SEROQUEL (Tablet, Coated)
Bipolar Disorder: Depression Usual Dose: SEROQUEL should be administered once daily at bedtime to reach 300 mg/day by day 4. 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 at both 300 mg and 600 mg however, no additional benefit was seen in the 600 mg group.<br/>Mania: Usual Dose: When used as monotherapy or adjunct therapy (with lithium or divalproex), SEROQUEL should be initiated in bid doses totaling 100 mg/day on Day 1, increased to 400 mg/day on Day 4 in increments of up to 100 mg/day in bid divided doses. Further dosage adjustments up to 800 mg/day by Day 6 should be in increments of no greater than 200 mg/day. Data indicates that the majority of patients responded between 400 to 800 mg/day. The safety of doses above 800mg/day has not been evaluated in clinical trials.<br/>Schizophrenia: Usual Dose: SEROQUEL should generally be administered with an initial dose of 25 mg bid, with increases in increments of 25-50 mg bid or tid on the second and third day, as tolerated, to a target dose range of 300 to 400 mg daily by the fourth day, given bid or tid. Further dosage adjustments, if indicated, should generally occur at intervals of not less than 2 days, as steady-state for SEROQUEL would not be achieved for approximately 1-2 days in the typical patient. When dosage adjustments are necessary, dose increments/decrements of 25-50 mg bid are recommended. Most efficacy data with SEROQUEL were obtained using tid regimens, but in one controlled trial 225 mg bid was also effective. Efficacy in schizophrenia was demonstrated in a dose range of 150 to 750 mg/day in the clinical trials supporting the effectiveness of SEROQUEL. 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 400-500 mg/day appeared to be needed. The safety of doses above 800 mg/day has not been evaluated in clinical trials.<br/>Dosing in Special Populations: 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 . 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 25-50 mg/day to an effective dose, depending on the clinical response and tolerability of the patient. The elimination of quetiapine was enhanced in the presence of phenytoin. Higher maintenance doses of quetiapine may be required when it is coadministered with phenytoin and other enzyme inducers such as carbamazepine and phenobarbital . Maintenance Treatment: While there is no body of evidence available to answer the question of how long the patient treated with SEROQUEL 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. Reinitiation of Treatment in Patients Previously Discontinued: Although there are no data to specifically address reinitiation of treatment, it is recommended that when restarting patients who have had an interval of less than one week off SEROQUEL, titration of SEROQUEL is not required and the maintenance dose may be reinitiated. When restarting therapy of patients who have been off SEROQUEL for more than one week, the initial titration schedule should be followed. Switching from Antipsychotics: There are no systematically collected data to specifically address switching patients with schizophrenia from antipsychotics to SEROQUEL, or concerning concomitant administration with antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized. When switching patients with schizophrenia from depot antipsychotics, if medically appropriate, initiate SEROQUEL therapy in place of the next scheduledinjection. The need for continuing existing EPS medication should be reevaluated periodically.
SEROQUEL (quetiapine fumarate) is a psychotropic agent belonging to a chemical class, the dibenzothiazepine derivatives. The chemical designation is 2-[2-(4-dibenzo [b,f ] [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���CHOand 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 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.
