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FDA Approves Injectable Form of Olanzapine

INDIANAPOLIS, IN -- March 30, 2004-- Physicians have a new fast-acting option for controlling the potentially crippling effects of acute agitation in patients suffering with schizophrenia and bipolar mania. The U.S. Food and Drug Administration (FDA) has approved Zyprexa® IntraMuscular (olanzapine for injection), an injectable form of Lilly's top-selling medication.

Clinical data demonstrate that Zyprexa IntraMuscular enables physicians to rapidly and dependably relieve patients of the effects of acute agitation without many of the debilitating side effects of conventional injectable therapies. This new formulation of Zyprexa is the first medication in its class to be indicated for the treatment of acute agitation associated with both bipolar mania and schizophrenia.

Sixty-five percent of hospital-based psychiatrists or emergency room physicians are not satisfied with current intramuscular antipsychotic therapies, primarily due to side effects that are difficult for patients to tolerate and because patients must be switched to a different oral therapy once they are stabilized, according to the Psychiatrist International Project conducted by PKS Research Partners in February 2004. In addition, 60 percent of these physicians said that currently available intramuscular treatments are not adequate in rapidly calming the agitated patient, which can help the physician to gain a patient's trust and cooperation.

"Acute agitation is terribly frightening and potentially dangerous for patients and their caregivers," said Barry Jones, M.D., professor of psychiatry, McMaster University, Toronto, Canada. "Zyprexa IntraMuscular enables doctors to help patients regain control quickly, often with just a single injection. Further, because Zyprexa IntraMuscular is not overly sedating, it can help the physician and patient to begin communicating and working together to achieve treatment goals and help move the patient's life forward."

Acute Agitation
Acute agitation is a well-recognized behavioral syndrome with a range of symptoms, including hostility, extreme excitement, poor impulse control, tension and uncooperativeness. The syndrome can occur with a number of conditions, including schizophrenia and bipolar disorder. Patients suffering from agitation in its severe forms are usually in an emergency situation and require immediate treatment to alleviate personal distress and to prevent harm to themselves and others.

Seamless Transition to Long-Term Therapy
FDA labeling for Zyprexa IntraMuscular specifically states that if ongoing Zyprexa therapy is needed, physicians may transition patients with schizophrenia and bipolar mania from Zyprexa IntraMuscular to oral Zyprexa as soon as clinically appropriate.

More than 56 percent of physicians say it is very important or important that an antipsychotic can be used in an injectable formulation for agitation and an oral formulation for long-term disease management.

"With Zyprexa IntraMuscular, physicians have a new option for treating agitation in schizophrenia and acute bipolar mania patients," said Mauricio Tohen, M.D., Dr.P.H., Lilly Distinguished Scholar. "We can offer highly agitated patients Zyprexa's dependable control from day one and then smoothly and assuredly transition them to oral Zyprexa for maintenance treatment."

Design and Results of Pivotal Trials
Zyprexa IntraMuscular's efficacy in controlling acute agitation was evaluated in three randomized, double-blind, placebo-controlled studies in patients with schizophrenia (two studies) and bipolar mania (one study). In these studies, the control of agitation with Zyprexa IntraMuscular was assessed using several scales, including the Positive and Negative Symptom Scale Excited Component (PANSS EC).

Using these scales, Zyprexa IntraMuscular was statistically superior to placebo in all studies. On the primary efficacy measure, the PANSS EC, 10 mg injections of Zyprexa IntraMuscular were significantly superior to placebo at the first time point measured (15 or 30 minutes) after injection

In the two studies in agitated patients with schizophrenia, Zyprexa IntraMuscular was compared to haloperidol (Haldol®) intramuscular and to placebo. The injectable formation of haloperidol, a first generation or "typical" antipsychotic, has been the standard of care for acutely agitated patients for many years.

Results showed that both Zyprexa IntraMuscular and haloperidol intramuscular were superior to placebo. No adverse event occurred significantly more often with Zyprexa IntraMuscular than with haloperidol intramuscular. In fact, in these studies, painful muscle contractions called dystonia occurred in 6.6 percent of haloperidol intramuscular-treated patients, but did not occur with Zyprexa IntraMuscular. Additional side effects that occurred significantly more often with haloperidol intramuscular - but not with Zyprexa IntraMuscular - included tremors, muscle spasms, indigestion and blurred vision.

