General Information

Seroquel XR is an atypical antipsychotic.

Seroquel XR is indicated for the treatment of:

• Schizophrenia
• Bipolar I disorder, manic, or mixed episodes
• Bipolar disorder, depressive episodes
• Major depressive disorder, adjunctive therapy with antidepressants

Seroquel XR tablets should be swallowed whole and not split, chewed or crushed. Take without food or with a light meal (approx. 300 calories. Administer once daily, preferably in the evening. The recommended dosage for each indication is below:

Mechanism of Action

The mechanism of action of quetiapine in the listed indications is unclear. However, the efficacy of quetiapine in these indications could be mediated through a combination of dopamine type 2 (D2) and serotonin type 2A (5HT2A) antagonism. The active metabolite, N-desalkyl quetiapine (norquetiapine), has similar activity at D2, but greater activity at 5HT2A receptors, than the parent drug (quetiapine).

Side Effects

Adverse effects associated with the use of Seroquel XR may include:

Adults:

• somnolence
• dry mouth
• constipation
• dizziness
• increased appetite
• dyspepsia
• weight gain
• fatigue
• dysarthria
• nasal congestion

Children and Adolescents:

• somnolence
• dizziness
• fatigue
• increased appetite
• nausea
• vomiting
• dry mouth
• tachycardia
• weight increased

Clinical Trial Results

Schizophrenia Short-term Trials – Adults

The efficacy of Seroquel XR in the treatment of schizophrenia was demonstrated in 1 short-term, 6-week, fixed-dose, placebo-controlled trial of inpatients and outpatients with schizophrenia (n=573) who met DSM-IV criteria for schizophrenia. Seroquel XR (once daily) was administered as 300 mg on Day 1, and the dose was increased to either 400 mg or 600 mg by Day 2, or 800 mg by Day 3. The primary endpoint was the change from baseline of the Positive and Negative Syndrome Scale (PANSS) total score at the end of treatment (Day 42). Seroquel XR doses of 400 mg, 600 mg and 800 mg once daily were superior to placebo in the PANSS total score at Day 42.

Short-term Trials –Adolescents (ages 13-17)

The efficacy of Seroquel XR in the treatment of schizophrenia in adolescents (13-17 years of age) was supported by a 6-week, double-blind, placebo-controlled trial. Patients who met DSM-IV diagnostic criteria for schizophrenia were randomized into one of three treatment groups: Seroquel 400 mg/day (n=73), Seroquel 800 mg/day (n=74), or placebo (n=75). Study medication was initiated at 50 mg/day and on day 2 increased to 100 mg/per day (divided and given two or three times per day). Subsequently, the dose was titrated to the target dose of 400 mg/day or 800 mg/day using increments of 100 mg/day, divided and given two or three times daily. The primary efficacy variable was the mean change from baseline in total Positive and Negative Syndrome Scale (PANSS). Seroquel at 400 mg/day and 800 mg/day was superior to placebo in the reduction of PANSS total score.

Maintenance Trials

In a longer-term trial (Study 3), clinically stable adult outpatients (n=171) meeting DSM-IV criteria for schizophrenia who remained stable following 16 weeks of open-label treatment with flexible doses of Seroquel XR (400 mg/day-800 mg/day) were randomized to placebo or to continue on their current Seroquel XR (400 mg/day-800 mg/day) for observation for possible relapse during the double-blind continuation (maintenance) phase. Stabilization during the open label phase was defined as receiving a stable dose of Seroquel XR and having a CGI-S≤4 and a PANSS score ≤60 from beginning to end of this open-label phase (with no increase of ≥10 points in PANSS total score). Relapse during the double-blind phase was defined in terms of a ≥30% increase in the PANSS Total score, or CGI-Improvement score of ≥6, or hospitalization due to worsening of schizophrenia, or need for any other antipsychotic medication. Patients on Seroquel XR experienced a statistically significant longer time to relapse than did patients on placebo.

Bipolar I Disorder, manic or mixed episodes

Adults

The efficacy of Seroquel XR in the acute treatment of manic episodes was established in one 3-week, placebo controlled trial 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 Seroquel XR 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). Seroquel XR was superior to placebo in the reduction of the YMRS total score at week 3.

The efficacy of Seroquel 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. The results of the trials follow:

Monotherapy: In two 12-week trials (n=300, n=299) comparing Seroquel to placebo, SeroquelL 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 Seroquel were dosed in a range between 400 mg/day and 800 mg/ day.

Adjunct Therapy: In a 3-week placebo-controlled trial, 170 patients with bipolar mania (YMRS ≥20) were randomized to receive Seroquel 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. Seroquel 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 Seroquel were dosed in a range between 400 mg/day and 800 mg/day.

Bipolar Disorder, Depressive Episodes

Adults

The efficacy of SEROQUEL XR 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 Seroquel XR 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. Seroquel XR was superior to placebo in reduction of MADRS score at week 8.

The efficacy of Seroquel 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 Seroquel 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, Seroquel was superior to placebo in reduction of MADRS score at week 8 (Studies 7 and 8 in Table 28). 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-LESQ(SF).

Major Depressive Disorder, Adjunctive Therapy to Antidepressants

The efficacy of Seroquel XR as adjunctive therapy to antidepressants in the treatment of MDD was demonstrated in two 6-week placebo-controlled, fixed-dose trials (n=936). Seroquel  XR 150 mg/day or 300 mg/day was given as adjunctive therapy to existing antidepressant therapy in patients who had previously shown an inadequate response to at least one antidepressant. Seroquel  XR was administered as 50 mg/day on Days 1 and 2, and increased to 150 mg/day on Day 3 for both dose groups. On Day 5, the dose was increased to 300 mg/day in the 300 mg/day fixed-dose group. Inadequate response was defined as having continued depressive symptoms for the current episode [Hamilton Depression Rating Scale (HAM-D) total score of ≥20] despite using an antidepressant for 6 weeks at or above the minimally effective labelled dose. The mean HAM-D total score at entry was 24, and 17% of patients scored 28 or greater. The primary endpoint in these trials was change from baseline to week 6 in the Montgomery-Asberg Depression Rating Scale (MADRS.), Seroquel  XR 300 mg once daily as adjunctive treatment to other antidepressant therapy was superior to antidepressant alone in reduction of MADRS total score in both trials. Seroquel  XR 150 mg once daily as adjunctive treatment was superior to antidepressant therapy alone in reduction of MADRS total score in one trial.