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Mechanism of Action
The mechanism of action of SEROQUEL XR, as with other drugs having efficacy in the treatment of schizophrenia, bipolar disorder and major depressive disorder (MDD), is unknown. However, it has been proposed that the efficacy of SEROQUEL XR in schizophrenia is 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). Quetiapine's efficacy in bipolar depression and MDD may partly be explained by the high affinity and potent inhibitory effects that norquetiapine exhibits for the norepinephrine transporter.
Antagonism at receptors other than dopamine and serotonin with similar or greater affinities may explain some of the other effects of quetiapine and norquetiapine: antagonism at histamine H1 receptors may explain the somnolence, antagonism at adrenergic α1b receptors may explain the orthostatic hypotension, and antagonism at muscarinic M1 receptors may explain the anticholinergic effects.
Quetiapine and norquetiapine have affinity for multiple neurotransmitter receptors including dopamine D1 and D2, serotonin 5HT1A and 5HT2A, histamine H1, muscarinic M1, and adrenergic α1b and α2 receptors. Quetiapine differs from norquetiapine in having no appreciable affinity for muscarinic M1 receptors whereas norquetiapine has high affinity. Quetiapine and norquetiapine lack appreciable affinity for benzodiazepine receptors.
Receptor Affinities (Ki, nM) for Quetiapine and Norquetiapine
|Norepinephrine transporter||> 10000||34.8|
|Benzodiazepine||> 10000||> 10000|
Following multiple dosing of quetiapine up to a total daily dose of 800 mg, administered in divided doses, the plasma concentration of quetiapine and norquetiapine, the major active metabolite of quetiapine, were proportional to the total daily dose. Accumulation is predictable upon multiple dosing. Steady-state mean Cmax and AUC of norquetiapine are about 21-27% and 46-56%, respectively of that observed for quetiapine. Elimination of quetiapine is mainly via hepatic metabolism. The mean-terminal half-life is approximately 7 hours for quetiapine and approximately 12 hours for norquetiapine within the clinical dose range. Steady-state concentrations are expected to be achieved within two days of dosing. SEROQUEL XR is unlikely to interfere with the metabolism of drugs metabolized by cytochrome P450 enzymes.
Quetiapine fumarate reaches peak plasma concentrations approximately 6 hours following administration. SEROQUEL XR dosed once daily at steady-state has comparable bioavailability to an equivalent total daily dose of SEROQUEL administered in divided doses, twice daily. A high-fat meal (approximately 800 to 1000 calories) was found to produce statistically significant increases in the SEROQUEL XR Cmax and AUC of 44% to 52% and 20% to 22%, respectively, for the 50 mg and 300 mg tablets. In comparison, a light meal (approximately 300 calories) had no significant effect on the Cmax or AUC of quetiapine. It is recommended that SEROQUEL XR be taken without food or with a light meal [see DOSAGE AND ADMINISTRATION].
Quetiapine is widely distributed throughout the body with an apparent volume of distribution of 10±4 L/kg. It is 83% bound to plasma proteins at therapeutic concentrations. In vitro, quetiapine did not affect the binding of warfarin or diazepam to human serum albumin. In turn, neither warfarin nor diazepam altered the binding of quetiapine.
Metabolism and Elimination
Following a single oral dose of 14C-quetiapine, less than 1% of the administered dose was excreted as unchanged drug, indicating that quetiapine is highly metabolized. Approximately 73% and 20% of the dose was recovered in the urine and feces, respectively. The average dose fraction of free quetiapine and its major active metabolite is < 5% excreted in the urine.
Quetiapine is extensively metabolized by the liver. The major metabolic pathways are sulfoxidation to the sulfoxide metabolite and oxidation to the parent acid metabolite; both metabolites are pharmacologically inactive. In vitro studies using human liver microsomes revealed that the cytochrome P450 3A4 isoenzyme is involved in the metabolism of quetiapine to its major, but inactive, sulfoxide metabolite and in the metabolism of its active metabolite norquetiapine.
Oral clearance of quetiapine was reduced by 40% in elderly patients ( > 65 years, n = 9) compared to young patients (n = 12), and dosing adjustment may be necessary [see DOSAGE AND ADMINISTRATION].
There is no gender effect on the pharmacokinetics of quetiapine.
There is no race effect on the pharmacokinetics of quetiapine.
Smoking has no effect on the oral clearance of quetiapine.
