Intramuscular (IM), immediate-release formulations of atypical antipsychotics olanzapine(Drug information on olanzapine) (Zyprexa IM) and ziprasidone(Drug information on ziprasidone) (Geodon IM) were assessed by a U.S. Food and Drug Administration advisory committee in February and recommended for FDA approval as safe and effective for the treatment of agitation.
Based on the populations in which the respective products were studied, the Psychopharmacologic Drugs Advisory Committee recommended each as safe and effective for treatment of agitation in patients with schizophrenia. Ziprasidone was also recommended for agitation in schizoaffective disorder, and olanzapine was recommended for agitation associated with bipolar mania and dementia.
Although the ziprasidone IM formulation had been ready several years before the IM olanzapine (Bender, 2000), deliberation over the effect of ziprasidone on cardiac conduction affecting the electrocardiogram QTc interval delayed final approval of oral ziprasidone until Feb. 5, with both injectable products considered by the advisory committee two weeks later.
Safety data of both products were found acceptable by the committee; it recommended, however, that the IM ziprasidone carry the cautionary labeling approved for the oral dosage form. Focused safety studies, investigating instances of bradycardia, were also conducted with olanzapine and appended to the New Drug Application (NDA). The manufacturer, Eli Lilly and Co., characterized these as "infrequent decreases in blood pressure and heart rate that were clinically manageable."
Although the injectable antipsychotic NDAs could have been submitted for treatment of schizophrenia, corresponding to the approved indication of the oral formulations, both manufacturers chose instead to target the treatment of agitation. It is likely that uses for the IM formulations will include those of the oral forms, regardless of labeling, and the manifestation of agitation in a range of illnesses presents a potentially broader market. In addition, the effectiveness for agitation could be demonstrated with shorter-term evaluations than would have been required for schizophrenia.
After discussion with the FDA about agitation as a nonspecific symptom of different illnesses, Lilly designed four studies for olanzapine treatment of agitation in three disease models: schizophrenia (two studies), bipolar mania and dementia. Such discussion was not held when Pfizer submitted the ziprasidone NDA approximately two years earlier, however, so they conducted two trials for the treatment of agitation in patients with schizophrenia.
The primary outcome in the olanzapine trials was the change from baseline in the Positive and Negative Syndrome Scale (PANSS) Excited Component. In patients with schizophrenia and bipolar mania, additional instruments for measurement were the Agitation-Calmness Evaluation Scale (ACES) and the Agitated Behavior Scale. In patients with dementia, the Cohen-Mansfield Agitation Inventory was used in addition to the ACES.
In each trial, IM olanzapine in all doses (2.5 mg, 5.0 mg, 7.5 mg and 10 mg) was, within two hours after injection, statistically superior to placebo and comparable to the active comparators haloperidol(Drug information on haloperidol) (Haldol) and lorazepam(Drug information on lorazepam) (Ativan) on the PANSS. In the two studies utilizing two additional efficacy measures, at least one of the dosage arms of olanzapine was similarly ranked. In the three studies not involving dementia, olanzapine was superior to both haloperidol and lorazepam at the earliest time (15 minutes) in at least one of the dosage arms. All active agents were sufficiently effective to require only one injection for most patients, in contrast to patients receiving multiple placebo injections for persistent agitation.
Pfizer developed and validated a new instrument called the Behavioral Activity Rating Scale (BARS), a seven-point scale assessing both agitation and level of consciousness. The BARS describes seven levels of activity: difficult or unable to arouse; asleep but responds normally to verbal or physical contact; drowsy, appears sedated; quiet and awake (normal level of activity); signs of overt (physical and verbal) activity, calms down with instructions; extremely or continuously active, not requiring restraint; violent, requires restraint.
In the two controlled trials with ziprasidone, patients with schizophrenia, schizoaffective disorder or bipolar disorder received injections of either 10 mg at intervals of two hours (up to a maximum of 40 mg in 24 hours), or 20 mg at intervals of four hours (up to a maximum of 80 mg in 24 hours), respectively, as required for symptoms of agitation. The results were compared to those with a low dose of 2 mg. In both studies, rapid improvements that were significantly greater than with low dosage were measured in patients receiving the respective initial doses of 10 mg or 20 mg. In each study, the transition from IM to oral ziprasidone was completed without remarkable changes in measures of efficacy or tolerability.
Both the olanzapine and ziprasidone IM products were deemed safe and well tolerated. The assessment of bradycardia with olanzapine was prompted by this reaction occurring in 64 of 850 patients. Forty of the 64 patients experienced an associated reduction in resting blood pressure or an orthostatic drop. The manufacturer indicated to the committee that this was likely from -1 adrenergic blockade leading to neurally mediated reflex bradycardia (NMRB). It was pointed out that the reaction occurred more often in the non-agitated patients serving as controls and in patients not recently receiving an oral antipsychotic dosage.
The mean change in QTc with IM ziprasidone in doses up to 160 mg/day did not exceed that already demonstrated with the oral formulation. In those studies, QTc prolongation was approximately 10 msec greater than with risperidone (Risperdal), olanzapine, quetiapine(Drug information on quetiapine) (Seroquel) or haloperidol and approximately 10 msec less than a 300 mg dosage of thioridazine(Drug information on thioridazine) (Mellaril) (Bender, 2000).
Pfizer documents submitted to the committee indicated that new agents to treat acute agitation are needed. They observed that the side-effect profiles of conventional antipsychotic drugs include disturbing extrapyramidal effects and excessive or prolonged sedation. Additionally, the coexistence of a history of abuse liability represents a relative contraindication to the administration of benzodiazepines.
Lilly documents concur, advising the committee, "Clearly there is an unmet medical need for an effective treatment of agitation that does not compromise short-term safety or long-term compliance."