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

"It is particularly important to note that patients may experience agitation with a number of different diagnoses," said John Kane, M.D., chair of the Department of Psychiatry, Hillside Hospital, and professor of psychiatry, neurology and neuroscience, Albert Einstein College of Medicine, both in New York. "In clinical studies, Zyprexa IntraMuscular rapidly calmed patients experiencing agitation with diagnoses of schizophrenia, bipolar mania or dementia."

Design and Results of Pivotal Trials

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

Using these scales, Zyprexa IntraMuscular was statistically superior to placebo in all four studies. At doses of 5 to 10 mg, Zyprexa IntraMuscular was significantly superior to placebo at the first time point measured (15 or 30 minutes) after injection. This latter measurement was based on the Excited Component of the PANSS.

Safety Information

In these trials, adverse events included somnolence (sleepiness), dizziness and asthenia (weakness). In addition, Zyprexa IntraMuscular was associated with infrequent decreases in blood pressure and heart rate that were clinically manageable.

No adverse event was significantly more frequent for Zyprexa IntraMuscular than for haloperidol intramuscular or lorazepam intramuscular. Movement disorders, including dystonia and uncontrolled tremors and muscle spasms, known as extrapyramidal side effects, were observed at a statistically significantly greater frequency with intramuscular haloperidol than with Zyprexa IntraMuscular. Dystonia, painful muscle contractions that can dissuade patients from continuing treatment, occurred at a frequency of 6.6 percent with intramuscular haloperidol and did not occur with Zyprexa IntraMuscular.

In addition, in the four clinical trials using Zyprexa IntraMuscular, there was no clinically significant effect on any ECG interval, including QTc.

Zyprexa Background

Oral Zyprexa is currently indicated for the treatment of schizophrenia, the short-term treatment of acute manic episodes associated with bipolar disorder and, most recently, for the long-term therapy and maintenance of treatment response of schizophrenia. Zyprexa is the first atypical antipsychotic to prove its long-term effectiveness in patients with schizophrenia. Since Zyprexa was introduced in 1996, it has been prescribed to nearly six million people worldwide.

In the original schizophrenia registration trials, Zyprexa was generally well tolerated. However, as with all medications, Zyprexa was associated with some side effects. In the original six-week, acute-phase schizophrenia trials, the most common treatment-emergent adverse event associated with Zyprexa was somnolence. Other common events were dizziness, weight gain, constipation, akathisia (restlessness) and postural hypotension. Modest elevations of prolactin were also seen, although mean changes from baseline to endpoint were not statistically significantly different between Zyprexa and placebo. A small number of patients experienced asymptomatic elevations of hepatic transaminase; none of these patients developed jaundice or drug-induced hepatitis.

In short-term (3- and 4-week) acute bipolar mania trials, the most common treatment-emergent adverse event associated with Zyprexa was somnolence. Other common events were dry mouth, dizziness, asthenia, constipation, dyspepsia, increased appetite and tremor.

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