Seroquel IR/Seroquel XR

Seroquel IR/Seroquel XR

quetiapine

Manufacturer:

AstraZeneca

Distributor:

Zuellig
/
Four Star
Full Prescribing Info
Contents
Quetiapine fumarate.
Description
Each 25-mg, 100-mg and 200-mg immediate-release tablet contains quetiapine fumarate delivering a dose of quetiapine free base 25 mg, 100 mg and 200 mg, respectively. It also contains the following excipients: Core: Povidone, calcium hydrogen phosphate dihydrate, microcrystalline cellulose, sodium starch glycollate type A, lactose monohydrate and magnesium stearate. Coating: Hypromellose, macrogol 400, titanium dioxide (E171), and yellow ferric oxide (E172).
Each 50-mg, 200-mg and 300-mg extended-release tablet contains quetiapine fumarate delivering a dose of quetiapine free base 50 mg, 200 mg and 300 mg, respectively. It also contains the following excipients: Core: Microcrystalline cellulose, sodium citrate, lactose monohydrate, magnesium stearate and hypromellose. Coating: Hypromellose, macrogol 400, titanium dioxide (E171), red ferric oxide (E172) (for 50-mg tablets), yellow ferric oxide (E172) (50-, 200-, 300-mg tablet). Seroquel XR does not contain gluten.
Quetiapine fumarate is Bis[2-(2-[4-(dibenzo[b,f][1,4]-thiazepin-11-yl)piperazin-1-yl] ethoxy) ethanol] fumarate.
Quetiapine fumarate is a weak acid (pKa 3.3, 6.8) which exhibits moderate pH-dependent solubility (94.3 to 2.37 mg/mL at pH values from 1-9) and lypophilicity characteristics (Log P) which vary with pH (0.45 in water, 1.37 at pH 5, 2.65 at pH 7 and 2.59 at pH 9). Quetiapine fumarate has an aqueous solubility of 3.29 mg/mL at 25°C.
Action
Pharmacotherapeutic Group: Antipsychotics. ATC Code: NO5AH04.
Pharmacology: Mechanism of Action: Quetiapine is an atypical antipsychotic agent. Quetiapine and the active human plasma metabolite, norquetiapine, interact with a broad range of neurotransmitter receptors. Quetiapine and norquetiapine exhibit affinity for brain serotonin (5HT2) and dopamine D1- and D2-receptors. It is this combination of receptor antagonism with a higher selectivity for 5HT2 relative to D2-receptors, is believed to contribute to the clinical antipsychotic properties and low extrapyramidal side effects (EPS) liability of quetiapine compared to typical antipsychotics. Additionally, norquetiapine has high affinity (higher than quetiapine) for the noradrenaline transporter [norepinephrine transporter (NET)], 5HT1B and muscarinic receptors. Quetiapine and norquetiapine also have high affinity at histaminergic H1 and adrenergic α1B- and α1A-receptors, with a lower affinity at adrenergic α2 and 5HT1A receptors. Quetiapine has no appreciable affinity at cholinergic, muscarinic or benzodiazepine receptors. The norquetiapine metabolite 7-hydroxy norquetiapine also has affinity for histaminergic H1 and 5HT2B and 5HT2C receptors at clinically relevant concentrations.
Pharmacodynamics: Quetiapine is active in tests for antipsychotic activity eg, conditioned avoidance. It also reverses the action of dopamine agonists, measured either behaviourally or electrophysiologically, and elevates dopamine metabolite concentrations, a neurochemical index of D2-receptor blockade. The results of animal studies predictive of EPS liability revealed that quetiapine causes only weak catalepsy at effective dopamine D2-receptor-blocking doses, that quetiapine causes selective reduction in the firing of mesolimbic A10 dopaminergic neurones versus the A9 nigrostriatal neurones involved in motor function, and that quetiapine exhibits minimal dystonic liability in neuroleptic-sensitised monkeys. The extent to which the metabolites norquetiapine and 7-hydroxy norquetiapine contribute to the pharmacological activity of quetiapine in humans is uncertain.
In preclinical tests predictive of EPS, quetiapine is unlike typical antipsychotics and has an atypical profile. Quetiapine does not produce dopamine D2-receptor supersensitivity after chronic administration. Quetiapine produces only weak catalepsy at effective dopamine D2-receptor-blocking doses. Quetiapine demonstrates selectivity for the limbic system by producing depolarisation blockade of the A10 mesolimbic but not the A9 nigrostriatal dopamine-containing neurones following chronic administration. Quetiapine exhibits minimal dystonic liability in haloperidol-sensitised or drug-naive Cebus monkeys after acute and chronic administration. The results of these tests predict that Seroquel should have minimal EPS liability, and it has been hypothesized that agents with a lower EPS liability may also have a lower liability to produce tardive dyskinesia.
Clinical Trials: Seroquel IR: Clinical Efficacy: The results of 3 placebo-controlled clinical trials in patients with schizophrenia, including one that used a dose range of Seroquel of 75-750 mg/day, identified no difference between Seroquel and placebo in the incidence of EPS or concomitant use of anticholinergics.
In 4 controlled trials, evaluating doses of Seroquel up to 800 mg for the treatment of bipolar mania, 2 each in monotherapy and as an adjunct therapy to lithium or valproate semisodium, there were no differences between the Seroquel and placebo treatment groups in the incidence of EPS or concomitant use of anticholinergics.
In clinical trials, Seroquel has been shown to be effective in the treatment of both positive and negative symptoms of schizophrenia. In 1 trial against chlorpromazine and 2 against haloperidol, Seroquel showed similar short-term efficacy.
In clinical trials, Seroquel has been shown to be effective as monotherapy or as an adjunct therapy in reducing manic symptoms in patients with bipolar mania. The mean last week median dose of Seroquel in responders, was approximately 600 mg/day and approximately 85% of the responders were in the dose range of 400-800 mg/day.
In 4 clinical trials in patients with depressive episodes in bipolar I or bipolar II disorder, with or without rapid cycling courses, 51% of quetiapine-treated patients had at least a 50% improvement in MADRS total score at week 8 compared to 37% of the placebo-treated patients. The antidepressant effect was significant at day 8 (week 1). There were fewer episodes of treatment-emergent mania with Seroquel than with placebo. In continuation treatment, the antidepressant effect was maintained for patients on Seroquel (mean duration of treatment 30 weeks). Seroquel produced a risk of a recurrent mood (manic and depressed) event by 49%. Seroquel was superior to placebo in treating the anxiety symptoms associated with bipolar depression as assessed by mean change from baseline to week 8 in Hamilton Rating Scale for Anxiety (HAM-A) total score.
Suicide/Suicidal Thoughts or Clinical Worsening: In short-term, placebo-controlled clinical trials across all indications and ages, the incidence of suicide-related events was 0.9% for both quetiapine (61/6270) and for placebo (27/3047).
In these trials of patients with schizophrenia, the incidence of suicide-related events was 1.4% (3/212) for quetiapine and 1.6% (1/62) for placebo in patients 18-24 years, 0.8% (13/1663) for quetiapine and 1.1% (5/463) for placebo in patients ≥25 years, and 1.4% (2/147) for quetiapine and 1.3% (1/75) for placebo in patients <18 years.
In these trials of patients with bipolar mania, the incidence of suicide-related events was 0% for both quetiapine (0/60) and placebo (0/58) in patients 18-24 years, 1.2% for both quetiapine (6/496) and placebo (6/503) in patients ≥25 years, and 1% (2/193) for quetiapine and 0% (0/90) for placebo in patients <18 years.
In these trials of patients with bipolar depression, the incidence of suicide-related events was 3% (7/233) for quetiapine and 0% (0/120) for placebo in patients 18-24 years, and 1.8% for both quetiapine (19/1616) and placebo (11/622) in patients ≥25 years. There have been no trials conducted in patients <18 years with bipolar depression (see Precautions).
Children and Adolescents (10-17 years): The efficacy and safety of Seroquel was studied in a 3-week placebo-controlled study for the treatment of mania (n=284 patients, aged 10-17) and a 6-week placebo-controlled study for the treatment of schizophrenia (n=222 patients, aged 13-17). Treatment with Seroquel was initiated at 50 mg/day and on day 2 increased to 100 mg/day, subsequently, the dose was titrated to a target dose (mania 400-600 mg/day; schizophrenia 400-800 mg/day) using increments of 100 mg/day given 2 or 3 times daily. A 26-week open-label extension to the acute trials (n=380 patients), with Seroquel flexibly dosed at 400-800 mg/day, provided additional safety data. Increases in blood pressure were reported in children and adolescents, and increased appetite, weight gain, extrapyramidal symptoms and elevations in serum prolactin were reported with higher frequency in children and adolescents than in adult patients (see Precautions).
Seroquel XR: Clinical pharmacology studies in patients with schizophrenia, schizo-affective and bipolar disorders were conducted to assess the tolerability of a 300-mg starting dose. Key safety assessments included vital sign measurements, adverse events, ECG, clinical laboratory tests and physical examinations. A starting dose of Seroquel XR 300 mg/day was well-tolerated in terms of the key assessments and the safety profile was similar to that seen with the recommended starting dose for Seroquel IR tablets. The recommended Seroquel XR starting dose was further supported by the Seroquel XR clinical efficacy studies in schizophrenia.
Bipolar Disorder (Adults): Efficacy of Seroquel XR in the treatment of bipolar disorder indications was established in part, on the basis of extrapolation from the established effectiveness of Seroquel.
Maintenance Treatment in Combination with Lithium or Sodium Valproate: The efficacy of Seroquel in the maintenance treatment of bipolar disorder was established in 2 similarly designed placebo-controlled trials in patients who met DSM-IV criteria for bipolar I disorder. These trials included patients whose most recent mood episode was mania (approximately 36%), depression (approximately 30%) or mixed state (approximately 34%) and patients with or without psychotic features. Patients with rapid cycling (approximately 37%) were also included.
Both trials consisted of an open-label phase followed by a randomised treatment phase. In the open-label phase (n=3414), patients were required to be stabilised on Seroquel (400-800 mg/day) in combination with a mood stabiliser (lithium or valproate) for at least 12 weeks prior to randomisation. In the randomisation phase, patients who were symptomatically stable for at least 12 weeks (n=1326) either continued treatment with Seroquel (at the same dose, then adjusted as clinically indicated) in combination with a mood stabiliser or received placebo in combination with a mood stabiliser for up to 104 weeks. Approximately 40% of patients received lithium and 60% received valproate.
The primary endpoint was time to recurrence of any mood event (mania, depression or mixed state). A mood event was defined as medication initiation, hospitalisation, Young Mania Rating Scale (YMRS) score ≥20 or Montgomery-Asberg Depression Rating Scale (MADRS) score ≥20 on 2 consecutive assessments or study discontinuation due to a mood event. Seroquel was superior to placebo in increasing the time to recurrence of a mood event in both studies. Patients on Seroquel had a 70% less risk of experiencing a recurrence of a mood event (see Figure 1 and Table 1) compared to patients on placebo. Patients on Seroquel had a lower risk of experiencing a mood event prior to weeks 28 and 52 compared to patients on placebo (see Table 2).

