Quetiapine Fumarate Extended Release (Page 11 of 12)

14.2 Bipolar Disorder

Bipolar I Disorder, manic or mixed episodes

Adults

The efficacy of quetiapine fumarate extended-release tablets in the acute treatment of manic episodes was established in one 3-week, placebo-controlled trial (Study 1 in Table 28) in patients who met DSM-IV criteria for bipolar I disorder with manic or mixed episodes with or without psychotic features (N=316). Patients were hospitalized for a minimum of 4 days at randomization. Patients randomized to quetiapine fumarate extended-release tablets received 300 mg on Day 1 and 600 mg on Day 2. Afterwards, the dose could be adjusted between 400 mg and 800 mg per day.

The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptoms in a range from 0 (no manic features) to 60 (maximum score). Quetiapine fumarate extended-release tablets was superior to placebo in the reduction of the YMRS total score at week 3.

The efficacy of quetiapine fumarate tablets in the treatment of acute manic episodes was also established in 3 placebo-controlled trials in patients who met DSM-IV criteria for bipolar I disorder with manic episodes. These trials included patients with or without psychotic features and excluded patients with rapid cycling and mixed episodes. Of these trials, 2 were monotherapy (12 weeks) and 1 was adjunct therapy (3 weeks) to either lithium or divalproex. Key outcomes in these trials were change from baseline in the YMRS score at 3 and 12 weeks for monotherapy and at 3 weeks for adjunct therapy. Adjunct therapy is defined as the simultaneous initiation or subsequent administration of quetiapine fumarate tablets with lithium or divalproex.

The results of the trials follow:

Monotherapy

In two 12-week trials (n=300, n=299) comparing quetiapine fumarate tablets to placebo, quetiapine fumarate tablets was superior to placebo in the reduction of the YMRS total score at weeks 3 and 12. The majority of patients in these trials taking quetiapine fumarate tablets were dosed in a range between 400 mg/day and 800 mg/ day (Studies 2 and 3 in Table 28).

Adjunct Therapy

In a 3-week placebo-controlled trial, 170 patients with bipolar mania (YMRS ≥ 20) were randomized to receive quetiapine fumarate tablets or placebo as adjunct treatment to lithium or divalproex. Patients may or may not have received an adequate treatment course of lithium or divalproex prior to randomization. Quetiapine fumarate tablets was superior to placebo when added to lithium or divalproex alone in the reduction of YMRS total score. The majority of patients in this trial taking quetiapine fumarate tablets were dosed in a range between 400 mg/day and 800 mg/day (study 4 in Table 28).

Children and Adolescents (ages 10-17)

The efficacy of quetiapine fumarate extended-release tablets in the acute treatment of manic episodes associated with bipolar I disorder in children and adolescents (10 — 17 years of age) was extrapolated from a 3-week, double-blind, placebo-controlled, multicenter trial. Patients who met DSM-IV diagnostic criteria for a manic episode were randomized into one of three treatment groups: quetiapine fumarate tablets 400 mg/day (n = 95), quetiapine fumarate tablets 600 mg/day (n = 98), or placebo (n = 91). Study medication was initiated at 50 mg/day and on day 2 increased to 100 mg/day (divided doses given two or three times daily). Subsequently, the dose was titrated to a target dose of 400 mg/day or 600 mg/day using increments of 100 mg/day, given in divided doses two or three times daily. The primary efficacy variable was the mean change from baseline in total YMRS score. Quetiapine fumarate tablets 400 mg/day and 600 mg/day were superior to placebo in the reduction of YMRS total score (study 5 in Table 28).

Table 28: Mania Trials
*
Adult data mean baseline score is based on patients included in the primary analysis; pediatric mean baseline score is based on all patients in the ITT population.
Difference (drug minus placebo) in least-squares mean change from baseline.
Doses that are statistically significantly superior to placebo.
§
Included in the trial as an active comparator.

Study Number

Treatment Group

Primary Efficacy Measure: YMRS Total

Mean Baseline Score (SD) *

LS Mean Change from Baseline (SE)

Placebo-subtracted Difference (95% CI)

Study 1

Quetiapine fumarate extended-release tablets (400-800 mg/day)

28.8 (5.4)

-14.3 (0.9)

-3.8 (-5.7, -2.0)

Placebo

28.4 (5.1)

-10.5 (0.9)

Study 2

Quetiapine fumarate tablets (200-800 mg/day)

34.0 (6.1)

-12.3 (1.3)

-4.0 (-7.0, -1.0)

Haloperidol , §

32.3 (6.0)

-15.7 (1.3)

-7.4 (-10.4, -4.4)

Placebo

33.1 (6.6)

-8.3 (1.3)

Study 3

Quetiapine fumarate tablets (200-800 mg/day)

32.7 (6.5)

-14.6 (1.5)

-7.9 (-10.9, -5.0)

Lithium , §

33.3 (7.1)

-15.2 (1.6)

-8.5 (-11.5, -5.5)

Placebo + mood stabilizer

34.0 (6.9)

-6.7 (1.6)

Study 4

Quetiapine fumarate tablets (200-800 mg/day) + mood stabilizer

31.5 (5.8)

-13.8 (1.6)

-3.8 (-7.1, -0.6)

Placebo + mood stabilizer

31.1 (5.5)

-10 (1.5)

Study 5

(children and adolescents)

Quetiapine fumarate tablets (400 mg/day)

29.4 (5.9)

-14.3 (0.96)

-5.2 (-8.1, -2.3)

Quetiapine fumarate tablets (600 mg/day)

29.6 (6.4)

-15.6 (0.97)

-6.6 (-9.5, -3.7)

Placebo

30.7 (5.9)

-9.0 (1.1)

Mood stabilizer: lithium or divalproex; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.