Pharmacodynamics: SEROQUEL is an antagonist at multiple neurotransmitter receptors in the brain: serotonin 5HTand 5HT(IC=717&148nM respectively), dopamine Dand D(IC=1268&329nM respectively), histamine H(IC=30nM), and adrenergic��and��receptors (IC=94&271nM, respectively). SEROQUEL has no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors (IC>5000 nM). The mechanism of action of SEROQUEL, 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 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 5HTwith similar receptor affinities may explain some of the other effects of SEROQUEL. SEROQUEL's antagonism of histamine Hreceptors may explain the somnolence observed with this drug. SEROQUEL's antagonism of adrenergic��receptors may explain the orthostatic hypotension observed with this drug.<br/>Pharmacokinetics: 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.<br/>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 Cand AUC values increased by 25% and 15%, respectively.<br/>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. In vitro, 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<br/>Metabolism and Elimination:: Following a single oral dose ofC-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. In vitro 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.<br/>Population Subgroups:: 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 .<br/>Clinical Efficacy Data:<br/>Bipolar Disorder: Depression The efficacy of SEROQUEL for the treatment of depressive episodes associated with bipolar disorder was established in 2 identical 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 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 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). Mania The efficacy of SEROQUEL in the treatment of acute 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 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:<br/>Monotherapy: In two 12-week trials (n=300, n=299) comparing SEROQUEL to placebo, SEROQUEL 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 were dosed in a range between 400 and 800 mg per day.<br/>Adjunct Therapy: In this 3-week placebo-controlled trial, 170 patients with acute bipolar mania (YMRS���20) were randomized to receive SEROQUEL 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 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 were dosed in a range between 400 and 800 mg per day. In a similarly designed trial (n=200), SEROQUEL was associated with an improvement in YMRS scores but did not demonstrate superiority to placebo, possibly due to a higher placebo effect.<br/>Schizophrenia: The efficacy of SEROQUEL 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 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 familiarwith the manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the Scale for Assessing Negative Symptoms (SANS), a more recently developed but less well evaluated scale, was employed for assessing negative symptoms. 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 compared to those older than 40. The clinical significance of this finding is unknown.
SEROQUEL is contraindicated in individuals with a known hypersensitivity to this medication or any of its ingredients.
25 mg Tablets (NDC 0310-0275) peach, round, biconvex, film coated tablets, identified with 'SEROQUEL' and���25' on one side and plain on the other side, are supplied in bottles of 100 tablets and 1000 tablets, and hospital unit dose packages of 100 tablets. 50 mg Tablets (NDC 0310-0278) white, round, biconvex, film coated tablets, identified with 'SEROQUEL' and���50' on one side and plain on the other side, are supplied in bottles of 100 tablets and 1000 tablets, and hospital unit dose packages of 100 tablets. 100 mg Tablets (NDC 0310-0271) yellow, round, biconvex film coated tablets, identified with 'SEROQUEL' and���100' on one side and plain on the other side, are supplied in bottles of 100 tablets and hospital unit dose packages of 100 tablets. 200 mg Tablets (NDC 0310-0272) white, round, biconvex, film coated tablets, identified with���SEROQUEL' and���200' on one side and plain on the other side, are supplied in bottles of 100 tablets and hospital unit dose packages of 100 tablets. 300 mg Tablets (NDC 0310-0274) white, capsule-shaped, biconvex, film coated tablets, intagliated with���SEROQUEL' on one side and���300' on the other side, are supplied in bottles of 60 tablets, and hospital unit dose packages of 100 tablets. 400 mg Tablets (NDC 0310-0279) yellow, capsule-shaped, biconvex, film coated tablets, intagliated with���SEROQUEL' on one side and���400' on the other side, are supplied in bottles of 100 tablets, and hospital unit dose packages of 100 tablets. Store at 25��C (77��F); excursions permitted to 15-30��C (59-86��F) [See USP].
Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen 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 (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. SEROQUEL (quetiapine) is not approved for the treatment of patients with Dementia-Related Psychosis. Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of SEROQUEL or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. 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 in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. SEROQUEL is not approved for use in pediatric patients. (See Warnings: Clinical Worsening and Suicide Risk, Precautions: Information for Patients, and Precautions: Pediatric Use)
dailymed-ingredient:dibasic_dicalcium_phosphate_dihydrate, dailymed-ingredient:hypromellose, dailymed-ingredient:lactose_monohydrate, dailymed-ingredient:magnesium_stearate, dailymed-ingredient:microcrystalline_cellulose, dailymed-ingredient:polyethylene_glycol, dailymed-ingredient:povidone, dailymed-ingredient:red_ferric_oxide, dailymed-ingredient:sodium_starch_glycolate, dailymed-ingredient:titanium_dioxide
Human experience:In clinical trials, survival has been reported in acute overdoses of up to 30 grams of quetiapine. Most patients who overdosed experienced no adverse events or recovered fully from the reported events. Death has been reported in a clinical trial following an overdose of 13.6 grams of quetiapine alone. In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, ie, drowsiness and sedation, tachycardia and hypotension. Patients with pre-existing severe cardiovascular disease may be at an increased risk of the effects of overdose One case, involving an estimated overdose of 9600 mg, was associated with hypokalemia and first degree heart block. In post-marketing experience, there have been very rare reports of overdose of SEROQUEL alone resulting in death, coma, or QTc prolongation.<br/>Management of 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. 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. 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 (Tablet, Coated)
The information below is derived from a clinical trial database for SEROQUEL consisting of over 3700 patients. This database includes 698 patients exposed to SEROQUEL for the treatment of bipolar depression, 405 patients exposed to SEROQUEL for the treatment of acute bipolar mania (monotherapy and adjunct therapy) and approximately 2600 patients and/or normal subjects exposed to 1 or more doses of SEROQUEL for the treatment of schizophrenia. Of these approximately 3700 subjects, approximately 3400 (2300 in schizophrenia, 405 in acute bipolar mania, and 698 in bipolar depression) were patients who participated in multiple dose effectiveness trials, and their experience corresponded to approximately 992.6 patient-years. The conditions and duration of treatment with SEROQUEL 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 events 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 events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and tabulations that follow, standard COSTART terminology has been used to classify reported adverse events for schizophrenia and bipolar mania. MedDRA terminology has been used to classify reported adverse events for bipolar depression. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.<br/>Adverse Findings Observed in Short-Term, Controlled Trials:<br/>Adverse Events Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials: Bipolar Disorder: Depression: Overall, discontinuations due to adverse events were 12.3% for SEROQUEL 300 mg vs 19.0% for SEROQUEL 600 mg and 5.2% for placebo. Mania: Overall, discontinuations due to adverse events were 5.7% for SEROQUEL vs. 5.1% for placebo in monotherapy and 3.6% for SEROQUEL vs. 5.9% for placebo in adjunct therapy. Schizophrenia: Overall, there was little difference in the incidence of discontinuation due to adverse events (4% for SEROQUEL vs. 3% for placebo) in a pool of controlled trials. However, discontinuations due to somnolence and hypotension were considered to be drug related :<br/>Adverse Events Occurring at an Incidence of 1% or More Among SEROQUEL 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 2 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events 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 (doses ranging from 75 to 800 mg/day) where the incidence in patients treated with SEROQUEL was greater than the incidence in placebo-treated patients. In these studies, the most commonly observed adverse events associated with the use of SEROQUEL (incidence of 5% or greater) and observed at a rate on SEROQUEL at least twice that of placebo were somnolence (18%), dizziness (11%), dry mouth (9%), constipation (8%), SGPT increased (5%), weight gain (5%), and dyspepsia (5%). Table 3 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during therapy (up to 3-weeks) of acute mania in 5% or more of patients treated with SEROQUEL (doses ranging from 100 to 800 mg/day) used as adjunct therapy to lithium and divalproex where the incidence in patients treated with SEROQUEL was greater than the incidence in placebo-treated patients. In these studies, the most commonly observed adverse events associated with the use of SEROQUEL (incidence of 5% or greater) and observed at a rate on SEROQUEL 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 4 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during therapy (up to 8-weeks) of bipolar depression in 5% or more of patients treated with SEROQUEL (doses of 300 and 600 mg/day) where the incidence in patients treated with SEROQUEL was greater than the incidence in placebo treated patients. In these studies, the most commonly observed adverse events associated with the use of SEROQUEL (incidence of 5% or greater) and observed at a rate on SEROQUEL at least twice that of placebo were dry mouth (44%), sedation (30%), somnolence (28%), dizziness (18%), constipation (10%), lethargy (5%), and nasal congestion (5%). Explorations for interactions on the basis of gender, age, and race did not reveal any clinically meaningful differences in the adverse event occurrence on the basis of these demographic factors.<br/>Dose Dependency of Adverse Events in Short-Term, Placebo-Controlled Trials:<br/>Dose-related Adverse Events:: Spontaneously elicited adverse event data from a study of schizophrenia comparing five fixed doses of SEROQUEL (75 mg, 150 mg, 300 mg, 600 mg, and 750 mg/day) to placebo were explored for dose-relatedness of adverse events. Logistic regression analyses revealed a positive dose response (p<0.05) for the following adverse events: dyspepsia, abdominal pain, and weight gain. Extrapyramidal Symptoms: Data from one 6-week clinical trial of schizophrenia comparing five fixed doses of SEROQUEL (75, 150, 300, 600, 750 mg/day) provided evidence for the lack of treatment-emergent extrapyramidal symptoms (EPS) and dose-relatedness for EPS associated with SEROQUEL treatment. Three methods were used to measure EPS: (1) Simpson-Angus total score (mean change from baseline) which evaluates parkinsonism and akathisia, (2) incidence of spontaneous complaints of EPS (akathisia, akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, neck rigidity, and tremor), and (3) use of anticholinergic medications to treat emergent EPS. In six additional placebo-controlled clinical trials (3 in acute mania and 3 in schizophrenia) using variable doses of SEROQUEL, there were no differences between the SEROQUEL 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 treatEPS. In two placebo-controlled clinical trials for the treatment of bipolar depression using 300 mg and 600 mg of SEROQUEL, the incidence of adverse events 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 events (eg, akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, muscle contractions involuntary, psychomotor hyperactivity and muscle rigidity) were generally lowand 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.<br/>Vital Signs and Laboratory Studies: Vital Sign Changes: SEROQUEL is associated with orthostatic hypotension . Weight Gain: In schizophrenia trials the proportions of patients meeting a weight gain criterion of���7% of body weight were compared in a pool of four 3- to 6-week placebo-controlled clinical trials, revealing a statistically significantly greater incidence of weight gain for SEROQUEL (23%) compared to placebo (6%). In mania monotherapy trials the proportions of patients meeting the same weight gain criterion were 21% compared to 7% for placebo and in mania adjunct therapy trials the proportion of patients meeting the same weight criterion were 13% compared to 4% for placebo. In bipolar depression trials, the proportions of patients meeting the same weight gain criterion were 8% compared to 2% for placebo. Laboratory Changes: An assessment of the premarketing experience for SEROQUEL suggested that it is associated with asymptomatic increases in SGPT and increases in both total cholesterol and triglycerides . In placebo controlled monotherapy clinical trials involving 3368 patients on SEROQUEL 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 SEROQUEL, compared to 0.1% (2/1349) in patients treated with placebo. In post-marketing clinical trials, elevations in total cholesterol (predominantly LDL cholesterol) have been observed. Hyperglycemia In 2 long-term placebo-controlled clinical trials, mean exposure 213 days for