- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
For the treatment of schizophreniaThe daily dose at the start of therapy is 300 mg on Day 1 and 600 mg on Day 2. The recommended daily dose is 600 mg. Enhanced efficacy at doses higher than 600 mg has not been demonstrated, although individual patients may benefit from a dose up to 800 mg daily. Doses greater than 600 mg should be initiated by a specialist. 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 disorderThe 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 the treatment of depressive episodes associated with bipolar disorderSeroquel XL should be administered once daily at bedtime. The total daily dose for the first four days of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3) and 300 mg (Day 4). The recommended daily dose is 300 mg. In clinical trials, no additional benefit was seen in the 600 mg group compared to the 300 mg group. Individual patients may benefit from a 600 mg dose. In individual patients, in the event of tolerance concerns, clinical trials have indicated that dose reduction to a minimum of 200 mg could be considered. When treating depressive episodes in bipolar disorder, treatment should be initiated by physicians experienced in treating bipolar disorder.
For preventing recurrence in bipolar disorderFor prevention of recurrence of manic, depressive or mixed episodes in bipolar disorder, patients who have responded to Seroquel XL for acute treatment of bipolar disorder should continue on Seroquel XL at the same dose administered at bedtime. The dose may be adjusted depending on clinical response and tolerability of the individual patient within the dose range of 300 mg to 800 mg/day. It is important that the lowest effective dose is used for maintenance therapy.
For add-on treatment of major depressive episodes in MDD:Seroquel XL should be administered prior to bedtime. The daily dose at the start of therapy is 50 mg on Day 1 and 2, and 150 mg on Day 3 and 4. Antidepressant effect was seen at 150 and 300 mg/day in short-term trials as add-on therapy (with amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline and venlafaxine - see section 5.1) and at 50 mg/day in short-term monotherapy trials. There is an increased risk of adverse events at higher doses. Clinicians should therefore ensure that the lowest effective dose, starting with 50 mg/day, is used for treatment. The need to increase the dose from 150 to 300 mg/day should be based on individual patient evaluation.
Switching from Seroquel immediate-release tablets:For more convenient dosing, patients who are currently being treated with divided doses of immediate-release Seroquel tablets (Seroquel IR, tradename Seroquel®) may be switched to Seroquel XL at the equivalent total daily dose taken once daily. Individual dosage adjustments may be necessary.
Elderly:As with other antipsychotics and antidepressants, Seroquel XL should be used with caution in the elderly, especially during the initial dosing period. The rate of dose titration of Seroquel XL may need to be slower, and the daily therapeutic dose lower, than that used in younger patients, depending on the clinical response and tolerability of the individual patient. The mean plasma clearance of quetiapine was reduced by 30% to 50% in elderly patients when compared to 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 tolerability of the individual patient.In elderly patients with major depressive episodes in MDD, dosing should begin with 50 mg/day on Days 1-3, increasing to 100 mg/day on Day 4 and 150 mg/day on Day 8. The lowest effective dose, starting from 50 mg/day should be used. Based on individual patient evaluation, if dose increase to 300 mg/day is required this should not be prior to Day 22 of treatment.Efficacy and safety has not been evaluated in patients over 65 years with depressive episodes in the framework of bipolar disorder.
Children and Adolescents:Seroquel XL is not recommended for use in children and adolescents below 18 years of age, due to a lack of data to support use in this age group. The available evidence from placebo-controlled clinical trials is presented in sections 4.4, 4.8, 5.1 and 5.2.
Renal impairment:Dosage adjustment is not necessary in patients with renal impairment.
Hepatic impairment:Seroquel XL is extensively metabolised by the liver. Therefore, Seroquel XL 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 tolerability of the individual patient.
Children and adolescents (10 to 17 years of age)Quetiapine is not recommended for use in children and adolescents below 18 years of age, due to a lack of data to support use in this age group. Clinical trials with quetiapine have shown that in addition to the known safety profile identified in adults (see section 4.8), certain adverse events occurred at a higher frequency in children and adolescents compared to adults (increased appetite, elevations in serum prolactin, vomiting, rhinitis and syncope) or may have different implications for children and adolescents (extrapyramidal symptoms) and one was identified that has not been previously seen in adult studies (increases in blood pressure). Changes in thyroid function tests have also been observed in children and adolescents.Furthermore, the long-term safety implications of treatment with quetiapine on growth and maturation have not been studied beyond 26 weeks. Long-term implications for cognitive and behavioural development are not known.In placebo-controlled clinical trials with children and adolescent patients quetiapine was associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for schizophrenia, bipolar mania and bipolar depression (see section 4.8).