Zyprexa IntraMuscular was compared to lorazepam (Ativan®) intramuscular and to placebo in the study involving agitated patients with bipolar mania. Lorazepam, which is an anti-anxiety, sedative and anticonvulsant medication, also has been used for decades. In this study, Zyprexa IntraMuscular was superior to placebo. No adverse event occurred significantly more often with Zyprexa IntraMuscular than with lorazepam intramuscular. In contrast, nausea and vomiting were reported significantly more often in lorazepam intramuscular-treated patients than in Zyprexa IntraMuscular-treated patients.

Zyprexa Background and Safety Information
In the three Zyprexa IntraMuscular trials, adverse events included drowsiness, dizziness and muscle weakness. In addition, Zyprexa IntraMuscular was associated with infrequent decreases in blood pressure and heart rate that were clinically manageable. However, in an open-label clinical pharmacology study in non-agitated patients with schizophrenia in which the safety and tolerability of intramuscular olanzapine were evaluated under a maximal dosing regimen (three 10 mg doses administered four hours apart), approximately one-third of these patients experienced a significant orthostatic decrease in systolic blood pressure (i.e., decrease > 30 mmHg). The risk for hypotension (low blood pressure), bradycardia (slowing of heart rate), and sinus pause may be greater in non-psychiatric patients compared to psychiatric patients who are possibly more adapted to certain effects of psychotropic drugs.

Oral Zyprexa is indicated in the United States for the short-term and long-term treatment of schizophrenia, for maintenance in the treatment of bipolar disorder, and either alone or in combination with lithium or valproate (Depakote®, Abbott) for the short-term treatment of acute mixed or manic episodes associated with bipolar disorder. Since Zyprexa was introduced in 1996, it has been prescribed to more than 14 million people worldwide.

The most common treatment-emergent adverse event associated with Zyprexa in placebo-controlled, short-term schizophrenia and bipolar mania trials was drowsiness. Other common events were dizziness, weight gain, personality disorder (COSTART term for nonaggressive objectionable behavior), constipation, restlessness, episodes of low blood pressure, dry mouth, weakness, upset stomach, increased appetite, and tremor. A small number of patients experienced asymptomatic elevations of certain liver enzymes; none of these patients experienced jaundice.

Hyperglycemia, in some cases associated with ketoacidosis, coma, or death, has been reported in patients treated with atypical antipsychotics including Zyprexa. 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. The available data are insufficient to provide reliable estimates of differences in hyperglycemia-related adverse event risk among the marketed atypical antipsychotics. All patients taking atypicals should be monitored for symptoms of hyperglycemia. Persons with diabetes who are started on atypicals should be monitored regularly for worsening of glucose control; those with risk factors for diabetes should undergo baseline and periodic fasting blood glucose testing. Patients who develop symptoms of hyperglycemia during treatment should undergo fasting blood glucose testing.

Prescribing should be consistent with the need to minimize the risk of neuroleptic malignant syndrome, tardive dyskinesia, seizures and low blood pressure.

In short-term (six-week) acute bipolar mania trials in combination with lithium or valproate, the most common treatment emergent adverse event associated with Zyprexa and lithium or valproate was dry mouth. Other common events were weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia and abnormal burning or tingling of the skin.

Although the efficacy of Zyprexa in elderly patients with dementia has not been established in clinical trials and Zyprexa is not approved for use in this patient population, it is important to note the label for Zyprexa includes a warning for elderly patients with dementia. The warning states that strokes or mini-strokes (also called transient ischemic attacks or TIAs), including fatalities were reported in elderly patients with dementia-related psychosis participating in Zyprexa clinical trials. In addition, Lilly has completed a medical review of five placebo-controlled trials in elderly patients with dementia, and found an increased incidence of mortality from any cause in the Zyprexa group compared to patients who took placebo (3.5% vs. 1.5%). In this review, risk factors that predisposed Zyprexa patients to increased mortality included age greater than 80 years, sedation, simultaneous use of certain sedative and anti-anxiety medications (called benzodiazepines) or presence of pulmonary conditions such as pneumonia. Lilly is currently addressing this mortality data with the FDA.

Full prescribing information is available at www.zyprexa.com.

Source: Eli Lilly

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