SEROQUEL (646 patients) and 152 days for placebo (680 patients), the exposure-adjusted rate of any increased blood glucose level (���126 mg/dl) for patients more than 8 hours since a meal was 18.0 per 100 patient years for SEROQUEL (10.7% of patients) and 9.5 for placebo per 100 patient years (4.6% of patients). In short-term (12 weeks duration or less) placebo-controlled clinical trials (3342 patients treated with SEROQUEL and 1490 treated with placebo), the percent of patients who had a fasting blood glucose���126 mg/dl or a non fasting blood glucose���200 mg/dl was 3.5% for quetiapine and 2.1% for placebo. In a 24 week trial (active-controlled, 115 patients treated with SEROQUEL) 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 post-glucose challenge glucose level���126 mg/dl was 2.6%. ECG Changes: Between group comparisons for pooled placebo-controlled trials revealed no statistically significant SEROQUEL/placebo differences in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc, and PR intervals. However, the proportions of patients meeting the criteria for tachycardia were compared in four 3- to 6-week placebo-controlled clinical trials for the treatment of schizophrenia revealing a 1% (4/399) incidence for SEROQUEL compared to 0.6% (1/156) incidence for placebo. In acute (monotherapy) bipolar mania trials the proportions of patients meeting the criteria for tachycardia was 0.5% (1/192) for SEROQUEL compared to 0% (0/178) incidence for placebo. In acute bipolar mania (adjunct) trials the proportions of patients meeting the same criteria was 0.6% (1/166) for SEROQUEL compared to 0% (0/171) incidence for placebo. In bipolar depression trials, no patients had heart rate increases to>120 beats per minute. SEROQUEL use was associated with a mean increase in heart rate, assessed by ECG, of 7 beats per minute compared to a mean increase of 1 beat per minute among placebo patients. This slight tendency to tachycardia may be related to SEROQUEL's potential for inducing orthostatic changes .<br/>Other Adverse Events Observed During the Pre-Marketing Evaluation of SEROQUEL: Following is a list of COSTART terms that reflect treatment-emergent adverse events as defined in the introduction to the ADVERSE REACTIONS section reported by patients treated with SEROQUEL 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 events are included except those already listed in Table 2 or elsewhere in labeling, those events for which a drug cause was remote, and those event terms which were so general as to be uninformative. It is important to emphasize that, although the events reported occurred during treatment with SEROQUEL, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events 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 events are those occurring in 1/100 to 1/1000patients; rare events are those occurring in fewer than 1/1000 patients. Nervous System: Frequent: hypertonia, dysarthria; Infrequent: abnormal dreams, dyskinesia, thinking abnormal, tardive dyskinesia, vertigo, involuntary movements, confusion, amnesia, psychosis, hallucinations, hyperkinesia, libido increased*, urinary retention, incoordination, paranoid reaction, abnormal gait, myoclonus, delusions, manic reaction, apathy, ataxia, depersonalization, stupor, bruxism, catatonic reaction, hemiplegia; Rare: aphasia, buccoglossal syndrome, choreoathetosis, delirium, emotional lability, euphoria, libido decreased*, neuralgia, stuttering, subdural hematoma. Body as a Whole:Frequent: flu syndrome; Infrequent: neck pain, pelvic pain*, suicide attempt, malaise, photosensitivity reaction, chills, face edema, moniliasis; Rare: abdomen enlarged. Digestive System:Frequent: anorexia; Infrequent: increased salivation, increased appetite, gamma glutamyl transpeptidase increased, gingivitis, dysphagia, flatulence, gastroenteritis, gastritis, hemorrhoids, stomatitis, thirst, tooth caries, fecal incontinence, gastroesophageal reflux, gum hemorrhage, mouth ulceration, rectal hemorrhage, tongue edema; Rare: glossitis, hematemesis, intestinal obstruction, melena, pancreatitis. Cardiovascular System: Frequent: palpitation; Infrequent: vasodilatation, QT interval prolonged, migraine, bradycardia, cerebral ischemia, irregular pulse, T wave abnormality, bundle branch block, cerebrovascular accident, deep thrombophlebitis, T wave inversion; Rare: angina pectoris, atrial fibrillation, AV block first degree, congestive heart failure, ST elevated, thrombophlebitis, T wave flattening, ST abnormality, increased QRS duration. Respiratory System:Frequent: pharyngitis, rhinitis, cough increased, dyspnea; Infrequent: pneumonia, epistaxis, asthma; Rare: hiccup, hyperventilation. Metabolic and Nutritional System: Frequent: peripheral edema; Infrequent: weight loss, alkaline phosphatase increased, hyperlipemia, alcohol intolerance, dehydration, hyperglycemia, creatinine increased, hypoglycemia; Rare: glycosuria, gout, hand edema, hypokalemia, water intoxication. Skin and Appendages System: Frequent: sweating; Infrequent: pruritus, acne, eczema, contact dermatitis, maculopapular rash, seborrhea, skin ulcer; Rare: exfoliative dermatitis, psoriasis, skin discoloration. Urogenital System:Infrequent: dysmenorrhea*, vaginitis*, urinary incontinence, metrorrhagia*, impotence*, dysuria, vaginal moniliasis*, abnormal ejaculation*, cystitis, urinary frequency, amenorrhea*, female lactation*, leukorrhea*, vaginal hemorrhage*, vulvovaginitis* orchitis*; Rare: gynecomastia*, nocturia, polyuria, acute kidney failure. Special Senses:Infrequent: conjunctivitis, abnormal vision, dry eyes, tinnitus, taste perversion, blepharitis, eye pain; Rare: abnormality of accommodation, deafness, glaucoma. Musculoskeletal System: Infrequent: pathological fracture, myasthenia, twitching, arthralgia, arthritis, leg cramps, bone pain. Hemic and Lymphatic System:Frequent: leukopenia; Infrequent: leukocytosis, anemia, ecchymosis, eosinophilia, hypochromic anemia; lymphadenopathy, cyanosis; Rare: hemolysis, thrombocytopenia. Endocrine System: Infrequent: hypothyroidism, diabetes mellitus; Rare: hyperthyroidism. *adjusted for gender<br/>Post Marketing Experience:: Adverse events reported since market introduction which were temporally related to SEROQUEL therapy include: anaphylactic reaction and restless legs. Other adverse events reported since market introduction, which were temporally related to SEROQUEL therapy, but not necessarily causally related, include the following: agranulocytosis, cardiomyopathy, hyponatremia, myocarditis, rhabdomyolysis, syndrome of inappropriate antidiuretic hormone secretion (SIADH), and Stevens Johnson syndrome (SJS).
Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. SEROQUEL (quetiapine) is not approved for the treatment of patients with dementia-related psychosis (see Boxed Warning).<br/>Clinical Worsening and Suicide Risk: 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 antidepressantdrugs (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 health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for SEROQUEL should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that SEROQUEL is approved for use in treating adult bipolar depression.<br/>Neuroleptic Malignant Syndrome (NMS): 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. Rare cases of NMS have been reported with SEROQUEL. 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 inthe 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 aboutspecific 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.<br/>Tardive Dyskinesia: A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. 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. 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 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, drug discontinuation should be considered. However, some patients may require treatment with SEROQUEL despite the presence of the syndrome.<br/>Hyperglycemia and Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including Seroquel . 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 events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events 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 (eg, 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.
Bipolar Disorder: SEROQUEL is indicated for the treatment of both:�� Depression The efficacy of SEROQUEL was established in two identical 8-week randomized, placebo-controlled double-blind clinical studies that included either bipolar I or II patients . Effectiveness has not been systematically evaluated in clinical trials for more than 8 weeks. Mania The efficacy of SEROQUEL in acute bipolar mania was established in two 12-week monotherapy trials and one 3-week adjunct therapy trial of bipolar I patients initially hospitalized for up to 7 days for acute mania . Effectiveness has not been systematically evaluated in clinical trials for more than 12 weeks in monotherapy 3 weeks in adjunct therapy. The physician who elects to use SEROQUEL for extended periods in bipolar disorder should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient .<br/>Schizophrenia: SEROQUEL is indicated for the treatment of schizophrenia. The efficacy of SEROQUEL in schizophrenia was established in short-term (6-week) controlled trials of schizophrenic inpatients . The effectiveness of SEROQUEL in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use SEROQUEL for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient .