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Seroquel XR
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"April 20, 2011 - The 10 most prescribed drugs in the U.S. aren't the drugs on which we spend the most, according to a report from the IMS Institute for Healthcare Informatics.
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Seroquel XR
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. Analysis of 17 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 is not approved for the treatment of patients with dementia-related psychosis [see BOXED WARNING].
Suicidal Thoughts And Behaviors In Adolescents And Young Adults
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 2.
Table 2: Drug-Placebo Difference in Number of Cases of
Suicidality per 1000 Patients Treated
|Age Range
|Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
|Increases Compared to Placebo
|14 additional cases
|5 additional cases
|Decreases Compared to Placebo
|1 fewer case
|6 fewer cases
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. 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, including SEROQUEL, 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.
Cerebrovascular Adverse Reactions, Including Stroke, In Elderly Patients With Dementia-Related Psychosis
In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. SEROQUEL is not approved for the treatment of patients with dementia-related psychosis [see also BOXED WARNING and Increased Mortality In Elderly Patients With Dementia-Related Psychosis].
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 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.
Metabolic Changes
Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. 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 metabolic profiles should be managed as clinically appropriate.
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 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.
Table 3: Fasting Glucose – Proportion of Patients
Shifting to ≥126 mg/dL in Short-Term (≤12 weeks) Placebo-Controlled
|Laboratory Analyte
|Category Change (At Least Once) from Baseline
|Treatment Arm
|Patients n (%)
|Fasting Glucose
|Normal to High (<100 mg/dL to ≥126 mg/dL)
|71 (2.4%)
|19 (1.4%)
|Borderline to High (≥ 100 mg/dL and <126 mg/dL to ≥126 mg/dL)
|67 (11.7%)
|33 (11.8%)
|2 Includes SEROQUEL and SEROQUEL XR data.
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 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 I disorder maintenance, mean exposure of 213 days for SEROQUEL (646 patients) and 152 days for placebo (680 patients), the mean change in glucose from baseline was +5.0 mg/dL for SEROQUEL 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 (10.7% of patients; n=556) and 9.5 for placebo per 100 patient years (4.6% of patients; n=581).
Children And Adolescents
In a placebo-controlled SEROQUEL monotherapy study of adolescent patients (13–17 years of age) with schizophrenia (6 weeks duration), the mean change in fasting glucose levels for SEROQUEL (n=138) compared to placebo (n=67) was – 0.75 mg/dL versus –1.70 mg/dL. In a placebo-controlled SEROQUEL monotherapy study of children and adolescent patients (10–17 years of age) with bipolar mania (3 weeks duration), the mean change in fasting glucose level for SEROQUEL (n=170) compared to placebo (n=81) was 3.62 mg/dL versus –1.17 mg/dL. No patient in either study with a baseline normal fasting glucose level (<100 mg/dL) or a baseline borderline fasting glucose level (≥100 mg/dL and <126 mg/dL) had a treatment-emergent blood glucose level of ≥126 mg/dL.
In a placebo-controlled SEROQUEL XR monotherapy study (8 weeks duration) of children and adolescent patients (10 – 17 years of age) with bipolar depression, in which efficacy was not established, the mean change in fasting glucose levels for SEROQUEL XR (n = 60) compared to placebo (n = 62) was 1.8 mg/dL versus 1.6 mg/dL. In this study, there were no patients in the SEROQUEL XR or placebo-treated groups with a baseline normal fasting glucose level (< 100 mg/dL) that had an increase in blood glucose level > 126 mg/dL. There was one patient in the SEROQUEL XR group with a baseline borderline fasting glucose level (> 100 mg/dL) and (< 126 mg/dL) who had an increase in blood glucose level of > 126 mg/dL compared to zero patients in the placebo group.
Table 4 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.
Table 4: Percentage of Adult Patients with Shifts in
Total Cholesterol, Triglycerides, LDL-Cholesterol and HDL-Cholesterol from
Baseline to Clinically Significant Levels by Indication
|Laboratory Analyte
|Treatment Arm
|Patients n (%)
|Total Cholesterol ≥240 mg/dL
|24 (18%)
|6 (7%)
|Bipolar Depression2
|41 (9%)
|15 (6%)
|Triglycerides≥200 mg/dL
|26 (22%)
|11 (16%)
|Bipolar Depression2
|59 (14%)
|20 (9%)
|LDL- Cholesterol ≥160 mg/dL
|Bipolar Depression2
|29 (6%)
|12 (5%)
|HDL- Cholesterol ≤ 40 mg/dL
|Bipolar Depression2
|56 (14%)
|29 (14%)
|16 weeks duration
28 weeks duration
3Parameters not measured in the SEROQUEL registration studies for schizophrenia. Lipid parameters also were not measured in the bipolar mania registration studies.
Children And Adolescents
Table 5 shows the percentage of children and adolescents with changes in total cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol from baseline in clinical trials with SEROQUEL.
