Seroquel Information
Seroquel (Quetiapine fumarate) Warning: Increased Mortality In Elderly Patients With Dementia-related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks) largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Seroquel (Quetiapine fumarate) (quetiapine) is not approved for the treatment of patients with dementia-related psychosis [ (5.1)].
Seroquel (Quetiapine fumarate) Suicidality And Antidepressant Drugs
Seroquel (Quetiapine fumarate) Indications And Usage
Seroquel (Quetiapine fumarate) is indicated for the acute treatment of manic episodes associated with bipolar I disorder, both as monotherapy and as an adjunct to lithium or divalproex. Efficacy was established in two 12-week monotherapy trials in adults, in one 3-week adjunctive trial in adults, and in one 3-week monotherapy trial in pediatric patients (10-17 years) [ (14.2)].
Seroquel (Quetiapine fumarate) is indicated as monotherapy for the acute treatment of depressive episodes associated with bipolar disorder. Efficacy was established in two 8-week monotherapy trials in adult patients with bipolar I and bipolar II disorder [ (14.2)].
Seroquel (Quetiapine fumarate) is indicated for the maintenance treatment of bipolar I disorder, as an adjunct to lithium or divalproex. Efficacy was established in two maintenance trials in adults. The effectiveness of Seroquel (Quetiapine fumarate) as monotherapy for the maintenance treatment of bipolar disorder has not been systematically evaluated in controlled clinical trials [ (14.2)].
Seroquel (Quetiapine fumarate) Dosage And Administration
Seroquel (Quetiapine fumarate) can be taken with or without food.
Adults
Dose Selection
Efficacy in schizophrenia was demonstrated in a dose range of 150 mg/day to 750 mg/day in the clinical trials supporting the effectiveness of Seroquel (Quetiapine fumarate) . In a dose response study, doses above 300 mg/day were not demonstrated to be more efficacious than the 300 mg/day dose. In other studies, however, doses in the range of 400 mg/day - 500 mg/day appeared to be needed. The safety of doses above 800 mg/day has not been evaluated in clinical trials.
Maintenance Treatment
Adolescents (13-17 years)
Dose Selection
The total daily dose for the initial five days of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3), 300 mg (Day 4) and 400 mg (Day 5). After Day 5, the dose should be adjusted within the recommended dose range of 400 mg/day to 800 mg/day based on response and tolerability. Dosage adjustments should be in increments of no greater than 100 mg/day. Efficacy was demonstrated with Seroquel (Quetiapine fumarate) at both 400 mg and 800 mg; however, no additional benefit was seen in the 800 mg group.
Maintenance Treatment
Adults
Acute Treatment of Manic Episodes in Bipolar I Disorder
Dose Selection
Acute Treatment of Depressive Episodes in Bipolar Disorder
Dose Selection
In the clinical trials supporting effectiveness, the dosing schedule was 50 mg, 100 mg, 200 mg and 300 mg/day for Days 1-4 respectively. Patients receiving 600 mg increased to 400 mg on Day 5 and 600 mg on Day 8 (Week 1). Antidepressant efficacy was demonstrated with Seroquel (Quetiapine fumarate) at both 300 mg and 600 mg; however, no additional benefit was seen in the 600 mg group.
Maintenance Treatment of Bipolar I Disorder
Maintenance of efficacy in bipolar I disorder was demonstrated with Seroquel (Quetiapine fumarate) (administered twice daily totaling 400 to 800 mg per day) as adjunct therapy to lithium or divalproex. Generally, in the maintenance phase, patients continued on the same dose on which they were stabilized during the stabilization phase [ (14.2)].
Children and Adolescents (10 to 17 years)
Acute Treatment of Manic Episodes in Bipolar I Disorder
Dose Selection
The total daily dose for the initial five days of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3), 300 mg (Day 4) and 400 mg (Day 5). After Day 5, the dose should be adjusted within the recommended dose range of 400 to 600 mg/day based on response and tolerability. Dosage adjustments should be in increments of no greater than 100 mg/day. Efficacy was demonstrated with Seroquel (Quetiapine fumarate) at both 400 mg and 600 mg; however, no additional benefit was seen in the 600 mg group.
Maintenance Treatment of Bipolar I Disorder
The effectiveness of Seroquel (Quetiapine fumarate) for longer than 3 weeks has not been evaluated in controlled clinical trials of children and adolescents. While there is no body of evidence available to answer the question of how long the patient treated with Seroquel (Quetiapine fumarate) should be maintained, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.
Consideration should be given to a slower rate of dose titration and a lower target dose in the elderly and in patients who are debilitated or who have a predisposition to hypotensive reactions [ (12)]. When indicated, dose escalation should be performed with caution in these patients.
Patients with hepatic impairment should be started on 25 mg/day. The dose should be increased daily in increments of 25 mg/day – 50 mg/day to an effective dose, depending on the clinical response and tolerability of the patient.
Seroquel (Quetiapine fumarate) Dosage Forms And Strengths
25 mg tablets
50 mg tablets
100 mg tablets
200 mg tablets
300 mg tablets
400 mg tablets
Seroquel (Quetiapine fumarate) Contraindications
Seroquel (Quetiapine fumarate) Warnings And Precautions
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Seroquel (Quetiapine fumarate) is not approved for the treatment of patients with dementia-related psychosis
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Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers.
Screening Patients for Bipolar Disorder:
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including Seroquel (Quetiapine fumarate) . Rare cases of NMS have been reported with Seroquel (Quetiapine fumarate) . Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored since recurrences of NMS have been reported.
Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including quetiapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment.
Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
In some patients, a worsening of more than one of the metabolic parameters of weight, blood glucose and lipids was observed in clinical studies. Changes in these parameters should be managed as clinically appropriate.
Adults:
In a 24-week trial (active-controlled, 115 patients treated with Seroquel (Quetiapine fumarate) ) designed to evaluate glycemic status with oral glucose tolerance testing of all patients, at week 24 the incidence of a treatment-emergent post-glucose challenge glucose level ≥ 200 mg/dL was 1.7% and the incidence of a fasting treatment-emergent blood glucose level ≥ 126 mg/dL was 2.6%. The mean change in fasting glucose from baseline was 3.2 mg/dL and mean change in 2 hour glucose from baseline was -1.8 mg/dL for quetiapine.
In 2 long-term placebo-controlled randomized withdrawal clinical trials for bipolar maintenance, mean exposure of 213 days for Seroquel (Quetiapine fumarate) (646 patients) and 152 days for placebo (680 patients), the mean change in glucose from baseline was +5.0 mg/dL for Seroquel (Quetiapine fumarate) and –0.05 mg/dL for placebo. The exposure-adjusted rate of any increased blood glucose level (≥ 126 mg/dL) for patients more than 8 hours since a meal (however, some patients may not have been precluded from calorie intake from fluids during fasting period) was 18.0 per 100 patient years for Seroquel (Quetiapine fumarate) (10.7% of patients; n=556) and 9.5 for placebo per 100 patient years (4.6% of patients; n=581).
Children and Adolescents:
Undesirable alterations in lipids have been observed with quetiapine use. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using quetiapine is recommended.
In some patients, a worsening of more than one of the metabolic parameters of weight, blood glucose and lipids was observed in clinical studies. Changes in these parameters should be managed as clinically appropriate.
Adults:
Table 3 shows the percentage of adult patients with changes in total cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol from baseline by indication in clinical trials with Seroquel (Quetiapine fumarate) .
Children and Adolescents:
Increases in weight have been observed in clinical trials. Patients receiving quetiapine should receive regular monitoring of weight [ (17)].
