Each extended-release tablet contains quetiapine fumarate delivering a dose of 50 mg, 150 mg, 300 mg, 400 mg of quetiapine free base, respectively.
Excipients/Inactive Ingredients: Core: Microcrystalline cellulose (Ph.Eur), sodium citrate (Ph.Eur), lactose monohydrate (Ph.Eur), magnesium stearate (Ph.Eur), hydroxypropyl methylcellulose (hypromellose) (Ph.Eur). Coating: Hydroxypropyl methylcellulose (hypromellose) (Ph.Eur), polyethylene glycol 400 (macrogol) (Ph.Eur), titanium dioxide (E171), red iron oxide (E172) (50 mg tablet), yellow iron oxide (E172) (50, 200 and 300 mg tablet).
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.
Seroquel XR is indicated for the treatment of schizophrenia; preventing relapse in stable schizophrenic patients who have been maintained on Seroquel XR; bipolar disorder including: manic episodes associated with bipolar disorder, depressive episodes associated with bipolar disorder, preventing recurrence in maintenance treatment of bipolar disorder (manic, mixed or depressive episode) as monotherapy or in combination with mood stabilizers (lithium or valproate); major depressive disorder; preventing relapse in stable major depressive disorder patients who have been maintained on Seroquel XR.
Seroquel XR should be administered once daily, with or without food. The tablets should be swallowed whole and not split, chewed or crushed.
Adults: For the treatment of schizophrenia: The daily dose at the start of therapy is 300 mg on Day 1; 600 mg on Day 2 and up to 800 mg after Day 2. The dose should be adjusted within the effective dose range of 400 mg to 800 mg per day, depending on the clinical response and tolerability of the patient. For maintenance therapy in schizophrenia no dosage adjustment is necessary.
For the treatment of manic episodes associated with bipolar disorder: The daily dose at the start of therapy is 300 mg on Day 1; 600 mg on Day 2 and up to 800 mg after Day 2. The dose should be adjusted within the effective dose range of 400 to 800 mg per day, depending on the clinical response and tolerability of the patient.
For the treatment of depressive episodes associated with bipolar disorder: Seroquel XR should be administered once daily in the evening.
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.
Antidepressant efficacy was demonstrated with Seroquel at 300 mg and 600 mg, however no additional benefit was seen in the 600 mg group during short-term treatment (see Adverse Reactions and Pharmacology: Clinical Efficacy under Actions).
For preventing recurrence in maintenance treatment of bipolar disorder: Patients who have responded to Seroquel XR in combination therapy to a mood stabilizer (lithium or valproate) for acute treatment of bipolar disorder should continue on Seroquel XR therapy at the same dose. The Seroquel XR dose can be re-adjusted depending on clinical response and tolerability of the individual patient within the dose range of 400 mg to 800 mg/day. Patients who have responded to Seroquel XR for acute treatment of bipolar disorder should continue on Seroquel XR therapy at the same dosing regimen. Seroquel XR dose can be re-adjusted depending on clinical response and tolerability of the individual patient within the dose range of 300 mg to 800 mg/day.
For the treatment of major depressive disorder: Seroquel XR should be administered once daily in the evening.
Initial dosing should begin at 50 mg on Day 1 and 2, increased to 150 mg on Day 3 and 4. Further adjustments can be made upwards or downwards within the recommended dose range of 50 mg to 300 mg depending upon the clinical response and tolerability of the patient.
For maintenance therapy in major depressive disorder 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 patient.
Switching from Seroquel immediate-release tablets: For more convenient dosing, patients who are currently being treated with divided doses of Seroquel immediate-release tablets (Seroquel) may be switched to Seroquel XR at the equivalent total daily dose taken once daily. Individual dosage adjustments may be necessary.
Elderly: As with other antipsychotics, Seroquel XR should be used with caution in the elderly, especially during the initial dosing period. The rate of dose titration of Seroquel XR 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% to 50% in elderly patients when compared with younger patients. 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 tolerance of the individual patient.
In elderly patients with major depressive disorder initial dosing should begin at 50 mg on Day 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 (see Pharmacology: Pharmacodynamics under Actions).
Children and adolescents: The safety and efficacy of Seroquel XR have not been evaluated in children and adolescents.
Renal Impairment: Dosage adjustment is not necessary.
Hepatic Impairment: Quetiapine is extensively metabolised by the liver. Therefore, Seroquel XR should be used with caution in patients with known hepatic impairment, especially during the initial dosing period. 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 tolerance of the individual patient.
In clinical trials, survival has been reported in acute overdoses of up to 30 grams of quetiapine. 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 13.6 grams of quetiapine 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 pre-existing severe cardiovascular (CV) disease may be at an increased risk of the effects of overdose (see Precautions).
