Aripiprazole (Page 9 of 11)

13.2 Animal Pharmacology & OR Toxicology

Aripiprazole produced retinal degeneration in albino rats in a 26-week chronic toxicity study at a dose of 60 mg/kg/day and in a 2-year carcinogenicity study at doses of 40 and 60 mg/kg/day which are 13 and 19 times the MRHD of 30 mg/day based on mg/m2 body surface area. Evaluation of the retinas of albino mice and of monkeys did not reveal evidence of retinal degeneration. Additional studies to further evaluate the mechanism have not been performed. The relevance of this finding to human risk is unknown.

14 CLINICAL STUDIES

Efficacy of the oral formulations of aripiprazole was established in the following adequate and well-controlled trials:
• Four short-term trials and one maintenance trial in adult patients and one short-term trial in adolescents (ages 13-17) with schizophrenia [see Clinical Studies (14.1)]

Additional pediatric use information is approved for Otsuka America Pharmaceutical, Inc.’s ABILIFY® (aripiprazole) product. However, due to Otsuka America Pharmaceutical, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

14.1 Schizophrenia

Adults
The efficacy of aripiprazole in the treatment of schizophrenia was evaluated in five short-term (4-week and 6-week), placebo-controlled trials of acutely relapsed inpatients who predominantly met DSM-III/IV criteria for schizophrenia. Four of the five trials were able to distinguish aripiprazole from placebo, but one study, the smallest, did not. Three of these studies also included an active control group consisting of either risperidone (one trial) or haloperidol (two trials), but they were not designed to allow for a comparison of aripiprazole and the active comparators.

In the four positive trials for aripiprazole, four primary measures were used for assessing psychiatric signs and symptoms. Efficacy was evaluated using the total score on the Positive and Negative Syndrome Scale (PANSS). The PANSS is a 30 item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); total PANSS scores range from 30 to 210. The Clinical Global Impression (CGI) assessment reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient.
In a 4-week trial (n=414) comparing two fixed doses of aripiprazole (15 or 30 mg/day) to placebo, both doses of aripiprazole were superior to placebo in the PANSS total score (Study 1 in Table 26), PANSS positive subscale, and CGI-severity score. In addition, the 15 mg dose was superior to placebo in the PANSS negative subscale.
In a 4-week trial (n=404) comparing two fixed doses of aripiprazole (20 or 30 mg/day) to placebo, both doses of aripiprazole were superior to placebo in the PANSS total score (Study 2 in Table 26), PANSS positive subscale, PANSS negative subscale, and CGI-severity score.
In a 6-week trial (n=420) comparing three fixed doses of aripiprazole (10, 15, or 20 mg/day) to placebo, all three doses of aripiprazole were superior to placebo in the PANSS total score (Study 3 in Table 26), PANSS positive subscale, and the PANSS negative subscale.
In a 6-week trial (n=367) comparing three fixed doses of aripiprazole (2, 5, or 10 mg/day) to placebo, the 10 mg dose of aripiprazole was superior to placebo in the PANSS total score (Study 4 in Table 26), the primary outcome measure of the study. The 2 and 5 mg doses did not demonstrate superiority to placebo on the primary outcome measure.

Thus, the efficacy of 10, 15, 20, and 30 mg daily doses was established in two studies for each dose. Among these doses, there was no evidence that the higher dose groups offered any advantage over the lowest dose group of these studies.
An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, gender, or race.

A longer-term trial enrolled 310 inpatients or outpatients meeting DSM-IV criteria for schizophrenia who were, by history, symptomatically stable on other antipsychotic medications for periods of 3 months or longer. These patients were discontinued from their antipsychotic medications and randomized to aripiprazole 15 mg/day or placebo for up to 26 weeks of observation for relapse. Relapse during the double-blind phase was defined as CGI-Improvement score of ≥5 (minimally worse), scores ≥5 (moderately severe) on the hostility or uncooperativeness items of the PANSS, or ≥20% increase in the PANSS total score. Patients receiving aripiprazole 15 mg/day experienced a significantly longer time to relapse over the subsequent 26 weeks compared to those receiving placebo (Study 5 in Figure 6).

Pediatric Patients
The efficacy of aripiprazole in the treatment of schizophrenia in pediatric patients (13 to 17 years of age) was evaluated in one 6-week, placebo-controlled trial of outpatients who met DSM-IV criteria for schizophrenia and had a PANSS score ≥70 at baseline. In this trial (n=302) comparing two fixed doses of aripiprazole (10 or 30 mg/day) to placebo, aripiprazole was titrated starting from 2 mg/day to the target dose in 5 days in the 10 mg/day treatment arm and in 11 days in the 30 mg/day treatment arm. Both doses of aripiprazole were superior to placebo in the PANSS total score (Study 6 in Table 26), the primary outcome measure of the study. The 30 mg/day dosage was not shown to be more efficacious than the 10 mg/day dose. Although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.
Table 26: Schizophrenia Studies

Study Number Treatment Group Primary Efficacy Measure: PANSS
Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Differencea (95% CI)
Study 1 Aripiprazole (15 mg/day)* Aripiprazole (30 mg/day)* Placebo 98.5 (17.2)99.0 (19.2)100.2 (16.5)-15.5 (2.40)-11.4 (2.39)-2.9 (2.36)-12.6 (-18.9, -6.2)-8.5 (-14.8, -2.1)–
Study 2Aripiprazole (20 mg/day)* Aripiprazole (30 mg/day)* Placebo 92.6 (19.5)94.2 (18.5)94.3 (18.5)-14.5 (2.23)-13.9 (2.24)-5.0 (2.17)-9.6 (-15.4, -3.8)-9.0 (-14.8, -3.1)–
Study 3 Aripiprazole (10 mg/day)* Aripiprazole (15 mg/day)*Aripiprazole (20 mg/day)* Placebo 92.7 (19.5)93.2 (21.6)92.5 (20.9)92.3 (21.8)-15.0 (2.38)-11.7 (2.38)-14.4 (2.45)-2.3 (2.35)-12.7 (-19.00, -6.41)-9.4 (-15.71, -3.08)-12.1 (-18.53, -5.68)–
Study 4 Aripiprazole (2 mg/day) Aripiprazole (5 mg/day)Aripiprazole (10 mg/day)* Placebo 90.7 (14.5)92.0 (12.6)90.0 (11.9)90.8 (13.3)-8.2 (1.90)-10.6 (1.93)-11.3 (1.88)-5.3 (1.97)-2.9 (-8.29, 2.47)-5.2 (-10.7, 0.19)-5.9 (-11.3, -0.58)–
Study 6 (Pediatric 13-17 years) Aripiprazole (10 mg/day)* Aripiprazole (30 mg/day)* Placebo 93.6 (15.7)94.0 (16.1)94.6 (15.6)-26.7 (1.91)-28.6 (1.92)-21.2 (1.93)-5.5 (-10.7, -0.21)-7.4 (-12.7, -2.13)–
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. a Difference (drug minus placebo) in least-squares mean change from baseline. * Doses statistically significantly superior to placebo.

Figure 6: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (Schizophrenia Study 5)

fig6
(click image for full-size original)

Additional pediatric use information is approved for Otsuka America Pharmaceutical, Inc.’s ABILIFY (aripiprazole) product. However, due to Otsuka America Pharmaceutical, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

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