National PBM Drug Monograph

Aripiprazole Intramuscular Injection (Abilify IM)

December 2007

VHA Pharmacy Benefits Management Service and the Medical Advisory Panel

*The purpose of VACO PBM drug monographs is to provide a comprehensive
drug review for making formulary decisions. These documents will be
updated when new clinical data warrant additional formulary discussion.
Documents will be placed in the Archive section when the information is
deemed to be no longer current.*

# Executive Summary: 

Aripiprazole intramuscular injection (AIM) has been marketed with
labeling for the treatment of acute agitation due to schizophrenia,
schizoaffective disorder or bipolar disorder. Oral aripiprazole is
currently on the VA National Formulary.

Aripiprazole injection's efficacy and safety have been reported in three
published clinical trials: 2 enrolling patients with schizophrenia and
the remaining trial enrolled patients with bipolar disorder (mania or
mixed episode). Aripiprazole demonstrated efficacy as measured by
changes in the Positive and Negative Syndrome Scale-Excited Component
(PEC) in all 3 trials and other secondary outcome measures of agitation
and extrapyramidal effects. Response was generally seen within 1 hour of
the initial injection; approximately 50% of patients required a second
dose of AIM. The response to AIM and need for additional doses were
comparable to other active agents, namely haloperidol and lorazepam, and
superior to placebo.

Aripiprazole injection was generally well tolerated with headache,
nausea, dizziness, somnolence/sedation, insomnia, and pain or burning at
the injection site being the most commonly reported adverse events. The
extrapramidal reactions dystonia and akathisia were reported by a small
number of patients.

Short term IM aripiprazole is appropriate for patients experiencing
psychomotor agitation associated with schizophrenia or bipolar disorder,
manic or mixed as defined in DSM-IV. Psychomotor agitation is defined in
DSM-IV as "excessive motor activity associated with a feeling of inner
tension." Such agitation should be severe and distressing enough to
interfere with a patient's assessment or care, or place the patient,
staff or other patients at risk for harm necessitating immediate control
of their agitation.

# Introduction {#introduction .Style-Heading-1-+-Black}

Aripiprazole is an atypical antipsychotic currently available on the VA
National Formulary as an oral formulation. Aripiprazole intramuscular
injection has been marketed for the treatment of acute agitation due to
schizophrenia, schizoaffective disorder or bipolar disorder.

The purposes of this monograph are to (1) evaluate the available
evidence of safety, tolerability, efficacy, cost, and other
pharmaceutical issues that would be relevant to evaluating aripiprazole
IM for possible addition to the VA National Formulary; (2) define its
role in therapy; and (3) identify parameters for its rational use in the
VA.

Additional information on aripiprazole can be found in its original
monograph at <http://vaww.pbm.va.gov/drugmonograph/Aripiprazole.pdf>

# Pharmacology/Pharmacokinetics {#pharmacologypharmacokinetics .Style-Heading-1-+-Black}

Aripiprazole's mechanism of action is unknown. The proposed mechanism of
action hypothesizes that aripiprazole is both a partial agonist of
dopamine (D~2~) and serotonin (5HT~1A~) receptors and an antagonist of
5HT~2A~ receptors. Aripiprazole may also affect other receptors
resulting in other pharmacologic effects such as orthostatic hypotension
due inhibition of adrenergic alpha~1~ receptors.

Table 1. Pharmacokinetic Comparison of IM Aripiprazole, Olanzapine and
Haloperidol

+----------------+------------------+----------------+----------------+
| **Parameter**  | **Aripiprazole   | **Olanzapine   | **Haloperidol  |
|                | IM**             | IM**           | IM**           |
+----------------+------------------+----------------+----------------+
| Time to Onset  | 1 -- 3 hours     | [\<            | [\<            |
|                |                  | ]{.underline}2 | ]{.underline}1 |
|                |                  | hours          | hour           |
+----------------+------------------+----------------+----------------+
| Metabolism     | CYP3A4 and 2D6   | 1^st^ pass     | CYP1A2, 2D6,   |
|                |                  | metabolism,    | 3A4            |
|                |                  |                |                |
|                |                  | CYP 1A2 & 2D6, |                |
|                |                  | and            |                |
|                |                  | g              |                |
|                |                  | lucuronidation |                |
+----------------+------------------+----------------+----------------+
| Elimination    | 25% (urine, \<1% | \~7% unchanged | Hepatic        |
|                | unchanged)       | in urine       |                |
+----------------+------------------+----------------+----------------+
| Half-life      | 75 hrs EM; 146   | 30 hrs (21 --  | 20 hrs         |
|                | hrs PM           | 54 hrs)        |                |
+----------------+------------------+----------------+----------------+
| Protein        | 99%              | 93%            | 90%            |
| Binding        |                  |                |                |
+----------------+------------------+----------------+----------------+
| B              | 100%             | 100%           | 100%           |
| ioavailability |                  |                |                |
+----------------+------------------+----------------+----------------+