In some patients, a worsening of more than one of the metabolic parameters of weight, blood glucose and lipids was observed in clinical studies. Changes in these parameters should be managed as clinically appropriate.
Adults:
Children and Adolescents:
The mean change in body weight in the schizophrenia trial was 2.0 kg in the Seroquel (Quetiapine fumarate) group and -0.4 kg in the placebo group and in the bipolar mania trial it was 1.7 kg in the Seroquel (Quetiapine fumarate) group and 0.4 kg in the placebo group.
In an open-label study that enrolled patients from the above two pediatric trials, 63% of patients (241/380) completed 26 weeks of therapy with Seroquel (Quetiapine fumarate) . After 26 weeks of treatment, the mean increase in body weight was 4.4 kg. Forty-five percent of the patients gained ≥ 7% of their body weight, not adjusted for normal growth. In order to adjust for normal growth over 26 weeks an increase of at least 0.5 standard deviation from baseline in BMI was used as a measure of a clinically significant change; 18.3% of patients on Seroquel (Quetiapine fumarate) met this criterion after 26 weeks of treatment.
When treating pediatric patients with Seroquel (Quetiapine fumarate) for any indication, weight gain should be assessed against that expected for normal growth.
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs, including quetiapine. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, Seroquel (Quetiapine fumarate) should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who appear to suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient on Seroquel (Quetiapine fumarate) , drug discontinuation should be considered. However, some patients may require treatment with Seroquel (Quetiapine fumarate) despite the presence of the syndrome.
Quetiapine may induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α-adrenergic antagonist properties. Syncope was reported in 1% (28/3265) of the patients treated with Seroquel (Quetiapine fumarate) , compared with 0.2% (2/954) on placebo and about 0.4% (2/527) on active control drugs. Orthostatic hypotension, dizziness, and syncope may lead to falls.
Seroquel (Quetiapine fumarate) should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease or conditions which would predispose patients to hypotension (dehydration, hypovolemia and treatment with antihypertensive medications) [ (6.2)]. The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 25 mg twice daily [ (2)]. If hypotension occurs during titration to the target dose, a return to the previous dose in the titration schedule is appropriate.
In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to atypical antipsychotic agents, including Seroquel (Quetiapine fumarate) . Agranulocytosis (including fatal cases) has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue Seroquel (Quetiapine fumarate) at the first sign of a decline in WBC in absence of other causative factors.
Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm) should discontinue Seroquel (Quetiapine fumarate) and have their WBC followed until recovery [ (6.2)].
In clinical trials quetiapine was not associated with a persistent increase in QT intervals. However, the QT effect was not systematically evaluated in a thorough QT study. In post marketing experience, there were cases reported of QT prolongation in patients who overdosed on quetiapine [], in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval [].
The use of quetiapine should be avoided in combination with other drugs that are known to prolong QTc including Class 1A antiarrythmics (e.g., quinidine, procainamide) or Class III antiarrythmics (e.g., amiodarone, sotalol), antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, methadone).
Quetiapine should also be avoided in circumstances that may increase the risk of occurrence of torsade de pointes and/or sudden death including (1) a history of cardiac arrhythmias such as bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.
Caution should also be exercised when quetiapine is prescribed in patients with increased risk of QT prolongation (e.g. cardiovascular disease, family history of QT prolongation, the elderly, congestive heart failure and heart hypertrophy).
In all quetiapine trials, the incidence of potentially clinically significant shifts in thyroid hormones and TSH were*: decrease in free T4, 2.0% (357/17513); decrease in total T4, 4.0% (75/1861); decrease in free T3, 0.4% (53/13766); decrease in total T3, 2.0% (26/1312), and increase in TSH, 4.9% (956/19412). In eight patients, where TBG was measured, levels of TBG were unchanged.
Table 7 shows the incidence of these shifts in short-term placebo-controlled clinical trials.
In short-term placebo-controlled monotherapy trials, the incidence of reciprocal, potentially clinically significant shifts in T and TSH was 0.0 % for both quetiapine (1/4800) and placebo (0/2190) and for T and TSH the shifts were 0.1% (7/6154) for quetiapine versus 0.0% (1/3007) for placebo.
Generally, these changes in thyroid hormone levels were of no clinical significance.
Children and Adolescents:
Adults:
Children and Adolescents:
Like other drugs that antagonize dopamine D2 receptors, Seroquel (Quetiapine fumarate) elevates prolactin levels in some patients and the elevation may persist during chronic administration. Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.
Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent , a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in carcinogenicity studies conducted in mice and rats. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive [ (13.1)].
The possibility of a suicide attempt is inherent in bipolar disorder and schizophrenia; close supervision of high risk patients should accompany drug therapy. Prescriptions for Seroquel (Quetiapine fumarate) should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.
In two 8-week clinical studies in patients with bipolar depression (N=1048), the incidence of treatment emergent suicidal ideation or suicide attempt was low and similar to placebo (Seroquel (Quetiapine fumarate) 300 mg, 6/350, 1.7%; Seroquel (Quetiapine fumarate) 600 mg, 9/348, 2.6%; Placebo, 7/347, 2.0%).
Clinical experience with Seroquel (Quetiapine fumarate) in patients with certain concomitant systemic illnesses is limited [ (12.3)].
Seroquel (Quetiapine fumarate) has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical studies. Because of the risk of orthostatic hypotension with Seroquel (Quetiapine fumarate) , caution should be observed in cardiac patients [ (5.8)].
Acute withdrawal symptoms, such as insomnia, nausea, and vomiting have been described after abrupt cessation of atypical antipsychotic drugs, including Seroquel (Quetiapine fumarate) . In short-term placebo-controlled, monotherapy clinical trials with Seroquel (Quetiapine fumarate) XR that included a discontinuation phase which evaluated discontinuation symptoms, the aggregated incidence of patients experiencing one or more discontinuation symptoms after abrupt cessation was 12.1% (241/1993) for Seroquel (Quetiapine fumarate) XR and 6.7% (71/1065) for placebo. The incidence of the individual adverse events (i.e., insomnia, nausea, headache, diarrhea, vomiting, dizziness and irritability) did not exceed 5.3% in any treatment group and usually resolved after 1 week post-discontinuation. Gradual withdrawal is advised.
Seroquel (Quetiapine fumarate) Adverse Reactions
Adults
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
The information below is derived from a clinical trial database for Seroquel (Quetiapine fumarate) consisting of over 4300 patients. This database includes 698 patients exposed to Seroquel (Quetiapine fumarate) for the treatment of bipolar depression, 405 patients exposed to Seroquel (Quetiapine fumarate) for the treatment of acute bipolar mania (monotherapy and adjunct therapy), 646 patients exposed to Seroquel (Quetiapine fumarate) for the maintenance treatment of bipolar I disorder as adjunct therapy, and approximately 2600 patients and/or normal subjects exposed to 1 or more doses of Seroquel (Quetiapine fumarate) for the treatment of schizophrenia.
Of these approximately 4300 subjects, approximately 4000 (2300 in schizophrenia, 405 in acute bipolar mania, 698 in bipolar depression, and 646 for the maintenance treatment of bipolar I disorder) were patients who participated in multiple dose effectiveness trials, and their experience corresponded to approximately 2400 patient-years. The conditions and duration of treatment with Seroquel (Quetiapine fumarate) varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and dose-titration studies, and short-term or longer-term exposure. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, ECGs, and results of ophthalmologic examinations.
Adverse reactions during exposure were obtained by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a smaller number of standardized reaction categories.
In the tables and tabulations that follow, standard COSTART terminology has been used to classify reported adverse reactions for schizophrenia and bipolar mania. MedDRA terminology has been used to classify reported adverse reactions for bipolar depression.
The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.
