Seroquel XR

Seroquel XR Mechanism of Action

quetiapine

Manufacturer:

AstraZeneca

Distributor:

DKSH
Full Prescribing Info
Action
Pharmacotherapeutic Group: Antipsychotics. ATC Code: N05A H04.
Pharmacology: Pharmacodynamics: 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 dopamine D2 receptors which is believed to contribute to the clinical antipsychotic properties and low extrapyramidal side effect (EPS) liability of quetiapine compared to typical antipsychotics. Additionally, norquetiapine has high affinity for the norepinephrine transporter (NET). Quetiapine and norquetiapine also have high affinity at histaminergic and adrenergic alpha1receptors, with a lower affinity at adrenergic alpha2 and serotonin 5HT1A receptors. Quetiapine has no appreciable affinity at cholinergic muscarinic or benzodiazepine receptors.
Pharmacodynamic Effects: Quetiapine is active in tests for antipsychotic activity, such as conditioned avoidance. It also reverses the action of dopamine agonists, measured either behaviourally or electrophysiologically, and elevates dopamine metabolite concentrations, a neurochemical index of dopamine D2 receptor blockade.
In pre-clinical 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-sensitized or drug-naive Cebus monkeys after acute and chronic administration.
Clinical Efficacy: Schizophrenia: The efficacy of Seroquel XR in the treatment of schizophrenia was demonstrated in one 6-week placebo-controlled trial in patients who met DSM-IV criteria for schizophrenia, and one active-controlled Seroquel-to-Seroquel XR switching study in clinically stable outpatients with schizophrenia.
The primary outcome variable in the placebo-controlled trial was change from baseline to final assessment in the PANSS total score. 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 the 6-week active-controlled switching study, the primary outcome variable was the proportion of patients who showed lack of efficacy i.e., who discontinued study treatment due to lack of efficacy or whose PANSS total score increased 20% or more from randomisation to any visit. In patients stabilised on Seroquel 400 to 800 mg, efficacy was maintained when patients were switched to an equivalent daily dose of Seroquel XR given once daily.
In a long-term study on stable schizophrenic patients who had been maintained on Seroquel XR for 16 weeks, Seroquel XR was more effective than placebo in preventing relapse. The estimated risks of relapse after 6 months treatments was 14.3% for the Seroquel XR treatment group compared to 68.2% for placebo. The mean dose was 669 mg.
Bipolar Mania: In a clinical trial, Seroquel XR has been shown to be effective as monotherapy in reducing manic symptoms in patients with bipolar mania at doses between 400 and 800 mg/day. The effect of Seroquel XR was significant at Day 4 and was maintained through the end of the trial (Week 3).
In clinical trials, quetiapine (Seroquel) has been shown to be effective as monotherapy or as adjunct therapy in reducing manic symptoms in patients with bipolar mania. The mean last week median dose of quetiapine in responders, was approximately 600 mg/day and approximately 85% of the responders were in the dose range of 400 to 800 mg/day.
Bipolar Depression: In a clinical trial, which included patients who are bipolar I, bipolar II and patients with and without rapid cycling courses, Seroquel XR has been shown to be effective in patients with bipolar depression at doses of 300 mg/day. Seroquel XR was superior to placebo in reduction of MADRS total score. The antidepressant effect of Seroquel XR was significant at Day 8 (Week 1) and was maintained through the end of the trial (Week 8).
In two clinical trials, which included patients who are bipolar I, bipolar II and patients with and without rapid cycling courses, Seroquel has been shown to be effective in patients with bipolar depression at doses of 300 and 600 mg/day, however, no additional benefit was seen with the 600 mg dose during short-term treatment.
In both studies, Seroquel was superior to placebo in reduction of MADRS total score. The antidepressant effect of Seroquel was significant at Day 8 (Week 1) and was maintained through the end of the studies (Week 8). Treatment with either Seroquel 300 or 600 mg at bedtime reduced depressive symptoms and anxiety symptoms in patients with bipolar depression. There were fewer episodes of treatment emergent mania with either dose of Seroquel than with placebo. For the 300 mg dose group, statistically significant improvements over placebo were seen in reductions in suicidal thinking as measured by MADRS item 10 and overall quality of life and satisfaction related to various areas of functioning, as measured using the Q-LES-Q (SF).
In two bipolar depression clinical trials with Seroquel, maintenance of antidepressant efficacy was established. These trials included an 8-week placebo-controlled acute phase, followed by a placebo-controlled continuation phase of at least 26 weeks but up to 52 weeks in duration. Patients were required to be stable at the end of the acute phase in order to be in the randomized into continuation phase. In both trials, Seroquel was superior to placebo in increasing the time to recurrence of any mood event (depressed, mixed or manic). The risk reduction from the pooled trials was 49%. The risk of a mood event for Seroquel versus placebo was reduced by 41% for the 300-mg dose and by 55% for the 600-mg dose.