Bipolar Disorder, Depressive Episodes

Adults

The efficacy of quetiapine fumarate extended-release tablets for the acute treatment of depressive episodes associated with bipolar disorder in patients who met DSM-IV criteria for bipolar disorder was established in one 8-week, randomized, double-blind, placebo-controlled study (N=280 outpatients). This study included patients with bipolar I and II disorder, and those with and without a rapid cycling course. Patients randomized to quetiapine fumarate extended-release tablets were administered 50 mg on Day 1, 100 mg on Day 2, 200 mg on Day 3, and 300 mg on Day 4 and after.

The primary rating instrument used to assess depressive symptoms was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale with scores ranging from 0 (no depressive features) to 60 (maximum score). The primary endpoint was the change from baseline in MADRS score at week 8. Quetiapine fumarate extended-release tablets was superior to placebo in reduction of MADRS score at week 8 (study 6 in Table 29).

The efficacy of quetiapine fumarate tablets for the treatment of depressive episodes associated with bipolar disorder was established in 2 identical 8-week, randomized, double-blind, placebo-controlled studies (N=1045). These studies included patients with either bipolar I or II disorder and those with or without a rapid cycling course. Patients randomized to quetiapine fumarate tablets were administered fixed doses of either 300 mg or 600 mg once daily.

The primary rating instrument used to assess depressive symptoms in these studies was the MADRS. The primary endpoint in both studies was the change from baseline in MADRS score at week 8. In both studies, quetiapine fumarate tablets was superior to placebo in reduction of MADRS score at week 8 (Studies 7 and 8 in Table 29). In these studies, no additional benefit was seen with the 600 mg dose. For the 300 mg dose group, statistically significant improvements over placebo were seen in overall quality of life and satisfaction related to various areas of functioning, as measured using the Q-LES-Q(SF).

Table 29: Depressive Episodes Associated with Bipolar Disorder
*
Difference (drug minus placebo) in least-squares mean change from baseline.
Doses that are statistically significantly superior to placebo.

Study Number

Treatment Group

Primary Efficacy Measure: MADRS Total

Mean Baseline Score (SD)

LS Mean Change from Baseline (SE)

Placebo-subtracted Difference * (95% CI)

Study 6

Quetiapine fumarate extended-release tablets (300 mg/day)

29.8 (5.2)

-17.4 (1.2)

-5.5 (-7.9, -3.2)

Placebo

30.1 (5.5)

-11.9 (1.2)

Study 7

Quetiapine fumarate tablets (300 mg/day)

30.3 (5.0)

-16.4 (0.9)

-6.1 (-8.3, -3.9)

Quetiapine fumarate tablets (600 mg/day)

30.3 (5.3)

-16.7 (0.9)

-6.5 (-8.7, -4.3)

Placebo

30.6 (5.3)

-10.3 (0.9)

Study 8

Quetiapine fumarate tablets (300 mg/day)

31.1 (5.7)

-16.9 (1.0)

-5.0 (-7.3, -2.7)

Quetiapine fumarate tablets (600 mg/day)

29.9 (5.6)

-16.0 (1.0)

-4.1 (-6.4, -1.8)

Placebo

29.6 (5.4)

-11.9 (1.0)

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.

Maintenance Treatment as an Adjunct to Lithium or Divalproex

The efficacy of quetiapine fumarate tablets in the maintenance treatment of bipolar I disorder was established in 2 placebo-controlled trials in patients (n=1326) who met DSM-IV criteria for bipolar I disorder (studies 9 and 10). The trials included patients whose most recent episode was manic, depressed, or mixed, with or without psychotic features. In the open-label phase, patients were required to be stable on quetiapine fumarate tablets plus lithium or divalproex for at least 12 weeks in order to be randomized. On average, patients were stabilized for 15 weeks. In the randomization phase, patients continued treatment with lithium or divalproex and were randomized to receive either quetiapine fumarate tablets (administered twice-daily totaling 400 mg/day to 800 mg/day) or placebo. Approximately 50% of the patients had discontinued from the quetiapine fumarate tablets group by day 280 and 50% of the placebo group had discontinued by day 117 of double-blind treatment. The primary endpoint in these studies was time to recurrence of a mood event (manic, mixed or depressed episode). A mood event was defined as medication initiation or hospitalization for a mood episode; YMRS score ≥ 20 or MADRS score ≥ 20 at 2 consecutive assessments; or study discontinuation due to a mood event.

In both studies, quetiapine fumarate tablets was superior to placebo in increasing the time to recurrence of any mood event (Figure 2 and Figure 3). The treatment effect was present for increasing time to recurrence of both manic and depressed episodes. The effect of quetiapine fumarate tablets was independent of any specific subgroup (assigned mood stabilizer, sex, age, race, most recent bipolar episode, or rapid cycling course).

Figure 2: Kaplan-Meier Curves of Time to Recurrence of a Mood Event (Study 9)

Figure 2 kaplan-Maier Curves of Time to recurrence of A Mood Event.jpg
(click image for full-size original)

Figure 3: Kaplan-Meier Curves of Time to Recurrence of a Mood Event (Study 10)

Figure 3 Kaplan-Meier Curves of Time to Recurrence of A Mood Event (Study 19).jpg
(click image for full-size original)

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