Incidence of Adverse Reactions in Short-Term, Placebo-Controlled Trials in Adults
Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials:
Bipolar Disorder:
Mania:
Depression:
Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials:
In the acute therapy of schizophrenia (up to 6 weeks) and bipolar mania (up to 12 weeks) trials, the most commonly observed adverse reactions associated with the use of Seroquel (Quetiapine fumarate) monotherapy (incidence of 5% or greater) and observed at a rate on Seroquel (Quetiapine fumarate) at least twice that of placebo were somnolence (18%), dizziness (11%), dry mouth (9%), constipation (8%), ALT increased (5%), weight gain (5%), and dyspepsia (5%).
Adverse Reactions Occurring at an Incidence of 1% or More Among Seroquel (Quetiapine fumarate) Treated Patients in Short-Term, Placebo-Controlled Trials:
The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence in the population studied.
Table 8 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during acute therapy of schizophrenia (up to 6 weeks) and bipolar mania (up to 12 weeks) in 1% or more of patients treated with Seroquel (Quetiapine fumarate) (doses ranging from 75 to 800 mg/day) where the incidence in patients treated with Seroquel (Quetiapine fumarate) was greater than the incidence in placebo-treated patients.
In the acute adjunct therapy of bipolar mania (up to 3 weeks) studies, the most commonly observed adverse reactions associated with the use of Seroquel (Quetiapine fumarate) (incidence of 5% or greater) and observed at a rate on Seroquel (Quetiapine fumarate) at least twice that of placebo were somnolence (34%), dry mouth (19%), asthenia (10%), constipation (10%), abdominal pain (7%), postural hypotension (7%), pharyngitis (6%), and weight gain (6%).
Table 9 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during therapy (up to 3 weeks) of acute mania in 1% or more of patients treated with Seroquel (Quetiapine fumarate) (doses ranging from 100 to 800 mg/day) used as adjunct therapy to lithium and divalproex where the incidence in patients treated with Seroquel (Quetiapine fumarate) was greater than the incidence in placebo-treated patients.
In bipolar depression studies (up to 8 weeks), the most commonly observed treatment emergent adverse reactions associated with the use of Seroquel (Quetiapine fumarate) (incidence of 5% or greater) and observed at a rate on Seroquel (Quetiapine fumarate) at least twice that of placebo were somnolence (57%), dry mouth (44%), dizziness (18%), constipation (10%), and lethargy (5%).
Table 10 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during therapy (up to 8 weeks) of bipolar depression in 1% or more of patients treated with Seroquel (Quetiapine fumarate) (doses of 300 and 600 mg/day) where the incidence in patients treated with Seroquel (Quetiapine fumarate) was greater than the incidence in placebo-treated patients.
Explorations for interactions on the basis of gender, age, and race did not reveal any clinically meaningful differences in the adverse reaction occurrence on the basis of these demographic factors.
Dose Dependency of Adverse Reactions in Short-Term, Placebo-Controlled Trials
Dose-related Adverse Reactions:
Adverse Reactions in clinical trials with quetiapine and not listed elsewhere in the label:
The following adverse reactions have also been reported with quetiapine: nightmares, hypersensitivity and elevations in serum creatine phosphokinase (not associated with NMS).
Extrapyramidal Symptoms:
Dystonia
Class Effect:
Adults:
Parkinsonism incidence rates as measured by the Simpson-Angus total score for placebo and the five fixed doses (75, 150, 300, 600, 750 mg/day) were: -0.6; -1.0, -1.2; -1.6; -1.8 and -1.8. The rate of anticholinergic medication use to treat emergent EPS for placebo and the five fixed doses was: 14%; 11%; 10%; 8%; 12% and 11%.
In six additional placebo-controlled clinical trials (3 in acute mania and 3 in schizophrenia) using variable doses of Seroquel (Quetiapine fumarate) , there were no differences between the Seroquel (Quetiapine fumarate) and placebo treatment groups in the incidence of EPS, as assessed by Simpson-Angus total scores, spontaneous complaints of EPS and the use of concomitant anticholinergic medications to treat EPS.
In two placebo-controlled clinical trials for the treatment of bipolar depression using 300 mg and 600 mg of Seroquel (Quetiapine fumarate) , the incidence of adverse reactions potentially related to EPS was 12% in both dose groups and 6% in the placebo group. In these studies, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, muscle contractions involuntary, psychomotor hyperactivity and muscle rigidity) were generally low and did not exceed 4% in any treatment group.
The 3 treatment groups were similar in mean change in SAS total score and BARS Global Assessment score at the end of treatment. The use of concomitant anticholinergic medications was infrequent and similar across the three treatment groups.
Children and Adolescents:
The information below is derived from a clinical trial database for Seroquel (Quetiapine fumarate) consisting of over 1000 pediatric patients. This database includes 677 patients exposed to Seroquel (Quetiapine fumarate) for the treatment of schizophrenia and 393 patients exposed to Seroquel (Quetiapine fumarate) for the treatment of acute bipolar mania.
Incidence of Adverse Reactions in Short-Term, Placebo-Controlled Trials in Children and Adolescents
Adolescents 13 to 17 years of age with Schizophrenia
The following findings were based on a 6-week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 800 mg/day.
Adverse Reactions Associated with Discontinuation of Treatment
The incidence of discontinuation due to adverse reactions for quetiapine-treated and placebo-treated patients was 8.2% and 2.7%, respectively. The adverse event leading to discontinuation in 1% or more of patients on Seroquel (Quetiapine fumarate) and at a greater incidence than placebo was somnolence (2.7% and 0% for placebo).
Commonly Observed Adverse Reactions
In therapy for schizophrenia (up to 6 weeks), the most commonly observed adverse reactions associated with the use of quetiapine in adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (34%), dizziness (12%), dry mouth (7%), tachycardia ( 7%).
Table 12 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during therapy (up to 6 weeks) of schizophrenia in 5% or more of patients treated with Seroquel (Quetiapine fumarate) (doses of 400 or 800 mg/day) where the incidence in patients treated with Seroquel (Quetiapine fumarate) was at least twice the incidence in placebo-treated patients.
Adverse events that were potentially dose-related with higher frequency in the 800 mg group compared to the 400 mg group included dizziness (8.2% vs. 14.9%), dry mouth (4.1% vs. 9.5%), and tachycardia (5.5% vs. 8.1%).
Children and Adolescents 10 to 17 years of age with Bipolar Mania
The following findings were based on a 3-week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 600 mg/day.
Adverse Reactions Associated with Discontinuation of Treatment
The incidence of discontinuation due to adverse reactions for quetiapine-treated and placebo-treated patients was 11.4% and 4.4%, respectively. The adverse events leading to discontinuation in 1% or more of patients on Seroquel (Quetiapine fumarate) and at a greater incidence than placebo were somnolence (4.1% vs. 1.1%), fatigue (2.1% vs. 0), irritability (1.6% vs. 0) and syncope (1% vs. 0).
Commonly Observed Adverse Reactions
In bipolar mania therapy (up to 3 weeks) the most commonly observed adverse reactions associated with the use of quetiapine in children and adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (53%), dizziness (18%), fatigue (11%), increased appetite (9%), nausea (8%), vomiting (8%), tachycardia (7%), dry mouth (7%), and weight increased (6%).
Table 13 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during therapy (up to 3 weeks) of bipolar mania in 5% or more of patients treated with Seroquel (Quetiapine fumarate) (doses of 400 or 600 mg/day) where the incidence in patients treated with Seroquel (Quetiapine fumarate) was at least twice the incidence in placebo-treated patients.
