Intramuscular Olanzapine

Intramuscular olanzapine (Zyprexa®) is a rapid-acting atypical antipsychotic drug that is also indicated for use in patients with agitation associated with schizophrenia or bipolar mania, the focus of this review. Evidence from three well designed trials indicates that this formulation of olanzapine is at least as effective as intramuscular haloperidol or lorazepam in the treatment of patients with acute agitation associated with schizophrenia or bipolar mania, and has a faster onset of action. Although transient reductions in blood pressure and heart rate may occur in some patients administered intramuscular olanzapine, preliminary evidence of a general lack of clinical effect on the corrected QT (QTc) interval and a low incidence of extrapyramidal symptoms (EPS) is promising. The parenteral formulation of olanzapine appears to offer an effective, fast-acting and generally well tolerated alternative in the treatment of this significant behavioural problem.

Olanzapine binds with serotonin (particularly 5-HT₂A and 5-HT_2C), histamine H₁, α₁-adrenergic, muscarinic and all known dopamine receptors. The occupancy of dopamine receptors increases with olanzapine dose. The drug is associated with depressed CNS motor activity, improved neurocognitive function, increased slow-wave sleep, improved sleep continuity and quality, increased latency to rapid eye movement (REM) sleep and decreased REM sleep time in healthy volunteers.

As with other atypical antipsychotic drugs, hyperglycaemia, diabetic ketoacidosis, diabetes mellitus, increased fasting triglyceride and cholesterol levels and significant bodyweight gain have been reported during treatment with oral olanzapine. Leptin levels are increased, but sustained increases in prolactin levels are not seen.

In a pooled analysis of data from all recipients of intramuscular olanzapine, bradycardia occurred in 4.7% of 765 patients and 32.9% of 85 healthy volunteers (three of whom experienced sinus pauses of up to 6 seconds, likely due to vasovagal reactions). Concomitant decreases in blood pressure occurred in 40 of these individuals (4.7% of the total cohort).

Maximum plasma olanzapine concentrations and areas under the plasma concentration-time curve are directly proportional to the dose after oral or intramuscular administration. While the overall pharmacokinetic profile of intramuscular olanzapine is broadly similar to that of the oral formulation, the rate of absorption is faster and maximum concentrations are reached more quickly (in 15–45 minutes) with the intramuscular formulation. The metabolic profile for the intramuscular formulation is similar to that for oral olanzapine (extensive metabolisation). The elimination half-life of intramuscular olanzapine is 30–39 hours and may be increased in elderly recipients and women.

Pharmacokinetic interactions may occur with drugs that affect the cytochrome P450 enzymes responsible for formation of olanzapine metabolites. Smoking can increase the clearance of olanzapine.

The efficacy of up to three injections of intramuscular olanzapine in 24 hours was compared with that of intramuscular placebo, haloperidol or lorazepam in clinical trials in patients with agitation associated with schizophrenia or bipolar mania. Olanzapine was significantly more effective than placebo in treating agitation associated with schizophrenia (doses of 2.5–10mg) or bipolar mania (10mg) 2 hours after the first injection and at the 24-hour follow-up (using changes in the Positive and Negative Syndrome Scale — Excited Component [PANSS-EC] subscale). A dose-response relationship was seen in agitated patients with schizophrenia. Olanzapine 5–10mg was as effective as haloperidol 7.5mg in agitated patients with schizophrenia and olanzapine 10mg was significantly (p < 0.001) more effective than lorazepam 2mg in agitated patients with bipolar mania. The onset of action of olanzapine was faster than that of haloperidol in patients with agitation associated with schizophrenia, and of lorazepam in patients with agitation associated with bipolar mania.

In the two trials of patients with agitation associated with schizophrenia (total n = 581), decreases from baseline in the PANSS-EC subscale scores 2 hours after the first injection were 42% and 49% with olanzapine 10mg, 42% and 39% with haloperidol 7.5mg, and 20% and 15% with placebo. In patients with agitation associated with bipolar mania (n = 199), baseline PANSS-EC scores had decreased in 2 hours by 74% with olanzapine 10mg, 54% with lorazepam 2mg and 38% with placebo.

Response (≥40% improvement on the PANSS-EC subscale in the two hours after the first injection) rates were 63–80% with olanzapine 5 or 10mg, 60% and 69% with haloperidol 7.5mg and 20% and 33% with placebo in agitated patients with schizophrenia, and 81% with olanzapine 10mg, 65% with lorazepam 2mg and 44% with placebo in agitated patients with bipolar mania (p ≤ 0.01 vs placebo for all olanzapine values). A second or third injection over the 24-hour treatment period was required by fewer olanzapine recipients than placebo recipients in all three trials and than lorazepam recipients in patients with agitation associated with bipolar mania.

In clinical trials, the most frequently reported adverse events with intramuscular olanzapine 2.5–10mg were somnolence, dizziness, asthenia and hypotension. There were no statistically significant differences between olanzapine and placebo in the incidence of adverse events in any individual study, apart from some mild, transient cardiovascular changes. An overall analysis revealed that somnolence occurred more often with intramuscular olanzapine than with placebo (6% vs 3%) and that mild transient decreases in blood pressure and heart rate were significantly greater in intramuscular olanzapine recipients than in those receiving placebo (p < 0.01) or intramuscular haloperidol (p < 0.05) at 2 hours. There were no indications of oversedation associated with any active treatment in any trial. There were no significant changes in the heart-rate QTc interval in most clinical trials of intramuscular olanzapine 24 hours after the first injection. The incidence of prolonged QTc interval (≥430–500 msec) during treatment was similar for olanzapine and placebo recipients.

Individual treatment-emergent EPS such as dystonia and parkinsonism occurred more often in haloperidol than olanzapine recipients; acute dystonia was not reported in recipients of intramuscular olanzapine in clinical trials.