Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Accord Healthcare Limited, Sage House, 319, Pinner Road, North Harrow, Middlesex, HA1 4HF, United Kingdom
Pharmacotherapeutic group: Antipsychotics; Diazepines, oxazepines, thiazepines
ATC code: N05AH04
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, which is believed to contribute to the clinical antipsychotic properties and low extrapyramidal undesirable effect (EPS) liability of Quetiapine Prolonged-release Tablets compared to typical antipsychotics. Quetiapine and norquetiapine have no appreciable affinity at benzodiazepine receptors but high affinity at histaminergic and adrenergic alpha1 receptors moderate affinity at adrenergic alpha2 receptors. Quetiapine also has low or no affinity for muscarinic receptors, while norquetiapine has moderate to high affinity at several muscarinic receptors, which may explain anti-cholinergic (muscarinic effects). Inhibition of NET and partial agonist action at 5HT1A sites by norquetiapine may contribute to Quetiapine prolonged release tablet therapeutic efficacy as an antidepressant.
Quetiapine is active in tests for antipsychotic activity, such as conditioned avoidance. It also blocks the action of dopamine agonists, measured either behaviourally or electrophysiologically, and elevates dopamine metabolite concentrations, a neurochemical index of 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 mesolimbic but not the 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 (See Section 4.8).
The efficacy of Quetiapine Prolonged-release Tablets 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 Quetiapine immediate release tablet-to-Quetiapine prolonged-release tablets 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. Quetiapine Prolonged-release Tablets 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 randomization to any visit. In patients stabilised on Quetiapine immediate-release tablet 400 mg to 800 mg, efficacy was maintained when patients were switched to an equivalent daily dose of Quetiapine Prolonged-release Tablets given once daily.
In a long-term study in stable schizophrenic patients who had been maintained on Quetiapine Prolonged-release Tablets for 16 weeks, Quetiapine prolonged-release tablets was more effective than placebo in preventing relapse. The estimated risks of relapse after 6 months treatments was 14.3% for the Quetiapine prolonged-release tablets treatment group compared to 68.2% for placebo. The average dose was 669 mg. There were no additional safety findings associated with treatment with Quetiapine Prolonged-release Tablets for up to 9 months (median 7 months). In particular, reports of adverse events related to EPS and weight gain did not increase with longer-term treatment with Quetiapine Prolonged-release Tablets.
In the treatment of moderate to severe manic episodes, quetiapine demonstrated superior efficacy to placebo in reduction of manic symptoms at 3 and 12 weeks, in two monotherapy trials. The efficacy of Quetiapine Prolonged-release Tablets was further demonstrated with significance versus placebo in an additional 3 week study. Quetiapine Prolonged-release Tablets was dosed in the range of 400 to 800 mg/day and the mean dose was approximately 600 mg/day. Quetiapine data in combination with divalproex or lithium in acute moderate to severe manic episodes at 3 and 6 weeks is limited; however, combination therapy was well tolerated. The data showed an additive effect at week 3. A second study did not demonstrate an additive effect at week 6.
In a clinical trial, in patients with depressive episodes in bipolar I or bipolar II disorder, 300 mg/day Quetiapine Prolonged-release Tablets showed superior efficacy to placebo in reduction of MADRS total score.
In 4 additional clinical trials with quetiapine, with a duration of 8 weeks in patients with moderate to severe depressive episodes in bipolar I or bipolar II disorder, Quetiapine immediate release tablet 300 mg and 600 mg was significantly superior to placebo treated patients for the relevant outcome measures: mean improvement on the MADRS and for response defined as at least a 50% improvement in MADRS total score from baseline. There was no difference in magnitude of effect between the patients who received 300 mg Quetiapine immediate release tablet and those who received 600 mg dose.
In the continuation phase in two of these studies, it was demonstrated that long-term treatment, of patients who responded on Quetiapine immediate release tablet 300 or 600 mg, was efficacious compared to placebo treatment with respect to depressive symptoms, but not with regard to manic symptoms.