In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects i.e., drowsiness and sedation, tachycardia and hypotension.
There is no specific antidote to quetiapine. In cases of severe intoxication, 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. Close medical supervision and monitoring should be continued until the patient recovers.
Seroquel XR is contraindicated in patients who are hypersensitive to quetiapine and to any component of this product.
Suicide/suicidal thoughts or clinical worsening: Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery. In addition, physicians should consider the potential risk of suicide-related events after abrupt cessation of quetiapine treatment, due to the known risk factors for the disease being treated.
Other psychiatric conditions for which quetiapine is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.
Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.
A meta analysis of placebo controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.
Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.
In shorter-term placebo controlled clinical studies of patients with major depressive episodes in bipolar disorder an increased risk of suicide-related events was observed in young adult patients (younger than 25 years of age) who were treated with quetiapine as compared to those treated with placebo (3.0% vs. 0%, respectively). In clinical studies of patients with MDD the incidence of suicide-related events observed in young adult patients (younger than 25 years of age) was 2.1% (3/144) for quetiapine and 1.3% (1/75) for placebo.
Neutropenia: Severe neutropenia (<0.5 x 109/L) has been uncommonly reported in quetiapine clinical trials. Most cases of severe neutropenia have occurred within the first two months of starting therapy with quetiapine. There was no apparent dose relationship. Possible risk factors for neutropenia include pre-existing 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. These 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).
Increases in blood glucose and hyperglycaemia: Increases in blood glucose and hyperglycaemia, and occasional reports of diabetes, have been observed in clinical trials with quetiapine. Although a causal relationship with diabetes has not been established, patients who are at risk for developing diabetes are advised to have appropriate clinical monitoring. Similarly, patients with existing diabetes should be monitored for possible exacerbation (see Adverse Reactions).
Lipids: Increases in triglycerides and cholesterol, and decreases in HDL have been observed in clinical trials with quetiapine (see Adverse Reactions). Lipid changes should be managed as clinically appropriate.
Pancreatitis: Pancreatitis has been reported in clinical trials and during the post marketing experience, however a causal relationship has not been established. Among the post marketing reports, many patients had factors which are known to be associated with pancreatitis such as increased triglycerides (see previous text), gallstones, and alcohol consumption.
Concomitant Illness: Seroquel XR should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or other conditions predisposing to hypotension. Quetiapine may induce orthostatic hypotension especially during the initial dose-titration period.
Dysphagia (see Adverse Reactions) and aspiration have been reported with Seroquel XR. Although a causal relationship with aspiration pneumonia has not been established, Seroquel XR should be used with caution in patients at risk for aspiration pneumonia.
Seizures: In controlled clinical trials, there was no difference in the incidence of seizures in patients treated with quetiapine or placebo. As with other antipsychotics, caution is recommended when treating patients with a history of seizures (see Adverse Reactions).
Tardive Dyskinesia and Extrapyrimidal Symptoms (EPS): Tardive dyskinesia is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotic drugs including quetiapine. 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).
In placebo-controlled clinical trials for schizophrenia and bipolar mania, the incidence of extrapyramidal symptoms was no different from that of placebo across the recommended therapeutic dose range. This predicts that quetiapine has less potential than typical antipsychotic agents to induce tardive dyskinesia in schizophrenia and bipolar mania patients. In short-term, placebo-controlled clinical trials for bipolar depression and major depressive disorder, the incidence of EPS was higher in quetiapine treated patients than in placebo treated patients (see Adverse Reactions).
Neuroleptic Malignant Syndrome: This has been associated with antipsychotic treatment including quetiapine (see Adverse Reactions). Clinical manifestations include hyperthermia, altered mental status, muscular rigidity, autonomic instability, and increased creatine phosphokinase. In such an event, Seroquel XR should be discontinued and appropriate medical treatment given.
QT Prolongation: In clinical trials quetiapine was not associated with a persistent increase in absolute QT intervals. However, in post marketing experience there were cases reported of QT prolongation with overdose (see Overdose). As with other antipsychotics, caution should be exercised when quetiapine is prescribed in patients with cardiovascular disease or family history of QT prolongation. Also caution should be exercised when quetiapine is prescribed either with medicines known to increase QT interval or with concomitant neuroleptics, especially for patients with increased risk of QT prolongation, i.e., the elderly, patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalemia, or hypomagnesemia (see Interactions).
Withdrawal: Acute withdrawal symptoms eg, insomnia, nausea, and vomiting have been described after abrupt cessation of antipsychotic drugs including quetiapine. Gradual withdrawal over a period of at least one to two weeks is advisable (see Adverse Reactions).