Adverse events that were potentially dose-related with higher frequency in the 600 mg group compared to the 400 mg group included somnolence (49% vs. 57%), nausea (6.3% vs. 10.2%) and tachycardia (5.3% vs. 8.2%).
Adverse Reactions in Schizophrenia and Bipolar Mania Clinical Trials
Commonly Observed Adverse Reactions
In acute therapy for schizophrenia and bipolar mania (up to 6 weeks in schizophrenia and up to 3 weeks in bipolar mania) the most commonly observed adverse reactions associated with the use of quetiapine in children and adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (47%), dizziness (15%), fatigue (9%), increased appetite (8%), dry mouth (7%), tachycardia (7%), and weight increased (5%).
Table 14 enumerates the pooled incidence of adverse reactions that occurred during acute therapy of children and adolescents (up to 6 weeks in schizophrenia and up to 3 weeks in bipolar mania). The table includes only those reactions that occurred in 1% or more of patients treated with quetiapine (doses of 400, 600, or 800 mg/day) and for which the incidence in patients treated with quetiapine was greater than the incidence in patients treated with placebo.
Extrapyramidal Symptoms:
In a short-term placebo-controlled monotherapy trial in adolescent patients with schizophrenia (6-week duration), the aggregated incidence of extrapyramidal symptoms was 12.9% for Seroquel (Quetiapine fumarate) and 5.3% for placebo, though the incidence of the individual adverse events (akathisia, tremor, extrapyramidal disorder, hypokinesia, restlessness, psychomotor hyperactivity, muscle rigidity, dyskinesia) did not exceed 4.1% in any treatment group. In a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration), the aggregated incidence of extrapyramidal symptoms was 3.6% for Seroquel (Quetiapine fumarate) and 1.1% for placebo.
Table 15 below presents a listing of patients with AEs potentially associated with EPS in the short-term placebo-controlled monotherapy trial in adolescent patients with schizophrenia (6-week duration).
Table 16 below presents a listing of patients with Adverse Experiences potentially associated with EPS in a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration).
Adverse Reactions in Long-Term Open-Label Trial
The adverse reactions reported in a 26-week, open-label trial with Seroquel (Quetiapine fumarate) in 5% or greater of the children and adolescent patients with schizophrenia or bipolar mania were somnolence (30%), headache (19%), vomiting (11%), increased weight (13%), insomnia (8%), nausea (10%), fatigue (8%), dizziness (9%), increased appetite (7%), upper respiratory tract infection (7%), agitation (5%), tachycardia (5%), and irritability (5%).
Other Adverse Reactions Observed During the Pre-Marketing Evaluation of Seroquel (Quetiapine fumarate)
Following is a list of COSTART terms that reflect treatment-emergent adverse reactions as defined in the introduction to the ADVERSE REACTIONS section reported by patients treated with Seroquel (Quetiapine fumarate) at multiple doses 75 mg/day during any phase of a trial within the premarketing database of approximately 2200 patients treated for schizophrenia. All reported reactions are included except those already listed in the tables or elsewhere in labeling, those reactions for which a drug cause was remote, and those reaction terms which were so general as to be uninformative. It is important to emphasize that, although the reactions reported occurred during treatment with Seroquel (Quetiapine fumarate) , they were not necessarily caused by it.
Reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.
adjusted for gender
Musculoskeletal System:
Hyperglycemia, hyperlipidemia, weight gain, orthostatic hypotension and changes in thyroid hormone levels have been reported with quetiapine. Increases in blood pressure have also been reported with quetiapine in children and adolescents [see (5.4, 5.5, 5.6, 5.8, 5.9 and 5.14)].
Neutrophil Counts
In placebo-controlled monotherapy clinical trials involving 3368 patients on quetiapine fumarate and 1515 on placebo, the incidence of at least one occurrence of neutrophil count <1.0 x 10/L among patients with a normal baseline neutrophil count and at least one available follow up laboratory measurement was 0.3% (10/2967) in patients treated with quetiapine fumarate, compared to 0.1% (2/1349) in patients treated with placebo. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue Seroquel (Quetiapine fumarate) at the first sign of a decline in WBC in absence of other causative factors [see (5.10)].
Decreased Hemoglobin
In short-term placebo-controlled trials, decreases in hemoglobin to ≤ 13 g/dL males, ≤ 12 g/dL females on at least one occasion occurred in 8.3% (594/7155) of quetiapine-treated patients compared to 6.2% (219/3536) of patients treated with placebo. In a database of controlled and uncontrolled clinical trials, decreases in hemoglobin to ≤ 13 g/dL males, ≤ 12 g/dL females on at least one occasion occurred in 11% (2277/20729) of quetiapine-treated patients.
ECG Changes
Children and Adolescents:
Warnings and Precautions
In the acute (3 week) bipolar mania trial in children and adolescents, potentially clinically significant increases in heart rate (> 110 bpm) occurred in 1.1% (1/95) of patients receiving Seroquel (Quetiapine fumarate) 400 mg and 2.4% (2/98) of patients receiving Seroquel (Quetiapine fumarate) 600 mg compared to 0% (0/98) of patients receiving placebo. Mean increases in heart rate were 12.8 bpm and 13.4 bpm for Seroquel (Quetiapine fumarate) 400 mg and 600 mg groups, respectively, compared to a decrease of 1.7 bpm in the placebo group [ (5.8)].
The following adverse reactions were identified during post approval of Seroquel (Quetiapine fumarate) . Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Adverse reactions reported since market introduction which were temporally related to Seroquel (Quetiapine fumarate) therapy include: anaphylactic reaction and galactorrhea.
Other adverse reactions reported since market introduction, which were temporally related to Seroquel (Quetiapine fumarate) therapy, but not necessarily causally related, include the following: agranulocytosis, cardiomyopathy, hyponatremia, myocarditis, rhabdomyolysis, syndrome of inappropriate antidiuretic hormone secretion (SIADH), Stevens-Johnson syndrome (SJS), and decreased platelets.
In post-marketing clinical trials, elevations in total cholesterol (predominantly LDL cholesterol), somnambulism (and other related events) and hypothermia have been reported.
Seroquel (Quetiapine fumarate) Drug Interactions
The risks of using Seroquel (Quetiapine fumarate) in combination with other drugs have not been extensively evaluated in systematic studies. Given the primary CNS effects of Seroquel (Quetiapine fumarate) , caution should be used when it is taken in combination with other centrally acting drugs. Seroquel (Quetiapine fumarate) potentiated the cognitive and motor effects of alcohol in a clinical trial in subjects with selected psychotic disorders, and alcoholic beverages should be avoided while taking Seroquel (Quetiapine fumarate) .
Because of its potential for inducing hypotension, Seroquel (Quetiapine fumarate) may enhance the effects of certain antihypertensive agents.
Seroquel (Quetiapine fumarate) may antagonize the effects of levodopa and dopamine agonists.
The use of quetiapine should be avoided in combination with drugs known to increase QT interval, and caution should be exercised when quetiapine is used in combination with drugs known to cause electrolyte imbalance [
].
There have been literature reports suggesting false positive results in urine enzyme immunoassays for methadone and tricyclic antidepressants in patients who have taken quetiapine. Caution should be exercised in the interpretation of positive urine drug screen results for these drugs, and confirmation by alternative analytical technique (e.g. chromatographic methods) should be considered.