In two recurrence prevention studies evaluating quetiapine in combination with mood stabilizers, in patients with manic, depressed or mixed mood episodes, the combination with quetiapine was superior to mood stabilizers monotherapy in increasing the time to recurrence of any mood event (manic, mixed or depressed). Quetiapine was administered twice-daily totalling 400 mg to 800 mg a day as combination therapy to lithium or valproate.
In a 6-week, randomised, study of lithium and Quetiapine Prolonged-release tablets versus placebo and Quetiapine Prolonged-release tablets in adult patients with acute mania, the difference in YMRS mean improvement between the lithium add-on group and the placebo add-on group was 2.8 points and the difference in % responders (defined as 50% improvement from baseline on the YMRS) was 11% (79% in the lithium add-on group vs. 68% in the placebo add-on group).
In one long-term study (up to 2 years treatment) evaluating recurrence prevention in patients with manic, depressed or mixed mood episodes quetiapine was superior to placebo in increasing the time to recurrence of any mood event (manic, mixed or depressed), in patients with bipolar I disorder. The number of patients with a mood event was 91 (22.5%) in the quetiapine group, 208 (51.5%) in the placebo group and 95 (26.1%) in the lithium treatment groups respectively. In patients who responded to quetiapine, when comparing continued treatment with quetiapine to switching to lithium, the results indicated that a switch to lithium treatment does not appear to be associated with an increased time to recurrence of a mood event.
Two short-term (6 week) studies enrolled patients who had shown an inadequate response to at least one antidepressant. Quetiapine Prolonged-release Tablets 150 mg and 300 mg/day, given as add-on treatment to ongoing antidepressant therapy (amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline or venlafaxine) demonstrated superiority over antidepressant therapy alone in reducing depressive symptoms as measured by improvement in MADRS total score (LS mean change vs. placebo of 2-3.3 points).
Long-term efficacy and safety in patients with MDD has not been evaluated as add-on therapy, however long-term efficacy and safety has been evaluated in adult patients as monotherapy (see below).
The following studies were conducted with Quetiapine Prolonged-release Tablets as monotherapy treatment, however Quetiapine Prolonged-release Tablets is only indicated for use as add-on therapy:
In three out of four short term (up to 8 weeks) monotherapy studies, in patients with major depressive disorder, Quetiapine Prolonged-release Tablets 50 mg, 150 mg and 300 mg/day demonstrated superior efficacy to placebo in reducing depressive symptoms as measured by improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score (LS mean change vs. placebo of 2-4 points).
In a monotherapy relapse prevention study, patients with depressive episodes stabilised on open-label Quetiapine Prolonged-release Tablets treatment for at least 12 weeks were randomised to either Quetiapine Prolonged-release Tablets once daily or placebo for up to 52 weeks. The mean dose of Quetiapine Prolonged-release Tablets during the randomised phase was 177 mg/day. The incidence of relapse was 14.2% for Quetiapine Prolonged-release Tablets treated patients and 34.4% for placebo-treated patients.
In a short-term (9 week) study non-demented elderly patients (aged 66 to 89 years) with major depressive disorder, Quetiapine Prolonged-release Tablets dosed flexibly in the range of 50 mg to 300 mg/day demonstrated superior efficacy to placebo in reducing depressive symptoms as measured by improvement in MADRS total score (LS mean change vs placebo -7.54). In this study patients randomised to Quetiapine Prolonged-release Tablets received 50 mg/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. The mean dose of Quetiapine Prolonged-release Tablets was 160 mg/day. Other than the incidence of extrapyramidal symptoms (see Section 4.8 and ‘Clinical Safety’ below) the tolerability of Quetiapine Prolonged-release Tablets 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%.