EM: extensive metabolizers; PM: poor metabolizers

# FDA Approved Indication(s) and Off-label Uses^1^

Aripiprazole injection is indicated for the treatment of agitation
associated with schizophrenia or bipolar disorder, manic or mixed.

The extent which aripiprazole injection would be used off-label is
unknown. There currently is no evidence to support aripiprazole
injection's safety or efficacy outside its label indications.

# Current VA National Formulary Alternatives

Conventional antipsychotics chlorpromazine, fluphenazine, and
haloperidol are available in an intramuscular formulation for the
treatment of acute psychosis and agitation.

Ziprasidone and olanzapine are the other atypical antipsychotics
available in an IM formulation for acute treatment of psychosis and
agitation. Ziprasidone IM is not on the VA National Formulary and
non-formulary use includes criteria for use. Olanzapine IM is on the VA
National Formulary without any criteria for its use.

Benzodiazepines are alternatives to the antipsychotics for the acute
treatment of agitation and bipolar I mania; lorazepam (Ativan), a
benzodiazepine of intermediate duration, is frequently used for these
indications.

# Dosage and Administration^1^

*Dosage:*

The initial dose of aripiprazole IM is 9.75 mg. A lower dose of 5.25 mg
may be considered when clinical factors warrant. In cases where
additional IM doses are needed, the cumulative daily dose is not to
exceed 30 mg or administration more frequent than every 2 hours. In
clinical trials, a dose of 15 mg did not provide greater efficacy than
the 9.75 mg dose. Patients who require continued treatment with
aripiprazole should be switched to an oral formulation as soon as
possible.

*Dosage in Special Populations:*

A dosage adjustment based on a patient's age, gender, race, smoking
status, kidney or hepatic function is generally not necessary.

*Concomitant use with potent CYP3A4 or CYP2D6 inhibitors:*

The manufacture recommends that the dose of aripiprazole be reduced to
one-half of the usual dose.

*Concomitant use with CYP3A4 inducers:*

The manufacturer recommends that the usual dose of aripiprazole be
doubled to 20 mg or 30 mg.

*Administration:*

Aripiprazole injection is only to be administered via deep intramuscular
injection and should not be administered intravenously or
subcutaneously. Aripiprazole injection comes in a ready-to-use 9.75
mg/1.3 mL single-dose Type I glass vial. Dosage preparation is as
follows:

[Single-Dose]{.underline} [Required Volume of Solution]{.underline}

5.25 mg 0.7 mL

9.75 mg 1.3 mL

15 mg 2 mL

*Storage:*

Aripiprazole injection should be stored at 25^o^ C (77^o^ F); excursions
permitted between 15^o^ C to 30^o^ C (59^o^ F to 86^o^ F). Protect from
light and store in original container until time of use.

# Efficacy^2-4^ 

## Primary Efficacy Measure

[Positive and Negative Syndrome Scale-Excited Component
(PEC)]{.underline} -- often used as in entrant criteria as well as a
primary efficacy measure. The PEC is derived from the Positive and
Negative Syndrome Scale (PANSS) and assesses tension, uncooperativeness,
hostility, poor impulse control, and excitement. Each item is rated by
physician observation and scored from 1 to 7 (the greater the value, the
greater the severity). This scale has been validated.

**Secondary Efficacy Measures**

[Agitation Calmness Evaluation Scale (ACES)]{.underline} -- Developed by
Eli Lilly and Company as a single-item scale with a 1= marked agitation,
2 = moderate agitation, 3 = mild agitation, 4 = normal, 5 = mild
calmness, 6 = moderate calmness, 7 = marked calmness, 8 = deep sleep,
and 9 = unable to be aroused.