Seroquel (Quetiapine fumarate) Use In Specific Populations
Pregnancy Category C:
There are no adequate and well-controlled studies of Seroquel (Quetiapine fumarate) use in pregnant women. In limited published literature, there were no major malformations associated with quetiapine exposure during pregnancy. In animal studies, embryo-fetal toxicity occurred. Quetiapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
There are limited published data on the use of quetiapine for treatment of schizophrenia and other psychiatric disorders during pregnancy. In a prospective observational study, 21 women exposed to quetiapine and other psychoactive medications during pregnancy delivered infants with no major malformations. Among 42 other infants born to pregnant women who used quetiapine during pregnancy, there were no major malformations reported (one study of 36 women, 6 case reports). Due to the limited number of exposed pregnancies, these postmarketing data do not reliably estimate the frequency or absence of adverse outcomes.
When pregnant rats and rabbits were exposed to quetiapine during organogenesis, there was no increase in the incidence of major malformations in fetuses at doses up to 2.4 times the maximum recommended human dose for schizophrenia (MRHD, 800 mg/day on a mg/m basis); however, there was evidence of embryo-fetal toxicity. In rats, delays in skeletal ossification occurred at 0.6 and 2.4 times the MRHD and in rabbits at 1.2 and 2.4 times the MRHD. At 2.4 times the MRHD, there was an increased incidence of carpal/tarsal flexure (minor soft tissue anomaly) in rabbit fetuses and decreased fetal weights in both species. Maternal toxicity (decreased body weights and/or death) occurred at 2.4 times the MRHD in rats and at 0.6-2.4 times the MRHD (all doses) in rabbits.
In a peri/postnatal reproductive study in rats, no drug-related effects were observed when pregnant dams were treated with quetiapine at doses 0.01, 0.12, and 0.24 times the MRHD. However, in a preliminary peri/postnatal study, there were increases in fetal and pup death, and decreases in mean litter weight at 3.0 times the MRHD.
Non-Teratogenic Effects
Neonates exposed to antipsychotic drugs (including Seroquel (Quetiapine fumarate) ), during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
Seroquel (Quetiapine fumarate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Seroquel (Quetiapine fumarate) was excreted into human milk. It is recommended that women receiving Seroquel (Quetiapine fumarate) should not breast feed.
In published case reports, the level of quetiapine in breast milk ranged from undetectable to 170 μg/L. The estimated infant dose ranged from 0.09% to 0.43% of the weight-adjusted maternal dose. Based on a limited number (N=8) of mother/infant pairs, calculated infant daily doses range from less than 0.01 mg/kg (at a maternal daily dose up to 100 mg quetiapine) to 0.1 mg/kg (at a maternal daily dose of 400 mg).
In general, the adverse reactions observed in children and adolescents during the clinical trials were similar to those in the adult population with few exceptions. Increases in systolic and diastolic blood pressure occurred in children and adolescents and did not occur in adults. Orthostatic hypotension occurred more frequently in adults (4-7%) compared to children and adolescents (< 1%).
Schizophrenia
The efficacy and safety of Seroquel (Quetiapine fumarate) in the treatment of schizophrenia in adolescents aged 13 to 17 years were demonstrated in one 6–week, double-blind, placebo-controlled trial [ (1.1), (2.1), (6.1), (14.1)].
Safety and effectiveness of Seroquel (Quetiapine fumarate) in pediatric patients less than 13 years of age with schizophrenia have not been established.
Maintenance
The safety and effectiveness of Seroquel (Quetiapine fumarate) in the maintenance treatment of bipolar disorder has not been established in pediatric patients less than 18 years of age. The safety and effectiveness of Seroquel (Quetiapine fumarate) in the maintenance treatment of schizophrenia has not been established in any patient population, including pediatric patients.
Bipolar Mania
The efficacy and safety of Seroquel (Quetiapine fumarate) in the treatment of mania in children and adolescents ages 10 to 17 years with Bipolar I disorder was demonstrated in a 3-week, double-blind, placebo controlled, multicenter trial [ (1.2), (2.2), (6.1), (14.2)].
Safety and effectiveness of Seroquel (Quetiapine fumarate) in pediatric patients less than 10 years of age with bipolar mania have not been established.
Bipolar Depression
Safety and effectiveness of Seroquel (Quetiapine fumarate) in pediatric patients less than 18 years of age with bipolar depression have not been established.
Some differences in the pharmacokinetics of quetiapine were noted between children/adolescents (10 to 17 years of age) and adults. When adjusted for weight, the AUC and C of quetiapine were 41% and 39% lower, respectively, in children and adolescents compared to adults. The pharmacokinetics of the active metabolite, norquetiapine, were similar between children/adolescents and adults after adjusting for weight [ (12.3)].
Seroquel (Quetiapine fumarate) Overdosage
In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizure or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with acute overdosage of Seroquel (Quetiapine fumarate) . Similarly it is reasonable to expect that the alpha-adrenergic-blocking properties of bretylium might be additive to those of quetiapine, resulting in problematic hypotension.
There is no specific antidote to Seroquel (Quetiapine fumarate) . Therefore, appropriate supportive measures should be instituted. The possibility of multiple drug involvement should be considered. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of quetiapine-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.
Seroquel (Quetiapine fumarate) Description
Seroquel (Quetiapine fumarate) is a psychotropic agent belonging to a chemical class, the dibenzothiazepine derivatives. The chemical designation is 2-[2-(4-dibenzo [ ] [1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol fumarate (2:1) (salt). It is present in tablets as the fumarate salt. All doses and tablet strengths are expressed as milligrams of base, not as fumarate salt. Its molecular formula is CHNOS•CHO and it has a molecular weight of 883.11 (fumarate salt). The structural formula is:
Quetiapine fumarate is a white to off-white crystalline powder which is moderately soluble in water.
Seroquel (Quetiapine fumarate) is supplied for oral administration as 25 mg (round, peach), 50 mg (round, white), 100 mg (round, yellow), 200 mg (round, white), 300 mg (capsule-shaped, white), and 400 mg (capsule-shaped, yellow) tablets.
Inactive ingredients are povidone, dibasic dicalcium phosphate dihydrate, microcrystalline cellulose, sodium starch glycolate, lactose monohydrate, magnesium stearate, hypromellose, polyethylene glycol and titanium dioxide.
The 25 mg tablets contain red ferric oxide and yellow ferric oxide and the 100 mg and 400 mg tablets contain only yellow ferric oxide.
Seroquel (Quetiapine fumarate) Clinical Pharmacology
The mechanism of action of Seroquel (Quetiapine fumarate) , as with other drugs having efficacy in the treatment of schizophrenia and bipolar disorder, is unknown. However, it has been proposed that the efficacy of Seroquel (Quetiapine fumarate) in schizophrenia and its mood stabilizing properties in bipolar depression and mania are mediated through a combination of dopamine type 2 (D) and serotonin type 2 (5HT) antagonism. Antagonism at receptors other than dopamine and 5HT with similar receptor affinities may explain some of the other effects of Seroquel (Quetiapine fumarate) .
Seroquel (Quetiapine fumarate) ’s antagonism of histamine H receptors may explain the somnolence observed with this drug.
Seroquel (Quetiapine fumarate) ’s antagonism of adrenergic α receptors may explain the orthostatic hypotension observed with this drug.
Adults
Quetiapine fumarate activity is primarily due to the parent drug. The multiple-dose pharmacokinetics of quetiapine are dose-proportional within the proposed clinical dose range, and quetiapine accumulation is predictable upon multiple dosing. Elimination of quetiapine is mainly via hepatic metabolism with a mean terminal half-life of about 6 hours within the proposed clinical dose range. Steady-state concentrations are expected to be achieved within two days of dosing. Quetiapine is unlikely to interfere with the metabolism of drugs metabolized by cytochrome P450 enzymes.