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Maintenance treatment with Seroquel was superior to placebo in increasing the time to recurrence of a depressive or a manic event (see Table 1). Patients on Seroquel also had a lower risk of experiencing a depressive or a manic event prior to weeks 28 and 52 compared to patients on placebo (see Table 2).
Efficacy was demonstrated to be independent of the nature of the most recent episode (manic, mixed or depressed), the mood stabiliser (lithium or valproate), rapid cycling course, gender, age or ethnicity.
Maintenance Treatment As Monotherapy: The efficacy of Seroquel in the maintenance treatment of bipolar disorder as monotherapy was established in a placebo-controlled trial in 1172 patients who met DSM-IV criteria for bipolar I disorder. Approximately 50% of the 2438 patients initially treated with quetiapine for their index episode achieved stabilisation and were eligible for enrolment in the placebo-controlled randomised phase. The most recent mood episode of patients included was mania (approximately 54%), depression (approximately 28%) or mixed state (approximately 18%). Patients with rapid cycling were also included.
The trial consisted of an open-label phase followed by a randomised treatment phase. In the open-label phase, patients were required to be stabilised on Seroquel (300-800 mg/day) for at least 4 weeks prior to randomisation to Seroquel, placebo or lithium. In the randomisation phase, the dose of Seroquel and lithium could be adjusted as clinically indicated. Randomised treatment was intended for up to 104 weeks however the study was stopped early following a positive interim analysis.
The primary endpoint was time to relapse/recurrence of any mood event (mania, depression or mixed state). A mood event was defined as medication initiation, hospitalisation, YMRS score ≥20 or MADRS score ≥20 on 2 consecutive assessments or study discontinuation due to a mood event. Seroquel was superior to placebo in increasing the time to relapse/recurrence of a mood event. Patients on Seroquel had a 71% less risk of experiencing a relapse/recurrence of a mood event (see Figure 2 and Table 3) compared to patients on placebo. Seroquel was also superior to placebo in increasing time to relapse/recurrence of manic events and depressive events (see Table 3). Efficacy was demonstrated to be independent of the nature of the most recent episode (manic, mixed or depressive), rapid cycling course, gender, age or ethnicity.

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Bipolar Depression: The safety and efficacy of Seroquel XR for treatment of bipolar depression was demonstrated in an 8-week placebo controlled study (n=270) at a dose of 300 mg/day. Patients met the DSM-IV criteria for bipolar I or II disorder, with or without rapid cycling courses.
Antidepressant activity was assessed by the change from baseline for MADRS total score (primary endpoint) at 8 weeks (day 57). The antidepressant effect of Seroquel XR was superior compared to placebo as early as day 8 (week 1) and was maintained through to week 8 (see Figure 3). The proportion of patients showing ≥50% reduction in MADRS total score (responders) was higher for Seroquel XR compared to placebo by week 2 and continued to end-of-treatment (p<0.001). The proportion of patients showing a MADRS total score ≤12 (remission) was higher for Seroquel XR compared to placebo group by week 1 and continued to end-of-treatment (p<0.05). The Clinical Global Impression-Bipolar-Severity of Illness (CGI-BP-S) and CGI-BP-Improvement (CGI-BP-I), measures of the clinician's impression of the severity of the patients' overall illness and improvement from baseline, were also assessed with Seroquel XR superior to placebo at week 8. Efficacy was demonstrated to be independent of bipolar I or II diagnosis, rapid cycling course, gender, age or ethnicity.

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The safety and efficacy of quetiapine 300 mg nd 600 mg once daily for the treatment of bipolar depression were established in 4 similarly designed placebo-controlled clinical trials (n=2461) over 8 weeks, with 2 of these studies assessing maintenance of effect for up to 52 weeks. In all 4 studies, quetiapine doses of 300 mg/day and 600 mg/day demonstrated clinical and statistical superiority to placebo in the treatment of depression at 8 weeks. The magnitude of the antidepressant effect was also supported by the secondary outcome variables. Alleviation of anxiety symptoms by quetiapine in all 4 studies was confirmed by a statistically superior HAM-A total score change from baseline compared to placebo. Efficacy was demonstrated to be independent of bipolar I or II diagnosis, rapid cycling course, gender, age or ethnicity.
Maintenance of the quetiapine effect in bipolar depression was demonstrated during the continuation phase with patients treated with quetiapine experiencing a significantly longer time to recurrence of any mood event (depression, mixed state or mania; defined as a MADRS score ≥20 or a YMRS score ≥16; initiation of an antipsychotic, antidepressant, mood stabilizer etc; hospitalization for symptoms of depression and/or mania/hypomania; discontinuation due to symptoms of depression and/or mania/hypomania), compared to placebo as shown in Figure 4 (see Figure 4). Quetiapine patients had a lower risk of experiencing a mood event at weeks 26 and 52 compared to patients on placebo. Patients on quetiapine had a 49% less risk of experiencing a mood event compared with patients treated with placebo [HR 0.51 (95% CI 0.38, 0.69; p <0.001)]. The risk of a mood event for quetiapine versus placebo was reduced by 41% for the 300-mg dose and by 55% for the 600-mg dose.

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Quetiapine patients also had a lower risk of experiencing a depressive event at weeks 26 and 52 compared to patients on placebo. The analysis of time to a depressive event mirrored the overall mood event results with patients on quetiapine having a 57% less risk of experiencing a depressive event compared with patients treated with placebo (HR 0.43, 95% CI 0.3, 0.62, p<0.001). The risk of a depressive event for quetiapine versus placebo was reduced by 52% for the 300-mg dose and by 61% for the 600-mg dose.
No increased risk for a manic or hypomanic event was observed. Quetiapine treatment of a depressive episode was also not associated with a switch to mania or hypomania.
Time to all cause discontinuation, including the composite mood event, was also examined with the Kaplan-Meier estimate of time to 50% all cause discontinuation being 311 days for quetiapine treatment, compared to 156 days for placebo treatment.
The maintenance of effect observed in patients treated with quetiapine was demonstrated to be independent of bipolar diagnosis (ie, I or II), gender or age.
There was no increased risk of suicidal behaviour or ideation associated with quetiapine treatment for bipolar depression in either the acute or continuation phase.
Acute Mania: The safety and efficacy of Seroquel XR for treatment of bipolar mania was demonstrated in a 3-week placebo-controlled study (n=308) at doses of 400-800 mg/day. Patients met the DSM-IV criteria for bipolar I disorder, with the most recent episode being either manic or mixed. Patients with or without rapid cycling courses were also included.
The primary outcome variable for this trial was changed from baseline to day 22 in the YMRS total score. Seroquel XR was demonstrated to be superior to placebo in reducing the level of manic symptoms as early as day 4 and for up to 3 weeks (day 22) of treatment (see Figure 5).

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The proportion of patients showing ≥50% reduction in YMRS total score (responders) was statistically significantly higher for the Seroquel XR group compared to the placebo group at day 8 (week 1) and at the end of treatment. The proportion of patients showing a YMRS total score ≤12 (remission) was statistically significantly higher for the Seroquel XR group compared to the placebo group by day 8 (week 1) and at the end of treatment. The changes in CGI-BP-S and CGI-BP-I overall illness scores were statistically significant in favour of Seroquel XR at day 4 and at end of treatment.
The efficacy of quetiapine in the treatment of manic episodes was further established in 3 short-term placebo-controlled trials in patients who met DSM-IV criteria for bipolar I disorder. The primary outcome variable for these trials was changed from baseline to day 21 in the YMRS total score. In two 12-week trials (n=300, n=299) comparing quetiapine to placebo, quetiapine was superior to placebo in reducing manic symptoms. The majority of patients who responded at day 21 maintained responses to day 84. In a 3-week placebo-controlled trial (n=170) comparing quetiapine to placebo in patients on a mood stabiliser (lithium or valproate), quetiapine was superior to placebo in reducing manic symptoms.
Schizophrenia (Adults): The efficacy of Seroquel XR in the treatment of schizophrenia was demonstrated in the following clinical studies: A 6-week placebo-controlled trial in patients who met DSM-IV criteria for schizophrenia; an active-controlled Seroquel IR-to-Seroquel XR switching study in clinically stable outpatients with schizophrenia; a placebo-controlled relapse prevention study conducted in patients with stabilised schizophrenia.
Placebo-Controlled Efficacy and Safety Data: The primary outcome variable in the placebo-controlled trial was changed from baseline to final assessment in the Positive and Negative Symptom Scale (PANSS) total score. Seroquel XR (once daily) was administered as 300 mg on (day 1) and increased up to the required dose by day 2 or 3. Seroquel XR 400 mg/day, 600 mg/day and 800 mg/day were associated with statistically significant improvements in psychotic symptoms compared to placebo. The effect size of the 600-mg and 800-mg doses was greater than that of the 400-mg dose. In three 6-week clinical studies in patients with schizophrenia (N=951), the incidence of treatment emergent suicidal ideation or suicide attempt, as measured by the Columbia Analysis of Suicidal Behaviour, was low in Seroquel XR-treated patients (0.6%) and similar to placebo (0.9%).
Switching from Seroquel IR to Seroquel XR: In the 6-week active-controlled switching study, the primary outcome variable was the proportion of patients who showed lack of efficacy ie, who discontinued study treatment due to lack of efficacy or whose PANSS total score increased ≥20% from randomisation to any visit. In patients stabilised on Seroquel IR 400-800 mg, efficacy was maintained when patients were switched to an equivalent daily dose of Seroquel XR given once daily. Switching patients from Seroquel IR to Seroquel XR at equivalent total doses was safe and well-tolerated in terms of adverse events, vital signs, ECG and laboratory parameters. The safety profile of Seroquel XR was comparable to Seroquel IR.
Relapse Prevention: A long-term, placebo-controlled relapse prevention study was conducted in patients with stabilised schizophrenia who had been maintained on Seroquel XR for 16 weeks. Randomised treatment was planned for 12 months (or until relapse), however, the maximum duration was approximately 9 months due to early termination as a result of a positive interim analysis. This study concluded that Seroquel XR was significantly more effective than placebo in preventing relapse (hospitalisation due to worsening of schizophrenia and increase in PANSS total score of 30% from baseline, score 6 or 7 on CGI-I scale or need for other antipsychotic medication to treat psychosis) with 11 (11.7%) with relapse in the Seroquel XR group and 50 (48.5%) in the placebo group (p<0.0001). The estimated risks of relapse after 6 months treatments was 14.3% for the Seroquel XR treatment group compared to 68.2% for placebo (p<0.0001). The mean dose of Seroquel XR was 669 mg. There were no additional safety findings associated with treatment with Seroquel XR for up to 12 months. In particular, reports of adverse events related to EPS and weight gain did not increase with longer-term treatment with Seroquel XR.
Major Depressive Disorder (MDD) (Adults): The efficacy of Seroquel XR in the treatment of MDD was established in 4 placebo-controlled monotherapy clinical trials (including 1 study in elderly patients), 2 clinical trials as combination therapy with an antidepressant and 1 monotherapy, placebo-controlled maintenance trial. All trials included patients who met DSM-IV criteria for MDD, single or recurrent episodes, with and without psychotic features. The majority of patients in all studies were diagnosed as having recurrent MDD.
Acute Treatment of MDD: The efficacy of Seroquel XR as monotherapy in the treatment of MDD was demonstrated in two 6-week placebo-controlled, fixed-dose trials and one 8-week placebo-controlled, modified fixed-dose trial (n=1445). The majority of patients were dosed once daily with either 150 mg or 300 mg with 1 trial (study 1) assessing a 50-mg dose. The primary endpoint in these trials was the change from baseline to week 6 or 8 in the MADRS total score.
Seroquel XR at a dose of 50 mg, 150 mg and 300 mg once daily was superior to placebo in reduction of depressive symptoms as measured by change in MADRS total score, with significant improvement observed within the 1st week and continuing throughout the study. Duloxetine included as an active comparator in 1 study (study 2) did not demonstrate statistically significant superiority compared to placebo until day 15. (See Table 4.)