[Corrigan Agitated Behavior Scale (CABS)]{.underline} - The Agitated
Behavior Scale (ABS; Corrigan, 1989) is a 14-item scale developed to
monitor agitation during the acute phase of recovery from acquired brain
injury.

[Brief Psychiatric Rating Scale (BPRS)]{.underline} -- A validated scale
consisting of 18-symptom constructs, each rated on a 7-point scale
ranging from 1 = "not present" to 7 = "extremely severe," that measures
major psychotic and nonpsychotic symptoms in persons with schizophrenia
and other psychiatric conditions. A sub-scale measuring positive
symptoms is sometimes used.

[Simpson Angus Scale (SAS)]{.underline} -- This validated 10 item
instrument is used to measure the symptoms of Parkinsonism or
drug-induced parkinsonian side effects. The clinician rates each item
from 0 (normal or absence of the condition) to 4 (the condition is
extreme in severity). The global score is the sum of all scores divided
by the number of items.

[Barnes Akathisia Scale (BAS)]{.underline} -- Used to evaluate akathisia
associated with antipsychotic medications, including an objective and a
subjective component plus a global impression rating for the overall
disorder. The objective and subjective items are rated from 0 (normal,
no evidence) to 3 (constant, severe, intense); the global assessment is
rated from 0 (absent) to 5 (severe). This scale has been validated.

**Efficacy in Schizophrenia^2,\ 3^**

Two clinical trials in patients with schizophrenia or schizoaffective
disorder have been published: one a dose finding study and the other
used the marketed 9.75 mg dose of aripiprazole; both included IM placebo
and haloperidol comparison groups. The trials are described in Table 2.