In short-term, placebo-controlled clinical trials in schizophrenia and bipolar mania the aggregated incidence of extrapyramidal symptoms was similar to placebo (schizophrenia: 7.8% for quetiapine and 8.0% for placebo; bipolar mania: 11.2% for quetiapine and 11.4% for placebo). Higher rates of extrapyramidal symptoms were seen in quetiapine treated patients compared to those treated with placebo in short-term, placebo-controlled clinical trials in MDD and bipolar depression. In short-term, placebo-controlled bipolar depression trials the aggregated incidence of extrapyramidal symptoms was 8.9% for quetiapine compared to 3.8% for placebo. In short-term, placebo-controlled monotherapy clinical trials in major depressive disorder the aggregated incidence of extrapyramidal symptoms was 5.4% for Quetiapine Prolonged-release Tablets and 3.2% for placebo. In a short-term placebo-controlled monotherapy trial in elderly patients with major depressive disorder, the aggregated incidence of extrapyramidal symptoms was 9.0% for Quetiapine Prolonged-release Tablets and 2.3% for placebo. In both bipolar depression and MDD, the incidence of the individual adverse events (eg, akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, muscle contractions involuntary, psychomotor hyperactivity and muscle rigidity) did not exceed 4% in any treatment group.
In short term, fixed dose (50 mg/d to 800 mg/d), placebo-controlled studies (ranging from 3 to 8 weeks), the mean weight gain for quetiapine-treated patients ranged from 0.8 kg for the 50 mg daily dose to 1.4 kg for the 600 mg daily dose (with lower gain for the 800 mg daily dose), compared to 0.2 kg for the placebo treated patients. The percentage of quetiapine treated patients who gained ≥7% of body weight ranged from 5.3% for the 50 mg daily dose to 15.5% for the 400 mg daily dose (with lower gain for the 600 and 800 mg daily doses), compared to 3.7% for placebo treated patients.
A 6-week, randomised, study of lithium and Quetiapine Prolonged-release tablets versus placebo and Quetiapine Prolonged-release tablets in adult patients with acute mania indicated that the combination of Quetiapine Prolonged-release tablets with lithium leads to more adverse events (63% versus 48% in Quetiapine Prolonged-release tablets in combination with placebo). The safety results showed a higher incidence of extrapyramidal symptoms reported in 16.8% of patients in the lithium add-on group and 6.6% in the placebo add-on group, the majority of which consisted of tremor, reported in 15.6% of the patients in the lithium add-on group and 4.9% in the placebo add-on group. The incidence of somnolence was higher in the Quetiapine Prolonged-release tablets with lithium add-on group (12.7%) compared to the Quetiapine Prolonged-release tablets with the placebo add-on group (5.5%). In addition, a higher percentage of patients treated in the lithium addon group (8.0%) had weight gain (7%) at the end of treatment compared to patients in the placebo add-on group (4.7%).
Longer term relapse prevention trials had an open label period (ranging from 4 to 36 weeks) during which patients were treated with quetiapine, followed by a randomized withdrawal period during which patients were randomized to quetiapine or placebo. For patients who were randomized to quetiapine, the mean weight gain during the open label period was 2.56 kg, and by week 48 of the randomized period, the mean weight gain was 3.22 kg, compared to open label baseline. For patients who were randomized to placebo, the mean weight gain during the open label period was 2.39 kg, and by week 48 of the randomized period the mean weight gain was 0.89 kg, compared to open label baseline.
In placebo-controlled studies in elderly patients with dementia-related psychosis, the incidence of cerebrovascular adverse events per 100 patient years was not higher in quetiapine-treated patients than in placebo-treated patients.
In all short-term placebo-controlled monotherapy trials in patients with a baseline neutrophil count ≥1.5 X 109/L, the incidence of at least one occurrence of a shift to 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 of shifts to >0.5 - <1.0 X 109/L was the same (0.2%) in patients treated with quetiapine as with placebo-treated patients. In all clinical trials (placebo-controlled, open-label, active comparator) in patients with a baseline neutrophil count ≥1.5 X 109/L, the incidence of at least one occurrence of a shift to neutrophil count <1.5 X 109/L was 2.9% and to <0.5 X 109/L was 0.21% in patients treated with quetiapine.
