Questax XR

Pharmacotherapeutic group: Antipsychotics; Diazepines, oxazepines and thiazepines ATC code: N05A H04 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 (5HT 2 ) and dopamine D 1 - and D 2 - receptors. It is this combination of receptor antagonism with a higher selectivity for 5HT 2 relative to D 2 - receptors, which is believed to contribute to the clinical antipsychotic properties and low extrapyramidal undesirable effect (EPS) liability of quetiapine compared to typical antipsychotics. Additionally, norequetiapine has high affinity for the norepinephrine transporter (NET). Quetiapine and norquetiapine have no appreciable affinity at benzodiazepine receptors but high affinity at histaminergic and adrenergic α 1 - receptors, moderate affinity at adrenergic α 2 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's therapeutic efficacy as an antidepressant. Pharmacodynamic effects: 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 D 2 -receptor blockade. In pre-clinical tests predictive of EPS, quetiapine is unlike typical antipsychotics and has an atypical profile. Quetiapine does not produce dopamine D 2 -receptor supersensitivity after chronic administration. Quetiapine produces only weak catalepsy at effective dopamine D 2 - 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) Clinical efficacy: Schizophrenia The efficacy of quetiapine 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-to- quetiapine prolonged release 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 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, ie, 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 400 mg to 800 mg, efficacy was maintained when patients were switched to an equivalent daily dose of quetiapine prolonged release given once daily. In a long-term study in stable schizophrenic patients who had been maintained on quetiapine prolonged release for 16 weeks, quetiapine prolonged release was more effective than placebo in preventing relapse. The estimated risk of relapse after 6 months treatment was 14.3% for the quetiapine prolonged release 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 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. Bipolar Disorder 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 was further demonstrated with significance versus placebo in an additional 3 week study. Quetiapine prolonged release 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 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 IR 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 IR 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 IR 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 versus placebo and quetiapine 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. Major depressive episodes in MDD Two short-term (6 week) studies enrolled patients who had shown an inadequate response to at least one antidepressant. Quetiapine prolonged release 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 as monotherapy treatment, however quetiapine prolonged release 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 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 treatment for at least 12 weeks were randomised to either quetiapine prolonged release once daily or placebo for up to 52 weeks. The mean dose of quetiapine prolonged release during the randomised phase was 177 mg/day. The incidence of relapse was 14.2% for quetiapine prolonged release 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 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 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 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 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%. Clinical safety 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 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 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 (50mg/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 versus placebo and quetiapine in adult patients with acute mania indicated that the combination of quetiapine with lithium leads to more adverse events (63% versus 48% in quetiapine 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 with lithium add-on group (12.7%) compared to the quetiapine with the placebo add-on group (5.5%). In addition, a higher percentage of patients treated in the lithium add-on 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 10 9 /L, the incidence of at least one occurrence of a shift to neutrophil count <1.5 X 10 9 /L, was 1.9% in patients treated with quetiapine compared to 1. 5% in placebo-treated patients. The incidence of shifts to >0.5-<1.0 x 10 9 /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 10 9 /L, the incidence of at least one occurrence of a shift to neutrophil count <1.5 x 10 9 /L was 2.9% and to <0.5 X 10 9 /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 T 3 or T 4 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 T 4 was maximal within the first six weeks of quetiapine treatment, with no further reduction during long-term treatment. For about 2/3 of all cases, cessation of quetiapine treatment was associated with a reversal of the effects on total and free T 4 , irrespective of the duration of treatment. Cataracts/lens opacities 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. Children and adolescents (10 to 17 years of age) Clinical efficacy 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 400 mg/day and –6.56 for quetiapine 600 mg/day. Responder rates (YMRS improvement ≥50%) were 64% for quetiapine 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 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 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. Clinical safety In the short-term paediatric 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. Long-term safety 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 sections 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.