Prescribing Information SEROQUEL XL (quetiapine prolonged release)

Consult Summary of Product Characteristics before prescribing.

Use:
Treatment of schizophrenia including preventing relapse in stable schizophrenic patients who have been maintained on Seroquel XL. Treatment of bipolar disorder including manic episodes, major depressive episodes, and preventing recurrence in bipolar disorder. Add-on treatment of major depressive episodes in Major Depressive Disorder (MDD) patients who have had sub-optimal response to antidepressant monotherapy (prior to initiating treatment, clinicians should consider safety profile).

Presentation:
Prolonged-release tablets containing 50mg, 150mg, 200mg, 300mg or 400mg of quetiapine (as fumarate).

Dosage and administration:
Ensure patient receives clear information on appropriate dose for their condition. Administer once daily without food (at least one hour before a meal). Adults: Schizophrenia: Daily dose is 300mg on day 1, 600mg on day 2. Recommended daily dose is 600mg. Enhanced efficacy above 600mg has not been demonstrated, however doses above 600mg and up to 800mg/day may benefit some patients and should be initiated by a specialist. Adjust dose between 400mg-800mg/day depending on clinical response and tolerability. Bipolar mania: Daily dose is 300mg on day 1, 600mg on day 2 and up to 800mg after day 2. Adjust dose between 400mg 800mg/day depending on clinical response and tolerability. Depressive episodes in bipolar disorder: Administer once daily at bedtime. Total daily dose for first four days is 50mg (Day 1), 100mg (Day 2), 200mg (Day 3) and 300mg (Day 4). Recommended daily dose is 300mg. In clinical trials, no additional benefit seen in 600mg group compared to 300mg group. Individual patients may benefit from a 600mg dose. In individual patients, in the event of tolerance concerns, clinical trials have indicated that dose reduction to 200mg could be considered. Treatment should be initiated by physicians experienced in treating bipolar disorder. Preventing recurrence in bipolar disorder (manic, mixed or depressive episodes): Patients who have responded to Seroquel XL for acute treatment of bipolar disorder should continue at same dose administered at bedtime. Adjust dose depending on clinical response and tolerability between 300mg to 800mg/day. Use lowest effective dose for maintenance. Add-on treatment of major depressive episodes in

MDD:
Administer prior to bedtime. Daily dose is 50mg on days 1 and 2 and 150mg on days 3 and 4. Antidepressant effect seen at 150 and 300mg/day in short-term trials as add-on therapy and at 50mg/day in short-term monotherapy trials. Increased risk of adverse events at higher doses. Use lowest effective dose starting with 50mg/day. Need to increase dose from 150 to 300mg/day should be based on individual evaluation. Switching from Seroquel: Patients may be switched to Seroquel XL at the equivalent total daily dose taken once daily. To ensure maintenance of clinical response, a period of dose titration may be required. Elderly: Use with caution. Start with 50mg/day increasing daily by 50mg to an effective dose depending on clinical response and tolerability. In elderly patients with major depressive episodes in MDD, start with 50mg/day on days 1-3, increasing to 100mg/day on day 4 and 150mg/day on day 8. Use lowest effective dose starting from 50mg/day. If dose increase to 300mg/day required, this should not be before day 22. Efficacy and safety not evaluated in patients over 65 with depressive episodes in bipolar disorder.

Children and adolescents:
Not recommended for use below 18 years of age. Hepatic impairment: Use with caution. Start with 50mg/day increasing daily by 50mg to an effective dose depending on clinical response and tolerability.

Contraindications:
Hypersensitivity to any component of the product. Concomitant administration of cytochrome P450 3A4 inhibitors, such as HIV-protease inhibitors, azole-antifungal agents, erythromycin, clarithromycin and nefazodone.