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 Seroquel XL 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 episodes. The same precautions observed when treating patients with major depressive episodes 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.
Extrapyramidal symptoms:In placebo controlled clinical trials of adult patients quetiapine was associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for major depressive episodes in bipolar disorder and major depressive disorder (see sections 4.8 and 5.1).The use of quetiapine has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.
Tardive Dyskinesia: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 section 4.8).
Somnolence and dizziness:Quetiapine treatment has been associated with somnolence and related symptoms, such as sedation (see section 4.8). In clinical trials for treatment of patients with bipolar depression and major depressive disorder, onset was usually within the first 3 days of treatment and was predominantly of mild to moderate intensity. Bipolar depression patients and patients with major depressive episodes in MDD experiencing somnolence of severe intensity may require more frequent contact for a minimum of 2 weeks from onset of somnolence, or until symptoms improve and treatment discontinuation may need to be considered. Quetiapine treatment has been associated with orthostatic hypotension and related dizziness (see section 4.8) which, like somnolence has onset usually during the initial dose-titration period. This could increase the occurrence of accidental injury (fall), especially in the elderly population. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medication.
Cardiovascular:Quetiapine 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 and therefore dose reduction or more gradual titration should be considered if this occurs. A slower titration regimen could be considered in patients with underlying cardiovascular disease.
Seizures:In controlled clinical trials there was no difference in the incidence of seizures in patients treated with quetiapine or placebo. No data is available about the incidence of seizures in patients with a history of seizure disorder. As with other antipsychotics, caution is recommended when treating patients with a history of seizures (see section 4.8).
Neuroleptic Malignant Syndrome:Neuroleptic malignant syndrome has been associated with antipsychotic treatment, including quetiapine (see section 4.8). Clinical manifestations include hyperthermia, altered mental status, muscular rigidity, autonomic instability, and increased creatine phosphokinase. In such an event, Seroquel XL should be discontinued and appropriate medical treatment given.
Severe neutropenia:Severe neutropenia (neutrophil count <0.5 X 109/L) has been uncommonly reported in quetiapine clinical trials. Most cases of severe neutropenia have occurred within a couple of months of starting therapy with quetiapine. There was no apparent dose relationship. During post-marketing experience, resolution of leucopenia and/or neutropenia has followed cessation of therapy with quetiapine. 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 <1.0 X 109/L. Patients should be observed for signs and symptoms of infection and neutrophil counts followed (until they exceed 1.5 X 109/L) (See section 5.1).
Interactions:See also section 4.5.Concomitant use of quetiapine with a strong hepatic enzyme inducer such as carbamazepine or phenytoin substantially decreases quetiapine plasma concentrations, which could affect the efficacy of quetiapine therapy. In patients receiving a hepatic enzyme inducer, initiation of Seroquel XL treatment should only occur if the physician considers that the benefits of Seroquel XL outweigh the risks of removing the hepatic enzyme inducer. It is important that any change in the inducer is gradual, and if required, replaced with a non-inducer (e.g. sodium valproate).
Weight:Weight gain has been reported in patients who have been treated with quetiapine, and should be monitored and managed as clinically appropriate as in accordance with utilised antipsychotic guidelines (see sections 4.8 and 5.1).
Hyperglycaemia:Hyperglycaemia and/or development or exacerbation of diabetes occasionally associated with ketoacidosis or coma has been reported rarely, including some fatal cases (see section 4.8). In some cases, a prior increase in body weight has been reported which may be a predisposing factor. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines. Patients treated with any antipsychotic agent including quetiapine, should be observed for signs and symptoms of hyperglycaemia, (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control. Weight should be monitored regularly.
Lipids:Increases in triglycerides, LDL and total cholesterol, and decreases in HDL cholesterol have been observed in clinical trials with quetiapine (see section 4.8). Lipid changes should be managed as clinically appropriate.
Metabolic Risk:Given the observed changes in weight, blood glucose (see hyperglycaemia) and lipids seen in clinical studies, patients (including those with normal baseline values) may experience worsening of their metabolic risk profile, which should be managed as clinically appropriate (see also section 4.8).