Table 2. Clinical Trials in Schizophrenia

+------------------+-------------------------+-------------------------+
| **Parameter**    | **Tran-Johnson, et      | **Andrezina, et         |
|                  | al.^2^**                | al.^3^**                |
|                  |                         |                         |
|                  | **J Clin Psychiatry     | **Psychopharmacology    |
|                  | 2007**                  | 2006**                  |
+------------------+-------------------------+-------------------------+
| Medication &     | Aripiprazole: 1, 5.25,  | Aripiprazole: 9.75 mg   |
| Dosage           | 9.75 or 15 mg           | (1.3 mL)                |
|                  |                         |                         |
| Route:           | Haloperidol: 7.5 mg     | Haloperidol 6.5 mg (1.3 |
| Intramuscular    |                         | mL)                     |
|                  | Placebo                 |                         |
|                  |                         | Placebo 1.3 mL          |
+------------------+-------------------------+-------------------------+
| Dose Frequency   | 1^st^ dose \<1 hour     | 1^st^ dose \<1 hour     |
|                  | after baseline          | after baseline          |
|                  | assessment, then q2     | assessment, then q2     |
|                  | hours post previous     | hours post previous     |
|                  | dose as needed x 2 (3   | dose as needed x 2 (3   |
|                  | total doses within 24   | total doses within 24   |
|                  | hours).                 | hours).                 |
|                  |                         |                         |
|                  | 3^rd^ placebo dose:     | 3^rd^ placebo dose:     |
|                  | Aripiprazole 15 mg      | Aripiprazole 9.75 mg    |
+------------------+-------------------------+-------------------------+
| Randomization    | 1:1:1:1:1:1             | 2:2:1 (placebo)         |
+------------------+-------------------------+-------------------------+
| Concurrent Meds. | Benzodiazepine          | Benzodiazepine          |
| Allowed          | (lorazepam 4mg/24h or   | (lorazepam 4mg/24h or   |
|                  | its equivalent.         | its equivalent.         |
+------------------+-------------------------+-------------------------+
| Study Design     | Randomized,             | Randomized,             |
|                  | double-blind, placebo   | double-blind, placebo   |
|                  | controlled, multicenter | controlled, multicenter |
|                  | clinical trial          | clinical trial          |
+------------------+-------------------------+-------------------------+
| -   Inclusion    | DSM-IV diagnosis:       | DSM-IV diagnosis:       |
|     criteria     | Schizophrenia or        | Schizophrenia or        |
|                  | schizoaffective         | schizoaffective         |
|                  | disorder; PEC score     | disorder; PEC score     |
|                  | [\>]{.underline}15 and  | [\>]{.underline}15 and  |
|                  | [\<]{.underline}32,     | [\<]{.underline}32,     |
|                  | plus [\>]{.underline}4  | plus [\>]{.underline}4  |
|                  | on [\>]{.underline}2 of | on [\>]{.underline}2 of |
|                  | 5 items.                | 5 items.                |
+------------------+-------------------------+-------------------------+
| -   Exclusion    | Substance abuse         | Substance abuse         |
|     criteria     | disorder within 2       | disorder within 2       |
|                  | months, required        | months, required        |
|                  | involuntary restraint,  | involuntary restraint,  |
|                  | suicidal; neurologic,   | suicidal; neurologic,   |
|                  | medical or other        | medical or other        |
|                  | psychiatric conditions; | psychiatric conditions; |
|                  | know nonresponder to    | know nonresponder to    |
|                  | antipsychotics.         | antipsychotics; and use |
|                  |                         | of a benzodiazepine or  |
|                  |                         | anticholinergic agent   |
|                  |                         | with 4 hours of 1^st^   |
|                  |                         | dose of study           |
|                  |                         | medication.             |
+------------------+-------------------------+-------------------------+
| Outcome Measures |                         |                         |
+------------------+-------------------------+-------------------------+
| -   Efficacy     | Primary: PEC            | Primary: PEC            |
|                  |                         |                         |
| -   Frequency    | Secondary: ACES, CABS,  | Secondary: ACES, CABS,  |
|                  | CGI-S, CGI-I, BPRS      | CGI-S, CGI-I, BPRS      |
|                  |                         |                         |
|                  | Baseline, q15 min x 2h, | Baseline, q15 min x 2h, |
|                  | then at 4, 6, 12 + 24 h | then at 4, 6, 12 + 24 h |
|                  | post 1^st^ dose.        | post 1^st^ dose.        |
+------------------+-------------------------+-------------------------+
| -   Safety       | SAS, BARNES: Baseline,  | SAS, BARNES: Baseline,  |
|                  | 2, 4, 6, 12 and 24 h    | 2, 4, 6, 12 and 24 h    |
|                  | post 1^st^ dose         | post 1^st^ dose         |
+------------------+-------------------------+-------------------------+
| Blinding         | Investigators assessing | Not specified in text.  |
|                  | outcomes were blinded   |                         |
+------------------+-------------------------+-------------------------+
| Analysis         | LOCF (1 dose, 1         | LOCF (1 dose, 1         |
|                  | evaluation)             | evaluation)             |
+------------------+-------------------------+-------------------------+

## Summary of Efficacy Findings 

Tran-Johnson, 2007^2^

A total of 357 patients were randomized to the six treatment arms with
57 to 62 patients in each arm. Ninety-five percent of patients completed
the study.

[Primary Outcome Measures]{.underline}

Aripiprazole IM (AIM), excluding the 1 mg dose, and haloperidol
significantly reduced PEC scores over the first 2 hours compared to
placebo. Aripiprazole 9.75 mg separated statistically the earliest from
placebo at 45 minutes post dose. At 60 minutes post dose, the mean
reduction in PEC score for both the AIM 9.75 mg and 15 mg doses was
significantly greater than placebo and remained so through the 120
minute mark. The PEC scores for AIM 5.25 mg dose did not separate from
placebo until 75 minutes post dose and did not maintain this difference
at 90 minutes although it was statistically different from placebo at
105 and 120 minutes post dose. The AIM 1 mg dose never separated from
placebo over the 2 hour observation period. Mean PEC scores for IM
haloperidol (HAL) 7.5 mg separated from placebo at 105 and 120 minutes
post dose. Response rates (the proportion of patients with a PEC score
reduction [\>]{.underline} 40% from baseline) were \~45% after 60
minutes with AIM 9.75 mg and 15 mg doses (p[\<]{.underline} .05 vs.
placebo, \~25% response rate) and 54% after 120 minutes (AIM 9.75mg,
p[\<]{.underline}0.05) and 55% AIM 15 mg (p=0.053) vs. placebo, 36%. The
response rate to HAL was \~40% at 60 minutes (p\>0.05 vs. placebo) and
60% after 120 minutes (p[\<]{.underline}0.05 vs. placebo). The response
rates at 60 and 120 minutes with the other AIM doses did not differ
significantly from placebo. The mean changes in the PEC scores after 60
minutes for the AIM 9.75 mg and HAL were \~5.5 and \<4 and \>6 and 6
after 120 minutes, respectively.

