Central Nervous System-Antidepressants
Central Nervous System-Antipsychotics
= Additional active ingredients
Quetiapine (as fumarate).
PRESENTATION AND DOSSAGE
TABS: 30 x 25 mg + 4 day starter pack.
TABS: 60 x 25 mg + 4 day starter pack.
TABS: 30 x 100 mg + 4 day starter pack.
TABS: 60 x 100 mg + 4 day starter pack.
TABS: 30 x 200 mg + 4 day starter pack.
TABS: 60 x 200 mg + 4 day starter pack.
TABS: 30 x 300 mg + 4 day starter pack.
Treatment of schizophrenia; manic episodes associated with bipolar disorder. Treatment of major depressive episodes in bipolar disorder. Not indicated for the prevention of recurrence of manic or depressive episodes.
This product is contraindicated in patients who are hypersensitive to any component of this product. Concomitant administration of cytochrome P450 3A4 inhibitors, such as HIV-protease inhibitors, azole-antifungal agents, erythromycin, clarithromycin and nefazodone, is contraindicated.
Seroquel 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 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 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 and bipolar mania.
Suicide/suicidal thoughts or clinical worsening: Depression in bipolar disorder 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 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 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.
Somnolence:Quetiapine treatment has been associated with somnolence and related symptoms, such as sedation. In clinical trials for treatment of patients with bipolar depression, onset was usually within the first 3 days of treatment and was predominantly of mild to moderate intensity. 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.
Neutropenia: Severe neutropenia (<0.5 X 109/L) has been uncommonly reported in this product clinical trials. Most cases of severe neutropenia have occurred within the first two months of starting therapy with this product. There was no apparent dose relationship. During post-marketing experience, resolution of leucopenia and/or neutropenia has followed cessation of therapy with Seroquel. 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. These patients should be observed for signs and symptoms of infection and neutrophil counts followed (until they exceed 1.5 X 109/L).
Hyperglycaemia: 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 and cholesterol have been observed in clinical trials with quetiapine. Lipid increases should be managed as clinically appropriate.
Metabolic Risk: Given the observed changes in weight, blood glucose and lipids seen in clinical studies, there may be possible worsening of the metabolic risk profile in individual patients, which should be managed as clinically appropriate.
Concomitant illness: Dysphagia and aspiration have been reported with quetiapine. Although a causal relationship with aspiration pneumonia has not been established, quetiapine should be used with caution in patients at risk for aspiration pneumonia. 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.
Cardiovascular disease: This product should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or other conditions predisposing to hypotension. this product may induce orthostatic hypotension, this is more common in elderly patients than in younger patients 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.
QT Prolongation: In clinical trials and use in accordance with the SPC, quetiapine was not associated with a persistent increase in absolute QT intervals. However, with overdose QT prolongation was observed. 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 with medicines known to increase QTc interval, and concomitant neuroleptics, especially in the elderly, in patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia or hypomagnesaemia.
Seizures: In controlled clinical trials there was no difference in the incidence of seizures in patients treated with this product 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.
Tardive dyskinesia: As with other antipsychotics, there is a potential for this product to cause tardive dyskinesia after long-term treatment. If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of this product should be considered.
Neuroleptic malignant syndrome: Neuroleptic malignant syndrome has been associated with antipsychotic treatment, including this product. Clinical manifestations include hyperthermia, altered mental status, muscular rigidity, autonomic instability, and increased creatine phosphokinase. In such an event, this product should be discontinued and appropriate medical treatment given.
Withdrawal: Acute withdrawal symptoms such as insomnia, nausea, headache, diarrhoea, vomiting, dizziness, and irritability have been described after abrupt cessation of quetiapine. Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported. Gradual withdrawal over a period of at least one to two weeks is advisable.
Elderly Patients with Dementia: This product is not approved for the treatment of patients with 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. Seroquel should be used with caution in patients with risk factors for stroke. 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 this product studies in the same patient population (n=710; mean age: 83 years; range: 56-99 years) the incidence of mortality in this product-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 this product treatment and death in elderly patients with dementia.
Lactose: Seroquel tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
The most commonly reported Adverse Drug Reactions (ADRs) with Seroquel 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 edema, have been associated with Seroquel. The incidences of ADRs associated with this product therapy, are tabulated below according to the format recommended by the Council for International Organizations of Medical Sciences (CIOMS III Working Group; 1995).
Given the primary central nervous system effects of quetiapine, Seroquel should be used with caution in combination with other centrally acting drugs 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. 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 therapy. Co-administration of Seroquel 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 treatment should only occur if the physician considers that the benefits of Seroquel 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 Seroquel 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 Seroquel. The pharmacokinetics of sodium valproate and Seroquel were not altered to a clinically relevant extent when co-administered. Formal interaction studies with commonly used cardiovascular drugs have not been performed. Caution should be exercised when quetiapine is used concomitantly with drugs 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.
This product should be administered twice daily, with or without food.
Adults: For the treatment of schizophrenia : the total daily dose for the first 4 days of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3) and 300 mg (Day 4). From Day 4 onwards, the dose should be titrated to the usual effective dose range of 300 to 450 mg/day. Depending on the clinical response and tolerability of the individual patient, the dose may be adjusted within the range 150 to 750 mg/day.
For the treatment of manic episodes associated with bipolar disorder : as monotherapy or as adjunct therapy to mood stabilizers, the total daily dose for the first four days of therapy is 100 mg (Day 1), 200 mg (Day 2), 300 mg (Day 3) and 400 mg (Day 4). Further dosage adjustments up to 800 mg per day by Day 6 should be in increments of no greater than 200 mg per day. The dose may be adjusted depending on clinical response and tolerability of the individual patient, within the range of 200 to 800 mg per day. The usual effective dose is in the range of 400-800 mg per day.
For the treatment of depressive episodes in bipolar disorder: Seroquel should be administered once daily at bedtime as this may reduce the likelihood of daytime sedation. 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. Depending on the patient’s response Seroquel may be 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.
Elderly: As with other antipsychotics, this product should be used with caution in the elderly, especially during the initial dosing period. The rate of dose titration 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 – 50% in elderly subjects when compared to younger patients. 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 this product 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 metabolised by the liver. Therefore, Seroquel should be used with caution in patients with known hepatic impairment, especially during the initial dosing period. Patients with known hepatic impairment should be started with 25 mg/day. The dosage should be increased daily with increments of 25 – 50 mg/day until an effective dosage, depending on the clinical response and tolerability of the individual patient.
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 postmarketing experience, there have been very rare reports of overdose of Seroquel 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 drug’s known pharmacological effects, i.e. drowsiness and sedation, tachycardia and hypotension.
Management: 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. Whilst the prevention of absorption in overdose has not been investigated, gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. Close medical supervision and monitoring should be continued until the patient recov
PREGNANCY & LACTATION
The safety and efficacy of this product during human pregnancy have not 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, this product should only be used during pregnancy if the benefits justify the potential risks. Following pregnancies in which Seroquel 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 this product.
MANUFACTURER & DISTRIBUTER:
Manufacturer: AstraZeneca UK Ltd.
License Holder: AstraZeneca Israel