QT Prolongation:In clinical trials and use in accordance with the SPC, quetiapine was not associated with a persistent increase in absolute QT intervals. In post-marketing, QT prolongation was reported with quetiapine at the therapeutic doses (see Section 4.8) and in overdose (see Section 4.9). 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 in the elderly, in patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia or hypomagnesaemia (see section 4.5).
Withdrawal:Acute withdrawal symptoms such as nausea, vomiting, insomnia, headache, diarrhoea, dizziness and irritability have been described after abrupt cessation of quetiapine. Gradual withdrawal over a period of at least one to two weeks is advisable (see section 4.8).
Elderly patients with dementia-related psychosis:Quetiapine is not approved for the treatment of dementia-related psychosis. An approximately 3-fold increased risk of cerebrovascular adverse events has been seen in randomised placebo controlled trials in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Quetiapine should be used with caution in patients with risk factors for stroke. In a meta-analysis of atypical antipsychotics, it has been reported that elderly patients with dementia-related psychosis are at an increased risk of death compared to placebo. However 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.
Hepatic effects:If jaundice develops, quetiapine should be discontinued.
Dysphagia:Dysphagia (see section 4.8) and aspiration have been reported with quetiapine. Quetiapine should be used with caution in patients at risk for aspiration pneumonia.
Venous thromboembolism (VTE):Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with quetiapine and preventive measures undertaken.
PancreatitisPancreatitis has been reported in clinical trials and during post marketing experience. Among post marketing reports, while not all cases were confounded by risk factors, many patients had factors which are known to be associated with pancreatitis such as increased triglycerides (See section 4.4), gallstones and alcohol consumption.
Lactose:Seroquel XL tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
Additional information:Quetiapine data in combination with divalproex or lithium in acute moderate to severe manic episodes is limited; however, combination therapy was well tolerated (see section 4.8 and 5.1). The data showed an additive effect at week 3. A second study did not demonstrate an additive effect at week 6. There are no combination data available beyond week 6.
Table 1 ADRs associated with quetiapine therapy
|The frequencies of adverse events are ranked according to the following: Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000) and not known (cannot be estimated from the available data).|
|Blood and lymphatic system disorders|
|Very Common:||Decreased haemoglobin23|
|Common:||Leucopenia 1, 29, decreased neutrophil count, eosinophils increased 28|
|Uncommon:||Thrombocytopenia, Anaemia, Platelet count decreased14|
|Immune system disorders|
|Uncommon:||Hypersensitivity (including allergic skin reactions)|
|Very rare:||Anaphylactic reaction 6|
|Common:||Hyperprolactinaemia16, decreases in Total T425, decreases in Free T425, decreases in Total T325, increases in TSH25|
|Uncommon:||Decreases in free T325, Hypothyroidism22|
|Very rare:||Inappropriate antidiuretic hormone secretion|
|Metabolism and nutritional disorders|
|Very Common:||Elevations in serum triglyceride levels11, 31, Elevations in total cholesterol (predominantly LDL cholesterol)12, 31, Decreases in HDL cholesterol18, 31, Weight gain9,31|
|Common:||Increased appetite, Blood glucose increased to hyperglycaemic levels7, 31|
|Uncommon:||Hyponatraemia 20, Diabetes Mellitus 1, 5, 6|
|Common:||Abnormal dreams and nightmares, Suicidal ideation and suicidal behaviour 21|
|Rare:||Somnambulism and related reactions such as sleep talking and sleep related eating disorder|
|Nervous system disorders|
|Very Common:||Dizziness 4, 17, somnolence 2, 17, headache|
|Common:||Extrapyramidal symptoms 1,22, Dysarthria, syncope 4, 17|
|Uncommon:||Seizure 1, restless leg syndrome, Tardive dyskinesia 1, 6|
|Common:||Tachycardia 4, Palpitations 24|
|Uncommon:||QT prolongation1, 13, 19, bradycardia33|
|Common:||Orthostatic hypotension 4, 17|
|Rare:||Venous thromboembolism 1|
|Respiratory, thoracic and mediastinal disorder|
|Common:||Dyspnea 24. Rhinitis|
|Very Common:||Dry mouth|
|Common:||Constipation, dyspepsia, vomiting 26|
|Common:||Elevations in serum transaminases alanine aminotransferase (ALT, AST)3, Elevations in gamma-GT levels3|
|Rare:||Jaundice 6, Hepatitis|
|Skin and subcutaneous tissue disorders|
|Very rare:||Angioedema 6, Stevens-Johnson syndrome 6|
|Unknown:||Toxic Epidermal Necrolysis, Erythema Multiforme|
|Musculoskeletal and connective tissue disorders|
|Pregnancy, puerperium and perinatal conditions|
|Unknown:||Drug withdrawal syndrome neonatal 32|
|Reproductive system and breast disorders|
|Rare:||Priapism, Galactorrhoea, breast swelling, menstrual disorder|
|General disorders and administration site conditions|
|Very common||Withdrawal (discontinuation) symptoms 1, 10|
|Common:||Mild asthenia, peripheral oedema, irritability, pyrexia|
|Rare:||Neuroleptic malignant syndrome 1, hypothermia|