Table 5: Percentage of
Children and Adolescents with Shifts in Total Cholesterol, Triglycerides,
LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant
|Laboratory Analyte
|Treatment Arm
|Patients n (%)
|Total Cholesterol ≥200 mg/dL
|13 (12%)
|1 (2%)
|Bipolar Mania2
|16 (10%)
|2 (3%)
|Triglycerides ≥150 mg/dL
|17 (17%)
|4 (8%)
|Bipolar Mania2
|32 (22%)
|8 (13%)
|LDL-Cholesterol ≥130 mg/dL
|4 (4%)
|1 (2%)
|Bipolar Mania2
|13 (8%)
|4 (5%)
|HDL-Cholesterol ≤40 mg/dL
|16 (15%)
|10 (19%)
|Bipolar Mania2
|16 (10%)
|4 (7%)
|1 13-17 years, 6 weeks duration
2 10-17 years, 3 weeks duration
In a placebo-controlled SEROQUEL XR monotherapy study (8 weeks duration) of children and adolescent patients (1017 years of age) with bipolar depression, in which efficacy was not established, the percentage of children and adolescents with shifts in total cholesterol (≥200 mg/dL), triglycerides (≥150 mg/dL), LDL-cholesterol (≥ 130 mg/dL) and HDL-cholesterol (≤40 mg/dL) from baseline to clinically significant levels were: total cholesterol 8% (7/83) for SEROQUEL XR vs. 6% (5/84) for placebo; triglycerides 28% (22/80) for SEROQUEL XR vs. 9% (7/82) for placebo; LDL-cholesterol 2% (2/86) for SEROQUEL XR vs. 4% (3/85) for placebo and HDL-cholesterol 20% (13/65) for SEROQUEL XR vs. 15% (11/74) for placebo.
Weight Gain
Increases in weight have been observed in clinical trials. Patients receiving quetiapine should receive regular monitoring of weight.
Adults: In clinical trials with SEROQUEL the following increases in weight have been reported.
Table 6: Proportion of Patients with Weight Gain
≥7% of Body Weight (Adults)
|Vital Sign
|Treatment Arm
|Patients n (%)
|Weight Gain >7% of Body Weight
|89 (23%)
|11 (6%)
|Bipolar Mania (monotherapy)2
|44 (21%)
|13 (7%)
|Bipolar Mania (adjunct therapy)3
|25 (13%)
|8 (4%)
|Bipolar Depression4
|47 (8%)
|7 (2%)
|1up to 6 weeks duration
2up to 12 weeks duration
3up to 3 weeks duration
4up to 8 weeks duration
Children And Adolescents
In two clinical trials with SEROQUEL, one in bipolar mania and one in schizophrenia, reported increases in weight are included in table 7.
Table 7: Proportion of
Patients with Weight Gain ≥7% of Body Weight (Children and Adolescents)
|Vital Sign
|Treatment Arm
|Patients n (%)
|Weight Gain ≥7% of Body
|23 (21%)
|3 (7%)
|Bipolar Mania2
|18 (12%)
|0 (0%)
|16 weeks duration
23 weeks duration
The mean change in body weight in the schizophrenia trial was 2.0 kg in the SEROQUEL group and -0.4 kg in the placebo group and in the bipolar mania trial it was 1.7 kg in the SEROQUEL 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. 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 met this criterion after 26 weeks of treatment.
In a clinical trial for SEROQUEL XR in children and adolescents (10-17 years of age) with bipolar depression, in which efficacy was not established, the percentage of patients with weight gain ≥7% of body weight at any time was 15% (14/92) for SEROQUEL XR vs. 10% (10/100) for placebo. The mean change in body weight was 1.4 kg in the SEROQUEL XR group vs. 0.6 kg in the placebo group.
When treating pediatric patients with SEROQUEL for any indication, weight gain should be assessed against that expected for normal growth.
Tardive Dyskinesia
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 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.
Quetiapine may induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α1-adrenergic antagonist properties. Syncope was reported in 1% (28/3265) of the patients treated with SEROQUEL, 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 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). The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 25 mg twice daily [see DOSAGE AND ADMINISTRATION]. If hypotension occurs during titration to the target dose, a return to the previous dose in the titration schedule is appropriate.
Increases In Blood Pressure (Children And Adolescents)
In placebo-controlled trials in children and adolescents with schizophrenia (6-week duration) or bipolar mania (3-week duration), the incidence of increases at any time in systolic blood pressure (≥20 mmHg) was 15.2% (51/335) for SEROQUEL and 5.5% (9/163) for placebo; the incidence of increases at any time in diastolic blood pressure (≥10 mmHg) was 40.6% (136/335) for SEROQUEL and 24.5% (40/163) for placebo. In the 26-week open-label clinical trial, one child with a reported history of hypertension experienced a hypertensive crisis. Blood pressure in children and adolescents should be measured at the beginning of, and periodically during treatment.
In a placebo-controlled SEROQUEL XR clinical trial (8 weeks duration) in children and adolescents (10-17 years of age) with bipolar depression, in which efficacy was not established, the incidence of increases at any time in systolic blood pressure (≥20 mmHg) was 6.5% (6/92) for SEROQUEL XR and 6.0% (6/100) for placebo; the incidence of increases at any time in diastolic blood pressure (≥10 mmHg) was 46.7% (43/92) for SEROQUEL XR and 36.0% (36/100) for placebo.
Leukopenia, Neutropenia And Agranulocytosis
In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to atypical antipsychotic agents, including SEROQUEL. 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 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/mm³) should discontinue SEROQUEL and have their WBC followed until recovery.
The development of cataracts was observed in association with quetiapine treatment in chronic dog studies [see Nonclinical Toxicology]. Lens changes have also been observed in adults, children and adolescents during long-term SEROQUEL treatment, but a causal relationship to SEROQUEL use has not been established. Nevertheless, the possibility of lenticular changes cannot be excluded at this time. Therefore, examination of the lens by methods adequate to detect cataract formation, such as slit lamp exam or other appropriately sensitive methods, is recommended at initiation of treatment or shortly thereafter, and at 6-month intervals during chronic treatment.
QT Prolongation
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 [see OVERDOSAGE], in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval [see DRUG INTERACTIONS].
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).
During clinical trials, seizures occurred in 0.5% (20/3490) of patients treated with SEROQUEL compared to 0.2% (2/954) on placebo and 0.7% (4/527) on active control drugs. As with other antipsychotics, SEROQUEL should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer's dementia. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.
Adults: Clinical trials with quetiapine demonstrated dose-related decreases in thyroid hormone levels. The reduction in total and free thyroxine (T4) of approximately 20% at the higher end of the therapeutic dose range was maximal in the first six weeks of treatment and maintained without adaptation or progression during more chronic therapy. In nearly all cases, cessation of quetiapine treatment was associated with a reversal of the effects on total and free T4, irrespective of the duration of treatment. The mechanism by which quetiapine effects the thyroid axis is unclear. If there is an effect on the hypothalamic-pituitary axis, measurement of TSH alone may not accurately reflect a patient's thyroid status. Therefore, both TSH and free T4, in addition to clinical assessment, should be measured at baseline and at follow-up.
In the mania adjunct studies, where SEROQUEL was added to lithium or divalproex, 12% (24/196) of SEROQUEL treated patients compared to 7% (15/203) of placebo-treated patients had elevated TSH levels. Of the SEROQUEL treated patients with elevated TSH levels, 3 had simultaneous low free T4 levels (free T4 <0.8 LLN).
About 0.7% (26/3489) of SEROQUEL patients did experience TSH increases in monotherapy studies. Some patients with TSH increases needed replacement thyroid treatment.
In all quetiapine trials, the incidence of significant shifts in thyroid hormones and TSH were1: decrease in free T4 (free T4 <0.8 LLN), 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 8 shows the incidence of these shifts in short term placebo-controlled clinical trials.
Table 8: Incidence of shifts in thyroid hormone levels
and TSH in short-term placebo-controlled clinical trials1,2
|Total T4
|Free T4
|Total T3
|Free T3
|3.4 % (37/1097)
|0.6% (4/651)
|0.7% (52/7218)
|0.1% (4/3668)
|0.5% (2/369)
|0.0% (0/113)
|0.2% (11/5673)
|0.0% (1/2679)
|3.2% (240/7587)
|2.7% (105/3912)
|1Based on shifts from normal baseline to
potentially clinically important value at anytime post-baseline. Shifts in
total T4, free T4, total T3 and free T3 are defined as <0.8 x LLN (pmol/L)
and shift in TSH is >5 mlU/L at any time.
2Includes SEROQUEL and SEROQUEL XR data.
In short-term placebo-controlled monotherapy trials, the incidence of reciprocal, shifts in T3 and TSH was 0.0 % for both quetiapine (1/4800) and placebo (0/2190) and for T4 and TSH the shifts were 0.1% (7/6154) for quetiapine versus 0.0% (1/3007) for placebo.
Children And Adolescents
In acute placebo-controlled trials in children and adolescent patients with schizophrenia (6-week duration) or bipolar mania (3-week duration), the incidence of shifts for thyroid function values at any time for SEROQUEL treated patients and placebo-treated patients for elevated TSH was 2.9% (8/280) vs. 0.7% (1/138), respectively and for decreased total thyroxine was 2.8% (8/289) vs. 0% (0/145, respectively). Of the SEROQUEL treated patients with elevated TSH levels, 1 had simultaneous low free T4 level at end of treatment.
Adults: During clinical trials with quetiapine, the incidence of shifts in prolactin levels to a clinically significant value occurred in 3.6% (158/4416) of patients treated with quetiapine compared to 2.6% (51/1968) on placebo.
Children and Adolescents
In acute placebo-controlled trials in children and adolescent patients with bipolar mania (3-week duration) or schizophrenia (6-week duration), the incidence of shifts in prolactin levels to a value (>20 μg/L males; > 26 μg/L females at any time) was 13.4% (18/134) for SEROQUEL compared to 4% (3/75) for placebo in males and 8.7% (9/104) for SEROQUEL compared to 0% (0/39) for placebo in females.
Like other drugs that antagonize dopamine D2 receptors, SEROQUEL 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 in vitro, 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 [see Nonclinical Toxicology].
Potential For Cognitive And Motor Impairment
Somnolence was a commonly reported adverse event reported in patients treated with SEROQUEL especially during the 3-5 day period of initial dose-titration. In schizophrenia trials, somnolence was reported in 18% (89/510) of patients on SEROQUEL compared to 11% (22/206) of placebo patients. In acute bipolar mania trials using SEROQUEL as monotherapy, somnolence was reported in 16% (34/209) of patients on SEROQUEL compared to 4% of placebo patients. In acute bipolar mania trials using SEROQUEL as adjunct therapy, somnolence was reported in 34% (66/196) of patients on SEROQUEL compared to 9% (19/203) of placebo patients. In bipolar depression trials, somnolence was reported in 57% (398/698) of patients on SEROQUEL compared to 15% (51/347) of placebo patients. Since SEROQUEL has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating hazardous machinery until they are reasonably certain that SEROQUEL therapy does not affect them adversely. Somnolence may lead to falls.
Body Temperature Regulation
Although not reported with SEROQUEL, disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing SEROQUEL for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. SEROQUEL and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.
Discontinuation Syndrome
Acute withdrawal symptoms, such as insomnia, nausea, and vomiting have been described after abrupt cessation of atypical antipsychotic drugs, including SEROQUEL. In short-term placebo-controlled, monotherapy clinical trials with SEROQUEL 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 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.
1 Based on shifts from normal baseline to potentially clinically important value at anytime post-baseline. Shifts in total T4, free T4, total T3 and free T3 are defined as M0.8 x LLN (pmol/L) and shift in TSH is > 5 mlU/L at any time.
Patient Counseling Information
See FDA-approved patient labeling (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 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. 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.
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 [see WARNINGS AND PRECAUTIONS].
Suicidal Thoughts And Behaviors
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 [see WARNINGS AND PRECAUTIONS].
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 [see WARNINGS AND PRECAUTIONS].