[Secondary Outcome: Agitation]{.underline}

Agitation was measured using the ACES and CABS scales. Baseline scores
for the ACES scale did not differ across the six treatment groups and
signify moderate agitation (Table 3). Patients who received AIM 9.75 mg
and HAL improved to between mild agitation (ACES = 3) and normal (ACES =
4). After 2 hours the degree of agitation of patients in the placebo arm
was observed to be between moderate and mild. The change in ACES score
did not differ between other AIM doses and placebo at 120 minutes.
Baseline and mean change in CABS scores are shown in Table 3. Compared
to placebo a significant improvement was observed in patients randomized
to AIM 5.25 mg, AIM 9.75 mg, AIM 15 mg, and HAL arms.

Table 3. Changes in Agitation Scales from Baseline by Intervention

> Mean Change (95% CI) 2 Hours Post Dose

+------+---------+---------+----------+----------+---------+----------+
| A    | Placebo | AIM 1   | AIM 5.25 | AIM 9.75 | AIM 15  | HAL      |
| gita |         | mg      | mg       | mg       | mg      |          |
| tion |         |         |          |          |         |          |
|      |         |         |          |          |         |          |
| S    |         |         |          |          |         |          |
| cale |         |         |          |          |         |          |
+------+---------+---------+----------+----------+---------+----------+
| ACES | 2.07    | 2.09    | 2.14     | 2.11     | 2.08    | 2.07     |
|      | (1.9    | (1.9    | (2.      | (1.      | (1.9    | (1.      |
| -    | 5-2.19) | 6-2.21) | 02-2.25) | 98-2.23) | 5-2.20) | 95-2.19) |
| Base |         |         |          |          |         |          |
| line | 0.66    | 0.65    | 1.01     | \*1.50   | 0.99    | \*1.50   |
|      | (0.2    | (0.2    | (0.      | (1.      | (0.5    | (1       |
| -    | 3-1.08) | 2-1.08) | 60-1.42) | 06-1.94) | 5-1.44) | .06-1.94 |
|   Ch |         |         |          |          |         |          |
| ange |         |         |          |          |         |          |
+------+---------+---------+----------+----------+---------+----------+
| CABS | 31.18   | 31.45   | 30.05    | 31.51    | 31.22   | 32.10    |
|      | (29.44  | (29.68  | (28.3    | (29.7    | (29.42  | (30.3    |
| -    | -32.91) | -33.23) | 6-31.74) | 1-33.31) | -33.02) | 1-33.89) |
| Base |         |         |          |          |         |          |
| line | -2.95   | -5.15   | \*-5.97  | \^-7.08  | \^-7.04 | \^-8.13  |
|      | (-4.69  | (-6.94  | (-7.66   | (-8.89   | (8.85   | (-9.93   |
| -    | to      | to      | to       | to       | to      | to       |
|   Ch | -1.21)  | -3.38)  | -4.27)   | -5.28)   | -5.24)  | -6.33)   |
| ange |         |         |          |          |         |          |
+------+---------+---------+----------+----------+---------+----------+

\*.01 \< p value [\<]{.underline} .05 vs. placebo

\^p value [\<]{.underline} .0001 vs. placebo

Andrezina et al., 2006^3^

A total of 448 patients were randomized to the three treatment arms: 88
to placebo, 175 to AIM 9.75 mg, and 185 to HAL 6.5 mg. Ninety-seven
percent of patients completed the study. Forty-one percent of AIM
patients and 34% of HAL patients received a second injection, compared
with 57% of patients in the placebo arm. A greater percentage of
patients randomized to placebo received injections of lorazepam (or its
equivalent) with a higher mean number of doses, 19% and 1.47, compared
to AIM, 8% and 1.07, and HAL 12% and 1.10, respectively.

