Oral atypical antipsychotics are given to treat a variety of psychiatric illnesses. Intramuscular (IM) preparations of atypicals are increasingly becoming available for emergency use, such as treating acute agitation.
The FDA has approved IM olanzapine for treating acute agitation associated with schizophrenia and bipolar type I mania.
How it works
As with the agent’s oral formulations (tablets, capsules, wafers), IM olanzapine is primarily an antagonist at serotonergic (5-HT2A) and dopaminergic (D2) receptors. Olanzapine is about twice as active at 5-HT2A compared with D2 receptors, which may underlie the agent’s efficacy as an antipsychotic and mood stabilizer without significant extrapyramidal effects.
Olanzapine also shows primarily antagonistic binding affinity at the 5-HT2B/2C, D1/D3/D4/D5, muscarinic, histamine H1 and alpha1-adrenergic receptors.1 This binding profile is comparable to that of clozapine and predicts a similar clinical response.
Pharmacokinetics
On most pharmacokinetic measures, IM olanzapine is nearly identical to its oral formulations, allowing easy comparison when switching to oral dosing as the patient improves.2
Plasma clearance (linear pharmacokinetics), half-life (approximately 30 hours), and volume of distribution are similar for IM and oral olanzapine. Maximum plasma concentrations after one, two, or three 10-mg injections given over 24 hours were similar to steady-state concentrations after daily administration of oral olanzapine, 20 mg.
The one key difference between IM and oral olanzapine is rate of absorption, which influences onset of action. IM olanzapine generally reaches maximum concentration in 15 to 45 minutes, compared with 4 hours after an oral dose. This rapid peak absorption could prove valuable in the first hour of a psychiatric emergency.
Efficacy
Three double-blind, randomized, placebo and active comparator-controlled studies demonstrated IM olanzapine’s safety and efficacy for treating acute agitation in patients with schizophrenia and bipolar type I mania. A fourth study gauged its efficacy in treating acute agitation in dementia.
Schizophrenia. In a study of 285 patients,3 IM olanzapine, 10 mg, was significantly more effective in reducing agitation than IM haloperidol, 7.5 mg, and IM placebo 15, 30, and 45 minutes after injection. Agitation was measured with the Positive and Negative Symptom Scale-Excited Component (PANSS-EC), Agitated Behavior Scale, and Agitation-Calmness Evaluation scale. Olanzapine and haloperidol were similar in efficacy 1 and 2 hours after injection, and both were more effective than placebo.
In another study,4 270 acutely agitated inpatients with schizophrenia received 1 to 3 IM injections of olanzapine (2.5, 5, 7.5, or 10 mg), haloperidol (7.5 mg), or placebo. The higher the olanzapine dose, the greater the PANSS-EC score reduction 2 hours after the first injection. Olanzapine was more effective than haloperidol on some agitation measures at 7.5 and 10 mg, and olanzapine was significantly more effective than haloperidol 24 hours post-injection, based on Agitated Behavior Scale scores.4 Both agents were similarly effective 2 hours after injection.
Bipolar type I mania. Agitated patients (N = 201) received 1 to 3 IM injections of olanzapine (10 mg for the first two injections, 5 mg for the third), lorazepam (2 mg first two, 1 mg third), or placebo.
Two hours after the first injection, agitation was more greatly reduced within the olanzapine group than in the lorazepam or placebo groups based on PANSS-EC, Agitated Behavior Scale, and Agitation-Calmness Evaluation Scale scores. At 24 hours, olanzapine was more effective than placebo but similar in efficacy to lorazepam.5
Table
IM olanzapine: Fast facts
| Drug brand name: Zyprexa IntraMuscular |
| Class Atypical antipsychotic |
| FDA-approved indication: Acute agitation associated with bipolar type I mania and schizophrenia |
| Approval date: March 29, 2004 |
| Manufacturer: Eli Lilly and Co. |
| Dosing form: 10 mg |
| Dosing recommendations: 10 mg for adults with schizophrenia and bipolar type I mania (5 mg ages 65 and older); 2.5 mg for patients who are debilitated, predisposed to hypotensive reactions, or sensitive to olanzapine. Consider 5- or 7.5-mg doses if clinical factors warrant, such as reduced clearance/slower metabolism in older, nonsmoking women. |
Dementia. A total of 272 patients with Alzheimer’s dementia, mixed dementia, or both received IM olanzapine (2.5 mg or 5 mg), IM lorazepam (1 mg), or IM placebo. The 5-mg olanzapine dose significantly reduced agitation 30 minutes post-injection, whereas lorazepam separated from placebo 60 minutes post-injection based on PANSS-EC scores. At 24 hours, both olanzapine doses were more effective than lorazepam or placebo.6
Tolerability
No clinically significant side effects have been reported with IM olanzapine. Incidence of extrapyramidal symptoms and QTc interval changes has been similar to that reported with placebo. Most studies have reported little change in vital signs, although a 7-bpm increase in heart rate and 5- to 7-mm Hg decrease in systolic blood pressure have been noted (Eli Lilly and Co., data on file).