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 [see WARNINGS AND PRECAUTIONS].
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 [see WARNINGS AND PRECAUTIONS].
Weight Gain
Patients should be advised that they may experience weight gain. Patients should have their weight monitored regularly [see WARNINGS AND PRECAUTIONS].
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 [see WARNINGS AND PRECAUTIONS].
Increased Blood Pressure In Children And Adolescents
Children and adolescent patients should have their blood pressure measured at the beginning of, and periodically during, treatment [see WARNINGS AND PRECAUTIONS].
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 [see WARNINGS AND PRECAUTIONS].
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. [see WARNINGS AND PRECAUTIONS].
Heat Exposure And Dehydration
Patients should be advised regarding appropriate care in avoiding overheating and dehydration [see WARNINGS AND PRECAUTIONS].
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 DRUG INTERACTIONS].
Pregnancy And Nursing
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with SEROQUEL. [see Use In Specific Populations].
Need For Comprehensive Treatment Program
SEROQUEL 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 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 [see INDICATIONS AND USAGE].
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
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 (MRHD) of 800 mg/day based on mg/m² body surface area (mice) or 0.3, 1, and 3 times the MRHD based on mg/m² body surface area (rats). There were statistically significant increases in thyroid gland follicular adenomas in male mice at doses 1.5 and 4.5 times the MRHD on mg/m² body surface area and in male rats at a dose of 3 times the MRHD on mg/m² body surface area. Mammary gland adenocarcinomas were statistically significantly increased in female rats at all doses tested (0.3, 1, and 3 times the MRHD on mg/m² body surface area).
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 WARNINGS AND PRECAUTIONS].
The mutagenic potential of quetiapine was tested in the in vitro Ames bacterial gene mutation assay and in the in vitro mammalian gene mutation assay in Chinese Hamster Ovary cells. The clastogenic potential of quetiapine was tested in the in vitro chromosomal aberration assay in cultured human lymphocytes and in the in vivo bone marrow micronucleus assay in rats up to 500 mg/kg which is 6 times the maximum recommended human dose on mg/m² body surface area. Based on weight of evidence quetiapine was not mutagenic or clastogenic in these tests.
Impairment Of Fertility
Quetiapine decreased mating and fertility in male Sprague-Dawley rats at oral doses of 50 and 150 mg/kg or approximately 1 and 3 times the maximum human dose (MRHD) of 800 mg/day on mg/m² body surface area. 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 3 times the MRHD 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 MRHD dose on mg/m² body surface area. Quetiapine adversely affected mating and fertility in female Sprague-Dawley rats at an oral dose approximately 1 times the MRHD of 800 mg/day on mg/m² body surface area. 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 approximately 0.1 and 1 times the MRHD of 800 mg/day on mg/m² body surface area. The no-effect dose in female rats was 1 mg/kg, or 0.01 times the MRHD of 800 mg/day on mg/m² body surface area.
Use In Specific Populations
Pregnancy Category C:
Risk Summary
There are no adequate and well-controlled studies of SEROQUEL 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.
Human Data
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. Neonates exposed to antipsychotic drugs (including SEROQUEL), 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.
Animal Data
When pregnant rats and rabbits were exposed to quetiapine during organogenesis, there was no teratogenic effect at doses up to 2.4 times the maximum recommended human dose (MRHD) for schizophrenia of 800 mg/day based on mg/m² body surface area. However, there was evidence of embryo-fetal toxicity, which included delays in skeletal ossification occurring at approximately 1 and 2 times the MRHD of 800 mg/day in both rats and rabbits, and an increased incidence of carpal/tarsal flexure (minor soft tissue anomaly) in rabbit fetuses at approximately 2 times the MRHD. In addition, fetal weights were decreased in both species. Maternal toxicity (observed as decreased body weights and/or death) occurred at 2 times the MRHD in rats and approximately 1-2 times the MRHD (all doses tested) 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 of 800 mg/day based on mg/m² body surface area. However, in a preliminary peri/postnatal study, there were increases in fetal and pup death, and decreases in mean litter weight at 3 times the MRHD.
Labor And Delivery
The effect of SEROQUEL on labor and delivery in humans is unknown.
Nursing Mothers
SEROQUEL was excreted into human milk. Because of the potential for serious adverse reactions in nursing infants from SEROQUEL, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother's health.
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).
Pediatric Use
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%) [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].
The efficacy and safety of SEROQUEL in the treatment of schizophrenia in adolescents aged 13 to 17 years were demonstrated in one 6-week, double-blind, placebo-controlled trial [see INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, and Clinical Studies].
Safety and effectiveness of SEROQUEL in pediatric patients less than 13 years of age with schizophrenia have not been established.
The safety and effectiveness of SEROQUEL 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 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 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 [see INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, and Clinical Studies]. Safety and effectiveness of SEROQUEL in pediatric patients less than 10 years of age with bipolar mania have not been established.
Bipolar Depression
Safety and effectiveness of SEROQUEL in pediatric patients less than 18 years of age with bipolar depression have not been established. A clinical trial with SEROQUEL XR was conducted in children and adolescents (10 to 17 years of age) with bipolar depression, efficacy was not 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 Cmax 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 [see CLINICAL PHARMACOLOGY].
Geriatric Use
Of the approximately 3700 patients in clinical studies with SEROQUEL, 7% (232) were 65 years of age or over. In general, there was no indication of any different tolerability of SEROQUEL in the elderly compared to younger adults.
Nevertheless, the presence of factors that might decrease pharmacokinetic clearance, increase the pharmacodynamic response to SEROQUEL, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period in the elderly. The mean plasma clearance of SEROQUEL was reduced by 30% to 50% in elderly patients when compared to younger patients [see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION].