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The efficacy of Seroquel XR in the treatment of MDD was further demonstrated in two 6-week placebo-controlled, fixed-dose trials (n=936) as combination therapy with an antidepressant in patients who had previously shown an inadequate response to at least 1 antidepressant. Seroquel XR 300 mg once daily in combination with ongoing antidepressant therapy was superior to antidepressant therapy alone in reduction of MADRS total score in both trials while Seroquel XR 150 mg was superior to antidepressant therapy alone in 1 study only. Improvement in depressive symptoms was seen at week 1 through end of study (week 6).
Elderly: The safety and efficacy of Seroquel XR was evaluated in an 11-week, double-blind, randomised, placebo-controlled study in non-demented elderly patients (66-89 years) with MDD. The mean dose of Seroquel XR was 160 mg/day. Seroquel XR flexibly dosed in the range of 50-300 mg/day demonstrated superiority over placebo in reducing depressive symptoms as measured by improvement in MADRS total score, with significant improvement observed within the 1st week and continuing throughout the study (week 9).
Maintenance Treatment in MDD: The efficacy of Seroquel XR in the prevention of relapse in MDD was established in a long-term clinical trial consisting of an open-label phase followed by a double-blind randomised treatment phase. Patients stabilised in the open-label phase (n=771) were randomised to placebo or to continue on Seroquel XR for up to 52 weeks. At the end of the open-label phase, 21%, 46% and 32% of patients were prescribed Seroquel XR 50 mg, 150 mg and 300 mg, respectively. The dose of Seroquel XR could be adjusted during the randomisation period based on clinical need with 91.7% of patients remaining on the same dose throughout the randomisation period. The primary endpoint was time to occurrence of a depressive event. Patients on Seroquel XR (mean dose 177 mg/day) experienced a statistically significant longer time to relapse than did patients on placebo with patients on Seroquel XR having a 66% less risk of experiencing a depressive event compared to patients on placebo [HR (95% CI)=0.34 (0.25,0.47), p<0.0001] (see Figure 6). Based on analysis of the dose at randomisation, the risk of experiencing a depressive event decreased with increasing dose [HR: 50 mg, 0.46 (95% CI 0.23, 0.91), p=0.025; 150 mg, 0.36 (95% CI 0.22, 0.57), p<0.001; 300 mg, 0.26 (CI 0.15, 0.45), p<0.001].

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Generalised Anxiety Disorder (GAD) (Adults): The efficacy of Seroquel XR in the monotherapy treatment of GAD was established in 4 placebo-controlled clinical trials (including 1 study in elderly patients) and 1 placebo-controlled maintenance trial. All trials included patients who met DSM-IV criteria for GAD.
Acute Treatment of GAD: The efficacy of once daily Seroquel XR monotherapy in the treatment of GAD was demonstrated in three 10-week placebo-controlled, fixed-dose trials (n=2588 MITT population). Three (3) Seroquel XR doses were assessed 50 mg/day, 150 mg/day and 300 mg/day. Two (2) trials also included an active comparator (escitalopram 10mg/day in one and paroxetine 20mg/day in another). Patients had a mean HAM-A total score of 26 at enrolment.
Seroquel XR at a dose of 50 mg, 150 mg and 300 mg once daily was superior to placebo in reduction of anxiety symptoms as measured by HAM-A total score. Efficacy was demonstrated as early as day 4 and the treatment effect continued throughout the trial (8 weeks-primary endpoint; see Table 5). No additional benefit was provided by the 300-mg/day dose compared with the 150-mg/day dose. Both active comparators (escitalopram and paroxetine) were statistically superior to placebo at week 8, however, neither demonstrated superiority to placebo at day 4. The magnitude of the antianxiety effect of Seroquel XR was supported by various secondary outcome variables. Statistically significant improvements were also seen with Seroquel XR in depressive symptoms (as measured by MADRS total score; mean total score at enrolment was ≤16) and sleep symptoms [as measured with the Pittsburgh Sleep Quality Index (PSQI) global score].

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Elderly: The safety and efficacy of Seroquel XR was evaluated in an 11-week, double-blind, randomised, placebo-controlled study in non-demented elderly patients (66-86 years) with GAD. The proportion of randomised patients >75 years was 13%. Seroquel XR demonstrated superiority over placebo in reducing anxiety symptoms as measured by improvement in HAM-A total score, with significant improvement observed within the 1st week and continuing throughout the study (week 9-primary endpoint; see Table 5). All assessed secondary variables (including health-related quality of life and sleep quality) also demonstrated superiority of Seroquel XR to placebo in elderly patients.
Maintenance Treatment of Antianxiety Effects: The efficacy of Seroquel XR 50 mg, 150 mg or 300 mg once daily in the maintenance treatment of the antianxiety effect was established in a long-term clinical trial consisting of an open-label phase (4-8 week run-in phase and 12-18 week stabilisation phase) followed by a double-blind randomised treatment phase. Patients meeting randomisation criteria (ie, patients who remained stable for at least 12 weeks; n=433) were randomised to placebo or to continue on Seroquel XR (at the same dose as the open-label phase) for up to 52 weeks. Due to the efficacy of Seroquel XR, the mean randomised time of exposure was 56% greater in the Seroquel XR arm compared to placebo (106.9 vs 68.6 days), with 64 Seroquel XR patients on treatment for >28 weeks. The dose of Seroquel XR could be adjusted based on clinical need during both the open-label and the randomisation phases. At the end of the open-label period, 49% of patients received 150 mg/day, with 26% and 25% receiving 50 mg/day and 300 mg/day, respectively. Ninety-three percent (93%) of patients remained on the same dose throughout the randomisation period.
Patients on Seroquel XR (mean dose 163 mg/day) experienced a statistically significant longer time to occurrence of an anxiety event (primary endpoint) than did patients on placebo, with patients on Seroquel XR having an 81% less risk of experiencing an anxiety event compared to patients on placebo (HR 0.19; 95% CI 0.12, 0.31; p<0.0001) (see Figure 7). The efficacy of Seroquel XR in the maintenance treatment of patients with GAD was further supported by the secondary variables, including maintaining reduction of anxiety and depressive symptoms, and improved level of functioning, health-related quality of life and sleep quality.