[Primary Outcome Measures]{.underline}

Aripiprazole separated statistically from placebo at 45 minutes post
dose. At 60 minutes post dose, the mean change in PEC score for the AIM
group was significantly greater than and remained so through the 120
minute mark; mean change in PEC AIM -7.27 vs. placebo -4.78, p\<0.001.
Mean change PEC scores for HAL separated from placebo at 45 minutes, 60
minutes, 90 minutes, and at 120 minutes post dose the mean change was
--7.75 (p\<0.001 vs. placebo). Comparison of the change in PEC from
baseline at 120 minutes indicated that AIM was noninferior to HAL.
Response rates (the proportion of patients with a PEC score reduction
[\>]{.underline} 40% from baseline) was 55% after 60 minutes with AIM
and 58% with HAL compared to 36% with placebo (p[\<]{.underline} .005
both comparisons). Patients with schizophrenia or severe agitation at
baseline (PEC \> 18) randomized to AIM or HAL demonstrated significantly
greater mean reductions in PEC scores compared to placebo. Patients
requiring a second injection of AIM or HAL also demonstrated significant
reductions in mean change in PEC scores at 60 and 120 minutes after the
second dose compared to placebo.

[Secondary Outcome Measures]{.underline}

Both active treatment groups demonstrated improvement in symptoms as
measured by mean changes in CGI-S, ACES, and CABS scores and mean CGI-I
scores compared to placebo; these differences were statistically
significant for all measures at 120 minutes. Improvement was noted after
the first AIM dose at 45 minutes for the CABS and 60 minutes for the
CGI-I assessments. The mean changes in PANSS-derived BPRS scores after
120 minutes were also greater for AIM, -8.56, HAL, -8.80, compared to
placebo, -5.42, p\<0.005.

**Efficacy in Bipolar Mania^4^**

One clinical trial has been published studying the safety and efficacy
of AIM in patients with Bipolar Disorder I (manic or mixed episode with
or without psychotic features). A total of 291 participants were
randomized to doses of AIM 9.75 mg and 15 mg, IM lorazepam 2 mg or
placebo. Up to three doses of active medication could be given within 24
hours; patients in the placebo arm who required a third dose of
medication received AIM. The methodology was similar to that employed in
the schizophrenia trials described earlier (Table 2).

At the 2 hour post first injection time point, both doses of AIM were
statistically superior to placebo in the mean change in PEC score. Both
AIM and lorazepam produced a statistically significant greater reduction
in mean change in PEC score in patients with less agitation at baseline,
p\<0.01. There was no difference PEC score change with the three
treatments among those with more severe agitation at baseline (Table 4.)

Table 4. Mean Change in PEC Scores 2-hours After Injection by
Intervention: Bipolar Study

+-------------+-------------+-------------+-------------+-------------+
| Treatment   | Mean        | Mean change | Mean change |             |
| group       | baseline    | in PEC 2    | by level of |             |
|             | PEC         | hours post  | agitation   |             |
|             |             | injection   |             |             |
+-------------+-------------+-------------+-------------+-------------+
|             |             |             | Less (PEC   | More (PEC   |
|             |             |             | \<18)       | \>18)       |
+-------------+-------------+-------------+-------------+-------------+
| Placebo     | 18.04       | -3.1        | -4.4        | -7.9        |
+-------------+-------------+-------------+-------------+-------------+
| AIM 9.75 mg | 18.84       | -7.7        | -7.9        | -9.9        |
|             |             |             |             |             |
|             |             |             | pooled data | pooled data |
+-------------+-------------+-------------+-------------+-------------+
| AIM 15 mg   | 18.25       | -6.0        |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Lorazepam 2 | 18.47       | \~-7.0      | -8.4        | -11.4       |
| mg          |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+

In total 123 patients (42%) received a second injection. The mean number
of doses received by patients receiving AIM or lorazepam injection (1.5
and 1.4, respectively) was significantly lower than with IM placebo
(2.1; all p\<0.001).

The authors of this study concluded that two hours after injection AIM
decreased agitation regardless of baseline level of agitation, although
the largest reduction in PEC scores were noted in more agitated
patients, although there was a high placebo response. AIM and IM
lorazepam produced comparable effects regardless of the level of
agitation.