Renal Impairment
Clinical experience with SEROQUEL in patients with renal impairment is limited [see CLINICAL PHARMACOLOGY].
Hepatic Impairment
Since quetiapine is extensively metabolized by the liver, higher plasma levels are expected in patients with hepatic impairment. In this population, a low starting dose of 25 mg/day is recommended and the dose may be increased in increments of 25 mg/day - 50 mg/day [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 7/25/2016
Seroquel XR FDA Prescribing Information
Additional Seroquel XR Information
Seroquel XR - User Reviews
Seroquel XR User Reviews
Now you can gain knowledge and insight about a drug treatment with Patient Discussions.
Here is a collection of user reviews for the medication Seroquel XR sorted by most helpful.
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
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Thanks for the update. It was a good episode, They all are trying to handle each other, some times by convincing, ignoring, pressurising,understanding, manipulating. It's fun to watch everyone.
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Morning roundup
Top Stories: Fort Hood Trial Resumes; Fire Spreads In Calif.
Good morning (and our apologies for being late with this).
Some of our early headlines:
— Judge Says Nidal Hasan Can Represent Himself In Fort Hood Trial
— Report: NSA Is Searching 'Vast Amounts' Of Americans' Emails
— 'Total Disgrace': Jackie Robinson Statue Defaced In Brooklyn
— 'New York Times' Is Not For Sale, Sulzberger Says
— Fannie Mae Books $10.1 Billion In Second-Quarter Profits
— 3 Winning Powerball Tickets Sold: 2 In N.J., 1 In Minnesota
— Burglars Return Loot To Group That Helps Sex Assault Victims
— Stars And Stripes: Pair Of Sumatran Tigers Born At National Zoo
— World-Record Snakehead Fish Caught In U.S.
Other stories in the news:
— Wildfire In Southern California "Grows To 10,000 Acres; One Person Burned 'Head To Toe.' " (Los Angeles Times)
— 4 Killed, 4 Wounded In Dallas-area Shooting Rampage. (The Dallas Morning News)
— "Suspect's Vehicle In California Murder-abduction Case Seen In Oregon." (Reuters)
— Suicide Bomber In Quetta, Pakistan, Kills At Least 28. (BBC News)
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Well, I never have. I don't intend to start doing so, either, mostly because I just don't see it as likely that I'd need a second gun. I'm not going into combat every day; I'm not even going into "bad areas" every day (or pretty much ever). I also don't think it's likely that my GLOCK is going to fail me if needed, and I don't think I've trained myself to be handling a "gun disabled by incoming fire" situation in the first place (another reason for having a backup, according to articles I've read).
I consider myself well-enough-defended with one gun; that's a compromise, since I really do understand that if one gun is good, two is even better. But I am not willing to weigh myself down with a second gun. It's hard enough concealing one, for me.


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Agriculture stocks open lower following the USDA's supply/demand report, which is slightly negative for grain prices due to an expected increase in global wheat and corn inventory levels. Fertilizer stocks: POT -4%, CF -3.9%, MOS -3.7%, IPI -3%, AGU -1.7%, RNF -1.2%. Seed names: MON -0.3%, SYT +0.3%. Farm equipment:AGCO -3.2%, TITN -1.7%, DE -1.5%, CNH -1.3%.
Agriculture stocks open lower following the USDA's supply/demand report, which is slightly...
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This is the second time I've purchased this wine. It is an inexpensive and pleasant wine to have in the home for meals, relaxation and guests.
This wine was offered as the house red at a local area restaurant. I enjoyed it very much and was pleased to see it carried by Wine Chateau at a very good price.
Light and smooth.
Technical Notes
Winemakers Chris Cooney and Rinaldi chose Merlot from two subappelations of Napa Valley: Los Carneros and Oak Knoll. The Oak Knoll fruit gives the wine rich, ripe flavors and softer texture, while the cooler Los Carneros region–closer to the San Francisco Bay–provides lively acidity and bright, red fruit Merlot character. They selected grapes from six blocks of the Beckstoffer Las Amigas Vineyard and two from an Oak Knoll vineyard. These well-drained, high quality vineyard blocks are trained and pruned to maximize flavor intensity from sun exposure and prolonged hangtime. Variations in soils and mesoclimate contribute to our Merlot's complex array of fruit and spice expression.


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26 reviews | 4.4 out of 5
Ordered these in black and store shipped them in dark grey. No big deal but due to how small the actual size was I just gave them away....
Finally found a sleeveless shirt that fits and is made from top quality. Only wish it had a breast pocket.
These used to come with a pocket. Would be better if they still did. Fits fairly well--washes nicely.
I am a woman and usually take a medium in t-shirts. I loved the old Fruit of the Loom Muscle shirts with the pocket but I don't think they make them any more. I have one old ratty one left that I cherish. I got the small men's size in Black Heather and White. Black Heather is really a very deep mottled gray. They are made of fairly thick cotton. On me the length falls below the rear end. The arm holes are slightly too long, but it's worth it for the comfort. They wash well.
Cotton blend means 50 polyester 50 cotton...which also means extremely uncomfortable in hot humid weather. Why fool yourself into thinking a cut off polyster non wick t shirt will cool you off...oops Just buy an under armour tshirt or another brand which still uses 100 cotton.