Preventing recurrence in maintenance treatment of bipolar disorder: The efficacy of Seroquel in the monotherapy treatment for recurrence prevention was established in 1 placebo-controlled trial in 1226 patients who met DSM-IV criteria for Bipolar I Disorder. The trial included patients whose most recent mood episode was manic, mixed, or depressive, with or without psychotic features. In the open-label phase, patients were required to be stabilised on Seroquel for a minimum of 4 weeks in order to be randomized. In the randomization phase, patients either continued treatment with Seroquel (300 to 800 mg per day: average dose 546 mg per day) or were to receive lithium or placebo for up to 104 weeks. Seroquel was superior to placebo in increasing the time to recurrence of any mood event (manic, mixed, or depressive), the primary endpoint. The risk reductions were 74%, 73%, and 75% for mood, manic and depressive events, respectively.
The efficacy of Seroquel in the combination treatment for recurrence prevention was established in 2 placebo-controlled trial in 1326 patients who met DSM-IV criteria for Bipolar I Disorder. The trials included patients whose most recent mood episode was manic, mixed, or depressive, with or without psychotic features. In the open-label phase, patients were required to be stabilised on Seroquel in combination with mood stabilizer (lithium or valproate) for a minimum of 12 weeks in order to be randomized. In the randomisation phase, patients either continued treatment with Seroquel (400 to 800 mg per day average dose 507 mg per day) in combination with mood stabiliser or received placebo in combination with mood stabiliser for up to 104 weeks. Seroquel was superior to placebo in increasing the time to recurrence of any mood event (manic, mixed or depressive), the primary endpoint. The risk reductions were 70%, 67%, and 74% for mood, manic and depressive events, respectively.
Major Depressive Disorder: In clinical trials, Seroquel XR has been shown to be effective as monotherapy and adjunct therapy for the treatment of patients who met DSM-IV criteria for major depressive disorder.
Three short-term (6 or 8 weeks) monotherapy trials, randomized 1445 patients who had a mean Hamilton Rating Scale for Depression (HAM-D) total score of 26 at enrollment. Seroquel XR at doses of 50 mg, 150 mg, and 300 mg demonstrated superiority over placebo in reducing depressive symptoms as measured by improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Statistically significant improvement of symptoms of major depressive disorder as measured by change in MADRS total score was observed by day 4. Seroquel XR also demonstrated improvement in anxiety symptoms as measured by the Hamilton Rating Scale for Anxiety (HAM-A) total score. The majority of the patients were dosed once daily with either 150 mg or 300 mg per day (one trial included a fixed dose Seroquel XR once daily 50 mg/day arm).
Two short-term (6 weeks) trials, enrolled 919 patients who had previously shown an inadequate response to at least one antidepressant and had a mean HAM-D total score of 24 at enrollment. Seroquel XR at doses of 150 mg and 300 mg, given as adjunct treatment to ongoing antidepressant therapy demonstrated superiority over antidepressant therapy alone in reducing depressive symptoms as measured by improvement in (MADRS) total score. Statistically significant improvement of symptoms of major depressive disorder as measured by the MADRS total score was observed by Week 1. Seroquel XR also demonstrated improvement in anxiety symptoms as measured by the HAM-A total score.
In a relapse prevention study, patients (n=771 randomised patients) responding to at least 12 weeks of acute open-label treatment with Seroquel XR were randomised to either Seroquel XR once daily or placebo for up to 52 weeks. Seroquel XR was more effective than placebo in preventing relapse. The risk of relapse was 14.2% for quetiapine XR-treated patients and 34.4% for placebo-treated patients. The mean dose was 177 mg/day.
In non-demented elderly patients (aged 66 to 89 years) Seroquel XR dosed flexibly in the range of 50 mg to 300 mg per day demonstrated superiority over placebo in reducing depressive symptoms as measured by improvement in MADRS total score. In this study patients randomised to Seroquel XR received 50mg/day on Days 1-3, the dose could be increased to 100 mg/day on Day 4, 150 mg/day on Day 8 and up to 300 mg/day depending on clinical response and tolerability. Other than the incidence of extrapyramidal symptoms (see Adverse Reactions) the tolerability of Seroquel XR once daily in elderly patients was comparable to that seen in adults (aged 18-65 years). The proportion of randomized patients over 75 years of age was 19%. The mean dose of Seroquel XR was 160 mg/day.
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 of age, 0.8% (13/1663) for quetiapine and 1.1% (5/463) for placebo in patients ≥25 years of age, and 1.4% (2/147) for quetiapine and 1.3% (1/75) for placebo in patients <8 years of age.
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 of age, 1.2% for both quetiapine (6/496) and placebo 6/503 in patients ≥25 years of age, and 1.0% (2/193) for quetiapine and 0% (0/90) for placebo in patients <8 years of age.