Patients with severe renal impairment (CLcr=10-30 mL/min/1.73m², n=8) had a 25% lower mean oral clearance than normal subjects (CLcr > 80 mL/min/1.73m², n=8), but plasma quetiapine concentrations in the subjects with renal insufficiency were within the range of concentrations seen in normal subjects receiving the same dose. Dosage adjustment is therefore not needed in these patients.
Hepatically impaired patients (n=8) had a 30% lower mean oral clearance of quetiapine than normal subjects. In 2 of the 8 hepatically impaired patients, AUC and Cmax were 3 times higher than those observed typically in healthy subjects. Since quetiapine is extensively metabolized by the liver, higher plasma levels are expected in the hepatically impaired population, and dosage adjustment may be needed [see DOSAGE AND ADMINISTRATION].
In vitro enzyme inhibition data suggest that quetiapine and 9 of its metabolites would have little inhibitory effect on in vivo metabolism mediated by cytochromes P450 1A2, 2C9, 2C19, 2D6 and 3A4.
Quetiapine oral clearance is increased by the prototype cytochrome P450 3A4 inducer, phenytoin, and decreased by the prototype cytochrome P450 3A4 inhibitor, ketoconazole. Dose adjustment of quetiapine will be necessary if it is coadministered with phenytoin or ketoconazole [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].
Quetiapine oral clearance is not inhibited by the non-specific enzyme inhibitor, cimetidine.
Animal Toxicology and/or Pharmacology
Quetiapine caused a dose-related increase in pigment deposition in thyroid gland in rat toxicity studies which were 4 weeks in duration or longer and in a mouse 2-year carcinogenicity study. Doses were 10250 mg/kg in rats, 75-750 mg/kg in mice; these doses are 0.1-3.0, and 0.1-4.5 times the maximum recommended human dose (on a mg/m² basis), respectively. Pigment deposition was shown to be irreversible in rats. The identity of the pigment could not be determined, but was found to be co-localized with quetiapine in thyroid gland follicular epithelial cells. The functional effects and the relevance of this finding to human risk are unknown.
In dogs receiving quetiapine for 6 or 12 months, but not for 1 month, focal triangular cataracts occurred at the junction of posterior sutures in the outer cortex of the lens at a dose of 100 mg/kg, or 4 times the maximum recommended human dose on a mg/m² basis. This finding may be due to inhibition of cholesterol biosynthesis by quetiapine. Quetiapine caused a dose-related reduction in plasma cholesterol levels in repeat-dose dog and monkey studies; however, there was no correlation between plasma cholesterol and the presence of cataracts in individual dogs. The appearance of delta 8 cholestanol in plasma is consistent with inhibition of a late stage in cholesterol biosynthesis in these species. There also was a 25% reduction in cholesterol content of the outer cortex of the lens observed in a special study in quetiapine treated female dogs. Drug-related cataracts have not been seen in any other species; however, in a 1-year study in monkeys, a striated appearance of the anterior lens surface was detected in 2/7 females at a dose of 225 mg/kg or 5.5 times the maximum recommended human dose on a mg/m² basis.
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.
In a longer-term trial, 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/day800 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.
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. 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 SEROQUEL with lithium or divalproex.
The results of the trials follow:
In two 12-week trials (n=300, n=299) comparing SEROQUEL to placebo, SEROQUEL 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.
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.
Depressive Episodes Associated with Bipolar Disorder
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. 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).
Maintenance Treatment as an Adjunct to Lithium or Divalproex
The efficacy of SEROQUEL 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. 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 SEROQUEL 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 SEROQUEL (administered twice daily totaling 400 mg/day to 800 mg/day or placebo. Approximately 50% of the patients had discontinued from the SEROQUEL 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, SEROQUEL was superior to placebo in increasing the time to recurrence of any mood event. The treatment effect was present for increasing time to recurrence of both manic and depressed episodes. The effect of SEROQUEL was independent of any specific subgroup (assigned mood stabilizer, sex, age, race, most recent bipolar episode, or rapid cycling course).
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 6week 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 (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. Patients were on various antidepressants prior to study entry including SSRI's (paroxetine, fluoxetine, sertraline, escitalopram, or citalopram), SNRI's, (duloxetine and venlafaxine,) TCA (amitriptyline) and other (bupropion).
The primary endpoint in these trials was change from baseline to week 6 in the Montgomery-Asberg Depression Rating Scale (MADRS), a 10item clinician-rated scale used to assess the degree of depressive symptomatology (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts) with total scores ranging from 0 (no depressive features) to 60 (maximum score).
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.
Last reviewed on RxList: 6/24/2011
This monograph has been modified to include the generic and brand name in many instances.
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