These are the normal, everyday, run of the mill, average sleeveless muscle tee shirts. They aren't even CLOSE to the style, comfort, fit, and durability of the Life by Jockey sleeveless muscle tee shirts that they have replaced.
should have this product available in all the walmart stores and please do not discontinue them whatever you do
I don't know how long these shirts will hold up, but so far I really like them and they were definitely worth the price. If you buy them, keep in mind that they're cotton, so they do shrink a bit. I generally wear men's small size, but I bought these in medium and they fit great after washing them. Of course, I wash everything in warm water and dry on "normal" so cotton is always going to shrink. So far, none of them have faded, but they may over time. I got the red, navy, and gray. Pay attention though--I didn't realize they came two to a package and ended up with 16 of them. That's why I put on here that I wear them daily. It's hot here in Kansas and they're perfect for that.
These shirts are absolutely perfect, you'll still stay cool in warm weather. They are made of good quality & I like the way the sleeves are double stitched to hold their shape; as opposed to other similar shirts I've purchased. You can't go wrong with these & btw why would you want pockets on sleeveless tees? Walmart does have them in stores if you can't live without pockets!
I was amazed that I received very good quality sleeveless T's for about $3.50 each! I bought 6 of them right away. Shipping was cheap also.
I only gave it a 4 star because, it wasn't exactly as pictured. A small detail and it does still look good.
I'll buy again if needed.
very nice shirts fit just right price was outstanding shipping very fast 3 days before Christmas and got it Christmas eve.
Fruit of the Loom - Men's Sleeveless Muscle Tee, 2-Pack
Grrandson enjoyed the white ones - showed off muscles
Nice weight fabric - cut long enough - nice finishing on sleeves and neckline.
Good product, great price delivered to my door. What else can you ask for?
I loved this purchase because two came in a package .
great price and great cool fit,nice comfy shirts
it was bigger then apparel same size


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Hello, I live in Paris, I love sports, literature and good restaurants. I love meeting people but I work very hard on my startup, so Airbnb is actually for me simply perfect. I love it !
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We stayed in Jose's apartment for three weeks and lived like locals. It is in a fantastic area in the Marais. Close to shops, restaurants and the metro. Also easy to walk to many of the fantastic attractions Paris has to offer. We did not meet Jose, but he was available for any queries. All his directions on how to access the apartment were very clear. Everything was very clean and the shower was great always with hot water. The apartment is large by Paris standards and we had plenty of room to spread out. Wifi excellent. Heating good. Lift very welcome after a day of sightseeing. Thanks Jose for a great stay.
This is a wonderful apartment. I spent nearly a month and enjoyed each day. I plan to reserve again in future.
José was immediately in contact with me from the moment I booked the apartment. He even offered a list of places to visit/eat, and was available to answer any questions or address concerns with the apartment. A lady he hires to clean the apartment stopped by to help set up the sofa bed and left the sweetest note for us! We loved the views of Paris streets from the windows, and having a comfortable, full living space and fully-stocked kitchen every day/night. It's a warm and cozy space that is ideally located in the heart of Paris' bustling Le Marais district. It's close to everything!
The apartment is a nice size and in a great location. One block from the St. Paul Metro stop. Shops and restaurants right outside the door. Lots of really good places to eat only 3 or 4 blocks away. Very near the Picasso Museum and Muse de Carnavalet. Loved the location and neighborhood. This is an older apartment with lots of character that will grow on you. That said it could use a little updating. A new mattress would be good as it is rather soft. Newer essentials such as sheets, towels and dishes would really help improve the feel of the place. We loved the little elevator and spiral stairs. Felt like we were in a building with true locals.
Wonderful stay in the Marais. Location is perfect, very nice neighborhood, close to everything, walked everywhere. Very generous host. Apt had everything needed, including a washing machine and soap. Right around the corner is the metro, a Starbucks, cafes and restaurants. Jeff, the caretaker allowed us to come a little early, gave us all the information needed for our stay and even mailed back to me a favorite sweater I left behind. The apt is simple, but very clean and comfortable. We walked a lot as it was my husbands first time in Paris and he wanted to explore, but with the great location of the St Paul metro, the next time we stay with Jose, we would get a metro pass for 2 or 3 days. The Marais also has so much to offer, we spent an entire day exploring. I don't think anyone would be disappointed with this apt if your looking to get out an enjoy Paris. There is even a small elevator if stairs are a problem. Our thanks to our host and Jeff from Texas for a wonderful stay. This was our first experience with air bnb, we would definitely do it again.
We loved this apartment. The apartment's aesthetic and age made the stay so quintessentially Parisian. Jose was very responsive as a host and considerate.
The apartment is at a perfect location, right in the center of things to do, to see, and of course to taste in Marais and its surrounding areas. Our stay included two Sundays when the streets around us were blocked off from car traffic and became full of people, many of them local, coming out to enjoy their brunches and shop at the numerous boutique shops. We can walk to so many places, for the 10 days, the two of us didn't even quite finish two carnets of Metro tickets. We just kept exploring on feet. The apartment is fairly large and the elevator is very nice if you have a big/heavy piece of luggage. The lady (we ran into her) who spent two hours cleaning the apartment after the last guests' stay did a wonderful job. We really enjoy the stay and would definitely stay at José's place again.
José was a very helpful host though I did not meet him in person. I stayed at his flat with my mum and it was the perfect size in an excellent location in the Marais. We were very close to the St Paul and Pont-Marie metro stations which meant that we had very easy access to two metro lines. We were a minute's walk from a couple of supermarkets (G20 and Franprix) and numerous eateries and boutiques. The flat is very close to lovely public spaces such as Place de Vosges. I can't recommend it enough - the location was excellent, the flat was clean and comfortable and José's instructions very clear and helpful. We really enjoyed staying there.
Had a lot of fun in a perfect location to walk the beautiful streets around Marais. Close to a lot of nice restaurants and bars and the luevre. Beautiful apartment, clean and everything needed was there.
Jose was very attentive and in touch to make sure everything was satisfactory! We love the neighborhood and only wish for more time there. We will be back.