|Rare:||Elevations in blood creatine phosphokinase 15|
|The frequencies of adverse events are ranked according to the following: Very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000) and very rare (<1/10,000).|
|Metabolism and nutritional disorders|
|Very common:||Increased appetite|
|Very common:||Elevations in prolactin 1, increases in blood pressure 2|
|Nervous system disorders|
|Respiratory, thoracic and mediastinal disorder|
|General disorders and administration site conditions|
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (website: www.mhra.gov.uk/yellowcard)
Management of overdoseThere is no specific antidote to quetiapine. In cases of severe signs, the possibility of multiple drug involvement should be considered, and intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system. Whilst the prevention of absorption in overdose has not been investigated, gastric lavage can be indicated in severe poisonings and if possible to perform within one hour of ingestion. The administration of activated charcoal should be considered.In cases of quetiapine overdose refractory hypotension should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should be avoided, since beta stimulation may worsen hypotension in the setting of quetiapine-induced alpha blockade).Close medical supervision and monitoring should be continued until the patient recovers.
Mechanism of action:Quetiapine is an atypical antipsychotic agent. Quetiapine and the active human plasma metabolite, norquetiapine interact with a broad range of neurotransmitter receptors. Quetiapine and norquetiapine exhibit affinity for brain serotonin (5HT2) and dopamine D1- and D2-receptors. It is this combination of receptor antagonism with a higher selectivity for 5HT2 relative to D2-receptors, which is believed to contribute to the clinical antipsychotic properties and low extrapyramidal side effect (EPS) liability of Seroquel 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 α1-receptors, with a lower affinity at adrenergic α2 and serotonin 5HT1A receptors. Quetiapine has no appreciable affinity at muscarinic or benzodiazepine receptors.
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 D2-receptor blockade. The extent to which the norquetiapine metabolite contributes to the pharmacological activity of Seroquel in humans is not known.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)
SchizophreniaThe efficacy of Seroquel XL 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 IR-to-Seroquel XL 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 XL 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 IR 400 mg to 800 mg, efficacy was maintained when patients were switched to an equivalent daily dose of Seroquel XL given once daily.In a long-term study in stable schizophrenic patients who had been maintained on Seroquel XL for 16 weeks, Seroquel XL was more effective than placebo in preventing relapse. The estimated risks of relapse after 6 months treatments was 14.3% for the Seroquel XL treatment group compared to 68.2% for placebo. The average dose was 669 mg. There were no additional safety findings associated with treatment with Seroquel XL 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 Seroquel XL.
Bipolar DisorderIn 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. There are no data from long-term studies to demonstrate quetiapine's effectiveness in preventing subsequent manic or depressive episodes. Quetiapine data in combination with divalproex or lithium in 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. There are no combination data available beyond week 6. 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. In a clinical trial, in patients with depressive episodes in bipolar I or bipolar II disorder, 300 mg/day Seroquel XL showed superior efficacy to placebo in reduction of MADRS total score. The antidepressant effect of Seroquel XL was significant at Day 8 (week 1) and was maintained through the end of the trial (week 8). In 4 additional clinical trials in patients with depressive episodes in bipolar I or bipolar II disorder, with and without rapid cycling courses, 51% of quetiapine treated patients had at least a 50% improvement in MADRS total score at week 8 compared to 37% of the placebo treated patients. The anti-depressant effect was significant at Day 8 (week 1). There were fewer episodes of treatment-emergent mania with Seroquel than with placebo. In continuation treatment the anti-depressant effect was maintained for patients on Seroquel (mean duration of treatment 30 weeks). Seroquel reduced the risk of a recurrent mood (manic and depressed) event by 49%. Seroquel was superior to placebo in treating the anxiety symptoms associated with bipolar depression as assessed by mean change from baseline to week 8 in HAM-A total score.In one long-term study (up to 2 years treatment, mean quetiapine exposure 191 days) 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.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). The risk of a recurrent event was reduced by 70%. 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 Seroquel XL versus placebo and Seroquel XL 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).