Children and Adolescents
At steady-state the pharmacokinetics of the parent compound, in children and adolescents (10-17 years of age), were similar to adults. However, when adjusted for dose and weight, AUC and C of the parent compound were 41% and 39% lower, respectively, in children and adolescents than in adults. For the active metabolite, norquetiapine, AUC and Cwere 45% and 31% higher, respectively, in children and adolescents than in adults. When adjusted for dose and weight, the pharmacokinetics of the metabolite, norquetiapine, was similar between children and adolescents and adults [see (8.4)].
Absorption
Quetiapine fumarate is rapidly absorbed after oral administration, reaching peak plasma concentrations in 1.5 hours. The tablet formulation is 100% bioavailable relative to solution. The bioavailability of quetiapine is marginally affected by administration with food, with C and AUC values increased by 25% and 15%, respectively.
Distribution
Quetiapine is widely distributed throughout the body with an apparent volume of distribution of 10±4 L/kg. It is 83% bound to plasma proteins at therapeutic concentrations. , quetiapine did not affect the binding of warfarin or diazepam to human serum albumin. In turn, neither warfarin nor diazepam altered the binding of quetiapine.
Metabolism and Elimination
Following a single oral dose of C-quetiapine, less than 1% of the administered dose was excreted as unchanged drug, indicating that quetiapine is highly metabolized. Approximately 73% and 20% of the dose was recovered in the urine and feces, respectively.
Quetiapine is extensively metabolized by the liver. The major metabolic pathways are sulfoxidation to the sulfoxide metabolite and oxidation to the parent acid metabolite; both metabolites are pharmacologically inactive. studies using human liver microsomes revealed that the cytochrome P450 3A4 isoenzyme is involved in the metabolism of quetiapine to its major, but inactive, sulfoxide metabolite and in the metabolism of its active metabolite N-desalkyl quetiapine.
Age
Oral clearance of quetiapine was reduced by 40% in elderly patients (≥ 65 years, n=9) compared to young patients (n=12), and dosing adjustment may be necessary [see (2)].
Gender
There is no gender effect on the pharmacokinetics of quetiapine.
Race
There is no race effect on the pharmacokinetics of quetiapine.
Smoking
Smoking has no effect on the oral clearance of quetiapine.
Renal Insufficiency
Patients with severe renal impairment (Clcr=10-30 mL/min/1.73 m, n=8) had a 25% lower mean oral clearance than normal subjects (Clcr > 80 mL/min/1.73 m, n=8), but plasma quetiapine concentrations in the subjects with renal insufficiency were within the range of concentrations seen in normal subjects receiving the same dose. Dosage adjustment is therefore not needed in these patients.
Hepatic Insufficiency
Hepatically impaired patients (n=8) had a 30% lower mean oral clearance of quetiapine than normal subjects. In two of the 8 hepatically impaired patients, AUC and C were 3 times higher than those observed typically in healthy subjects. Since quetiapine is extensively metabolized by the liver, higher plasma levels are expected in the hepatically impaired population, and dosage adjustment may be needed [see (2)].
Drug-Drug Interactions
Quetiapine oral clearance is increased by the prototype cytochrome P450 3A4 inducer, phenytoin, and decreased by the prototype cytochrome P450 3A4 inhibitor, ketoconazole. Dose adjustment of quetiapine will be necessary if it is coadministered with phenytoin or ketoconazole [ (7.1)].
Quetiapine oral clearance is not inhibited by the non-specific enzyme inhibitor, cimetidine.
Quetiapine at doses of 750 mg/day did not affect the single dose pharmacokinetics of antipyrine, lithium or lorazepam [ (7.2)].
Seroquel (Quetiapine fumarate) Nonclinical Toxicology
Carcinogenesis
Carcinogenicity studies were conducted in C57BL mice and Wistar rats. Quetiapine was administered in the diet to mice at doses of 20, 75, 250, and 750 mg/kg and to rats by gavage at doses of 25, 75, and 250 mg/kg for two years. These doses are equivalent to 0.1, 0.5, 1.5, and 4.5 times the maximum human dose (800 mg/day) on a mg/m basis (mice) or 0.3, 0.9, and 3.0 times the maximum human dose on a mg/m basis (rats). There were statistically significant increases in thyroid gland follicular adenomas in male mice at doses of 250 and 750 mg/kg or 1.5 and 4.5 times the maximum human dose on a mg/m basis and in male rats at a dose of 250 mg/kg or 3.0 times the maximum human dose on a mg/m basis. Mammary gland adenocarcinomas were statistically significantly increased in female rats at all doses tested (25, 75, and 250 mg/kg or 0.3, 0.9, and 3.0 times the maximum recommended human dose on a mg/m basis).
Thyroid follicular cell adenomas may have resulted from chronic stimulation of the thyroid gland by thyroid stimulating hormone (TSH) resulting from enhanced metabolism and clearance of thyroxine by rodent liver. Changes in TSH, thyroxine, and thyroxine clearance consistent with this mechanism were observed in subchronic toxicity studies in rat and mouse and in a 1-year toxicity study in rat; however, the results of these studies were not definitive. The relevance of the increases in thyroid follicular cell adenomas to human risk, through whatever mechanism, is unknown.
Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum measurements in a 1-year toxicity study showed that quetiapine increased median serum prolactin levels a maximum of 32- and 13-fold in male and female rats, respectively. Increases in mammary neoplasms have been found in rodents after chronic administration of other antipsychotic drugs and are considered to be prolactin-mediated. The relevance of this increased incidence of prolactin-mediated mammary gland tumors in rats to human risk is unknown [see (5.15)].
Mutagenesis
The mutagenic potential of quetiapine was tested in six bacterial gene mutation assays and in an mammalian gene mutation assay in Chinese Hamster Ovary cells. However, sufficiently high concentrations of quetiapine may not have been used for all tester strains. Quetiapine did produce a reproducible increase in mutations in one tester strain in the presence of metabolic activation. No evidence of clastogenic potential was obtained in an chromosomal aberration assay in cultured human lymphocytes or in the micronucleus assay in rats.
Impairment of Fertility
Quetiapine decreased mating and fertility in male Sprague-Dawley rats at oral doses of 50 and 150 mg/kg or 0.6 and 1.8 times the maximum human dose on a mg/m basis. Drug-related effects included increases in interval to mate and in the number of matings required for successful impregnation. These effects continued to be observed at 150 mg/kg even after a two-week period without treatment. The no-effect dose for impaired mating and fertility in male rats was 25 mg/kg, or 0.3 times the maximum human dose on a mg/m basis. Quetiapine adversely affected mating and fertility in female Sprague-Dawley rats at an oral dose of 50 mg/kg, or 0.6 times the maximum human dose on a mg/m basis. Drug-related effects included decreases in matings and in matings resulting in pregnancy, and an increase in the interval to mate. An increase in irregular estrus cycles was observed at doses of 10 and 50 mg/kg, or 0.1 and 0.6 times the maximum human dose on a mg/m basis. The no-effect dose in female rats was 1 mg/kg, or 0.01 times the maximum human dose on a mg/m basis.
Quetiapine caused a dose-related increase in pigment deposition in thyroid gland in rat toxicity studies which were 4 weeks in duration or longer and in a mouse 2–year carcinogenicity study. Doses were 10-250 mg/kg in rats, 75-750 mg/kg in mice; these doses are 0.1-3.0, and 0.1-4.5 times the maximum recommended human dose (on a mg/m basis), respectively. Pigment deposition was shown to be irreversible in rats. The identity of the pigment could not be determined, but was found to be co-localized with quetiapine in thyroid gland follicular epithelial cells. The functional effects and the relevance of this finding to human risk are unknown.