Reviews From Hosts
José a été un voyageur respectueux et agréable. Tout s'est très bien passé!
José es un huésped excepcional, amable y respetuoso, hace muy agradable y fácil la convivencia. Nos ha gustado conocerlo y alojarlo en nuestro apartamento. Estamos seguros de que cualquiera se sentirá igual de cómodo que nosotros teniéndolo como huésped. Es siempre bienvenido. ¡Muy recomendable!
José es muy amable, cortés y ordenado. Lo recomiendo totalmente como invitado, Un placer haberlo conocido en su breve estancia, es bienvenido cuando vuelva a Ibiza!
José est resté 4 nuits à l'appartement. Je n'ai pas eu l'occasion de le rencontrer mais la communication a été très facile et tout s'est très bien passé. Voyageur respectueux et propre. L'appartement était nickel. Je recommande.
José est très gentil et aimable. Aucun soucis, le séjour c'est très bien passé !
Le court séjour de José s'est parfaitement déroulé. C'est un hôte sympathique et respectueux, que je recommande sans hésiter. José est le bienvenu s'il revient.
Très bonne communication José est très agréable
José est une personne sympathique qui discute facilement, et reste ouvert à beaucoup de sujets. Simple et sociable. Belle rencontre
Je n'ai pas eu l'occasion de rencontrer José car je n'étais pas là. Nos échanges ont été en tous les cas très fluide et il a l'air plutôt sympathique.
Bien que José a annulé au dernier moment la réservation, c'est une personne extrêmement honnête car il a vraiment insisté pour me régler la nuit. Le contact téléphonique a été parfait. Une autre fois, j'espère !
References (1)
Jose is a warm and condirerate gentleman. I am glad to be his very first Airbnb guest and I really enjoyed staying at his place. The apartment is super convenient (100 meters from Saint Paul metro, I don't think it could get any closer) in the lovely Marais district. Jose also showed me the restaurant serving food from Senegal in the area which was really good. I would definitely stay at his place again.


text:
Private Rental of Kyle Pool as Low as $60/hr*
Have your next party at the spacious Kyle Pool.
Your party rental can include swimming during swim season (May - September)
or no swimming (Rest of the Year).
Rates effective October 1, 2015 through September 30, 2016
*Non-Swimming Rentals:
Private rental rates for the day after October 1 thru April 30 (with no swimming) are $60/hour* - up to 200 guests.
Swimming Rentals:
Private Rental Rates of Kyle Pool with swimming are:
Number of Guest : Rate per Hour
1 - 50 Guests : $75/hour
51 - 75 Guests : $100/hour
76 - 100 Guests : $125/hour
101 - 125 Guests : $150/hour
126 - 150 Guests : $175/hour
151 - 175 Guests : $225/hour
176 - Max Capacity Guests: $250/hour
In order to properly schedule staff, 100% payment MUST be received at least 14 calendar days prior to date of reservation.
Pool Party "Lotto Draw"
Monday, April 18, 2016 at 7:00pm at Lake Kyle PARD Office. This is your opportunity to get ahead of open reservations. Each private party representative attending this event will enter a drawing to have their dates reserved before those not attending. The deposit is required to make this reservation, please bring your payment with you. After a short presentation by PARD staff, we will begin drawing tickets. When your ticket is drawn, you will be able to make the reservation of your choice of remaining dates and times. All remaining dates and times will be open to the public beginning April 19, 2016.
Times pool parties are available:
Friday 8:30pm -11:30pm (must rent the entire 3 hours)
Saturday 6:00pm-8:00pm (2 hours) or 8:30pm-11:30pm (3 hours) or 6:00pm-11:30pm (4 or more hours)
Sunday 6:00pm-8:00pm (2 hours) or 8:30pm-11:30pm (3 hours) or 6:00pm-11:30pm (4 or more hours)
Number of guests MUST be determined and set at least 30 days prior to rental. Guests include all through the gate, swimmers and non-swimmers. Max capacity of Kyle Pool is 245. City and school events will be scheduled prior to April 18 and are subject to change without notice.
Deposit and Payment
A $102.50 deposit is required to make reservation. The deposit is a Clean Up Deposit to ensure facility is returned to pre-event condition. After event, $100 of the clean up deposit will be refunded providing proper clean up.
(Deposit refunded in full if canceled more than 30 days from event, refunded 50% if canceled more than 15 days from event and not refundable if canceled within 14 days of event).
In order to properly schedule staff, 100% payment MUST be received at least 14 calendar days prior to date of reservation.
To make a reservation, please call: (512)262-3939.


text:
, Volume 21, Issue 1, pp 33-39
First online:
The Covering Law Model Applied to Dynamical Cognitive Science: A Comment on Joel Walmsley
- Raoul GervaisAffiliated withUniversiteit Gent Email author
- , Erik WeberAffiliated withUniversiteit Gent
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
In a 2008 paper, Walmsley argued that the explanations employed in the dynamical approach to cognitive science, as exemplified by the Haken, Kelso and Bunz model of rhythmic finger movement, and the model of infant preservative reaching developed by Esther Thelen and her colleagues, conform to Carl Hempel and Paul Oppenheim's deductive-nomological model of explanation (also known as the covering law model). Although we think Walmsley's approach is methodologically sound in that it starts with an analysis of scientific practice rather than a general philosophical framework, we nevertheless feel that there are two problems with his paper. First, he focuses only on the deductivenomological model and so neglects the important fact that explanations are causal. Second, the explanations offered by the dynamical approach do not take the deductive-nomological format, because they do not deduce the explananda from exceptionless laws. Because of these two points, Walmsley makes the dynamical explanations in cognitive science appear problematic, while in fact they are not.