Major depressive episodes in MDDTwo short-term (6 week) studies enrolled patients who had shown an inadequate response to at least one antidepressant. Seroquel XL 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 Seroquel XL as monotherapy treatment, however Seroquel XL 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, Seroquel XL 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 Seroquel XL treatment for at least 12 weeks were randomised to either Seroquel XL once daily or placebo for up to 52 weeks. The mean dose of Seroquel XL during the randomised phase was 177 mg/day. The incidence of relapse was 14.2% for Seroquel XL 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, Seroquel XL 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 Seroquel XL 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 Seroquel XL was 160 mg/day. Other than the incidence of extrapyramidal symptoms (see section 4.8 and 'Clinical Safety' below) the tolerability of Seroquel XL once daily in elderly patients was comparable to that seen in adults (aged 18-65 years). The proportion of randomised 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 Seroquel XL 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 Seroquel XL and 2.3% for placebo. In both bipolar depression and MDD, the incidence of the individual adverse events was generally low and 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 Seroquel XL versus placebo and Seroquel XL in adult patients with acute mania indicated that the combination of Seroquel XL with lithium leads to more adverse events (63% versus 48% in Seroquel XL 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 Seroquel XL with lithium add-on group (12.7%) compared to the Seroquel XL 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 randomised withdrawal period during which patients were randomised to quetiapine or placebo. For patients who were randomised to quetiapine, the mean weight gain during the open label period was 2.56 kg, and by week 48 of the randomised period, the mean weight gain was 3.22 kg, compared to open label baseline. For patients who were randomised to placebo, the mean weight gain during the open label period was 2.39 kg, and by week 48 of the randomised 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 1.5% 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.In fixed dose short-term placebo-controlled clinical trials, quetiapine treatment was associated with dose-related decreases in thyroid hormone levels. In short-term placebo-controlled clinical trials, the incidence of potentially clinically significant shifts in thyroid hormone levels were: total T4: 3.4% for quetiapine versus 0.6% for placebo; free T4: 0.7% for quetiapine versus 0.1% for placebo; total T3: 0.54% for quetiapine versus 0.0% for placebo and free T3: 0.2% for quetiapine versus 0.0% for placebo. The incidence of shifts in TSH was 3.2% for quetiapine versus 2.7% for placebo. In short-term placebo-controlled monotherapy trials, the incidence of reciprocal, potentially clinically significant shifts in T3 and TSH was 0.0% for both quetiapine and placebo and 0.1% for quetiapine versus 0.0% for placebo for shifts in T4 and TSH. These changes in thyroid hormone levels are generally not associated with clinically symptomatic hypothyroidism. The reduction in total and free T4 was maximal within the first six 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. In eight patients, where TBG was measured, levels of TBG were unchanged.Cataracts/lens opacitiesIn a clinical trial to evaluate the cataractogenic potential of Seroquel (200-800 mg/day) versus risperidone (2-8 mg) in patients with schizophrenia or schizoaffective disorder, the percentage of patients with increased lens opacity grade was not higher in Seroquel (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 Seroquel 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 Seroquel were excluded. Treatment with Seroquel was initiated at 50 mg/day and on day 2 increased to 100 mg/day; subsequently the dose was titrated to a target dose (mania 400-600 mg/day; schizophrenia 400-800 mg/day) using increments of 100 mg/day given 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 Seroquel 400 mg/day and 6.56 for Seroquel 600 mg/day. Responder rates (YMRS improvement ≥50%) were 64% for Seroquel 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 Seroquel 400 mg/day and 9.29 for Seroquel 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 Seroquel XL 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 12.5% vs. 6% 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 Seroquel flexibly dosed at 400-800 mg/day, provided additional safety data. Increases in blood pressure were reported in children and adolescents and increased appetite, 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.
CoatingHypromellose 2910Macrogol 400Titanium dioxide (E171)Ferric oxide, yellow (E172) (50 mg, 200 mg, 300 mg only)Ferric oxide, red (E172) (50 mg only)
|Carton (pack) contents||Blisters|
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|30 tablets||3 blisters of 10 tablets|
|50 tablets||10 blisters of 5 tablets|
|60 tablets||6 blisters of 10 tablets|
|100 tablets||10 blisters of 10 tablets|
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