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Children and Adolescents (<18 Years): The safety and efficacy of Seroquel XR have not been evaluated in patients <18 years, however, 3 clinical trials have been conducted with Seroquel in children and adolescents; 2 short-term, randomised, placebo-controlled trials: A 3-week trial in schizophrenia (patients 13-17 years) and a 6-week trial in bipolar mania (patients 10-17 years) and an open-label, 26-week safety and tolerability trial (see Clinical Study Experience under Adverse Reactions) which also assessed efficacy measures. The safety and efficacy of Seroquel in children and adolescents have not been assessed beyond these time periods.
Pharmacokinetics: Absorption: Quetiapine is well-absorbed and extensively metabolised by the liver following oral administration. Steady-state peak molar concentrations of the active metabolite norquetiapine are 35% of that observed for quetiapine.
The pharmacokinetics of quetiapine and norquetiapine are linear across the approved dosage range.
Peak plasma concentrations of quetiapine are achieved approximately 6 hrs after administration (Tmax) of Seroquel XR. Dose-proportional pharmacokinetics is displayed for doses of Seroquel XR of up to 800 mg administered once daily. The maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) for Seroquel XR administered once daily are comparable to those achieved for the same total daily dose of Seroquel IR administered twice daily.
When Seroquel XR administered once daily is compared to the same total daily dose of Seroquel immediate release administered once daily, the AUC is comparable and the Cmax is 59% lower for Seroquel XR. The AUC and Cmax for the metabolite norquetiapine are 18% and 37% lower than Seroquel respectively.
In a study examining the effects of food on the bioavailability of quetiapine, a high-fat meal was found to produce statistically significant increases in the Seroquel XR Cmax (44-52%) and AUC (20-22%). In comparison, a light meal had no significant effect on the Cmax or AUC of quetiapine. It is recommended that Seroquel XR is taken once daily without food.
There are no clinically relevant differences in the observed apparent oral clearance (CL/F) and exposure of quetiapine between subjects with schizophrenia and bipolar disorder.
Distribution: Quetiapine is approximately 83% bound to plasma proteins.
Metabolism: Quetiapine is extensively metabolised by the liver. In vitro investigations established that CYP3A4 is likely to be the primary enzyme responsible for cytochrome P-450-mediated metabolism of quetiapine. Norquetiapine is primarily formed and eliminated via CYP3A4. CYP2D6 and CYP2C9 are also involved in quetiapine metabolism.
Quetiapine and several of its metabolites (including norquetiapine) were found to be weak to modest inhibitors of human CYP450, 3A4, 2C19, 2D6, 1A2 and 2C9 activities in vitro. In vitro CYP inhibition is observed only at concentrations approximately 5- to 50-fold higher than those observed at a dose range of 300-800 mg/day in humans. Based on these in vitro results, it is unlikely that co-administration of quetiapine with other medicines will result in clinically significant drug inhibition of CYP450-mediated metabolism of the other drug. From animal studies, it appears that quetiapine can induce CYP450 enzymes. In a specific interaction study in psychotic patients, however, no increase in the CYP450 activity was found after administration of quetiapine.
Elimination: The elimination half-lives of quetiapine and norquetiapine are approximately 7 hrs and 12 hrs, respectively.
Following administration of radiolabeled quetiapine, <5% of unchanged drug related material is accounted for in the urine or faeces. Approximately 73% of the radioactivity is excreted in the urine and 21% in the faeces. The average molar dose fraction of free quetiapine and the active human plasma metabolite norquetiapine is <5% excreted in the urine.
Special Populations: Gender: The kinetics of quetiapine do not differ between men and women.
Renal Impairment: The mean plasma clearance of quetiapine was reduced by approximately 25% in subjects with severe renal impairment (creatinine clearance <30 mL/min/1.73 m2), but the individual clearance values are within the range for normal subjects.
Hepatic Impairment: The mean plasma clearance of quetiapine was reduced by approximately 25% in subjects with hepatic impairment (stable alcoholic cirrhosis), but the individual clearance values are within the range for normal subjects. Since quetiapine is extensively metabolised by the liver, higher plasma levels are expected in the hepatically impaired population and dosage adjustment may be needed in these patients (see Dosage & Administration).
Elderly: The mean clearance of quetiapine in the elderly is approximately 30-50% lower than that seen in adults 18-65 years (see Dosage & Administration).
Toxicology: Preclinical Safety Data: Acute Toxicity Studies: Quetiapine has low acute toxicity. Findings in mice and rats after oral (500 mg/kg) or intraperitoneal (100 mg/kg) dosing were typical of an effective neuroleptic agent and included decreased motor activity, ptosis, loss of righting reflex, fluid around the mouth and convulsion.
Repeat-Dose Toxicity Studies: In multiple-dose studies in rats, dogs and monkeys, anticipated central nervous system effects of an antipsychotic drug were observed with quetiapine (eg, sedation at lower doses and tremor, convulsions or prostration at higher exposures).
Hyperprolactinemia, induced through the dopamine D2-receptor antagonist activity of quetiapine or its metabolites, varied between species but was most marked in rat, and a range of effects consequent to this were seen in the 12-month study, including mammary hyperplasia, increased pituitary weight, decreased uterine weight and enhanced growth of females.
Reversible morphological and functional effects on the liver, consistent with hepatic enzyme induction, were seen in mouse, rat and monkey.
Thyroid follicular cell hypertrophy and concomitant changes in plasma thyroid hormone levels occurred in rat and monkey.
Pigmentation of a number of tissues, particularly the thyroid, was not associated with any morphological or functional effects.
Transient increases in heart rate, unaccompanied by an effect on blood pressure, occurred in dogs.
Posterior triangular cataracts seen after 6 months in dogs at 100 mg/kg/day were consistent with inhibition of cholesterol biosynthesis in the lens. No cataracts were observed in Cynomolgus monkeys dosed up to 225 mg/kg/day, nor in rodents. Monitoring in clinical studies did not reveal drug-related corneal opacities in man.
No evidence of neutrophil reduction or agranulocytosis was seen in any of the toxicity studies.
Carcinogenecity Studies: In the rat study (doses 0 mg/kg/day, 20 mg/kg/day, 75 mg/kg/day and 250 mg/kg/day), the incidence of mammary adenocarcinomas was increased at all doses in female rats, consequential to prolonged hyperprolactinaemia. In male rat (250 mg/kg/day) and mouse (250 mg/kg/day and 750 mg/kg/day), there was an increased incidence of thyroid follicular cell benign adenomas, consistent with known rodent-specific mechanisms resulting from enhanced hepatic thyroxine clearance.
Reproduction Studies: Effects related to elevated prolactin levels (marginal reduction in male fertility and pseudopregnancy, protracted periods of diestrus, increased precoital interval and reduced pregnancy rate) were seen in rats, although these are not directly relevant to humans because of species differences in hormonal control of reproduction.
Teratogenicity: Quetiapine had no teratogenic effects.
Mutagenicity Studies: Genetic toxicity studies with quetiapine show that it is not a mutagen or clastogen.
Indications/Uses
Seroquel IR: Treatment of schizophrenia, manic episodes associated with bipolar disorder and major depressive episodes in bipolar disorder.
Seroquel XR: Bipolar Disorder: Maintenance treatment of bipolar I disorder, as monotherapy or in combination with lithium or sodium valproate, for the prevention of relapse/recurrence of manic, depressive or mixed episodes; treatment of depressive episodes associated with bipolar disorder (see Dosage & Administration); acute mania associated with bipolar I disorder as monotherapy or in combination with lithium or sodium valproate.
Efficacy of Seroquel XR in the treatment of bipolar disorder indications was established in part, on the basis of extrapolation from the established effectiveness of Seroquel.
Treatment of schizophrenia, prevention of relapse and maintenance of clinical improvement during continuation therapy.
Treatment of recurrent major depressive disorder (MDD) in patients who are intolerant of, or who have an inadequate response to alternative therapies.
Treatment of generalised anxiety disorder (GAD).
Dosage/Direction for Use
Chronic antipsychotic treatment should generally be reserved for patients who appear to suffer from a chronic illness that is known to respond to antipsychotic drugs and for whom alternative equally effective but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory response should be sought. The need for continued treatment should be re-assessed periodically.
Adults: Seroquel IR: Schizophrenia: Seroquel should be administered twice daily. The total daily dose for the first 4 days of therapy is 50 mg (day 1), 100 mg (day 2), 200 mg (day 3) and 300 mg (day 4).
From day 4 onwards, the dose should be titrated to the usual effective dose range of 300-450 mg/day. Depending on the clinical response and tolerability of the individual patient, the dose may be adjusted within the range of 150-750 mg/day.
Treatment of Manic Episodes Associated with Bipolar Disorder: Seroquel should be administered twice daily. As monotherapy or as adjunct therapy to mood stabilizers, the total daily dose for the first 4 days of therapy is 100 mg (day 1), 200 mg (day 2), 300 mg (day 3) and 400 mg (day 4). Further dosage adjustments up to 800 mg/day by day 6 should be in increments of no greater than 200 mg/day.
The dose may be adjusted depending on clinical response and tolerability of the individual patient within the range of 200-800 mg/day. The usual effective dose is in the range of 400-800 mg/day.
Treatment of Depressive Episodes in Bipolar Disorders: Seroquel should be administered once daily at bedtime, with or without food. The total daily dose for the first 4 days of therapy is 50 mg (day 1), 100 mg (day 2), 200 mg (day 3) and 300 mg (day 4). The recommended daily dose is 300 mg. In clinical trials, no additional benefit was seen in the 600-mg group compared to the 300-mg group. Individual patients may benefit from a 600-mg dose. In individual patients, in the event of tolerance concerns, clinical trials have indicated that dose reduction to a minimum of 200 mg could be considered. When treating depressive episodes in bipolar disorder, treatment should be initiated by physicians experienced in treating bipolar disorder.
Seroquel XR: Bipolar Disorder: Maintenance: Patients who have responded to Seroquel XR for acute treatment of bipolar disorder should continue therapy at the same dose. It is generally recommended that responding patients be continued beyond the acute response, but at the lowest possible dose needed to maintain remission. Prevention of relapse/recurrence of manic, depressive and mixed episodes in bipolar disorder: 300-800 mg/day (see Clinical Trials under Pharmacology under Actions).
The dose of Seroquel XR can be re-adjusted depending on the clinical response and tolerability of the individual patient. Patients should be periodically re-assessed to determine the need for maintenance treatment.
Bipolar Depression: When treating depressive episodes in bipolar disorder, treatment should be initiated either by the treating psychiatrist or by the general practitioner after consultation with the psychiatrist.
Seroquel XR should be titrated as follows: 50 mg (day 1), 100 mg (day 2), 200 mg (day 3) and 300 mg (day 4). Seroquel XR can be titrated to 400 mg on day 5 and up to 600 mg by day 8. Acute Mania: Seroquel XR should be titrated as follows: 300 mg (day 1), 600 mg (day 2) and up to 800 mg (after day 2), alone or in combination with a mood stabiliser.
The dose should be adjusted within the usual effective dose range of 400-800 mg/day, depending on the clinical response and tolerability of the individual patient.
Schizophrenia: The daily dose at the start of therapy is 300 mg (day 1), 600 mg (day 2) and up to 800 mg (after day 2). The dose should be adjusted within the usual effective dose range of 400-800 mg/day, depending on the clinical response and tolerability of the individual patient. For maintenance therapy in schizophrenia, no dosage adjustment is necessary. The safety of doses >800 mg/day has not been evaluated.
Recurrent MDD: When treating recurrent MDD in patients who are intolerant of, or who have an inadequate response to alternative therapies, treatment should be initiated either by the treating psychiatrist or by the general practitioner after consultation with the psychiatrist.
Seroquel XR should be administered once daily in the evening.
Initial dosing should begin at 50 mg on days 1 and 2, increased to 150 mg on days 3 and 4. The usual effective dose in MDD is 150 mg (see Clinical Trials under Pharmacology under Actions). Further adjustments can be made upwards or downwards within the recommended dose range of 50-300 mg depending upon the clinical response and tolerability of the patient.
Patients who have not responded to Seroquel XR after 6 weeks treatment for MDD should have treatment re-evaluated (see Clinical Trials under Pharmacology under Actions).
For maintenance therapy in MDD in patients who have responded to acute treatment, the effective dose during initial treatment should be continued. It is generally recommended that responding patients be continued beyond the acute response, but at the lowest possible dose needed to maintain remission. The dose can be adjusted within the recommended dose range depending upon the clinical response and tolerability of the patient. Patients should be periodically re-assessed to determine the need for maintenance treatment.
GAD: Initial dosing should begin at 50 mg on days 1 and 2, increased to 150 mg on days 3 and 4. Further adjustments can be made within the recommended dose range of 50-150 mg depending upon the clinical response and tolerability of the patient. Efficacy was demonstrated with Seroquel XR at doses ranging from 50-300 mg/day, however no additional benefit was seen with the 300-mg group compared to the 150-mg group (see Clinical Trials under Pharmacology under Actions). Doses >150 mg/day are not recommended.
For maintenance therapy in GAD, the effective dose during initial treatment should be continued. The dose can be adjusted within the recommended dose range depending upon the clinical response and tolerability of the individual patient.
Switching from Seroquel IR Tablets: For more convenient dosing, patients who are currently being treated with divided doses of Seroquel IR tablets may be switched to Seroquel XR at the equivalent total daily dose taken once daily (see Clinical Trials under Pharmacology under Actions). For example, patients administered Seroquel IR 300 mg twice daily (total daily dose of 600 mg) would be switched to a dose of Seroquel XR 600 mg once daily on the next calendar day. Individual dosage adjustments may be necessary.
Children and Adolescents (<18 years): The safety and efficacy of Seroquel XR have not been evaluated in patients <18 years, however clinical trials have been conducted with Seroquel in children and adolescents 10-17 years with bipolar mania (as monotherapy) and 13-17 years with schizophrenia (see Clinical Trials under Pharmacology under Actions).
Elderly: As with other antipsychotics, Seroquel should be used with caution in the elderly, especially during the initial dosing period. The rate of dose titration may need to be slower, and the daily therapeutic dose lower than that used in younger patients. The mean plasma clearance of quetiapine was reduced by 30-50% in elderly subjects when compared with younger patients.
Seroquel IR:
Elderly patients should be started on 25 mg/day. The dose should be increased daily in increments of 25-50 mg/day to an effective dose, which is likely to be lower than that in younger patients.
Seroquel XR: Elderly patients should be started on 50 mg/day. The dose can be increased in increments of 50 mg/day to an effective dose, depending on the clinical response and tolerability of the individual patient.
In elderly patients with MDD, initial dosing should begin at 50 mg on days 1-3, the dose can be increased to 100 mg on day 4, 150 mg on day 8 and then up to 300 mg depending on clinical response and tolerability.
In elderly patients with GAD, initial dosing should begin at 50 mg on days 1-3, the dose can be increased to 100 mg on day 4, 150 mg on day 8. Further adjustments can be made within the recommended dose range of 50-150 mg depending on clinical response and tolerability.
Efficacy and safety have not been evaluated in patients >65 years with depressive episodes in the framework of bipolar disorder.
Renal Impairment: Dosage adjustment is not necessary.
Hepatic Impairment: Quetiapine is extensively metabolised by the liver, and therefore, should be used with caution in patients with known hepatic impairment especially during the initial dosing period.
Seroquel IR: The oral clearance of quetiapine is reduced by approximately 25% in patients with renal or hepatic impairment. Initially, 25 mg/day. The dose should be increased daily, in increments of 25-50 mg to an effective dose.
Seroquel XR: Patients with hepatic impairment should be started on 50 mg/day. The dose can be increased in increments of 50 mg/day to an effective dose, depending on the clinical response and tolerability of the individual patient.
Administration: Seroquel IR should be administered twice daily, with or without food.
Seroquel XR should be administered once daily, without food.
The tablets should be swallowed whole and not split, chewed or crushed.
Overdosage
In clinical trials, experience with quetiapine in overdosage is limited. Survival has been reported in acute overdoses of quetiapine up to 30 g. Most patients who overdosed reported no adverse events or recovered fully from the reported events. Death has been reported in a clinical trial following an overdose of quetiapine 13.6 g alone. In post-marketing experience, there have been very rare reports of overdose of quetiapine alone resulting in death or coma.
In post-marketing experience, there were cases reported of QT prolongation with overdose.
Patients with preexisting severe cardiovascular disease may be at an increased risk of overdose. (See Precautions.)
In general, reported signs and symptoms were those resulting from an exaggeration of quetiapine's known pharmacological effects ie, drowsiness and sedation, tachycardia and hypotension.
Management of Overdose: There is no specific antidote to quetiapine. In cases of severe signs, the possibility of multiple drug involvement should be considered, and intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system. Whilst the prevention of absorption in overdose has not been investigated, administration of activated charcoal together with a laxative should be considered.