KeywordsExplanation Covering law Dynamical cognitive science Cognition Causal asymmetry Dynamicism
Reference tools
- Title
- The Covering Law Model Applied to Dynamical Cognitive Science: A Comment on Joel Walmsley
- Journal
Minds and Machines
Volume 21, Issue 1 , pp 33-39
- Cover Date
- 2011-02
- 10.1007/s11023-010-9216-9
- Print ISSN
- 0924-6495
- Online ISSN
- 1572-8641
- Publisher
- Springer Netherlands
- Additional Links
- Topics
- Keywords
- Explanation
- Covering law
- Dynamical cognitive science
- Cognition
- Causal asymmetry
- Dynamicism
- Industry Sectors
- Authors
- Raoul Gervais (1)
- Erik Weber (1)
- Author Affiliations
- 1. Universiteit Gent, Gent, Belgium


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text:
NCF Nation
Print without images
Wednesday, September 15, 2010
Cincinnati's offense not humming yet
By Brian Bennett
When Cincinnati settled for a field goal on its opening drive last week against Indiana State, there was no celebrating on the sidelines.
Instead, as quarterback
Zach Collaros
recalls, players were hanging their heads in frustration. At halftime of that game against one of the worst FCS programs around, the Bearcats led only 12-7. This came after mustering just two touchdowns in a 28-14 loss to Fresno State in the opener.
Cincinnati quarterback Zach Collaros and the rest of the Bearcats offense has struggled early this season.
The offense that was the best in the Big East a year ago and predicted by many to be explosive again this year had suddenly become plodding.
"We were frustrated because we had great expectations for ourselves," Collaros said. "That kind of got us in a funk."
The Bearcats responded by scoring 28 points in the fourth quarter to blow last weekend's game open. Still, this offense hasn't yet looked like the one that scored 117 points in last season's first two games, or even like new coach Butch Jones' old high-scoring attack at Central Michigan. It ranks fifth in the Big East in scoring and just seventh in total offense, a neighborhood never known during the Brian Kelly era.
Cincinnati is hoping to get back to those high-flying days Thursday night at NC State (
"Our offense has something to prove this week," offensive guard Alex Hoffman said. "We've kind of got a chip on our shoulders, especially as an offensive line."
Collaros was sacked eight times at Fresno State and hurried countless more. After that game, Jones opened up the competition at every offensive line spot, though he made just one change to the starting lineup, with Randy Martinez moved up to start at guard. Jones said he thought the line made "great strides, but we're still a work in progress."
They will also have their hands full against a blitz-happy NC State team that will be a whole lot more physical than lowly Indiana State.
"Our chemistry has been great this week, and we're all on the same page," Hoffman said. "We're going to protect Zach a lot better. He's not going to get touched."
A huge year was expected from Collaros, who turned in dazzling numbers in four starts replacing the injured Tony Pike last season. Collaros' stats through two games this year are solid -- he's completing 60 percent of his passes and has three touchdowns with no interceptions. But he also held onto the ball too long at times against Fresno, leading to some of those sacks.
"I was trying to make too many plays in the second half," he said. "I was trying to win a game by myself."
Jones has cautioned all along that, despite those four starts last year, Collaros is basically still a first-year starter at quarterback.
"Zach is still going through the evolution stages," Jones said. "People look at those four games, but it's still different when you're the starting quarterback. There's so much that goes into the leadership at that position, from making the right reads and the right decisions."
Collaros also no longer has as many weapons around him as he once did. Receiver
Vidal Hazelton
was lost for the year with a torn ACL in the Fresno game. Wideouts
Kenbrell Thompkins
and Dyjuan Lewis are ineligible. Running back
Isaiah Pead
missed the Indiana State game with swelling in his knee. The starting receivers are still strong, but Jones said there have been too many incompletions.
"Dropped passes are like turnovers in our offense," he said.
When the Bearcats are completing passes and avoiding negative plays, they get into a hyper tempo in their no-huddle offense. The pace picked up considerably in that third quarter outburst last week, and that's the way Cincinnati wants to play.
If that happens at NC State, then maybe this offense will look like its old familiar self.
"If we execute the way we know how, there's no question we'll put up big points and big numbers," Collaros said.


text:
The Myth of not drafting Guards High
Everywhere I look, I see people saying that you do not draft guards high. But if you look at history, highly-drafted true guards have a higher success rate than any other position. Take alook at the history below -- you will see that most (if not all) of the true guards drafted in the top 20 have gone on to become pro bowlers.
Please note that some of the guards on the list never played OG in the NFL and moved straight to tackle. Jon Ogden, for example, is listed as a guard. Davis on Arizona is listed as a guard as well.
My point here is that we shouldn't be afraid to take Iupati if the opportunity presents itself. Scotty has an anti-OG bias, but he needs to get over it.


text:
SUMMARY: High-end consulting and research firm Economy.com also runs a little side-kick site Dismal.com. At first it was simply a promotional vehicle that relied on ad revenue to cover hosting costs. Then the team began to wonder, "Could we actually sell subscriptions to this?"
Best lesson from this Case Study: If you offer several options to buyers, *always* pre-check the option you want them to pick. This one tactic has gotten Dismal.com an unusually high percent of longer-term (more profitable) accounts.
Get the latest research on email, lead gen, and social media along with MarketingSherpa updates and promotions.
Content Marketing Generated a 5,100% ROI for Health Care Innovator Optum
Read More »


text: I am looking to have the author profile displayed above the posts when an individual author archive is called, but the template tags that I place in the archive template don't pull any info. Am I placing the tags in the wrong place, and if so, where do I put them in the loop? Is the loop only the index.php? I tried reading about the loop, but got kinda lost. Any help would be appreciated mucho!