Quetiapine treatment was associated with dose-related decreases in thyroid hormone levels..The incidences of shifts in TSH was 3.2% for quetiapine versus 2.7% for placebo. The incidence of reciprocal, potentially clinically significant shifts of both T3 or T4 and TSH in these trials were rare, and the observed changes in thyroid hormone levels were not associated with clinically symptomatic hypothyroidism. The reduction in total and free T4 was maximal within the first six weeks of quetiapine treatment, with no further reduction during long-term treatment. For about ⅔ of 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.
In a clinical trial to evaluate the cataractogenic potential of quetiapine (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 quetiapine (4%) compared with risperidone (10%), for patients with at least 21 months of exposure.
The efficacy and safety of Quetiapine was studied in a 3-week placebo controlled study for the treatment of mania (n=284 patients from the US, aged 10-17). About 45% of the patient population had an additional diagnosis of ADHD. In addition, a 6-week placebo controlled study for the treatment of schizophrenia (n=222 patients, aged 13-17) was performed. In both studies, patients with known lack of response to Quetiapine were excluded. Treatment with Quetiapine 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 two or three times daily.
In the mania study, the difference in LS mean change from baseline in YMRS total score (active minus placebo) was –5.21 for Quetiapine tablet 400 mg/day and –6.56 for Quetiapine tablet 600 mg/day. Responder rates (YMRS improvement ≥50%) were 64% for Quetiapine tablet 400 mg/day, 58% for 600 mg/day and 37% in the placebo arm.
In the schizophrenia study, the difference in LS mean change from baseline in PANSS total score (active minus placebo) was –8.16 for Quetiapine tablet 400 mg/day and –9.29 for Quetiapine 800 mg/day. Neither low dose (400 mg/day) nor high dose regimen (800 mg/day) quetiapine was superior to placebo with respect to the percentage of patients achieving response, defined as ≥30% reduction from baseline in PANSS total score. Both in mania and schizophrenia higher doses resulted in numerically lower response rates.
In a third short-term placebo-controlled monotherapy trial with Quetiapine Prolonged-release tablets in children and adolescent patients (10-17 years of age) with bipolar depression, efficacy was not demonstrated.
No data are available on maintenance of effect or recurrence prevention in this age group.
In the short-term pediatric trials with quetiapine described above, the rates of EPS in the active arm vs. placebo were 12.9% vs. 5.3% in the schizophrenia trial, 3.6% vs. 1.1% in the bipolar mania trial, and 1.1% vs. 0% in the bipolar depression trial. The rates of weight gain ≥7% of baseline body weight in the active arm vs. placebo were 17% vs. 2.5% in the schizophrenia and bipolar mania trials, and 13.7% vs. 6.8% in the bipolar depression trial. The rates of suicide related events in the active arm vs. placebo were 1.4% vs. 1.3% in the schizophrenia trial, 1.0% vs. 0% in the bipolar mania trial, and 1.1% vs. 0% in the bipolar depression trial. During an extended post-treatment follow-up phase of the bipolar depression trial, there were two additional suicide related events in two patients; one of these patients was on quetiapine at the time of the event.
A 26-week open-label extension to the acute trials (n=380 patients), with Quetiapine flexibly dosed at 400-800 mg/day, provided additional safety data. Increases in blood pressure were reported in children and adolescents and increased appetite, extrapyramidal symptoms and elevations in serum prolactin were reported with higher frequency in children and adolescents than in adult patients (see Section 4.4 and 4.8). With respect to weight gain, when adjusting for normal growth over the longer term, an increase of at least 0.5 standard deviation from baseline in Body Mass Index (BMI) was used as a measure of a clinically significant change; 18.3% of patients who were treated with quetiapine for at least 26 weeks met this criterion.