In cases of quetiapine overdose, refractory hypotension should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents (adrenaline and dopamine should be avoided, since β-stimulation may worsen hypotension in the setting of quetiapine-induced α-blockade).
Close medical supervision and monitoring should be continued until the patient recovers.
Contraindications
Hypersensitivity to quetiapine fumarate or to any of the components of Seroquel IR/Seroquel XR.
Special Precautions
Concomitant Cardiovascular Illness: Quetiapine should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease or other conditions predisposing to hypotension (dehydration, hypovolemia and treatment with antihypertensive medications).
Quetiapine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from pre-marketing clinical studies. Because of the risk of orthostatic hypotension with quetiapine, caution should be observed in cardiac patients.
Orthostatic Hypotension: Quetiapine may induce orthostatic hypotension associated with dizziness, tachycardia and in some patients, syncope especially during the initial dose titration period, probably reflecting its α1-adrenergic antagonist properties. Syncope has been commonly reported (see Adverse Reactions). Orthostatic hypotension, dizziness and syncope may lead to falls (see Adverse Reactions). If hypotension occurs during titration to the target dose, a return to the previous dose in the titration schedule is appropriate. This is more common in the elderly than in younger patients.
QT Interval: In clinical trials, quetiapine was not associated with a persistent increase in QTc intervals. However, in post-marketing experience, there were cases reported of QT prolongation with overdose (see Overdosage). As with other antipsychotics, caution should be exercised when quetiapine is prescribed in patients, including children and adolescents, with cardiovascular disease or family history of QT prolongation. Also, caution should be exercised when quetiapine is prescribed either with medicines known to prolong the QTc interval, and concomitant neuroleptics, especially the elderly, in patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia or hypomagnesaemia (see Interactions).
Seizures: In controlled clinical trials, there were no difference in the incidence of seizures in patients treated with quetiapine or placebo (see Adverse Reactions). As with other antipsychotics, caution is recommended when treating patients with a history of seizures or with conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of ≥65 years.
Clinical Worsening and Suicide Risk Associated with Psychiatric Disorders: The risk of suicide attempt is inherent in depression and may persist until significant remission occurs. The risk must be considered in all depressed patients.
Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviour (suicidality), whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. As improvement may not occur during the 1st few weeks or more of treatment, patients should be closely monitored for clinical worsening and suicidality, especially at the beginning of a course of treatment or at the time of dose changes, either increases or decreases, until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset or was not part of the patient's presenting symptoms.
Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition and/or the emergence of suicidal ideation/behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present. Patients with co-morbid depression associated with other psychiatric disorders being treated with antidepressants should be similarly observed for clinical worsening and suicidality.
Pooled analysis of 24 short-term (4-16 weeks) placebo-controlled trials of 9 antidepressant medicines [selective serotonin re-uptake inhibitors (SSRIs) and others] in 4400 children and adolescents with MDD (16 trials), obsessive compulsive disorder (4 trials) or other psychiatric disorders (4 trials) have revealed a greater risk of adverse events representing suicidal behaviour or thinking (suicidality) during the 1st few months of treatment in those receiving antidepressants. The average risk of such events in patients treated with an antidepressant was 4% compared with 2% of patients taking a placebo. There was considerable variation in risk among the antidepressants but there was a tendency towards an increase for almost all antidepressants studied. This meta-analysis did not include trials involving quetiapine.
The risk of suicidality was most consistently observed in the MDD trials but there were signals of risk arising from the trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in these trials. It is unknown whether the suicidality risk in children and adolescent patients extends to use beyond several months. The 9 antidepressant medicines in the pooled analyses included 5 SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and 4 non-SSRIs (bupropion, mirtazepine, nefazodone, venlafaxine).
Symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania and mania have been reported in adults, adolescents and children being treated with antidepressants for MDD as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either worsening of depression and/or emergence of suicidal impulses has not been established, there is concern that such symptoms may be precursors of emerging suicidality.
Families and caregivers of patients being treated with antidepressants for MDD or for any other condition (psychiatric or nonpsychiatric) should be informed about the need to monitor these patients for the emergence of agitation, irritability, unusual changes in behaviour and other symptoms described above, as well as emergence of suicidality, and to report such symptoms immediately to healthcare providers. It is particularly important that monitoring be undertaken during the initial few months of antidepressant treatment or at times of dose increase or decrease.
The possibility of a suicide attempt is inherent in schizophrenia; close supervision of high risk patients should accompany drug therapy.
Prescriptions for quetiapine should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.
Extrapyramidal Symptoms (EPS): In placebo-controlled clinical trials of adult patients with schizophrenia, bipolar mania and maintenance treatment of bipolar disorder, the incidence of EPS was no different from that of placebo across the recommended therapeutic dose range. In short-term, placebo-controlled clinical trials of adult patients with bipolar depression, MDD and GAD, the incidence of EPS was higher in quetiapine-treated patients than in placebo-treated patients (see Adverse Reactions).
Tardive Dyskinesia: Quetiapine should be prescribed in a manner that is most likely to minimise the occurrence of tardive dyskinesia.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and total cumulative dose of antipsychotic medicines administered to the patient increase. However, tardive dyskinesia can develop, although much less commonly after relatively brief treatment periods at low doses.
If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of quetiapine should be considered. The symptoms of tardive dyskinesia can worsen or even arise after discontinuation of treatment (see Adverse Reactions).
Neuroleptic Malignant Syndrome: Neuroleptic malignant syndrome has been associated with antipsychotic treatment, including quetiapine. Clinical manifestations include hyperthermia, altered mental status, muscular rigidity, autonomic instability and increased creatine phosphokinase (see Adverse Reactions). In such an event, quetiapine should be discontinued and appropriate medical treatment given.
Body Temperature Regulation: Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing quetiapine for patients who will be experiencing conditions which may contribute to an elevation in core body temperature eg, exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.
Somnolence: Quetiapine treatment has been associated with somnolence and related symptoms, eg, sedation (see Adverse Reactions). In clinical trials for treatment of patients with bipolar depression, onset was usually within the first 3 days of treatment and was predominantly of mild to moderate intensity. Bipolar depression patients experiencing somnolence of severe intensity may require more frequent contact for a minimum of 2 weeks from onset of somnolence, or until symptoms improve and treatment discontinuation may need to be considered.
Neutropenia: Severe neutropenia (neutrophil count <0.5 x 109/L) has been uncommonly reported in quetiapine clinical trials. Most cases of severe neutropenia have occurred within the first 2 months of starting therapy with quetiapine. There was no apparent dose relationship. Possible risk factors for neutropenia include preexisting low white cell count (WBC) and history of drug-induced neutropenia. Quetiapine should be discontinued in patients with a neutrophil count <1 x 109/L. Patients should be observed for signs and symptoms of infection and neutrophil counts followed (until they exceed 1.5 x 109/L) (see Adverse Reactions).
Withdrawal: Acute withdrawal symptoms eg, nausea, vomiting and insomnia have been described after abrupt cessation of antipsychotic medicines including quetiapine. Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (eg, akathisia, dystonia and dyskinesia) has been reported. Therefore, gradual withdrawal over a period of at least 1-2 weeks is advisable (see Adverse Reactions).
Hyperglycaemia and Diabetes Mellitus: Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including quetiapine (see Adverse Reactions). Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycaemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycaemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycaemia-related adverse events in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (eg, obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia and weakness. Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing.
In some cases, hyperglycaemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.
Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Quetiapine and other antipsychotic medicines should be used cautiously in patients at risk for aspiration pneumonia (eg, elderly patients).
Lipids: Increases in triglycerides and cholesterol and decreased in fasting HDL cholesterol have been observed in clinical trials with quetiapine (see Adverse Reactions). Monitoring is recommended at baseline and periodically during treatment for all patients. Lipid changes should be managed as clinically appropriate.
Metabolic Factors: In some patients, a worsening of more than one of the metabolic factors of weight, blood glucose and lipids was observed in clinical studies. Changes in these parameters should be managed as clinically appropriate.
Pancreatitis: Pancreatitis has been reported in clinical trials and during post-marketing experience. Among the post-marketing reports, many patients had factors which are known to be associated with pancreatitis such as increased triglycerides (see Lipids and in Effects on Laboratory Tests), gallstones and alcohol consumption.
Lactose: Seroquel IR/Seroquel XR contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Seroquel IR/Seroquel XR.
Effects on the Ability to Drive or Operate Machinery: Given its primary central nervous system effects, quetiapine may interfere with activities requiring mental alertness. Patients likely to drive or operate other machines should therefore be cautioned appropriately.
Carcinogenicity, Mutagenicity & Impairment of Fertility: Carcinogenicity: In the rat study (20 mg/kg/day, 75 mg/kg/day and 250 mg/kg/day), the incidence of mammary adenocarcinomas was increased at all doses in female rats, consequential to prolonged hyperprolactinaemia. The incidence of carcinoma of the adrenal cortex was increased in male rats at the highest dose.
In male rat (250 mg/kg/day) and mouse (250 mg/kg/day and 750 mg/kg/day), there was an increased incidence of thyroid follicular cell benign adenomas, consistent with known rodent-specific mechanisms resulting from enhanced hepatic thyroxine clearance.
Genotoxicity: Genetic toxicity studies with quetiapine show that it is not a mutagen or clastogen. Quetiapine showed no evidence of genotoxicity in a series of assays for gene mutation (bacteria and Chinese hamster ovary cells) and chromosomal damage (human lymphocytes and the in vivo micronucleus test).
Effects on Fertility: Effects related to elevated prolactin levels (marginal reduction in male fertility and pseudopregnancy, protracted periods of diestrus, increased precoital interval and reduced pregnancy rate) were seen in rats, although these are not directly relevant to humans because of species differences in hormonal control of reproduction.
Use in pregnancy: Pregnancy Category: C. The safety and efficacy of quetiapine during human pregnancy have not been established.
Neonates exposed to antipsychotic drugs during the 3rd trimester of pregnancy are at risk of extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied severity, while in some cases, symptoms have been self-limited, in other cases, neonates have required intensive care unit support and prolonged hospitalization. Seroquel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Teratogenic effects were not observed following administration of quetiapine at oral doses up to 200 mg/kg in rats (less than the exposure to quetiapine at the maximum recommended clinical dose based on AUC) and 100 mg/kg in rabbits (approximately twice the maximum clinical exposure based on BSA).
Use in lactation: There have been published reports of quetiapine excretion into human breast milk, however, the degree of excretion was not consistent. In a study in lactating rats, the concentration of quetiapine and/or its metabolites was higher in milk than in plasma. Women who are breastfeeding should therefore be advised to avoid breastfeeding while taking quetiapine.
Use in children & adolescents: The safety and efficacy of Seroquel IR/Seroquel XR have not been established in patients <18 years.
Paediatric schizophrenia and bipolar I disorder are serious mental disorders, however, diagnosis can be challenging. For paediatric schizophrenia, symptom profiles can be variable, and for bipolar I disorder, patients may have variable patterns of periodicity of manic or mixed symptoms. It is recommended that medication therapy for paediatric schizophrenia and bipolar I disorder be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the potential benefits and risks associated with medication treatment. Medication treatment for both paediatric schizophrenia and bipolar I disorder is indicated as part of a total treatment program that often includes psychological, educational and social interventions.
Efficacy and safety of Seroquel have been demonstrated in adolescents from 13 years with schizophrenia and in children/adolescents from 10 years with bipolar I disorder experiencing acute mania in 2 clinical trials of 3 weeks and 6 weeks duration, respectively. Safety data was provided for up to 26 weeks in a 3rd open-label safety and tolerability trial (see Clinical Trials under Pharmacology under Actions). The safety and efficacy of Seroquel in children and adolescents have not been assessed beyond these time periods.
Although not all adverse reactions that have been identified in adult patients have been observed in clinical trials with Seroquel in children and adolescents, the same precautions that appear above for adults should be considered for children and adolescents. As seen in adults, increases in TSH, serum cholesterol, triglycerides, and weight have been observed (see previously mentioned and Adverse Reactions).
The following events were reported more frequently in the short-term studies in children and adolescents than in studies in adults: EPS, increases in appetite and serum prolactin. Increased blood pressure has not been identified in the adult population but was seen in children and adolescents. Blood pressure should be monitored at the beginning of, and periodically during treatment in children and adolescents (see Adverse Reactions).
Long-term safety data including growth, maturation and behavioural development, beyond 26 weeks of treatment with Seroquel, are not available for children and adolescents (10-17 years).
Use in the elderly: Increased Risk of Mortality in Elderly Patients with Dementia-Related Psychosis: Elderly patients with dementia-related psychosis treated with atypical antipsychotics are at an increased risk of death compared to placebo. Seroquel IR: In a meta-analysis of atypical antipsychotic drugs, it has been reported that elderly patients with dementia-related psychosis are at an increased risk of death compared to placebo. In two 10-week, placebo-controlled Seroquel studies in the same population (n=710; mean age: 83 years; range: 56-99 years), the incidence of mortality in Seroquel-treated patients was 5.5% versus 3.2% in the placebo group. The patients in these trials died from a variety of causes that were consistent with expectations for this population. These data do not establish a causal relationship between Seroquel treatment and death in elderly patients with dementia. Seroquel XR: A meta-analysis of 17 placebo-controlled trials with dementia-related behavioural disorders showed a risk of death in the drug-treated patients of approximately 1.6-1.7 times that seen in placebo-treated patients. The clinical trials included in the meta-analysis were undertaken with olanzapine, aripiprazole, risperidone and quetiapine. Over the course of these trials averaging about 10 weeks in duration, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Quetiapine is not approved for the treatment of elderly patients with dementia-related psychosis or behavioural disorders.
Use In Pregnancy & Lactation
Use in pregnancy: Pregnancy Category: C. The safety and efficacy of quetiapine during human pregnancy have not been established.
Neonates exposed to antipsychotic drugs during the 3rd trimester of pregnancy are at risk of extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied severity, while in some cases, symptoms have been self-limited, in other cases, neonates have required intensive care unit support and prolonged hospitalization. Seroquel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Teratogenic effects were not observed following administration of quetiapine at oral doses up to 200 mg/kg in rats (less than the exposure to quetiapine at the maximum recommended clinical dose based on AUC) and 100 mg/kg in rabbits (approximately twice the maximum clinical exposure based on BSA).
Use in lactation: There have been published reports of quetiapine excretion into human breast milk, however, the degree of excretion was not consistent. In a study in lactating rats, the concentration of quetiapine and/or its metabolites was higher in milk than in plasma. Women who are breastfeeding should therefore be advised to avoid breastfeeding while taking quetiapine.
Adverse Reactions
Clinical Study Experience: Schizophrenia (Adults): The treatment-emergent adverse events that occurred during acute therapy (up to 6 weeks) of schizophrenia in at least 5% of patients treated with Seroquel XR in placebo-controlled trials are listed in Table 6 regardless of causality. (See Table 6.)