# Adverse Events (Safety Data)^1-5^

The reader is referred to the PBM's existing monograph on oral
aripiprazole for a comprehensive description of adverse events reported
with aripiprazole
(<http://vaww.pbm.va.gov/drugmonograph/Aripiprazole.pdf>)

The information that follows is specific to aripiprazole injection as
reported in clinical trials and the package insert.

## Deaths and Other Serious Adverse Events (optional)

One death was reported in the bipolar trial. A 41-year-old man who
received 2 doses of AIM 9.75 mg died 2 days post discharge (Day 3). His
significant medical history included psoriasis, COPD, 1 pack per day
tobacco use, and a history of polysubstance abuse. Medications at the
time of death were divalproex sodium, alprazolam, olanzapine, and
topiramate. Serious adverse events were usually not attributed to active
treatment and usually were symptomatic of the patient's underlying,
e.g., hallucinations and psychosis. One patient developed severe
dystonia that was attributable to IM haloperidol.

## Common Adverse Events

Overall in all three clinical trials (n=557) headache (12%), nausea
(11%), dizziness (8%), somnolence/sedation (7%), and insomnia (4%) were
the most common adverse events attributed to IM aripiprazole. By
comparison in the placebo group headache was reported by 7% of
participants followed by dizziness (5%), somnolence/sedation (4%), and
nausea (3%), respectively.

## Other Adverse Events

[Extrapyramidal Effects]{.underline}

In the clinical trials, the overall incidence of extrapyramidal-related
adverse events was generally higher in the patients receiving AIM or Hal
compared to placebo. See Table 5.

Table 5. Percentage of Patients Reporting EPS by Clinical Trial

<table>
<colgroup>
<col style="width: 12%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 10%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 10%" />
<col style="width: 8%" />
<col style="width: 13%" />
<col style="width: 10%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="2">ADE</td>
<td colspan="3">Tran-Johnson, 2007<sup>2</sup></td>
<td colspan="3">Andrezina, 2007<sup>3</sup></td>
<td colspan="3">Zimbroff, 2007<sup>4</sup></td>
</tr>
<tr class="even">
<td>AIM</td>
<td>HAL</td>
<td>Placebo</td>
<td>AIM</td>
<td>HAL</td>
<td>Placebo</td>
<td>AIM</td>
<td>Lorazepam</td>
<td>Placebo</td>
</tr>
<tr class="odd">
<td><p>EPS</p>
<ul>
<li><p>Dystonia</p></li>
<li><p>Akathisia</p></li>
</ul></td>
<td><p>NR</p>
<p>0.8%</p>
<p>2.0%</p></td>
<td><p>NR</p>
<p>7.0%</p>
<p>10.5%</p></td>
<td><p>NR</p>
<p>0</p>
<p>0</p></td>
<td><p>1.7%</p>
<p>NR</p>
<p>NR</p></td>
<td><p>12.6%</p>
<p>NR</p>
<p>NR</p></td>
<td><p>2.3%</p>
<p>NR</p>
<p>NR</p></td>
<td><p>5.3%</p>
<p>NR</p>
<p>NR</p></td>
<td><p>0</p>
<p>NR</p>
<p>NR</p></td>
<td><p>1.4%</p>
<p>NR</p>
<p>NR</p></td>
</tr>
</tbody>
</table>

Other adverse events report by \<2% of patients receiving AIM with
similar incidence to placebo: dyspepsia, dry mouth, fatigue,
tachycardia, increase blood pressure, orthostatic hypotension, and
musculoskeletal stiffness.

No clinically significant ECG abnormalities, including QTc interval
defined as clinically significant as \>450 msec, were associated with
AIM in the three trials.

## Tolerability

Aripiprazole IM was well tolerated with \<1% of patients discontinuing
due to adverse events; a rate similar to that reported with placebo.

Pain or burning at the injection sight was reported by \<1% to 4% of
patients receiving AIM compared to 3% to 4.2% receiving placebo.

# Precautions/Contraindications^1^

## Precautions

Aripiprazole is FDA Pregnancy Category C. It is not known whether
aripiprazole is excreted in human milk, hence it is recommended that
women not breast feed while taking aripiprazole.

