoptysis, hyperventilation, hypoxia, laryngitis, and  voice alteration; Rare: atelectasis, hiccup, hypoventilation, lung edema, and stridor.  Skin Appendages – Frequent: sweating; Infrequent: alopecia, contact dermatitis, dry skin, ecxema, maculopapular rash, pruritus,  seborrhea, skin discoloration, skin sulcer, urticaria, and vesiculobullous rash; Rare: hirsutism and pustular rash.