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Bipolar Disorder (Adults): The treatment-emergent adverse events that occurred during acute therapy of bipolar disorder in at least 5% of patients treated with Seroquel XR in placebo-controlled trials are listed in Table 7 regardless of causality. (See Table 7.)

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Major Depressive Disorder (Adults): The treatment-emergent adverse events that occurred during short-term monotherapy of MDD in at least 5% of patients treated with Seroquel XR in placebo-controlled trials are listed in Table 8 regardless of causality. (See Table 8.)

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The treatment-emergent adverse events that occurred during adjunct therapy (up to 6 weeks) of MDD in at least 5% of patients treated with Seroquel XR in placebo-controlled trials are listed in Table 9 regardless of causality. (See Table 9.)

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The pattern of adverse events in the elderly population treated with Seroquel XR (short-term monotherapy) was similar to that seen in younger patients, with somnolence, headache, dry mouth and dizziness predominating.
The treatment-emergent adverse events that occurred during maintenance monotherapy of MDD in at least 5% of patients treated with Seroquel XR in placebo-controlled trials are listed in Table 10 regardless of causality. (See Table 10.)

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Generalised Anxiety Disorder (Adults): The safety results of 5 placebo-controlled clinical trials show that Seroquel XR is generally safe and well-tolerated when used for treatment of GAD. The treatment-emergent adverse events that occurred in at least 5% of patients (regardless of causality) treated with Seroquel XR in non-elderly placebo-controlled trials are listed in Tables 11 (pooled non-elderly short term trials) and 12 (non-elderly maintenance trial). The pattern of adverse events in the elderly population treated with Seroquel XR (short-term monotherapy) was similar to that seen in younger patients, with somnolence, dry mouth, dizziness and headache predominating. (See Tables 11 and 12.)