## Contraindications

Aripiprazole is contraindicated in patients with known hypersensitivity
to the product.

# Look-alike / Sound-alike (LA / SA) Error Risk Potential

The VA PBM and Center for Medication Safety is conducting a pilot
program which queries a multi-attribute drug product search engine for
similar sounding and appearing drug names based on orthographic and
phonologic similarities, as well as similarities in dosage form,
strength and route of administration. Based on similarity scores as well
as clinical judgment, the following drug names [may]{.underline} be
potential sources of drug name confusion:

LA/SA for generic name aripiprazole: rabeprazole, aripiprazole oral

LA/SA for trade name Abilify: Abelcet, Abilify oral

# 

# Drug Interactions^1^

## Drug-Drug Interactions

Aripiprazole is metabolized by the CYP2D6 and CYP3A4 isoenzymes;
aripiprazole does not appear to induce or inhibit the CYP450 enzymes.

The manufacture recommends that the dose of aripiprazole be reduced to
one-half of the usual dose when given to patients receiving potent
CYP3A4 or CYP2D6 inhibitors, e.g., azole antifungals, clarithromycin,
paroxetine and fluoxetine.

According to the manufacturer's recommendation, patients receiving
concomitant CYP3A4 inducers should receive double the usual dose, e.g.,
carbamazepine.

## Drug-Lab Interactions

No significant laboratory interactions have been reported with
aripiprazole injection.

# Acquisition Costs

Table 6. Current VA Prices for Selected Injectable Antipsychotics

  -------------------------- ---------------------- ----------------------
  **Drug**                   **Dose**               **Cost/Dose (\$)**

  Aripiprazole IM            9.75 mg/1.3 mL         7.95

  Olanzapine IM              10 mg                  14.10

  Ziprasidone IM             20 mg                  7.89

  Haloperidol multidose vial 5 mg                   1.10
  -------------------------- ---------------------- ----------------------

# Pharmacoeconomic Analysis

No pharmacoeconomic analyses have been reported.

# Conclusions

Based on the three published clinical trials, aripiprazole intramuscular
injection has demonstrated efficacy superior to placebo and comparable
to alternative pharmacologic interventions for the management of acute
agitation due to schizophrenia, schizoaffective disorder or bipolar
disorder.

Aripiprazole injection was generally well tolerated with headache,
nausea, dizziness, somnolence/sedation, insomnia, and pain or burning at
the injection site being the most commonly reported adverse events. The
extrapramidal reactions dystonia and akathisia were reported by a small
number of patients.

# Recommendations

Short term IM aripiprazole is appropriate for patients experiencing
psychomotor agitation associated with schizophrenia or bipolar disorder,
manic or mixed as defined in DSM-IV. Psychomotor agitation is defined in
DSM-IV as "excessive motor activity associated with a feeling of inner
tension." Such agitation should be severe and distressing enough to
interfere with a patient's assessment or care, or place the patient,
staff or other patients at risk for harm necessitating immediate control
of their agitation.

# References:

## Anonymous. Abilify (aripiprazole) Package Insert 

## Tran-Johnson TK, Sack DA, Marcus RN, et al. Efficacy and safety of intramuscular aripiprazole in patients with acute agitation: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2007;68:111-9.

1.  Andrezina R, Josiassen RC, Marcus RN, et al. Intramuscular
    aripiprazole for the treatment of acute agitation in patients with
    schizophrenia or schizoaffective disorder: a double-blind,
    placebo-controlled comparison with intramuscular haloperidol.
    Psychopharmacology 2006;188:281-92.

2.  Zimbroff DL, Marcus RN, Mano G, et al. Management of acute agitation
    in patients with bipolar disorder: efficacy and safety of
    intramuscular aripiprazole. J Clin Psychopharmacol 2007;27:171-6.

3.  Currier GW, Citrome LL, Zimbroff DL, et al. Intramuscular
    aripiprazole in the control of agitation. J of Psychiatric Practice
    2007;13:159-69.

**[\*Note: Please point out information through the review that is
especially significant in defining usage, safety, and application to VA
patients.]{.underline}**

**Approved December 2007. Contact person: Todd Semla, MS, Pharm.D.,
BCPS, FCCP, AGSF**