In dogs receiving quetiapine for 6 or 12 months, but not for 1 month, focal triangular cataracts occurred at the junction of posterior sutures in the outer cortex of the lens at a dose of 100 mg/kg, or 4 times the maximum recommended human dose on a mg/m basis. This finding may be due to inhibition of cholesterol biosynthesis by quetiapine. Quetiapine caused a dose-related reduction in plasma cholesterol levels in repeat-dose dog and monkey studies; however, there was no correlation between plasma cholesterol and the presence of cataracts in individual dogs. The appearance of delta–8–cholestanol in plasma is consistent with inhibition of a late stage in cholesterol biosynthesis in these species. There also was a 25% reduction in cholesterol content of the outer cortex of the lens observed in a special study in quetiapine treated female dogs. Drug-related cataracts have not been seen in any other species; however, in a 1-year study in monkeys, a striated appearance of the anterior lens surface was detected in 2/7 females at a dose of 225 mg/kg or 5.5 times the maximum recommended human dose on a mg/m basis.
Seroquel (Quetiapine fumarate) Clinical Studies
Adults
The efficacy of Seroquel (Quetiapine fumarate) in the treatment of schizophrenia was established in 3 short-term (6-week) controlled trials of inpatients with schizophrenia who met DSM III-R criteria for schizophrenia. Although a single fixed dose haloperidol arm was included as a comparative treatment in one of the three trials, this single haloperidol dose group was inadequate to provide a reliable and valid comparison of Seroquel (Quetiapine fumarate) and haloperidol.
Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients. A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient.
The results of the trials follow:
Examination of population subsets (race, gender, and age) did not reveal any differential responsiveness on the basis of race or gender, with an apparently greater effect in patients under the age of 40 years compared to those older than 40. The clinical significance of this finding is unknown.
Adolescents (ages 13-17)
The efficacy of Seroquel (Quetiapine fumarate) in the treatment of schizophrenia in adolescents (13–17 years of age) was demonstrated in a 6–week, double-blind, placebo-controlled trial. Patients who met DSM-IV diagnostic criteria for schizophrenia were randomized into one of three treatment groups: Seroquel (Quetiapine fumarate) 400 mg/day (n = 73), Seroquel (Quetiapine fumarate) 800 mg/day (n = 74), or placebo (n = 75). Study medication was initiated at 50 mg/day and on day 2 increased to 100 mg/per day (divided and given two or three times per day). Subsequently, the dose was titrated to the target dose of 400 mg/day or 800 mg/day using increments of 100 mg/day, divided and given two or three times daily. The primary efficacy variable was the mean change from baseline in total Positive and Negative Syndrome Scale (PANSS).
Seroquel (Quetiapine fumarate) at 400 mg/day and 800 mg/day was superior to placebo in the reduction of PANSS total score.
Manic Episodes
Adults
The efficacy of Seroquel (Quetiapine fumarate) in the acute treatment of manic episodes was established in 3 placebo-controlled trials in patients who met DSM-IV criteria for bipolar I disorder with manic episodes. These trials included patients with or without psychotic features and excluded patients with rapid cycling and mixed episodes. Of these trials, 2 were monotherapy (12 weeks) and 1 was adjunct therapy (3 weeks) to either lithium or divalproex. Key outcomes in these trials were change from baseline in the Young Mania Rating Scale (YMRS) score at 3 and 12 weeks for monotherapy and at 3 weeks for adjunct therapy. Adjunct therapy is defined as the simultaneous initiation or subsequent administration of Seroquel (Quetiapine fumarate) with lithium or divalproex.
The primary rating instrument used for assessing manic symptoms in these trials was YMRS, an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score).
The results of the trials follow:
Monotherapy
The efficacy of Seroquel (Quetiapine fumarate) in the acute treatment of bipolar mania was established in 2 placebo-controlled trials. In two 12-week trials (n=300, n=299) comparing Seroquel (Quetiapine fumarate) to placebo, Seroquel (Quetiapine fumarate) was superior to placebo in the reduction of the YMRS total score at weeks 3 and 12. The majority of patients in these trials taking Seroquel (Quetiapine fumarate) were dosed in a range between 400 mg/day and 800 mg per day.
Adjunct Therapy
In this 3-week placebo-controlled trial, 170 patients with bipolar mania (YMRS 20) were randomized to receive Seroquel (Quetiapine fumarate) or placebo as adjunct treatment to lithium or divalproex. Patients may or may not have received an adequate treatment course of lithium or divalproex prior to randomization. Seroquel (Quetiapine fumarate) was superior to placebo when added to lithium or divalproex alone in the reduction of YMRS total score.
The majority of patients in this trial taking Seroquel (Quetiapine fumarate) were dosed in a range between 400 mg/day and 800 mg per day. In a similarly designed trial (n=200), Seroquel (Quetiapine fumarate) was associated with an improvement in YMRS scores but did not demonstrate superiority to placebo, possibly due to a higher placebo effect.
Children and Adolescents (ages 10-17)
The efficacy of Seroquel (Quetiapine fumarate) in the acute treatment of manic episodes associated with bipolar I disorder in children and adolescents (10 to 17 years of age) was demonstrated in a 3-week, double-blind, placebo-controlled, multicenter trial. Patients who met DSM-IV diagnostic criteria for a manic episode were randomized into one of three treatment groups: Seroquel (Quetiapine fumarate) 400 mg/day (n = 95), Seroquel (Quetiapine fumarate) 600 mg/day (n = 98), or placebo (n = 91). Study medication was initiated at 50 mg/day and on day 2 increased to 100 mg/day (divided doses given two or three times daily). Subsequently, the dose was titrated to a target dose of 400 mg/day or 600 mg/day using increments of 100 mg/day, given in divided doses two or three times daily. The primary efficacy variable was the mean change from baseline in total YMRS score.
Seroquel (Quetiapine fumarate) 400 mg/day and 600 mg/day were superior to placebo in the reduction of YMRS total score.
Depressive Episodes
Adults
The efficacy of Seroquel (Quetiapine fumarate) for the acute treatment of depressive episodes associated with bipolar disorder was established in 2 identically designed 8-week, randomized, double-blind, placebo-controlled studies (N=1045). These studies included patients with either bipolar I or II disorder and those with or without a rapid cycling course. Patients randomized to Seroquel (Quetiapine fumarate) were administered fixed doses of either 300 mg or 600 mg once daily.
The primary rating instrument used to assess depressive symptoms in these studies was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10–item clinician-rated scale with scores ranging from 0 to 60. The primary endpoint in both studies was the change from baseline in MADRS score at week 8. In both studies, Seroquel (Quetiapine fumarate) was superior to placebo in reduction of MADRS score. Improvement in symptoms, as measured by change in MADRS score relative to placebo, was seen in both studies at Day 8 (week 1) and onwards. In these studies, no additional benefit was seen with the 600 mg dose. For the 300 mg dose group, statistically significant improvements over placebo were seen in overall quality of life and satisfaction related to various areas of functioning, as measured using the Q-LES-Q(SF).
Maintenance Treatment as an Adjunct to Lithium or Divalproex
The efficacy of Seroquel (Quetiapine fumarate) in the maintenance treatment of bipolar I disorder was established in 2 placebo-controlled trials in patients (n=1326) who met DSM-IV criteria for bipolar I disorder. The trials included patients whose most recent episode was manic, depressed, or mixed, with or without psychotic features. In the open-label phase, patients were required to be stable on Seroquel (Quetiapine fumarate) plus lithium or divalproex for at least 12 weeks in order to be randomized. On average, patients were stabilized for 15 weeks. In the randomization phase, patients continued treatment with lithium or divalproex and were randomized to receive either Seroquel (Quetiapine fumarate) (administered twice daily totaling 400 mg/day to 800 mg/day) or placebo. Approximately 50% of the patients had discontinued from the Seroquel (Quetiapine fumarate) group by day 280 and 50% of the placebo group had discontinued by day 117 of double-blind treatment. The primary endpoint in these studies was time to recurrence of a mood event (manic, mixed or depressed episode). A mood event was defined as medication initiation or hospitalization for a mood episode; YMRS score ≥ 20 or MADRS score ≥ 20 at 2 consecutive assessments; or study discontinuation due to a mood event.