Precautions:
Consider safety profile with respect to each patient’s diagnosis and dose. Long term efficacy and safety in MDD not evaluated as add-on therapy. Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide. This risk persists until significant remission occurs - closely monitor patients until such improvement occurs. Risk of suicide may increase in early stages of recovery. Consider risk of suicide-related events after abrupt cessation of quetiapine. Observe same precautions with other psychiatric disorders. Patients with history of suicide-related events or exhibiting significant suicidal ideation prior to start of treatment are at greater risk – monitor carefully. In clinical studies of patients with major depressive episodes in bipolar disorder an increased risk of suicide-related events observed in patients younger than 25 years of age treated with quetiapine compared to those treated with placebo (3.0% vs 0%). In MDD studies, incidence in under-25s was 2.1% for quetiapine and 1.3% for placebo. Quetiapine treatment associated with somnolence and related symptoms, such as sedation. Bipolar depression patients and patients with major depressive episodes in MDD experiencing somnolence of severe intensity may require more frequent contact for minimum of 2 weeks from onset of somnolence, or until symptoms improve - consider need for treatment discontinuation. Quetiapine treatment associated with orthostatic hypotension and related dizziness which could increase occurrence of accidental injury/fall especially in elderly. Patients should exercise caution until familiar with effects. Caution in patients with cardiovascular or cerebrovascular disease or other conditions predisposing to hypotension. Quetiapine may induce orthostatic hypotension, especially during initial dose-titration period. Consider dose reduction or more gradual titration if this occurs. Caution in patients with history of seizures. In placebo controlled clinical trials quetiapine associated with increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for major depressive episodes in bipolar disorder and MDD. Use of quetiapine associated with development of akathisia most likely to occur in first few weeks of treatment – in patients who develop symptoms, increasing dose may be detrimental. If signs and symptoms of tardive dyskinesia appear, consider dose reduction or discontinuation. In cases of neuroleptic malignant syndrome, discontinue Seroquel XL and give appropriate medical treatment. Severe neutropenia reported uncommonly in quetiapine clinical trials. Discontinue quetiapine where neutrophil count <1.0 X 109/L. Observe patients for signs and symptoms of infection and follow neutrophil counts (until they exceed 1.5 X 109/L). Weight gain reported – monitor and manage as clinically appropriate. Hyperglycaemia and/or development or exacerbation of diabetes reported rarely including some fatal cases. Appropriate clinical monitoring advisable. Observe patients for signs and symptoms of hyperglycaemia and regularly monitor patients with diabetes mellitus or risk factors for diabetes mellitus for worsening of glucose control. Monitor weight regularly. Increases in triglycerides, LDL and total cholesterol and decreases in HDL cholesterol observed in clinical trials with quetiapine, manage lipid changes as clinically appropriate. Possible worsening of metabolic risk profile, manage as clinically appropriate. Caution in patients with family history of QT prolongation, and in combination with drugs known to prolong the QTc interval, especially in elderly, in patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia or hypomagnesaemia. Acute withdrawal symptoms described after abrupt cessation of high doses - gradual withdrawal advisable. Caution in patients with risk factors for stroke. Seroquel XL not approved for treatment of dementia-related psychosis and may increase the risk of stroke and death in these patients. Discontinue if jaundice develops. Dysphagia and aspiration reported. Use with caution in patients at risk for aspiration pneumonia. Cases of venous thromboembolism reported with antipsychotic drugs. All possible risk factors for VTE should be identified before and during treatment with quetiapine and preventive measures undertaken. Contains lactose - patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take Seroquel XL. Caution in combination with other centrally acting drugs and alcohol, and on coadministration with thioridazine, phenytoin, carbamazepine, other hepatic enzyme inducers and drugs known to cause electrolyte imbalance or increase QTc interval. Not recommended to take quetiapine together with grapefruit juice. Use in pregnancy only if benefits justify risks. Avoid breastfeeding. Caution patients about operating hazardous machines, including motor vehicles. Post-marketing experience: very rare reports of overdose of quetiapine alone resulting in death or coma or QT-prolongation.

Undesirable events:

Very common:
Dizziness and somnolence (may lead to falls), headache, dry mouth, withdrawal symptoms such as nausea, vomiting, insomnia, headache, diarrhoea, dizziness and irritability, elevations in serum triglyceride levels and total cholesterol, decreases in HDL cholesterol, weight gain.

Common:
Leucopenia, hyperprolactinaemia, increased appetite, abnormal dreams and nightmares, suicidal ideation and suicidal behaviour, syncope and orthostatic hypotension (may lead to falls), extrapyramidal symptoms, dysarthria, tachycardia, blurred vision, rhinitis, constipation, dyspepsia, mild asthenia, peripheral oedema, irritability, elevations in serum transaminases, decreased neutrophil count, increased blood glucose to hyperglycaemic levels.

Uncommon:
Eosinophilia, thrombocytopenia, hypersensitivity, seizures, restless leg syndrome, tardive dyskinesia, dysphagia, elevations in gamma-GT levels, platelet count decreased.

Rare:
Venous thromboembolism, jaundice, priapism, galactorrhoea, neuroleptic malignant syndrome, elevations in blood creatine phosphokinase.

Very rare:
Anaphylactic reaction, diabetes mellitus, hepatitis, angioedema, Stevens-Johnson syndrome.

Frequency unknown:
Neutropenia. QT prolongation, ventricular arrhythmia, sudden death, cardiac arrest and torsades de pointes reported very rarely. Decreases in thyroid hormone levels (particularly total T4 and free T4) usually reversible on cessation of therapy.

Legal category: POM.

Marketing Authorisation numbers and Basic NHS cost (60 tablets):
50mg: 17901/0249 - £67.66; 150mg: 17901/0259 - £113.10; 200mg: 17901/0250 - £113.10; 300mg: 17901/0251 - £170.00; 400mg: 17901/0252 - £226.20.

Further information is available from: AstraZeneca UK Limited, 600 Capability Green, Luton, LU1 3LU, UK.

Seroquel XL is a trade mark of the AstraZeneca group of companies.

Date of Prep 09/2010

Prescribing Information SEROQUEL* (quetiapine)
*Intensive monitoring is requested only when used for the recently licensed indication of bipolar depression.

Consult Summary of Product Characteristics before prescribing.

Use:
Treatment of schizophrenia. Treatment of bipolar disorder including manic episodes, major depressive episodes, and preventing recurrence in bipolar disorder.

Presentation:
Tablets containing 25mg, 100mg, 150mg, 200mg and 300mg of quetiapine (as fumarate).

Dosage and administration: Adults:
For the treatment of schizophrenia: Seroquel should be administered twice daily. The total daily dose for the first four days of therapy is 50mg (Day 1), 100mg (Day 2), 200mg (Day 3) and 300mg (Day 4). From Day 4 onwards, titrate to usual effective range of 300 to 450mg/day. Dose may be adjusted within the range 150 to 750mg/day according to clinical response and tolerability. For the treatment of manic episodes associated with bipolar disorder: Seroquel should be administered twice daily. As monotherapy or as adjunct therapy to mood stabilizers, the total daily dose for the first four days of therapy is 100mg (Day 1), 200mg (Day 2), 300mg (Day 3) and 400mg (Day 4). Further dosage adjustments up to 800mg/day by Day 6 should be in increments of no greater than 200mg/day. Dose may be adjusted within the range 200 to 800mg/day according to clinical response and tolerability. The usual effective dose is in the range of 400 to 800 mg/day. For the treatment of depressive episodes in bipolar disorder: Seroquel should be administered once daily at bedtime. The total daily dose for the first four days of therapy is 50mg (Day 1), 100mg (Day 2), 200mg (Day 3) and 300mg (Day 4). The recommended daily dose is 300mg. In clinical trials, no additional benefit was seen in the 600mg group compared to the 300mg group. Individual patients may benefit from a 600mg dose. In individual patients, in the event of tolerance concerns, clinical trials have indicated that dose reduction to a minimum of 200mg 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 disorder (manic, mixed or depressive episodes): Patients who have responded to quetiapine for acute treatment of bipolar disorder should continue therapy at the same dose. The dose may then be adjusted depending on clinical response and tolerability of the individual patient, within the range of 300 to 800mg/day administered twice daily. It is important that the lowest effective dose is used for maintenance therapy. Elderly patients: Use with caution, starting with 25mg/day and increasing daily by 25 to 50mg to an effective dose. Efficacy and safety have not been evaluated in patients over 65 years with depressive episodes in the framework of bipolar disorder. Children and adolescents: Seroquel is not recommended for use in children and adolescents below 18 years of age. Hepatic impairment: Use with caution. Start with 25mg/day increasing daily by 25 to 50mg to an effective dose depending on the clinical response and tolerability of the individual patient.

Contraindications:
Hypersensitivity to any component of the product. Concomitant administration of cytochrome P450 3A4 inhibitors, such as HIV-protease inhibitors, azole-antifungal agents, erythromycin, clarithromycin and nefazodone.