Effects on the ability to drive or operate machines: Given its primary CNS effects, quetiapine may interfere with activities requiring mental alertness. Therefore, patients should be advised not to drive or operate machinery, until individual susceptibility is known.
Use in Children: Children and adolescents (10 to 17 years of age): Although not all adverse reactions that have been identified in the adult patients have been observed in clinical trials with Seroquel in children and adolescent patients, the same special warnings and special precautions for use that appear above for adults should be considered for pediatrics. Additionally, changes in blood pressure and thyroid function tests and increases in weight and prolactin levels have been observed and should be managed as clinically appropriate. (See Adverse Reactions.)
Long-term safety data including growth, maturation, and behavioural development, beyond 26 weeks of treatment with Seroquel, is not available for children and adolescents (10 to 17 years of age).
Use in the Elderly: Elderly with dementia: Seroquel XR is not approved for the treatment of patients with dementia-related psychosis. 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 quetiapine studies in the same patient population (n = 710; mean age: 83 years; range: 56-99 years) the incidence of mortality in quetiapine 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 quetiapine treatment and death in elderly patients with dementia.
The safety and efficacy of quetiapine during human pregnancy have not been established. Therefore, Seroquel XR should only be used during pregnancy if the benefits justify the potential risks.
The degree to which quetiapine is excreted into human milk is unknown. Women who are breastfeeding should therefore avoid taking Seroquel XR.
The most commonly reported Adverse Drug Reactions (ADRs) with quetiapine are somnolence, dizziness, dry mouth, mild asthenia, constipation, tachycardia, orthostatic hypotension and dyspepsia.
As with other antipsychotics, weight gain, syncope, neuroleptic malignant syndrome, leucopenia, neutropenia and peripheral oedema, have been associated with quetiapine.
The incidences of ADRs associated with quetiapine therapy, are tabulated according to the format recommended by the Council for International Organizations of Medical Sciences (CIOMS III Working Group; 1995). (See Table 1.)
Click on icon to see table/diagram/image
The following clinical trials (monotherapy and combination therapy) included treatment with Seroquel and Seroquel XR.
In short-term, placebo-controlled clinical trials in schizophrenia and bipolar mania the aggregated incidence of EPS was similar to placebo [schizophrenia: 7.8% for quetiapine and 8% for placebo; bipolar mania: 11.2% for quetiapine and 11.4% for placebo. In short-term, placebo-controlled clinical trials in bipolar depression the aggregated incidence of extrapyrimidal symptoms was 8.9% for quetiapine compared to 3.8% for placebo, though the incidence of the individual adverse events (e.g., akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, muscle contractions involuntary, psychomotor hyperactivity and muscle rigidity) were generally low and did not exceed 4% in any treatment group). In short-term, placebo controlled monotherapy trial in major depressive disorder the aggregated incidence of extrapyramidal symptoms was 5.4% for Seroquel XR and 3.2% for placebo. In a short-term placebo controlled monotherapy in elderly patients with major depressive disorder, the aggregated incidence of extrapyrimidal symptoms was 9.0% for Seroquel XR and 2.3% for placebo. In long-term studies of schizophrenia, bipolar disorder and major depressive disorder the aggregated incidence of treatment-emergent extrapyrimidal symptoms was similar between quetiapine and placebo.
Quetiapine treatment was associated with small dose-related decreases in thyroid hormone levels, particularly total T4
and free T4
. The reduction in total and free T4
was maximal within the first two to four 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. Smaller decreases in total T3
and reverse T3
were seen only at higher doses. Levels of TBG were unchanged and in general, reciprocal increases in TSH were not observed, with no indication that quetiapine causes clinically relevant hypothyroidism.
Children and adolescents (10 to 17 years of age):
The same ADRs described in previously mentioned for adults should be considered for children and adolescents. Based on clinical data with Seroquel the following table summarises ADRs that occur in a higher frequency category in children and adolescent s patients (10-17 years of age) than in the adult population or ADRs that have not been identified in the adult population. (See Table 2.)
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Weight Gain in Children and Adolescents:
In one 6-week, placebo-controlled trial in adolescent patients (13-17 years of age) with schizophrenia, the mean increase in body weight, was 2.0 kg in the Seroquel group and -0.4 kg in the placebo group. Twenty-one percent of Seroquel-treated patients and 7% of placebo-treated patients gained ≥7 % of their body weight.