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Other Findings Observed During Clinical Studies: Somnolence: Somnolence may occur, usually during the first 2 weeks of treatment and generally resolves with the continued administration of quetiapine. Somnolence may lead to falls.
Weight Gain (Adults): In schizophrenia trials, the proportions of patients meeting a weight gain criterion of ≥7% of bodyweight from baseline were 10% for Seroquel XR compared to 5% for placebo. In Seroquel XR mania trials, the proportions of patients meeting the same weight gain criterion were 5.1% compared to 0% for placebo. In bipolar depression trials, the proportions of patients meeting the same weight gain criterion were 8.2% for Seroquel XR compared to 0.8% for placebo. In MDD monotherapy trials (8 weeks), the proportions of patients meeting the same weight gain criterion were 3.9% for Seroquel XR compared to 2.4% for placebo. In MDD adjunctive therapy trials (6 weeks), the proportions of patients meeting the same weight gain criterion were 5.1% for Seroquel XR compared to 1.7% for placebo.
In schizophrenia trials, the proportions of patients meeting a weight gain criterion of ≥7% of bodyweight from baseline were compared in a pool of four 3- to 6-week placebo-controlled clinical trials, revealing a statistically significantly greater incidence of weight gain for Seroquel (23%) compared to placebo (6%). In Seroquel mania monotherapy trials, the proportions of patients meeting the same weight gain criterion were 21% compared to 7% for placebo and in mania adjunct therapy trials, the proportion of patients meeting the same weight criterion were 13% for Seroquel compared to 4% for placebo. In bipolar depression trials, the proportions of patients meeting the same weight gain criterion were 8% for Seroquel compared to 2% for placebo.
Withdrawal (Discontinuation Symptoms): In acute, placebo-controlled, monotherapy clinical trials in adults which evaluated discontinuation symptoms, the aggregated incidence of discontinuation symptoms after abrupt cessation was 16% for quetiapine and 7.3% for placebo. The aggregated incidence of individual adverse events (eg, insomnia, nausea, headache, diarrhoea, vomiting, dizziness and irritability) did not exceed 6.7% in any treatment group and usually resolved after 1 week post-discontinuation (see Precautions).
Leukopenia/Neutropenia: Possible risk factors for leukopenia and/or neutropenia include preexisting low white cell count and history of drug-induced leukopenia and/or neutropenia. Neutrophil count decreases have commonly been observed. In all short-term placebo-controlled, monotherapy clinical trials, among patients with a baseline neutrophil count ≥1.5 x 109/L, the incidence of at least 1 occurrence of neutrophil count <1.5 x 109/L was 1.9% in patients treated with quetiapine, compared to 1.3% in placebo-treated patients. The incidence ≥0.5 to <1.0 x 109/L (moderate neutropenia) was 0.2% (uncommon) in patients treated with quetiapine and 0.2% in placebo-treated patients. In clinical trials conducted prior to a protocol amendment for discontinuation of patients with treatment-emergent neutrophil count <1.0 x 109/L, among patients with a baseline neutrophil count ≥1.5 x 109/L, the incidence of at least 1 occurrence of neutrophil count <0.5 x 109/L (severe neutropenia) was 0.21% (uncommon) in patients treated with quetiapine and 0% in placebo-treated patients (see Precautions).
Lipid Changes (Adults): In schizophrenia trials, the proportions of patients with elevations to levels of cholesterol ≥6.2064 mmol/L and triglycerides ≥2.258 mmol/L were 9% and 18% for Seroquel XR-treated patients, respectively, compared to 9% and 5% for placebo-treated patients, respectively. In bipolar mania trials, the proportion of patients with cholesterol and triglycerides elevations to these levels were 7% and 15% for Seroquel XR-treated patients, respectively, compared to 4% and 6% for placebo-treated patients, respectively. In bipolar depression trials, the proportion of patients with cholesterol and triglycerides elevations to these levels were 7% and 8% for Seroquel XR-treated patients, respectively, compared to 3% and 8% for placebo-treated patients, respectively. In MDD monotherapy trials (8 weeks), the proportion of patients with cholesterol and triglycerides elevations to these levels were 5% and 12% for Seroquel XR treated patients, respectively, compared to 3% and 9% for placebo-treated patients, respectively. In MDD adjunctive therapy trials (6 weeks), the proportion of patients with cholesterol and triglycerides elevations to these levels were 17% and 16% for Seroquel XR-treated patients, respectively, compared to 6% and 5% for placebo-treated patients, respectively.
In schizophrenia trials, the proportions of patients with elevations to levels of cholesterol ≥6.2064 mmol/L and triglycerides ≥2.258 mmol/L were 16% and 23% for Seroquel-treated patients, respectively, compared to 7% and 16% for placebo-treated patients, respectively. In bipolar depression trials, the proportion of patients with cholesterol and triglycerides elevations to these levels were 9% and 14% for Seroquel-treated patients, respectively, compared to 6% and 9% for placebo-treated patients, respectively.
In placebo controlled trials decreases in fasting HDL cholesterol have been observed. In short-term placebo-controlled clinical trials the incidence of patients who shifted from ≥1.025 mmol/L to <1.025 mmol/L was slightly higher in the quetiapine group compared to placebo (9.8% and 8.1% respectively). In long-term trials the incidence of patients who shifted from ≥1.025 mmol/L to <1.025 mmol/L was 18.3% in quetiapine and 10.9% in placebo.
Increases in Blood Glucose Levels: In placebo-controlled clinical trials in adults, the percentage of patients who had a shift to a high blood glucose level (fasting blood glucose ≥7 mmol/L or a non-fasting blood glucose ≥11.1 mmol/L on at least 1 occasion) was 5.1% in patients treated with quetiapine and 4.2% in placebo-treated patients (see Precautions).
Decreases in Haemoglobin Levels: Decreased haemoglobin to 8.07 mmol/L males, 7.45 mmol/L females on at least 1 occasion occurred in 11% of quetiapine patients in all trials including open-label extensions. In short-term, placebo-controlled trials, decreased haemoglobin to 8.07 mmol/L males, 7.45 mmol/L females on at least 1 occasion in 8.3% of quetiapine patients compared to 6.2% of placebo patients.
Extrapyramidal Symptoms (EPS) (Adults): The following clinical trials included treatment with Seroquel and Seroquel XR. In short-term, placebo-controlled clinical trials in schizophrenia and bipolar mania, the aggregate incidence of EPS was similar to placebo (schizophrenia: quetiapine 7.8%, placebo 8%; bipolar mania quetiapine 11.2%, placebo 11.4%). In short-term, placebo-controlled clinical trials in bipolar depression, the aggregate incidence of EPS from the combined data was 8.9% for quetiapine compared to 3.8% for placebo, though the incidence of the individual adverse events (eg, akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, involuntary muscle contractions, psychomotor hyperactivity and muscle rigidity) were generally low and did not exceed 4% in any treatment group. In short-term, placebo-controlled, monotherapy clinical trials in MDD, the aggregated incidence of EPS was 5.4% for Seroquel XR and 3.2% for placebo. In a short-term, placebo-controlled, monotherapy trial in elderly patients with MDD, the aggregated incidence of EPS was 9% for Seroquel XR and 2.3% for placebo. In 2 placebo-controlled, short-term, adjunct therapy clinical trials for the treatment of MDD utilising between 150 mg and 300 mg of Seroquel XR, the incidence of any adverse reactions potentially related to EPS was 5.1% for Seroquel XR and 4.2% for the placebo group. In short-term, placebo-controlled monotherapy clinical trials in GAD, the aggregated incidence of EPS was 4.9% for Seroquel XR and 3.2% for placebo. In a short-term, placebo-controlled monotherapy trial in elderly patients with GAD, the aggregated incidence of EPS was 5.4% for Seroquel XR and 2.2% for placebo. In long-term studies of schizophrenia, bipolar disorder, MDD and GAD, the aggregated exposure adjusted incidence of treatment emergent EPS was similar between quetiapine and placebo. (See Precautions.)
Irritability: In acute placebo-controlled clinical trials in patients ≥18 years, the incidence of irritability was 2.3% for quetiapine and 1.7% for placebo.
Dysphagia: An increase in the rate of dysphagia with quetiapine versus placebo was only observed in the adult clinical trials in bipolar depression.
Others: In addition to the previous text, the following adverse drug reactions have also been observed in adult clinical trials (placebo-controlled, active-arm controlled and open-label uncontrolled trials) with quetiapine:
Very Common (≥10%): Nervous System Disorders: Extrapyramidal symptoms.
Common (≥1% to <10%): Eye Disorders: Blurred vision.
Cardiac Disorders: Tachycardia2. Palpitations4.
Gastrointestinal Disorders: Vomiting6.
General Disorders and Administration Site Conditions: Mild asthenia, peripheral oedema, irritability, pyrexia.
Investigations: Elevations in serum transaminases (ALT, AST), γ-GT levels8 and serum prolactin3. Decreases in total T4, free T4 and total T3 and increases in TSH5. Eosinophils increased7.
Nervous System Disorders: Syncope2, dysarthria.
Metabolism & Nutritional Disorders: Increased appetite.
Psychiatric Disorders: Abnormal dreams and nightmares.
Respiratory, Thoracic and Mediastinal Disorders: Rhinitis. Dyspnoea4.
Uncommon (≥0.1% to <1%): Cardiac Disorders: Bradycardia9.
Gastrointestinal Disorders: Dysphagia2.
Investigations: Decreased platelet count1. Decreases in free T35.
Immune System Disorders: Hypersensitivity.
Nervous System Disorders: Seizure2, restless legs syndrome, tardive dyskinesia2.
Rare (≥0.01% to <0.1%): General Disorders and Administration Site Conditions: Neuroleptic malignant syndrome2, hypothermia.
Investigations: Elevations in blood creatine phosphokinase (not associated with neuroleptic malignant syndrome). Reproductive System and Breast Disorders: Priapism.
Psychiatric Disorders: Somnambulism and other related events.
1Platelets ≤100 x 109/L on at least one occasion.
2See Precautions.
3Prolactin Levels (Patients ≥18 Years): >20 mcg/L males; >30 mcg/L females at any time.
4These reports often occurred in the setting of tachycardia, dizziness, orthostatic hypotension and/or underlying cardiac/respiratory disease.
5Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline in all trials. Shifts in total T4, free T4, total T3 and free T3 are defined as <0.08x LLN (pmol/L) and shift in TSH is >5 mIU/L at any time.
6Based upon the increased rate of vomiting in elderly patients (≥65 years of age).
7Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline in all trials. Shifts in eosinophils are defined as ≥1x109 cells/L at any time.
8Asymptomatic elevations (shift from normal to ≥3 x ULN at any time) in serum transaminases (ALT and AST) or γ-GT levels have been observed in some patients administered quetiapine. These elevations were usually reversible on continued quetiapine treatment.
9May occur at or near initiation of treatment and be associated with hypotension and/or syncope. Frequency based on adverse event reports of bradycardia and related events in all clinical trials with quetiapine.
Children and Adolescents: The same adverse drug reactions described for adults should be considered for children and adolescents. The following are adverse drug reactions that occur in a higher frequency category in children and adolescents patients (10-17 years are summarised as follows) than in the adult population, or adverse drug reactions that have not been identified in the adult population:
Very Common (≥10%): Metabolism & Nutrition Disorders: Increased appetite.
Investigations: Elevations in serum prolactin1, increases in blood pressure2.
Gastrointestinal Disoders: Vomiting.
Common (≥1% to <10%): Repiratory, Thoracic & Mediastinal Disorders: Rhinitis.
Nervous System Disorders: Syncope.
1Prolactin Levels (Patients <18 Years): >20 mcg/L males; >26 mcg/L females at any time. Less than 1% of patients had an increase to a prolactin level >100 mcg/L.
2Based on shifts above clinically significant thresholds (adapted from the National Institutes of Health criteria) or increases >20 mmHg for systolic or >10 mmHg for diastolic blood pressure at any time in 2 acute (3-6 weeks) placebo-controlled trials in children and adolescents.
3Refer to text as follows.
Weight Gain (Children and Adolescents): In one 6-week, placebo-controlled trial in adolescent patients (13-17 years) with schizophrenia, the mean increase in bodyweight, was 2 kg in the Seroquel group and -0.4 kg in the placebo group. Twenty-one percent (21%) of Seroquel-treated patients and 7% of placebo-treated patients gained ≥7% of their bodyweight.
In one 3-week, placebo-controlled trial in children and adolescent patients (10-17 years) with bipolar mania, the mean increase in bodyweight was 1.7 kg in the Seroquel group and 0.4 kg in the placebo group. Twelve percent (12%) of Seroquel-treated patients and 0% of placebo-treated patients gained ≥7% of their bodyweight.