In both studies, Seroquel (Quetiapine fumarate) was superior to placebo in increasing the time to recurrence of any mood event. The treatment effect was present for increasing time to recurrence of both manic and depressed episodes. The effect of Seroquel (Quetiapine fumarate) was independent of any specific subgroup (assigned mood stabilizer, sex, age, race, most recent bipolar episode, or rapid cycling course).
Seroquel (Quetiapine fumarate) How Supplied/storage And Handling
25 mg Tablets peach, round, biconvex, film coated tablets, identified with 'Seroquel (Quetiapine fumarate) ' and ‘25’ on one side and plain on the other side, are supplied in
50 mg Tablets (NDC 0310-0278) white, round, biconvex, film coated tablets, identified with 'Seroquel (Quetiapine fumarate) ' and ‘50’ on one side and plain on the other side, are supplied in
100 mg Tablets (NDC 0310-0271) yellow, round, biconvex film coated tablets, identified with 'Seroquel (Quetiapine fumarate) ' and ‘100’ on one side and plain on the other side, are supplied in
300 mg Tablets (NDC 0310-0274) white, capsule-shaped, biconvex, film coated tablets, intagliated with ‘Seroquel (Quetiapine fumarate) ’ on one side and ‘300’ on the other side, are supplied in
Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF) [See USP].
Seroquel (Quetiapine fumarate) Patient Counseling Information
[see Medication Guide]
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Seroquel (Quetiapine fumarate) and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for Seroquel (Quetiapine fumarate) . The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Seroquel (Quetiapine fumarate) .
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Patients and caregivers should be advised that elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at increased risk of death compared with placebo. Quetiapine is not approved for elderly patients with dementia-related psychosis [ (5.1)].
Clinical Worsening and Suicide Risk
Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication [ (5.2)].
Neuroleptic Malignant Syndrome (NMS)
Patients should be advised to report to their physician any signs or symptoms that may be related to NMS. These may include muscle stiffness and high fever [ (5.3)].
Hyperglycemia and Diabetes Mellitus
Patients should be aware of the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus. Patients who are diagnosed with diabetes, those with risk factors for diabetes, or those that develop these symptoms during treatment should have their blood glucose monitored at the beginning of and periodically during treatment [ (5.4)].
Hyperlipidemia
Patients should be advised that elevations in total cholesterol, LDL–cholesterol and triglycerides and decreases in HDL-cholesterol may occur. Patients should have their lipid profile monitored at the beginning of and periodically during treatment [(5.5)].
Weight Gain
Patients should be advised that they may experience weight gain. Patients should have their weight monitored regularly [ (5.6)].
Orthostatic Hypotension
Patients should be advised of the risk of orthostatic hypotension (symptoms include feeling dizzy or lightheaded upon standing, which may lead to falls), especially during the period of initial dose titration, and also at times of re-initiating treatment or increases in dose [ (5.8)].
Increased Blood Pressure in Children and Adolescents
Blood pressure should be measured at the beginning of, and periodically during, treatment [ (5.9)].
Leukopenia/Neutropenia
Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should be advised that they should have their CBC monitored while taking Seroquel (Quetiapine fumarate) [see (5.10)].
Interference with Cognitive and Motor Performance
Patients should be advised of the risk of somnolence or sedation (which may lead to falls), especially during the period of initial dose titration. Patients should be cautioned about performing any activity requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating machinery, until they are reasonably certain quetiapine therapy does not affect them adversely. Patients should limit consumption of alcohol during treatment with quetiapine [see (5.17)].
Heat Exposure and Dehydration
Patients should be advised regarding appropriate care in avoiding overheating and dehydration [see (5.19)].
Concomitant Medication
As with other medications, patients should be advised to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs [see (5.22)].
Pregnancy and Nursing
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be advised not to breast feed if they are taking quetiapine [ (8.1) and (8.3)].
Need for Comprehensive Treatment Program
Seroquel (Quetiapine fumarate) is indicated as an integral part of a total treatment program for adolescents with schizophrenia and pediatric bipolar disorder that may include other measures (psychological, educational, and social). Effectiveness and safety of Seroquel (Quetiapine fumarate) have not been established in pediatric patients less than 13 years of age for schizophrenia or less than 10 years of age for bipolar mania. Appropriate educational placement is essential and psychosocial intervention is often helpful. The decision to prescribe atypical antipsychotic medication will depend upon the physician’s assessment of the chronicity and severity of the patient’s symptoms.
Seroquel (Quetiapine fumarate) Spl Medguide Section
MEDICATION GUIDE
Seroquel (Quetiapine fumarate) (SER-oh-kwell)
(quetiapine fumarate)
Tablets
Read this Medication Guide before you start taking Seroquel (Quetiapine fumarate) and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment.
Increases in blood sugar can happen in some people who take Seroquel (Quetiapine fumarate) . Extremely high blood sugar can lead to coma or death. If you have diabetes or risk factors for diabetes (such as being overweight or a family history of diabetes) your healthcare provider should check your blood sugar before you start Seroquel (Quetiapine fumarate) and during therapy.
Seroquel (Quetiapine fumarate) has not been studied in patients younger than 10 years of age.
Before taking Seroquel (Quetiapine fumarate) , tell your healthcare provider if you have or have had:
Seroquel (Quetiapine fumarate) and other medicines may affect each other causing serious side effects. Seroquel (Quetiapine fumarate) may affect the way other medicines work, and other medicines may affect how Seroquel (Quetiapine fumarate) works.
Especially tell your healthcare provider if you take or plan to take medicines for:
Also tell your healthcare provider if you take or plan to take any of these medicines:
This is not a complete list of medicines that can affect or be affected by Seroquel (Quetiapine fumarate) . Your doctor can tell you if it is safe to take Seroquel (Quetiapine fumarate) with your other medicines. Do not start or stop any medicines while taking Seroquel (Quetiapine fumarate) without talking to your healthcare provider first. Know the medicines you take. Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine.
Tell your healthcare provider if you are having a urine drug screen because Seroquel (Quetiapine fumarate) may affect your test results. Tell those giving the test that you are taking Seroquel (Quetiapine fumarate) .
If you suddenly stop taking Seroquel (Quetiapine fumarate) , you may experience side effects such as trouble sleeping or trouble staying asleep (insomnia), nausea, and vomiting.
Do not drive, operate machinery, or do other dangerous activities until you know how Seroquel (Quetiapine fumarate) affects you. Seroquel (Quetiapine fumarate) may make you drowsy.
These are not all the possible side effects of Seroquel (Quetiapine fumarate) . For more information, ask your healthcare provider or pharmacist.
Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Do not take Seroquel (Quetiapine fumarate) unless your healthcare provider has prescribed it for you for your condition. Do not share Seroquel (Quetiapine fumarate) with other people, even if they have the same condition. It may harm them.
This Medication Guide provides a summary of important information about Seroquel (Quetiapine fumarate) . For more information about Seroquel (Quetiapine fumarate) , talk with your healthcare provider or pharmacist or call 1-800-236-9933. You can ask your healthcare provider for information about Seroquel (Quetiapine fumarate) that is written for health professionals.
Seroquel (Quetiapine fumarate) is a trademark of the AstraZeneca group of companies.
©AstraZeneca 2011
Distributed by:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
SIC 35534–XX
Rev. 11/2011