Precautions:
Depression in bipolar disorder is associated with an increased risk of suicidal thoughts, self-harm and suicide. This risk persists until significant remission occurs and patients should be closely monitored until such improvement occurs. In clinical studies of patients with major depressive episodes in bipolar disorder an increased risk of suicide-related events was observed in young adult patients less than 25 years of age who were treated with quetiapine as compared to those treated with placebo. Quetiapine treatment has been associated with somnolence and related symptoms, such as sedation. Bipolar depression patients 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. Caution in patients with cardiovascular disease, cerebrovascular disease or other conditions predisposing to hypotension. Quetiapine may induce orthostatic hypotension, especially during the initial dose-titration period. Dose reduction or more gradual titration should be considered if this occurs. Caution in patients with a history of seizures. In placebo controlled clinical trials quetiapine was associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for major depressive episodes in bipolar disorder. If signs and symptoms of tardive dyskinesia appear, consider dosage reduction or discontinuation of Seroquel. In cases of neuroleptic malignant syndrome, discontinue Seroquel and give appropriate medical treatment. Severe neutropenia (neutrophil count <0.5 X 109/L) has been uncommonly reported in Seroquel clinical trials. Patients should be observed for signs and symptoms of infection and neutrophil counts followed (until they exceed 1.5 X 109/L). Hyperglycaemia or exacerbation of pre-existing diabetes reported during treatment with quetiapine. Appropriate clinical monitoring advisable in diabetic patients and in patients with risk factors for the development of diabetes mellitus. Increases in triglycerides, LDL and total cholesterol and decreases in HDL cholesterol have been observed in clinical trials with quetiapine, lipid changes should be managed as clinically appropriate. Caution in patients with a family history of QT prolongation, and in combination with drugs known to prolong the QTc interval, especially in the elderly, in patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia or hypomagnesaemia. Acute withdrawal symptoms have been described after abrupt cessation of antipsychotic drugs. Therefore, gradual withdrawal over a period of at least one to two weeks is advisable. Caution in patients with risk factors for stroke. Seroquel is not approved for the treatment of dementia-related psychosis and may increase the risk of stroke and death in these patients. If jaundice develops, Seroquel should be discontinued. Dysphagia and aspiration have been reported with Seroquel. Use with caution in patients at risk for aspiration pneumonia. Cases of venous thromboembolism have been reported with antipsychotic drugs. All possible risk factors for VTE should be identified before and during treatment with quetiapine and preventive measures undertaken. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take Seroquel. Caution in combination with other centrally acting drugs and alcohol, and on coadministration with thioridazine, phenytoin, carbamazepine or other hepatic enzyme inducers. It is not recommended to take quetiapine together with grapefruit juice. Seroquel should only be used during pregnancy if benefits justify the potential risks. Avoid breastfeeding whilst taking Seroquel. Patients should be cautioned about operating hazardous machines, including motor vehicles. In post-marketing experience, there have been very rare reports of overdose of quetiapine alone resulting in death or coma or QT-prolongation.

Undesirable events:
Very common: Dizziness and somnolence (may lead to falls), headache, dry mouth, withdrawal symptoms such as nausea, vomiting, insomnia, headache, diarrhoea, dizziness and irritability, elevations in serum triglyceride levels and total cholesterol (predominantly LDL cholesterol), decreases in HDL cholesterol, weight gain. Common: Leucopenia, hyperprolactinaemia, increased appetite, abnormal dreams and nightmares, syncope and orthostatic hypotension (may lead to falls), extrapyramidal symptoms, dysarthria, tachycardia, blurred vision, rhinitis, constipation, dyspepsia, mild asthenia, peripheral oedema, irritability, elevations in serum transaminases (ALT, AST), decreased neutrophil count, increased blood glucose to hyperglycaemic levels. Uncommon: Eosinophilia, thrombocytopenia, hypersensitivity, seizures, restless leg syndrome, tardive dyskinesia, dysphagia, elevations in gamma-GT levels, platelet count decreased. Rare: Jaundice, priapism, galactorrhoea, neuroleptic malignant syndrome, elevations in blood creatine phosphokinase, venous thromboembolism. Very rare: Anaphylactic reaction, diabetes mellitus, hepatitis, angioedema, Stevens-Johnson syndrome. QT prolongation, ventricular arrhythmia, sudden death, cardiac arrest and torsades de pointes have been reported very rarely. Decreases in thyroid hormone levels, particularly total T4 and free T4 are usually reversible on cessation of therapy.

Legal category: POM.

Marketing Authorisation numbers: 25mg tablet: 17901/0038; 100mg tablet: 17901/0039; 150mg tablet: 17901/0041; 200mg tablet: 17901/0040; 300mg tablet: 17901/0088

Basic NHS cost: 60 x 25mg tablets £33.83; 60 x 100mg tablets £113.10; 60 x 150mg tablets £113.10; 60 x 200mg tablets £113.10; 60 x 300mg tablets £170.00.

Further information is available from the Marketing Authorisation Holder:
AstraZeneca UK Limited, 600 Capability Green, Luton, LU1 3LU, UK. Seroquel is a trade mark of the AstraZeneca group of companies.

Date of Prep 01/2010.