Quetiapine is well absorbed following oral administration. Quetiapine Prolonged-release Tablets achieves peak quetiapine and norquetiapine plasma concentrations at approximately 6 hours after administration (Tmax). 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 and dose-proportional for doses up to 800 mg administered once daily. When Quetiapine Prolonged-release Tablets administered once daily is compared to the same total daily dose of immediate-release quetiapine fumarate (Quetiapine immediate release tablet) administered twice daily, the area under the plasma concentration-time curve (AUC) is equivalent, but the maximum plasma concentration (Cmax) is 13% lower at steady state. When Quetiapine Prolonged-release Tablets is compared to Quetiapine immediate release, the norquetiapine metabolite AUC is 18% lower.
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 Quetiapine Prolonged-release Tablets Cmax and AUC of approximately 50% and 20% respectively., It cannot be excluded that the effect of a high fat meal on the formulation may be larger. In comparison, a light meal had no significant effect on the Cmax or AUC of quetiapine. It is recommended that Quetiapine Prolonged-release Tablets is taken once daily without food.
Quetiapine is approximately 83% bound to plasma proteins.
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.
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 a dose range of 300 to 800 mg/day in humans. Based on these in vitro results, it is unlikely that co-administration of quetiapine with other drugs will result in clinically significant drug inhibition of cytochrome P450 mediated metabolism of the other drug. From animal studies it appears that quetiapine can induce cytochrome P450 enzymes. In a specific interaction study in psychotic patients, however, no increase in the cytochrome P450 activity was found after administration of quetiapine.
The elimination half lives of quetiapine and norquetiapine are approximately 7 and 12 hours, respectively. Approximately 73% of a radiolabelled drug was excreted in the urine and 21% in the faeces with less than 5% of the total radioactivity representing unchanged drug-related material. The average molar dose fraction of free quetiapine and the active human plasma metabolite norquetiapine is <5% excreted in the urine.
The pharmacokinetics of quetiapine does not differ between men and women.
The mean clearance of quetiapine in the elderly is approximately 30 to 50% lower than that seen in adults aged 18 to 65 years.
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 mean quetiapine plasma clearance decreases with approximately 25% in persons with known hepatic impairment (stable alcoholcirrhosis). As quetiapine is extensively metabolised by the liver, elevated plasma levels are expected in the population with hepatic impairment. Dose adjustments may be necessary in these patients (see Section 4.2).
Pharmacokinetic data were sampled in 9 children aged 10-12 years old and 12 adolescents, who were on steady-state treatment with 400 mg quetiapine twice daily. At steady-state, the dose-normalised plasma levels of the parent compound, quetiapine, in children and adolescents (10-17 years of age) were in general similar to adults, though Cmax in children was at the higher end of the range observed in adults. The AUC and Cmax for the active metabolite, norquetiapine, were higher, approximately 62% and 49% in children (10-12 years), respectively and 28% and 14% in adolescents (13-17 years), respectively, compared to adults.
No information is available for Quetipine Prolonged-release Tablets in children and adolescents.
There was no evidence of genotoxicity in a series of in vitro and in vivo genotoxicity studies. In laboratory animals at a clinically relevant exposure level the following deviations were seen, which as yet have not been confirmed in long-term clinical research:
In rats, pigment deposition in the thyroid gland has been observed; in cynomolgus monkeys thyroid follicular cell hypertrophy, a lowering in plasma T3 levels, decreased haemoglobin concentration and a decrease of red and white blood cell count have been observed; and in dogs lens opacity and cataracts. (For cataracts/lens opacities see Section 5.1).
In an embryofoetal toxicity study in rabbits the foetal incidence of carpal/tarsal flexure was increased. This effect occurred in the presence of overt maternal effects such as reduced body weight gain. These effects were apparent at maternal exposure levels similar or slightly above those in humans at the maximal therapeutic dose. The relevance of this finding for humans is unknown.
In a fertility study in rats, marginal reduction in male fertility and pseudopregnancy, protracted periods of diestrus, increased precoital interval and reduced pregnancy rate were seen. These effects are related to elevated prolactin levels and not directly relevant to humans because of species differences in hormonal control of reproduction.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