In one 3-week, placebo-controlled trial in children and adolescent patients (10-17 years of age) with bipolar mania, the mean increase in body weight was 1.7 kg in the Seroquel group and 0.4 kg in the placebo group. Twelve percent of Seroquel-treated patients and 0% of placebo-treated patients gained ≥7 % of their body weight.
In the open-label study that enrolled patients from the above two trials, 63% of patients (241/380) completed 26 weeks of therapy with Seroquel. After 26 weeks of treatment, the mean increase in body weight was 4.4 kg. Forty-five percent of the patients gained ≥7% of their body weight, not adjusted for normal growth. In order to adjust for normal growth over 26 weeks an increase of at least 0.5 standard deviation from baseline in BMI was used as a measure of a clinically significant change; 18.3% of patients on Seroquel met this criterion after 26 weeks of treatment.
Extrapyramidal Symptoms in Children and Adolescent Population:
In a short-term placebo-controlled monotherapy trial in adolescent patients (13-17 years of age) with schizophrenia, the aggregated incidence of extrapyramidal symptoms 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 of age) with bipolar mania, the aggregated incidence of extrapyramidal symptoms was 3.6% for Seroquel and 1.1% for placebo.
See also 'Interaction with other medicaments and other forms of interaction' in the following text.
Concomitant use of quetiapine with hepatic enzyme inducers such as carbamazepine may substantially decrease systemic exposure to quetiapine. Depending on clinical response, higher doses of Seroquel XR may need to be considered if quetiapine is used concomitantly with a hepatic enzyme inducer.
During concomitant administration of drugs, which are potent CYP3A4 inhibitors (such as azole antifungals, macrolide antibiotics, and protease inhibitors), plasma concentrations of quetiapine can be significantly higher than observed in patients in clinical trials. As a consequence of this, lower doses of Seroquel XR should be used. Special consideration should be given in elderly and debilitated patients. The risk-benefit ratio needs to be considered on an individual basis in all patients.
Interaction with other medicinal products and other forms of interaction: Given the primary central nervous system effects of quetiapine, Seroquel XR should be used with caution in combination with other centrally acting drugs and alcohol.
Caution should be exercised when quetiapine is used concomitantly with drugs known to cause electrolyte imbalance or to increase QT interval (see Precautions).
The pharmacokinetics of lithium was not altered when co-administered with Seroquel.
The pharmacokinetics of sodium valproate and quetiapine were not altered to a clinically relevant extent when co-administered.
The pharmacokinetics of quetiapine were not significantly altered following co-administration with the antipsychotics risperidone or haloperidol. However co-administration of Seroquel and thioridazine caused increases in the clearance of quetiapine.
Quetiapine did not induce the hepatic enzyme systems involved in the metabolism of antipyrine. However, 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 Seroquel XR, depending on clinical response, should be considered. The safety of doses above 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. Co-administration of Seroquel XR with another microsomal enzyme inducer, phenytoin, also caused increases in the clearance of quetiapine. Increased doses of Seroquel XR may be required to maintain control of psychotic symptoms in patients co-administered Seroquel XR and phenytoin, and other hepatic enzyme inducers (e.g., barbiturates, rifampicin etc.). The dose of Seroquel XR may need to be reduced if phenytoin or carbamazepine or other hepatic enzyme inducers are withdrawn and replaced with a non-inducer (e.g., sodium valproate).
CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of quetiapine. The pharmacokinetics of quetiapine were not altered following co-administration with cimetidine, a known P450 enzyme inhibitor. The pharmacokinetics of quetiapine were not significantly altered following co-administration with the antidepressants imipramine (a known CYP2D6 inhibitor) or fluoxetine (a known CYP3A4 and CYP2D6 inhibitor). 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 resulted in an increase in mean Cmax and AUC of quetiapine of 235% and 522%, respectively, with a corresponding decrease in mean oral clearance of 84%. The mean half-life of quetiapine increased from 2.6 to 6.8 hours. Due to the potential for an interaction of a similar magnitude in a clinical setting, the dosage of Seroquel XR should be reduced during concomitant use of quetiapine and potent CYP3A4 inhibitors (such as azole antifungals, macrolide antibiotics, and protease inhibitors).
N05AH04 - quetiapine ; Belongs to the class of diazepines, oxazepines and thiazepines antipsychotics.
XR tab 50 mg (capsule-shaped, 16.24 mm x 6.52 mm, peach coloured, film-coated) x 60's. 150 mg (capsule-shaped, 17.22 mm x 6.65 mm, white coloured, film-coated) x 60's. 300 mg (capsule-shaped, 19 mm x 7.62 mm, pale yellow coloured, film-coated) x 60's. 400 mg (capsule-shaped, 19 mm x 7.62 mm, white coloured, film-coated) x 6 x 10's.