Seroquel XR

/ Tzamal

Different dosing schedules exist for each indication. It must therefore be ensured that patients receive clear information on the appropriate dosage for their condition.2 Seroquel XR should be administered once daily, without food (Seroquel XR should be administrated at least one hour before a meal). The tablets should be swallowed whole and not split, chewed or crushed.
Adults
For the treatment of schizophrenia and manic episodes associated with bipolar disorder: The 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, however if clinically justified the dose may be increased to 800 mg daily. 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 depressive episodes associated with bipolar disorder Seroquel XR should be administered at -evening . The 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. Depending on the patient’s response Seroquel XR maybe titrated up to 600 mg daily. Antidepressant efficacy was demonstrated at 300 mg and 600 mg/day, however no additional benefit was seen in the 600 mg group above 300 mg daily during short-term treatment. When treating depressive episodes in bipolar disorder, treatment should be prescribed by physicians experienced in treating bipolar disorder.
For preventing recurrence in bipolar disorder: For prevention of recurrence of manic, depressive or mixed episodes in bipolar disorder, patients who have responded to Seroquel XR for acute treatment of bipolar disorder should continue on Seroquel XR at the same dose. 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 XR should be administered once daily in the evening. 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 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 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 and antidepressant , 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 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 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: The safety and efficacy of Seroquel XR have not been evaluated in children and adolescents.
Renal impairment: Dosage adjustment is not necessary in patients with renal impairment.
Hepatic impairment: Quetiapine is extensively metabolized 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 tolerability of the individual patient.

For the treatment of schizophrenia.Therapy is effective in preventing relapse in stable schizophrenic patients who have been maintained on Seroquel XR.For the treatment of moderate to severe manic episodes associated with bipolar disorder.For the treatment of major depressive episodes in bipolar disorder. Treatment of acute mania associated with bipolar I disorder as monotherapy or in combination with lithium or sodium valproate.For preventing recurrence in bipolar disorder in patients whose manic, mixed or depressive episode has responded to quetiapine treatment, as monotherapy or in combination with lithium or sodium valproate.For add-on treatment of major depressive episods in patients with Major Depressive Disorder (MDD) who have had sub-optimal response to antidepressant monotherapy. Prior to initiating treatment, clinicians should consider the safety profile of Seroquel XR.

Hypersensitivity to the active substance or to any of the excipients of this product. Concomitant administration of cytochrome P450 3A4 inhibitors, such as HIV-protease inhibitors, azole-antifungal agents, erythromycin, clarithromycin and nefazodone, is contraindicated.

As Seroquel XR is indicated for the treatment of schizophrenia, bipolar disorder and add-on treatment of major depressive episodes in patients with MDD, the safety profile should be considered with respect to the individual patient’s diagnosis and the dose being administered.
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.
Children and adolescents (10 to 17 years of age): Seroquel XR 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 Seroquel have shown that in addition to the known safety profile identified in adults, certain adverse events occurred at a higher frequency in children and adolescents compared to adults (increased appetite, elevations in serum prolactin and 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 Seroquel 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 treated with Seroquel, Seroquel was associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for schizophrenia and bipolar mania.
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 XR 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 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 (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.
Somnolence: Quetiapine treatment has been associated with somnolence and related symptoms, such as sedation. 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 patinets with major depressive disorder 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 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: 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 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. As with other antipsychotics, caution is recommended when treating patients with a history of seizures.
Extrapyramidal symptoms: 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 and major depressive disorder. 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: If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of Seroquel XR should be considered. The symptoms of tardive dyskinesia can worsen or even arise after discontinuation of treatment
Neuroleptic Malignant Syndrome: Neuroleptic malignant syndrome has been associated with antipsychotic treatment, including quetiapine. Clinical manifestations include hyperthermia, altered mental status, muscular rigidity, autonomic instability, and increased creatinine phosphokinase. In such an event, Seroquel XR 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 10^9/L).
For full details see prescribing information.

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 below according to the format recommended by the Council for International Organizations of Medical Sciences.
For full details see prescribing information.

Given the primary central nervous system effects of quetiapine, Seroquel XR should be used with caution in combination with other centrally acting medicinal products and alcohol. Cytochrome P450 (CYP) 3A4 is the enzyme that is primarily responsible for the cytochrome P450 mediated metabolism of quetiapine. In an interaction study in healthy volunteers, concomitant administration of quetiapine (dosage of 25 mg) with ketoconazole, a CYP3A4 inhibitor, caused a 5- to 8-fold increase in the AUC of quetiapine. On the basis of this, concomitant use of quetiapine with CYP3A4 inhibitors is contraindicated. It is also not recommended to take quetiapine together with grapefruit juice while on quetiapine therapy. 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, which could affect the efficacy of Seroquel XR therapy. Co-administration of quetiapine and phenytoin (another microsomal enzyme inducer) caused a greatly increased clearance of quetiapine by approx. 450%. In patients receiving a hepatic enzyme inducer, initiation of Seroquel XR treatment should only occur if the physician considers that the benefits of Seroquel XR 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). The pharmacokinetics of quetiapine were not significantly altered by co-administration of the antidepressants imipramine (a known CYP 2D6 inhibitor) or fluoxetine (a known CYP 3A4 and CYP 2D6 inhibitor). The pharmacokinetics of quetiapine were not significantly altered by co-administration of the antipsychotics risperidone or haloperidol. Concomitant use of quetiapine and thioridazine caused an increased clearance of quetiapine with approx. 70%. The pharmacokinetics of quetiapine were not altered following co-administration with cimetidine. The pharmacokinetics of lithium were not altered when co-administered with quetiapine. The pharmacokinetics of sodium valproate and quetiapine were not altered to a clinically relevant extent when co-administered. Formal interaction studies with commonly used cardiovascular medicinal products have not been performed. Caution should be exercised when quetiapine is used concomitantly with medicinal products known to cause electrolyte imbalance or to increase QTc interval. There have been reports of false positive results in enzyme immunoassays for methadone and tricyclic antidepressants in patients who have taken quetiapine. Confirmation of questionable immunoassay screening results by an appropriate chromatographic technique is recommended.
Not recommended to take together with grapefruit juice.

The safety and efficacy of quetiapine during human pregnancy have not yet been established. Up to now there are no indications for harmfulness in animal tests, possible effects on the foetal eye have not been examined, though. Therefore, Seroquel XR should only be used during pregnancy if the benefits justify the potential risks. Following pregnancies in which quetiapine was used, neonatal withdrawal symptoms were observed. The degree to which quetiapine is excreted into human milk is unknown. Women who are breast-feeding should therefore be advised to avoid breast-feeding while taking Seroquel XR.

Fatal outcome has been reported in clinical trials following an acute overdose at 13.6 grams, and in post-marketing on doses as low as 6 grams of Seroquel alone. However, survival has also been reported following acute overdoses of up to 30 grams. In post marketing experience, there have been very rare reports of overdose of quetiapine alone resulting in death or coma or QT-prolongation. Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose. In general, reported signs and symptoms were those resulting from an exaggeration of the active substance’s known pharmacological effects, ie, drowsiness and sedation, tachycardia and hypotension.
Management of overdose: There 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. Close medical supervision and monitoring should be continued until the patient recovers.