In these trials of patients with bipolar depression the incidence of suicide related events was 3.0% (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 of age. There have been no trials conducted in patients <18 years of age with bipolar depression.
In these trials of patients with major depressive disorder 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 of age. There have been no trials conducted in patients <18 years of age with major depressive disorder.
In these trials of patients with generalized anxiety disorder the incidence of suicide related events was 0% for quetiapine (0/178) and 1.0% for placebo (1/101) in patients 18-24 years of age an d 0.6% for quetiapine (8/1391) and 0.2% for placebo (1/564) in patients ≥25 years of age. There have been no trials conducted in patients <18 years of age with generalized anxiety disorder (see Precautions).
Pharmacokinetics: General: Quetiapine is well absorbed and extensively metabolised following oral administration. Quetiapine is approximately 83% bound to plasma proteins. 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 dosing range. The kinetics of quetiapine does not differ between men and women.
Seroquel XR achieves peak plasma concentrations at approximately 6 hrs after administration (Tmax). Seroquel XR displays dose-proportional pharmacokinetics for doses 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 immediate-release quetiapine fumarate (Seroquel) administered twice daily. When Seroquel XR administered once daily is compared to the same total daily dose of immediate-release quetiapine fumarate (Seroquel) administered twice daily, the area under the quetiapine plasma concentration-time curve (AUC) is equivalent, but the maximum plasma concentration (Cmax) is 13% lower. When Seroquel XR administered once daily is compared to the same total daily dose of immediate-release quetiapine (Seroquel) administered once daily, the quetiapine XR AUC is equivalent; and Cmax is 59% lower. The AUC and Cmax for the metabolite norquetiapine are 37% and 18% lower than the Seroquel, respectively. The elimination half lives of quetiapine and norquetiapine are approximately 7 and 12 hrs, respectively.
The mean clearance of quetiapine in the elderly is approximately 30% to 50% lower than that seen in adults 18 to 65 years.
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.
The mean plasma clearance of quetiapine was reduced by approximately 25% in subjects with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m2) but the individual clearance values are within the range for normal subjects. The average molar dose fraction of free quetiapine and the active human plasma metabolite norquetiapine is <5% excreted in the urine.
Metabolism: Quetiapine is extensively metabolised by the liver with parent compound accounting for less than 5% of unchanged drug-related material in the urine or faeces, following the administration of radiolabelled quetiapine. Approximately 73% of the radioactivity is excreted in the urine and 21% in the faeces. The mean plasma clearance of quetiapine is reduced by approximately 25% in subjects with hepatic impairment (stable alcoholic cirrhosis). 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).
In vitro investigations established that CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of quetiapine. Norquetiapine is primarily formed and eliminated via CYP3A4.
Quetiapine and several of its metabolites (including norquetiapine) were found to be weak inhibitors of human cytochrome P450 1A2, 2C9, 2C19, 2D6 and 3A4 activities in vitro. In vitro CYP inhibition is observed only at concentrations approximately 5 to 50 fold higher than those observed at dose range of 300 to 800 mg/day in humans. Based on these in vitro results, it is unlikely that co-administration of Seroquel XR with other drugs will result in clinically significant drug inhibition of cytochrome P450 mediated metabolism of the other drug.
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 and AUC of 44% to 52% and 20% to 22%, respectively, for the 50-mg and 300-mg tablets. In comparison, a light meal had no significant effect on the Cmax or AUC of quetiapine. This increase in exposure is not clinically significant, and therefore Seroquel XR can be taken with or without food.
Toxicology: Pre-clinical 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 convulsions.
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 (e.g., sedation at lower doses and tremor, convulsions or prostration at higher exposures).
Hyperprolactinaemia, induced through the dopamine D2 receptor antagonist activity of quetiapine or its metabolites, varied between species but was most marked in the 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.
Carcinogenicity Studies: In the rat study (doses 0, 20, 75 and 250 mg/kg/day), the incidence of mammary adenocarcinomas was increased at all doses in female rats, consequential to prolonged hyperprolactinemia.
In male rat (250 mg/kg/day) and mouse (250 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.
Quetiapine had no teratogenic effects.
Mutagenicity Studies: Genetic toxicity studies with quetiapine show that it is not a mutagen or clastogen.
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