Included as part of the PRECAUTIONS section.
Increased Mortality In Elderly Patients With Dementia-Related
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
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
||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,
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.
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
||Category Change (At Least Once) from Baseline
||Patients n (%)
||Normal to High (<100 mg/dL to ≥126 mg/dL)
|Borderline to High (≥ 100 mg/dL and <126 mg/dL to ≥126 mg/dL)
|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
||Patients n (%)
|Total Cholesterol ≥240 mg/dL
|LDL- Cholesterol ≥160 mg/dL
|HDL- Cholesterol ≤ 40 mg/dL
|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
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
Table 5: Percentage of
Children and Adolescents with Shifts in Total Cholesterol, Triglycerides,
LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant
||Patients n (%)
|Total Cholesterol ≥200 mg/dL
|Triglycerides ≥150 mg/dL
|LDL-Cholesterol ≥130 mg/dL
|HDL-Cholesterol ≤40 mg/dL
|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.
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)
||Patients n (%)
|Weight Gain >7% of Body Weight
|Bipolar Mania (monotherapy)2
|Bipolar Mania (adjunct therapy)3
|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)
||Patients n (%)
|Weight Gain ≥7% of Body
|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
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
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
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
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.
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
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
|3.4 % (37/1097)
|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
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
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.
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].
Patients should be advised that they may experience
weight gain. Patients should have their weight monitored regularly [see WARNINGS AND PRECAUTIONS].
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].
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].
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
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
Use In Specific Populations
Pregnancy Category C:
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
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
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
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).
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
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.
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.
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].
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
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].
Clinical experience with SEROQUEL in patients with renal
impairment is limited [see CLINICAL PHARMACOLOGY].
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].