In the open-label study that enrolled patients from the above 2 trials, 63% of patients (241/380) completed 26 weeks of therapy with Seroquel. After 26 weeks of treatment, the mean increases in bodyweight and body mass index (BMI) were 4.4 kg and 1.1 kg/m2, respectively. Fourty-five percent (45%) of the patients gained ≥7% of their bodyweight (not adjusted for normal growth). 18.3% of the patients had a clinically significant change in BMI (adjusted for growth).
Extrapyramidal Symptoms (EPS) (Children and Adolescents): In a short-term, placebo-controlled monotherapy trial in adolescent patients (13-17 years) with schizophrenia, the aggregated incidence of EPS was 12.9% for Seroquel and 5.3% for placebo, though the incidence of the individual adverse events (eg, akathisia, tremor, extrapyramidal disorder, hypokinesia, restlessness, psychomotor hyperactivity, muscle rigidity, dyskinesia) was generally low and did not exceed 4.1% in any treatment group. In a short-term, placebo-controlled monotherapy trial in children and adolescent patients (10-17 years) with bipolar mania, the aggregated incidence of EPS was 3.6% for Seroquel and 1.1% for placebo.
Suicide/Suicidal Thoughts or Clinical Worsening (All Ages): In short-term, placebo-controlled clinical trials across all indications and ages, the incidence of suicide-related events was 0.8% for both quetiapine (75/9238) and placebo (37/4745).
In these trials of patients with schizophrenia, the incidence of suicide-related events was 1.4% (3/212) for quetiapine and 1.6% (1/62) for placebo in patients 18-24 years, 0.8% (13/1663) for quetiapine and 1.1% (5/463) for placebo in patients ≥25 years, and 1.4% (2/147) for quetiapine and 1.3% (1/75) for placebo in patients <18 years.
In these trials of patients with bipolar mania, the incidence of suicide-related events was 0% for both quetiapine (0/60) and placebo (0/58) in patients 18-24 years, 1.2% for both quetiapine (6/496) and placebo (6/503) in patients ≥25 years, and 1% (2/193) for quetiapine and 0% (0/90) for placebo in patients <18 years.
In these trials of patients with bipolar depression, the incidence of suicide-related events was 3% (7/233) for quetiapine and 0% (0/120) for placebo in patients 18-24 and 1.8% for both quetiapine (19/1616) and placebo (11/622) in patients ≥25 years. There have been no trials conducted in patients <18 years with bipolar depression.
In these trials of patients with MDD, the incidence of suicide-related events was 2.1% (3/144) for quetiapine and 1.3% (1/75) for placebo in patients 18-24 and 0.6% (11/1798) for quetiapine and 0.7% for placebo (7/1054) in patients ≥25 years. There have been no trials conducted in patients <18 years with MDD.
In these trials of patients with GAD, the incidence of suicide-related events was 0.5% for quetiapine (1/194) and 0.9% for placebo (1/109) in patients 18-24 years and 0.6% for quetiapine (7/1810) and 0.1% for placebo (1/983) in patients ≥25 years. There have been no trials conducted in patients <18 years with GAD (see Precautions).
Cataracts/Lens Opacities: In a clinical trial to evaluate the cataractogenic potential of Seroquel (200-800 mg/day) versus risperidone (2-8 mg/day) in patients with schizophrenia or schizoaffective disorder, the percentage of patients with increased lens opacity grade was not higher in Seroquel compared with risperidone for patients with at least 21 months of exposure.
Post-Marketing Experience: Rare (≥0.01 to <1%): Reproductive System & Breast Disorders: Galactorrhea.
Very Rare (<0.01%): Immune System Disorders: Anaphylactic reaction.
Very rare cases of cataract and urinary retention have been reported in the post-marketing data, but no causal link between these reports and quetiapine has been established.
Very rare cases of exacerbation of preexisting diabetes have been reported.
There have been rare post-marketing reports of pancreatitis. Among the post-marketing reports, many patients had factors which are known to be associated with pancreatitis such as increased triglycerides (see discussion on Lipids and Effects on Laboratory Tests), gallstones and alcohol consumption.
Drug Interactions
Antipsychotic and Other Centrally-Acting Medicines: Given the primary central nervous system effects of quetiapine, it should be used with caution in combination with other centrally-acting drugs and alcohol.
Thioridazine: Thioridazine (200 mg twice daily) increased the oral clearance of quetiapine (300 mg twice daily) by 65%.
Lorazepam: The mean oral clearance of lorazepam (2 mg, single dose) was reduced by 20% in the presence of quetiapine administered as 250 mg 3 times daily. Dosage adjustment is not required.
Levodopa and Dopamine Agonists: As it exhibits in vitro dopamine antagonism, quetiapine may antagonise the effects of levodopa and dopamine agonists.
Potential interactions that have been excluded: Antipsychotics: The pharmacokinetics of quetiapine were not significantly altered following co-administration with the antipsychotics risperidone (3 mg twice daily) or haloperidol (7.5 mg twice daily). The pharmacokinetics of lithium were not altered when co-administered with quetiapine (250 mg 3 times daily). The pharmacokinetics of sodium valproate and quetiapine were not altered to a clinically relevant extent when co-administered.
Imipramine and Fluoxetine: See CYP inhibitors as follows.
CYP Inhibitors: CYP3A4 is the primary enzyme responsible for CYP450-mediated metabolism of quetiapine (see Pharmacokinetics under Actions).
CYP3A4 Inhibitors (eg, Azole Antifungals, Macrolide Antibiotics and Protease Inhibitors): During concomitant administration of medicines which are potent CYP3A4 inhibitors (eg, azole antifungals, macrolide antibiotics and protease inhibitors), plasma concentrations of quetiapine can be significantly higher than observed in patients in clinical trials (see Ketoconazole as follows). As a consequence of this, lower doses of quetiapine should be used. Special consideration should be given in elderly or debilitated patients. The risk-benefit ratio needs to be considered on an individual basis.
It is also not recommended to take quetiapine together with grapefruit juice.
Ketoconazole: In a multiple-dose trial in healthy volunteers to assess the pharmacokinetics of quetiapine given before and during treatment with ketoconazole, co-administration of ketoconazole (200 mg once daily for 4 days) resulted in an increase in mean Cmax and AUC of quetiapine of 335% and 522%, respectively, with a corresponding decrease in mean oral clearance of 84%. The mean half-life (t½) of quetiapine increased from 2.6 to 6.8 hrs, but the mean Tmax was unchanged.
Potential interactions that have been excluded: Cimetidine: The pharmacokinetics of quetiapine (150 mg 3 times daily) was not significantly altered (20% decrease in clearance) following co-administration with cimetidine (400 mg 3 times daily for 4 days), a known P-450 enzyme inhibitor. Dosage adjustment for quetiapine is not required when it is given with cimetidine.
Imipramine and Fluoxetine: The pharmacokinetics of quetiapine was not significantly altered following co-administration with the antidepressants imipramine (75 mg twice daily; a known CYP2D6 inhibitor) or fluoxetine (60 mg once daily; a known CYP3A4 and CYP2D6 inhibitor).
Hepatic Enzyme Inducers (eg, Carbamazepine and Phenytoin): Quetiapine (administration of multiple daily doses up to 750 mg/day, on a 3 times daily dosing schedule) did not induce the hepatic enzyme systems involved in the metabolism of antipyrine. However, concomitant use of quetiapine with hepatic enzyme inducers eg, carbamazepine or phenytoin may substantially decrease systemic exposure to quetiapine (see Carbamazepine and Phenytoin as follows). Depending on clinical response, increased doses of quetiapine may be required to maintain control of psychotic symptoms in patients co-administered with quetiapine and hepatic enzyme inducers (eg, carbamazepine, phenytoin, barbiturates, rifampicin, glucocorticoids). The safety of doses >800 mg/day has not been established in the clinical trials. Continued treatment at higher doses should only be considered as a result of careful consideration of the benefit-risk assessment for an individual patient.
The dose of quetiapine may need to be reduced if phenytoin, carbamazepine or other hepatic enzyme inducers are withdrawn and replaced with a non-inducer (eg, sodium valproate).
Carbamazepine and Phenytoin: In a multiple-dose trial in patients to assess the pharmacokinetics of quetiapine given before and during treatment with carbamazepine (a known hepatic enzyme inducer), co-administration of carbamazepine significantly increased the clearance of quetiapine. This increase in clearance reduced systemic quetiapine exposure (as measured by AUC) to an average of 13% of the exposure during administration of quetiapine alone; although a greater effect was seen in some patients. As a consequence of this interaction, lower plasma concentrations can occur, and hence, in each patient, consideration for a higher dose of quetiapine, depending on clinical response, should be considered.
Co-administration of quetiapine (250 mg 3 times daily) and phenytoin (100 mg 3 times daily; another microsomal enzyme inducer) also caused increases in clearance of quetiapine by 5-fold.
Cardiovascular Medicines: Caution should be used when quetiapine is used concomitantly with medicines known to cause electrolyte imbalance or to increase QTc interval (see QT Interval under Precautions).
Because of its potential for inducing hypotension, quetiapine may enhance the effects of certain antihypertensive medicines.
Medications to Manage Attention Deficit Hyperactivity Disorder (ADHD): The data regarding safety and efficacy of Seroquel for the treatment of bipolar mania in children and adolescents receiving psychostimulants for co-morbid ADHD are limited. Therefore, concomitant use of ADHD medication and quetiapine is not recommended. If concomitant therapy is considered necessary, patients should be carefully monitored for the effect of the combination of treatments on the signs and symptoms of both ADHD and acute mania. Effects on blood pressure may be cumulative and blood pressure should be carefully monitored.
Effects on Laboratory Tests: Leukopenia and/or Neutropenia: As with other antipsychotics, transient leukopenia and/or neutropenia have been observed in patients administered with quetiapine. Possible risk factors for leukopenia and/or neutropenia include preexisting low white cell count and history of drug-induced leukopenia and/or neutropenia. Occasionally, eosinophilia has been observed (see Adverse Reactions).
Serum Transaminase: Asymptomatic elevations in serum transaminase (ALT, AST) or γ-GT levels have been observed in some patients administered with quetiapine. These elevations were usually reversible on continued quetiapine treatment (see Adverse Reactions).
Lipids: Increases in triglyceride levels and total cholesterol (predominantly LDL cholesterol) have been observed during treatment with quetiapine. Decreases in fasting HDL cholesterol have also been observed (see Adverse Reactions). Thyroid Hormone Levels: Quetiapine treatment was associated with dose-related decreases in thyroid hormone levels. In short-term placebo-controlled clinical trials, the incidence of potentially clinically significant shifts in thyroid hormone levels were: total T4 - 3.4% for quetiapine versus 0.6% for placebo; free T4 - 0.7% for quetiapine versus 0.1% for placebo; total T3 - 0.54% for quetiapine versus 0.0% for placebo and free T3 - 0.2% for quetiapine versus 0.0% for placebo. The incidence of shifts in TSH was 3.2% for quetiapine versus 2.7% for placebo. In short term placebo-controlled monotherapy trials, the incidence of reciprocal, potentially clinically significant shifts in T3 and TSH was 0.0% for both quetiapine and placebo and 0.1% for quetiapine versus 0.0% for placebo for shifts in T4 and TSH. As supported by the literature, these changes in thyroid hormone levels are generally not associated with clinically symptomatic hypothyroidism. The reduction in total and free T4 was maximal within the first 6 weeks of quetiapine treatment, with no further reduction during long-term treatment. In nearly all cases, cessation of quetiapine treatment was associated with a reversal of the effects on total and free T4, irrespective of the duration of treatment. See Adverse Reactions.
Methadone and Tricyclic Antidepressant Enzyme Immunoassays: There have been reports of false-positive results in enzyme immunoassays for methadone and tricyclic antidepressants in patients who have taken quetiapine. Confirmation of questionable immunoassay screening results by an appropriate chromatographic technique is recommended.
Incompatibilities: None known.
Storage
Do not store above 30°C.
MIMS Class
ATC Classification
N05AH04 - quetiapine ; Belongs to the class of diazepines, oxazepines and thiazepines antipsychotics.
Presentation/Packing
Seroquel IR: Film-coated tab 25 mg (peach, round, 6 mm, biconvex) x 60's. 100 mg (yellow, round, 8.5 mm, biconvex) x 60's. 200 mg (white, round, 11 mm, biconvex) x 60's.
Seroquel XR: Extended-release tab 50 mg (peach, capsule-shaped, embossed with "XR 50" on one side and plain on the other) x 60's. 200 mg (yellow, capsule-shaped, embossed with "XR 200" on one side and plain on the other) x 60's. 300 mg (pale yellow, capsule-shaped, embossed with "XR 300" on one side and plain on the other) x 60's.
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