The efficacy of intramuscular olanzapine for injection for the treatment of agitation was established in 3 short-term (24 hours of IM treatment) placebo-controlled trials in agitated inpatients from two diagnostic groups: schizophrenia and Bipolar I Disorder (manic or mixed episodes). Each of the trials included a single active comparator treatment arm of either haloperidol injection (schizophrenia studies) or lorazepam injection (bipolar mania study). Patients enrolled in the trials needed to be: (1) judged by the clinical investigators as clinically agitated and clinically appropriate candidates for treatment with intramuscular medication, and (2) exhibiting a level of agitation that met or exceeded a threshold score of ≥ 14 on the five items comprising the Positive and Negative Syndrome Scale (PANSS) Excited Component (i.e., poor impulse control, tension, hostility, uncooperativeness and excitement items) with at least one individual item score ≥ 4 using a 1-7 scoring system (1=absent, 4=moderate, 7=extreme). In the studies, the mean baseline PANSS Excited Component score was 18.4, with scores ranging from 13 to 32 (out of a maximum score of 35), thus suggesting predominantly moderate levels of agitation with some patients experiencing mild or severe levels of agitation. The primary efficacy measure used for assessing agitation signs and symptoms in these trials was the change from baseline in the PANSS Excited Component at 2 hours post-injection. Patients could receive up to three injections during the 24 hour IM treatment periods; however, patients could not receive the second injection until after the initial 2 hour period when the primary efficacy measure was assessed. The results of the trials follow:

1. In a placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for schizophrenia (n=270), four fixed intramuscular olanzapine for injection doses of 2.5 mg, 5 mg, 7.5 mg and 10 mg were evaluated. All doses were statistically superior to placebo on the PANSS Excited Component at 2 hours post-injection. However, the effect was larger and more consistent for the three highest doses. There were no significant pairwise differences for the 7.5 and 10 mg doses over the 5 mg dose.
2. In a second placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for schizophrenia (n=311), one fixed intramuscular olanzapine for injection dose of 10 mg was evaluated. Olanzapine for injection was statistically superior to placebo on the PANSS Excited Component at 2 hours post-injection.
3. In a placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for Bipolar I Disorder (and currently displaying an acute manic or mixed episode with or without psychotic features) (n=201), one fixed intramuscular olanzapine for injection dose of 10 mg was evaluated. Olanzapine for injection was statistically superior to placebo on the PANSS Excited Component at 2 hours post-injection.

Examination of population subsets (age, race, and gender) did not reveal any differential responsiveness on the basis of these subgroupings.

ANIMAL TOXICOLOGY

In animal studies with olanzapine, the principal hematologic findings were reversible peripheral cytopenias in individual dogs dosed at 10 mg/kg (17 times the maximum recommended human daily oral dose on a mg/m² basis), dose-related decreases in lymphocytes and neutrophils in mice, and lymphopenia in rats. A few dogs treated with 10 mg/kg developed reversible neutropenia and/or reversible hemolytic anemia between 1 and 10 months of treatment. Dose-related decreases in lymphocytes and neutrophils were seen in mice given doses of 10 mg/kg (equal to 2 times the maximum recommended human daily oral dose on a mg/m² basis) in studies of 3 months' duration. Nonspecific lymphopenia, consistent with decreased body weight gain, occurred in rats receiving 22.5 mg/kg (11 times the maximum recommended human daily oral dose on a mg/m² basis) for 3 months or 16 mg/kg (8 times the maximum recommended human daily oral dose on a mg/m² basis) for 6 or 12 months. No evidence of bone marrow cytotoxicity was found in any of the species examined. Bone marrows were normocellular or hypercellular, indicating that the reductions in circulating blood cells were probably due to peripheral (non-marrow) factors.

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